The significance of the kidney in diabetes

Ferrannini • Fioretto • Groop • Hach Nauck • Thomas

Edited by Piper & Raderschadt Published by infill Kommunikation GmbH

The significance of the kidney in diabetes
Professor Ele Ferrannini
Department of Internal Medicine University of Pisa School of Medicine Pisa, Italy

Professor Paola Fioretto

University of Padova Department of Medical and Surgical Sciences Padova, Italy

Professor Per Henrik Groop
University of Helsinki Folkhälsan Research Centre Helsinki, Finland

Dr Thomas Hach

TA Metabolism Boehringer Ingelheim Pharma GmbH & Co. KG Ingelheim, Germany

Professor Michael Nauck

Diabeteszentrum Bad Lauterberg Bad Lauterberg im Harz, Germany

Dr Merlin Thomas

Danielle Alberti Memorial Centre for Diabetic Complications Baker Medical Research Institute Melbourne, Australia

Edited by Dr Emma Raderschadt & Ross Piper infill Kommunikation GmbH Königswinter, Germany

Published by infill Kommunikation GmbH

Disclaimer
Every effort has been made by the authors, editor, publisher and sponsor of THE SIGNIFICANCE OF THE KIDNEY IN DIABETES to provide the reader with accurate and up-to-date information. However, medicine is a rapidly changing subject, and therefore the reader is advised to always be attentive and to check the information contained herein with the current guidelines, procedure and product information supplied by the manufacturers. Treatment guidelines, regulations and strategies also vary between countries and therefore the reader should confirm the current standard of practice for their region with local regulatory bodies. The authors, editor, publisher and financial sponsor hereby issue a disclaimer and will take no responsibility for any errors or omissions or consequences resulting from the use of information contained herein.

© 2012 infill Kommunikation, Königswinter, Germany www.infill.com ISBN 978-3-00-037347-3

Financially supported by Boehringer Ingelheim GmbH

Table of Contents

1. T2DM: an introduction 2. The Kidneys and Diabetes – Dealing with Hypoglycaemia 3. T2DM therapy in patients at risk of and with declining renal function 4. DPP-4 inhibitors in general and linagliptin in particular as a new treatment option in T2DM 5. The future of anti-diabetics in T2DM therapy

4 29 41 56 81

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1. T2DM: an introduction

Professor Michael Nauck

Diabeteszentrum Bad Lauterberg Bad Lauterberg im Harz, Germany

Professor Ele Ferrannini

Department of Internal Medicine University of Pisa School of Medicine Pisa, Italy

What is T2DM?
Definition and diagnosis Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease,1 characterised by hyperglycaemia. Insulin resistance (i.e., a reduced cellular response to the hormone)2 and impaired pancreatic β-cell function are the chief pathogenetic mechanisms.3 They often occur in concert, resulting in over-production of glucose from the liver, diminished glucose uptake in tissues throughout the body, and consequently a net increase in blood glucose levels. Simple blood tests allow for the diagnosis of T2DM as well as prediabetes, which is a condition of milder dysglycaemia at high risk of progressing to overt T2DM. The criteria for the diagnosis of prediabetes and diabetes are presented in Table 1 and 2.
Table 1. WHO and ADA criteria for the diagnosis of prediabetes

Criteria for the diagnosis of prediabetes Fasting plasma glucose (FPG) (4, 5) 110 to 125 mg/dL (6.1 mmol/l to 6.9 mmol/l) (WHO) 100 to 125 mg/dL (5.6 mmol/l to 6.9 mmol/l) (ADA) or Post-prandial glucose (PPG)a (5) 140 to 199 mg/dL (7.8 mmol/l to 11.0 mmol/l) or HbA1c
a

b (5)

5.7–6.4%

b

Defined using the 2h oral glucose tolerance test (OGTT) after ingesting the 75g glucose load.4 The test should be performed in a laboratory using a method that is NGSP certified and standardised to the DCCT assay.5 IFG and IGT represent intermediate states of abnormal glucose regulation that exist between normal glucose homeostasis and diabetes.6 Impaired fasting glucose (IFG) is now defined by an elevated fasting plasma glucose (FPG) concentration (≥100 and <126 mg/dl; ≥5.6 and <7 mmol/l).7 Impaired glucose tolerance (IGT) is defined by an elevated 2-h plasma glucose concentration (≥140 and <200 mg/dl; ≥7.8 and <11.1 mmol/l) after a 75-g glucose load on the oral glucose tolerance test (OGTT) in the presence of an FPG concentration <126 mg/dl.7 8

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Table 2. WHO and ADA criteria for the diagnosis of diabetes

Criteria for the diagnosis of diabetes Fasting plasma glucose (FPG)* (4, 5) ≥126 mg/dl (7.0 mmol/l) or Post-prandial glucose (PPG)a* (4, 5) ≥200 mg/dl (11.1 mmol/l) or HbA1c *
b (5)

≥6.5% or

Random plasma glucosec (5)
a B

≥200 mg/dl (11.1 mmol/l)

Defined using the 2h oral glucose tolerance test (OGTT) after ingesting the 75g glucose load.4 The test should be performed in a laboratory using a method that is NGSP certified and standardised to the DCCT assay.5 c In a patient with classic symptoms of hyperglycaemia or hyperglycaemic crisis.5 * In the absence of unequivocal hyperglycaemia, FPG, PPG and HbA1c should be confirmed by repeat testing.

Glucose metabolism: an overview
T2DM is a disease of glucose homeostasis, so it is pertinent here to briefly review the basics of glucose metabolism. ATP, the universal energy currency of life, is generated via the oxidation of glucose, non-esterified fatty acids (NEFA) and, to a lesser extent, amino acids. Glucose can be obtained from food via digestion or it can be synthesised in the body. Glucose obtained from carbohydrates in the diet is actively transported from the lumen of the intestine into the blood by the main transporter protein, sodium-glucose transport protein 1 (SGLT-1)9 10 The majority of absorbed glucose reaches the liver where it is in part stored as glycogen (glycogen synthesis), whilst the remainder is taken up by peripheral tissues for both oxidative and non-oxidative (storage) use; excess glucose is converted into lipids (de novo lipogenesis) in the liver and, to a lesser degree, in adipose tissue.11 12

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The many roles of insulin Insulin is the key hormone in glucose homeostasis. This peptide has a number of key functions, including promoting the uptake of glucose by cells throughout the body. Insulin, secreted by the β-cells of the pancreas, is transported to and binds to its receptor, a tyrosine kinase enzyme consisting of two extracellular α-subunits and two β-subunits that span the cell membrane. These receptors are ubiquitous, with almost every cell in the body expressing them.9 10 When insulin binds to the receptor, it phosphorylates various intracellular proteins, activating a cascade of events resulting, among other effects, in stimulated glucose uptake via active transport (Figure 1).9 10

Figure 1: Schematic diagram showing insulin-induced glucose uptake by a cell.9 10

As a first step, insulin activates the hexokinase enzyme, which phosphorylates glucose, effectively trapping it within the cell.12 In hepatocytes, insulin inhibits the activity of glucose-6-phosphatase, the enzyme responsible for liberating free glucose from the glucose-6-phosphate originating from glycogen (glycogenolysis) and de novo glucose synthesis (gluconeogenesis).12 As well as preventing the release of glucose from the hepatocytes, insulin also activates several of the enzymes that are directly involved in glycolysis and glycogen synthesis, including phosphofructokinase and glycogen synthase, respectively.12 When glucose is abundant, insulin stimulates the liver to convert it to glycogen for storage and later use.12

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The synthesis of glycogen cannot continue unabated and as the stores of this molecule reach around 10% of the liver’s entire mass, further glycogenesis is strongly suppressed and any additional glucose taken up by the liver cells is shunted into pathways leading to the production of fatty acids.12 13 Once synthesised, these fatty acids are exported from the liver as lipoproteins, which are degraded in the circulation into free fatty acids that can be used by a number of tissues.12 13 In addition to regulating the uptake of glucose and the synthesis of fatty acids, insulin also promotes the accumulation of triglycerides in adipocytes. Insulin facilitates the entry of glucose into adipocytes where it is broken down to glycerol-phosphate, which esterifies fatty acids (synthesised in the liver) yielding a triglyceride.12 13 These processes highlight the importance of insulin in everything to do with how the body stores, mobilises and utilises its energy sources. Furthermore, in regulating these process, insulin also stimulates the uptake of amino acids, increases the permeability of many cells to potassium, magnesium and phosphate ions, and activates sodium-potassium ATPase enzymes in many cells, causing a flux of potassium into cells.12 14

The pathophysiology of T2DM
In essence, the pathophysiological mechanisms involved in the development of T2DM are the deterioration of β-cell function accompanied by a reduced incretin effect, an over-activity of α-cells resulting in hyperglucagonaemia, and insulin resistance. Simply stating these mechanisms belies the true complexity of T2DM pathophysiology. We are still a very long way from a complete understanding of the processes that lead to the development of this disease, but with each new advance in understanding there comes a better appreciation of how to tackle T2DM. Insulin resistance Insulin resistance at the tissue level contributes significantly to hyperglycaemia by impeding the degree to which target cells respond to the presence of insulin.9 10 15-17 For example, with respect to hepatocytes and adipocytes, insulin resistance reduces glucose uptake with a consequent increase in glucose and free fatty acid output, respectively (Figure 2).15 16 18 Elevated levels of glucose and free fatty acids are believed to negatively impact β-cell function (discussed below), underlining the intimate relationship between these two pathophysiological mechanisms.

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Obesity is known to be the most common cause of insulin resistance.16 The exact relationship between the two is not fully understood, but it is thought to involve a number of processes, involving excessive storage of triglycerides in the liver (steatosis).19 Lipids are more abundant in obese individuals and it is thought that these may interfere with the signalling processes crucial to the correct functioning of insulin.20 Obesity also triggers inflammatory responses, some of which are important in intracellular signalling within insulin-responsive cells.20 Furthermore, the adipose tissue is far from being an inert storage ‘depot’ (see below).20

Figure 2. The consequences of insulin resistance.21

β-cell dysfunction The β-cells of the pancreas do not respond to rising glucose levels or other stimuli that regulate insulin secretion to match the current metabolic requirements. This results in a relative lack of insulin contributing to chronic hyperglycaemia, especially in the situation of insulin resistance with its higher insulin needs.16 In the early stages of T2DM, with the advent of resistance, there is a compensatory increase in insulin secretion in an attempt to maintain glucose and lipid homeostasis.17 However, the time dynamics of insulin release is abnormal even at this stage because of a reduced sensitivity of β-cells to glucose. This defect is accentuated in overt T2DM. In long-standing disease, there is usually a reduction in the islet number and/or diminished β-cell mass in the pancreas of people with T2DM due to increased apoptosis and inadequate regeneration.22 Why this should occur is not clear, but it is likely to be due to a combination of genetic susceptibility and acquired factors. Many β-cell ‘aggressors’ have been identified, such as elevated glucose and free fatty acid levels (Figure 3), all of which lead to β-cell damage and apoptosis. For example, increased levels of free fatty acids within β-cells can inhibit proper glucose utilisation, disrupt normal cell signalling cascades and damage mitochondria due to the 8

generation of reactive oxygen species.16 Interestingly, β-cells have a very low antioxidant capacity.23

Figure 3. β-cell failure24 25

Reduced incretin effect The incretin system and the defects therein observed in people with T2DM are reviewed in Chapter 4. Incretins are a quantitatively important stimulus to insulin secretion after meals, so that defects in this entero-insular axis will contribute to relative insulin deficiency in type 2 diabetes.

The scope of the T2DM problem
Epidemiology T2DM is a huge public health problem, the growth of which shows no signs of abating. The epidemiological statistics of this disease are staggering. Every ten seconds two people develop diabetes.26 Globally, it is estimated that 285 million people have this disease (just over 6% of the global population) and by 2030, there are projected to be more than 430 million people with this disease.26 The rise of T2DM as a global epidemic has accompanied the rapid cultural and social changes - shifting demographics, increasing urbanization, dietary changes, reduced physical activity and other unhealthy lifestyle and behavioural patterns - that have taken place over the last five decades or so.26 Globally, diabetes is the fourth leading cause of death. Every year, diabetes kills nearly four million people, almost half of whom are less than 70 years old.26 An even greater number die from cardiovascular disease made worse by diabetes-related complications.26 T2DM alone 9

constitutes about 85% to 95% of all diabetes cases in developed countries and accounts for an even higher percentage in developing countries.26 The impact of T2DM is certainly comparable to other diseases of modern society, such as hypertension and obesity, and often coexists with these other conditions. When we think of diabetes we tend to imagine a disease that afflicts affluent, western societies, but increasingly T2DM respects neither wealth nor social status and the places with the most serious T2DM are countries such as India (see below). Indeed, almost 80% of diabetes deaths occur in low- and middle-income countries as these countries often lack the necessary healthcare resources to manage this disease effectively.26 These developing countries are also likely to see the largest increases in the prevalence of T2DM in the coming years and decades.26 A silent disease The epidemiological figures certainly make disturbing reading, but they are not the whole story. T2DM, especially in its early stages, is a silent disease. Symptoms, even if they occur, are mild and are easily overlooked even though hyperglycaemia and the consequences thereof are insidiously causing damage. At least 50% of all people with diabetes are unaware of their condition and in some countries this figure may reach 80%.26 By the time they are diagnosed, a considerable proportion of people have already started to develop diabetes-associated complications, such as retinal abnormalities with a potential to lead to visual impairment in the long run, initial damage to the kidneys (albuminuria) eventually threatening kidney function, heart disease, stroke and nerve damage.26 Studies suggest that the typical patient with new-onset T2DM has had the disease for at least 4–7 years before it is diagnosed.27 It seems that undiagnosed T2DM is far from being a benign condition.27 Clinically significant morbidity is present at diagnosis and for years before diagnosis.27 Among people with T2DM, 25% are believed to have retinopathy; 9%, neuropathy; and 8%, nephropathy at the time of diagnosis.28 Economic burden T2DM and its complications (considered later in this chapter) have a significant economic impact on individuals, families, health systems and countries. Costs include those for healthcare, loss of earnings, and economic costs to society in terms of loss of productivity and associated lost opportunities for economic development.29 The CODE study revealed that hospitalisations account for 55% of all T2DM expenditure in Europe.30 10

In developing countries such as India, where almost 51 million people have T2DM,26 lack of access to health care services, as well as lack of national welfare schemes and health insurance coverage for diabetes make treatment unaffordable for the masses resulting in late diagnosis and the early onset of complications, with their heavy economic burden.31 In the United States, almost 27 million people have diabetes and an additional 57 million are estimated to have pre-diabetes, putting them at an increased risk for developing diabetes.26 29 The total cost of diabetes in 2007 was $174 billion, including $116 billion in excess medical expenditures and $58 billion in reduced national productivity.32 Medical costs attributed to diabetes include $27 billion for care to directly treat diabetes, $58 billion to treat the chronic complications that are attributed to diabetes, and $31 billon in excess general medical costs.32 The largest components of medical expenditures attributed to diabetes are hospital inpatient care (50% of total cost), diabetes medication and supplies (12%), retail prescriptions to treat complications of diabetes (11%), and physician office visits (9%).32 Of the chronic complications of diabetes, peripheral vascular disease accounts for the greatest proportion of expenditure in that category (Figure 4).32

Figure 4. Proportion of category expenditures associated with diabetes in the US.32

In the UK, the cost of diabetes to the National Health Service is approximately £1 million per hour, and is increasing rapidly.33 Around 2.1 million people in the UK have diabetes, which is forecast to rise to 2.5 million by 2030.26 Diabetes accounts for approximately a tenth of the NHS’ budget each year, a total exceeding £9 billion.33 In 2004-2005, primary care units in England dispensed by prescription 24.8 million items for the 11

drug management of diabetes (to control hyperglycaemia), costing the NHS £458 million.34 In 2009-2010 this had risen by more than 40% to more than 35.5 million different items prescribed, at a cost of nearly £650 million.34 The largest increase in diabetes prevalence is predicted to occur in India and China. By 2030, there are predicted to be 62 million and 87 million people with diabetes in China and India, respectively.26 The WHO estimates that in the period 2006–2015, China will lose $558 billion in national income due to heart disease, stroke and diabetes alone. A 2007 study from India shows that total, annual median expenditure on diabetes health care was $227 in urban areas and $142 in rural areas.35 This not may seem a great deal, but when we consider that the mean annual income in urban areas is $2,273 and $818 in rural areas we get a sense of how economically debilitating this condition is for people in developing countries.35 People with diabetes in urban India spend around a tenth of their income on diabetes healthcare, whereas those in rural areas spend around a fifth. In developing countries, grinding poverty and an extreme shortage of state healthcare collude to reveal the huge burden of diabetes. Societal burden Aside from the obvious economic burden of T2DM there are the negative impacts on society that are much harder to quantify. The complications of T2DM and the treatments patients have to take for the rest of their life can lead to depression, which has ramifications for the way in which an individual interacts with family and friends. Similarly, family members may be placed under great pressure by the need to juggle family life, their career and the needs of a spouse or child with T2DM. Quantifying these aspects of the T2DM burden is practically impossible, but they must be considered in the development of disease management strategies and in attempts to define the full impact of the disease.

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Risk factors in the development of T2DM
Genetic predisposition Genetics are of fundamental importance in the emergence and the progression of T2DM, but deciphering which genes code for which proteins in the bewildering complexities of the metabolic regulatory mechanisms and how they interact will take many more years of intense study to fully elucidate. This area has been further complicated by our growing understanding of epigenetics. Epigenetics relates to heritable differences that are not caused directly by underlying genetic mechanisms.36 Typically, these can be caused by methylation of the genome causing some genes to be activated and others to be deactivated, although other mechanisms are also possible.36 Epigenetics aside, around 50 candidate genes involved mainly in pancreatic β-cell function, but also in insulin action/glucose metabolism and other metabolic mechanisms that increase T2DM risk have been identified,37 but their individual role enhances the risk for T2DM by less than 20-30 %. Thus multiple polymorphisms must be present to substantially influence individual diabetes risk. The more well-known candidate genes include transcription factor 7-like 2 (TCF7L2) gene, peroxisome proliferator-activated receptor-γ (PPARγ), ATP binding cassette, subfamily C, member 8 (ABCC8) and CAPN10. It has been postulated that TCF7L2 gene variants may affect the susceptibility to T2DM by indirectly altering GLP-1 levels.38 The PPARγ gene is important in adipocytes and lipid metabolism, with one form (Pro) decreasing insulin sensitivity and increasing T2DM risk several fold.37 ABCC8 codes for the receptors and potassium channels that regulate the release of hormones from the pancreas. A mutation in the receptor or channel can affect the secretion of hormones, such as insulin.37 CAPN10 codes an enzyme (calpain 10), variations in the activity of which can affect insulin secretion.37 Obesity Obesity is the most potent risk factor for developing T2DM. The correlation between diabetes and obesity is well-known (Figure 5).39 In an evolutionary context, the obesity epidemic is a consequence of maladaptation, i.e. the human genotype has not adapted to the modern lifestyle with food abundance relative to shortage (as was typical for our ancestors). Evolution equipped humans with the ability to survive on meagre, albeit intermittently abundant, food resources – a situation that prevailed for the vast majority of human evolution. Compared with our ancient ancestors, our anatomy and physiology are unchanged, but in recent centuries, lifestyles have changed immeasurably in the 13

vast majority of cultures. Today, humans are largely sedentary with easy access to an abundance of energy-rich, processed foods. The physiological links between obesity and diabetes are poorly understood, but what is important is that obesity leads to insulin resistance in the majority of cases.20 It is generally thought that defects in lipid metabolism in obese patients are the root cause of T2DM in these patients.20 In the obese patient, lipid molecules may leak from the adipocytes into the bloodstream where they are eventually taken up by liver and muscle cells.20 Once inside these cells, the lipids interfere with signalling processes crucial to the correct functioning of insulin.20 In addition, insulin resistance is associated with subclinical inflammatory responses throughout the body.20 Furthermore, it is also becoming increasingly clear that adipose tissue is far more than just a storage tissue, acting in many ways like an endocrine organ. In obesity, the para-endocrine functions of this tissue may be impaired.20

Figure 5. Age-adjusted prevalence of diabetes by ethnicity and BMI category, clearly showing the increasing prevalence of the disease with increasing BMI (upper – men; lower – women).39

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Increasing age T2DM can develop at any age. Typically, however, the prevalence of this disease increases with age (Figure 6) and one reason why T2DM is such a rapidly growing problem is the aging population.40 Internationally, T2DM is most common in the 40-59 age group, but the incidence of the disease is increasing more rapidly in adolescents and young adults.41 The fact that T2DM prevalence typically increases with age is probably a result of the progressive loss of β-cell function that occurs with age, particularly in susceptible individuals who have other risk factors, e.g. poor diet, sedentary lifestyle, etc.

Figure 6. The prevalence of T1D and T2D in England.40

Ethnicity The prevalence of T2DM around the world is heavily influenced by race/ethnicity. For example, the incidence of T2DM in white Europeans is relatively low compared with Asian/Pacific Islanders (Figure 7).41 Exactly why there should be such variation is not fully understood, but it is more than likely to be due to a complex interplay of factors involving genetic and environmental elements. Even in children, the prevalence of T2DM varies with ethnicity, as exemplified in Figure 8.42 The pattern in Figure 7 can be explained to some extent by the prevalence of obesity in these ethnic groups. For example, in children between the ages of 2 and 5 years, the prevalence of obesity in white non-Hispanics, black non-Hispanics and Mexican Americans was 8.6%, 8.8% and 13.1%, respectively.43 As children grow older (adolescents 12–19 years old), the differences in the prevalence of obesity become even more marked: 12.7% in white non-Hispanics; 23.6% in black non-Hispanics and 23.4% in Mexican Americans.43 15

Figure 7. Differences in the prevalence of T2DM among selected ethnic groups.41

Figure 8. Proportion of US children with T1D and T2D according to race/ethnicity (A = children 0-9 years; B = children 10-19 years). NHW = non-Hispanic white; AA = African American; H = Hispanic; API = Asian/Pacific Islander; American Indian.42

Lifestyle A variety of lifestyle factors are known to influence the risk of developing T2DM. Exercise has a definite effect on T2DM. Studies have shown that exercise appears to reduce the risk of developing T2DM even after adjusting for body-mass index (Figure 9).44 The relative risk of developing this disease in those people exercising vigorously once a week, 2–4 times a week and ≥5 times a week is 0.77 (95% CI: 0.55–1.07), 0.62 (95% CI: 0.46–0.82) and 0.58 (95% CI: 0.40–0.84), respectively.44 Exercise 16

appears to optimise the ways in which our body uses glucose, such as enhancing the uptake of this sugar by muscle cells. The effect of alcohol on the risk of developing T2DM appears to be less clear cut. A meta-analysis of 15 prospective cohort studies demonstrates a U-shaped relationship between alcohol consumption and the risk of developing T2DM.45 In those people who consume a moderate amount of alcohol (6–48 g/day) there is highly significant, 30% reduced risk of T2DM, but no risk reduction is observed in heavy consumers (≥48 g/day) or those who abstain from alcohol.45 Exactly why there should be such a relationship between alcohol consumption and risk of T2DM is not fully understood. Moderate alcohol consumption is known to increase HDL cholesterol concentration,46 whereas, higher consumption is known to be associated with increased body weight, triglyceride concentration and blood pressure increase.47-50 Alcohol also has anti-inflammatory effects and these may provide some degree of protection from the inflammatory mechanisms involved in the development of T2DM.51 52 Enhanced insulin sensitivity with lower plasma insulin concentrations is another potential mechanism that explains this relationship.48

Figure 9. Age-adjusted incidence rates of T2D with exercise frequency.44

Smoking is also known to increase the risk of developing T2DM. Tobacco, or at least some of the biologically active compounds in commercial tobacco, can result in high blood sugar levels and insulin insensitivity.53 54 A study in US male physicians showed that in past smokers and those who smoked <20 or ≥20 cigarettes per day the relative risk of developing T2DM was 1.2 (95% CI: 1.0–1.4), 1.4 (95% CI: 1.0–2.0) and 2.1 (95% CI: 1.7–2.6), respectively.55 17

Other risk factors A number of other factors are known to increase the risk of developing T2DM. For example, individuals with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) are at an increased risk of developing this disease.28 IGT and IFG are pre-diabetic states characterised by the same pathophysiological abnormalities of T2DM, only milder in degree. A history of gestational diabetes mellitus is known to increase the risk of developing T2DM later on in life.28 In around 3-8% of pregnancies, impaired glucose tolerance or full gestational diabetes can develop.56 The reason for this is not clear, but it is thought that the hormones produced during pregnancy, notably progesterone, can worsen insulin resistance in susceptible individuals, resulting in raised blood glucose levels.57 The transient demand on glucose-regulating mechanisms may contribute to T2DM later on.57 Additionally, an abnormal metabolic intrauterine milieu affects foetal development by permanently modifying expression of key genes regulating β-cell development (Pdx1) and glucose transport (Glut4) in muscle.58 Ultimately, this can lead to the development of T2DM in adulthood.58 This observation reinforces the importance of epigenetics in the development of T2DM (see Genetic predisposition section earlier in this chapter). Women with polycystic ovarian syndrome are also at an increased risk of developing T2DM.28 It is thought the hormonal imbalances associated with this condition, notably the overproduction of androgens can impair carbohydrate metabolism, ultimately leading to impaired glucose tolerance and T2DM.59

T2DM complications
Underlying aetiology T2DM causes a number of complications that together account for much of the morbidity, mortality and burden associated with this disease. These complications can be broadly divided into two categories: microvascular and macrovascular. Regardless of the classification, all complications of T2DM are a consequence of chronic hyperglycaemia and the other metabolic and haemodynamic abnormalities that accompany this disease such as central obesity, dyslipidaemia and hypertension.60 Several of these diabetic complications can also occur in patients with normal glucose tolerance and prediabetes.28

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Elevated levels of glucose are found throughout the body of an individual with T2DM from the blood in their arteries supplying oxygen and substrates to the fluid that bathes their cells. If these elevated glucose levels persist for an extended period of time then cellular damage ensues. Exactly how elevated glucose levels damage cells is not fully understood, but a number of candidate mechanisms have been identified. Elevated glucose levels result in the non-enzymatic formation of glycated proteins and, ultimately, advanced glycosylated end products (AGEs), the accumulation of sorbitol and fructose, increased hexosamine pathway flux and the activation of protein kinase C.61-63 One consequence of this over-abundance of sugars is an increase in oxidative stress, i.e. increased concentrations of free radicals generated during the metabolism of the overly abundant sugars.61 62 Similarly, this excess of sugars causes osmotic stress, i.e. the reduced ability of the cell to regulate its water and solute levels.61 62 The damage sustained by cells and tissues accumulates until compensatory mechanisms are insufficient to prevent a decline in function and diabetic complications become symptomatic (Figure 10).61 The cells particularly affected by hyperglycaemia are capillary endothelial cells throughout the body, mesangial cells in the renal glomerulus and neurons and Schwann cells in the autonomic and peripheral nerves.61 Unlike most other cells, the cell types above are unable to reduce their uptake of glucose when they are exposed to hyperglycaemic conditions.61

Figure 10. General features of hyperglycaemia-induced tissue damage.61

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Microvascular complications The microvascular complications are retinopathy, nephropathy and neuropathy all of which are characterised by non-inflammatory damage to the cells in question and progressive loss of function in the respective organs and systems. Retinopathy is the most frequent cause of new cases of blindness among adults aged 20-74 years of age.64 It is caused by damage to the capillary endothelial cells in the retina and risk factors include duration of T2DM, hypertension, and smoking.64 During the first two decades of diabetic disease, 60% of patients with T2DM develop some degree of retinopathy, which is often accompanied by glaucoma, cataracts and macular disease or other eye disorders, all of which occur earlier and more frequently in people with this disease.64 Diabetic retinopathy is often linked with diabetic nephropathy.65 Diabetic nephropathy is discussed in detail in Chapter 2, suffice to say here that it is a progressive kidney disease caused by changes in glomerular structure and function and expansion of extracellular matrix and that approximately onethird of all people with T2DM have some degree of renal impairment.66 Neuropathy is characterised by a progressive decline predominantly in sensation, but also in movement and other bodily functions due to damage of the neurons and their insulating Schwann cells.61 Neuropathy is broadly divided into peripheral and autonomic. The former is impaired sensation in the legs, feet, arm or hands – often accompanied by pain, carpal tunnel syndrome and erectile dysfunction,67 while the latter is characterised by problems with breathing, blood pressure, bladder control, vision and the gastrointestinal tract (e.g. gastroparesis).67 Neuropathy is a significant source of morbidity and mortality in people with diabetes and T2DM is the leading cause of this condition in the Western world.68 Recent studies have found that peripheral neuropathy affects approximately 70% of people with T2DM.69 70 Other studies have shown that peripheral nerve damage is a factor in 76% of all diabetic foot ulcers, implicating this T2DM complication in 50-75% of all non-traumatic amputations.68 71 Ulcers and amputations as a consequence of diabetes-induced peripheral neuropathy are a huge problem. Some estimates suggest that every 30 seconds a lower limb is lost somewhere in the world as a consequence of diabetes.72 The mortality rate in those diabetic patients with new-onset ulceration of the feet is 43%–55%. In those people who undergo an amputation, this rises to almost 75% – a mortality rate that is higher than several types of cancer.73-79 Needless to say, the burden of foot complications due to diabetesinduced peripheral neuropathy is huge. Economic analyses have suggested that the cost of treating diabetic foot ulcers in Europe alone may be as high as €10 billion per year.80 For all its debilitating and eco20

nomic impacts, diabetic neuropathy is a typically overlooked complication of T2DM. Macrovascular complications People with T2DM are at increased risk of macrovascular complications, such as stroke, transient ischaemic attacks, coronary artery disease, myocardial infarction, hypertension and peripheral vascular disease. As varied as these may seem, they are all a consequence of hyperglycaemia-induced damage to the endothelium of blood vessels, most notably the arteries. This injury to the endothelium triggers a cascade of events, collectively known as atherogenesis (Figure 11).60 This process also involves an inflammatory response within the vessel wall, which ultimately results in the formation of atherosclerotic lesions that effectively narrow the lumen of arteries throughout the body, as well as hardening the arterial walls (Figure 11). This narrowing impedes blood flow and can increase the chances of clot formation. However, the most catastrophic consequence of this inflammatory process is the potential for the lesion to rupture with debris and associated clots occluding a downstream portion of a blood vessel, which in some cases, can be fatal.60 The atherogenic cascade begins with the oxidation of lipids from LDL particles, which accumulate in the endothelial wall of arteries.60 Angiotensin II is thought to promote the oxidation and accumulation of lipids.60 Following this initial step, monocytes infiltrate the arterial wall and differentiate into macrophages, which accumulate oxidised lipids to form foam cells.60 Once formed, these foam cells stimulate macrophage proliferation as well as attracting T-lymphocytes.60 In turn, the T-lymphocytes induce smooth muscle proliferation and the accumulation of collagen in the arterial walls.60 The net result of this inflammatory cascade is the formation of a lipid-rich atherosclerotic lesion with a fibrous cap.60 In addition to the inflammatory mechanisms outlined above, there is also evidence of increased platelet adhesion and hypercoagulability in people with T2DM. These phenomena may be as a result of impaired nitric oxide generation, increased free radical formation and altered calcium regulation in the platelets, all of which promote platelet aggregation. Not only is platelet aggregation often increased in people with T2DM, but there is also evidence that the process of fibrinolysis may be impaired due to elevated levels of plasminogen activator inhibitor type 1.60 It is very likely this combination of increased coagulability and impaired fibrinolysis further increases the risk of vascular occlusion and cardiovascular (CV) events in T2DM.81

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The physical narrowing of the arteries and the potential for the atherosclerotic lesion to rupture and completely occlude a blood vessel significantly increases the risk of CV events. In people with diabetes, the risk of myocardial infarction is comparable to the risk in non-diabetic patients with a history of previous MI.82 T2DM increases the risk of stroke by 150–400% and the risk of death from CV causes by two to six-fold.83 Indeed, more than 70% of patients with T2DM die of CV causes.84 Needless to say, the societal and economic burden of macrovascular complications in the context of overall healthcare costs attributable to T2DM is huge. Data suggest that CV disease accounts for the largest proportion of all diabetes-related healthcare expenditure.85 86

Figure 11. The progression of atherosclerosis – the underlying cause of macrovascular complications (after Stary, et al. 1995).87

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Chapter 1 Summary
z Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease, characterised by hyperglycaemia. Insulin resistance (i.e., a reduced cellular response to the hormone) and impaired pancreatic β-cell function are the chief pathogenetic mechanisms. z Simple blood tests allow for the diagnosis of T2DM as well as prediabetes, which is a condition of milder dysglycaemia at high risk of progressing to overt T2DM. z The criteria for the diagnosis of diabetes are as follows:

◦ ◦ ◦ ◦

Fasting plasma glucose (FPG): ≥126 mg/dl (7.0 mmol/l) Post-prandial glucose (PPG): ≥200 mg/dl (11.1 mmol/l) HbA1c ≥6.5% Random plasma glucose: ≥200 mg/dl (11.1 mmol/l)

z Insulin has a number of key functions, including promoting the uptake of glucose by cells throughout the body. z In essence, the pathophysiological mechanisms involved in the development of T2DM are the deterioration of β-cell function accompanied by a reduced incretin effect, an over-activity of α-cells resulting in hyperglucagonaemia, and insulin resistance. z The β-cells of the pancreas do not respond to rising glucose levels appropriately, which results in a relative lack of insulin contributing to chronic hyperglycaemia.

Many β-cell ‘aggressors’ have been identified, such as elevated glucose and free fatty acid levels, all of which lead to β-cell damage and apoptosis. Globally, it is estimated that 285 million people have this disease (just over 6% of the global population) and by 2030, there are projected to be more than 430 million people with this disease. Every year it kills nearly four million people, almost half of whom are less than 70 years old.

z Every ten seconds, two people develop diabetes

z Diabetes is the fourth leading cause of death.

z The typical patient with new-onset T2DM has had the disease for at least 4–7 years before it is diagnosed. By the time they are diagnosed, a considerable proportion of people have already started to develop diabetesassociated complications. z The total cost of diabetes in the US in 2007 was $174 billion. z In the UK Diabetes accounts for approximately a tenth of the NHS’ budget each year, a total exceeding £9 billion. z Genetics are of fundamental importance in the emergence and the progression of T2DM and many candidate genes have been identified that increase the risk of developing T2DM.

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z Epigenetics is also thought to be very important in the development of T2DM. z Obesity is the most potent risk factor for developing T2DM. z The prevalence of T2DM around the world is heavily influenced by race/ ethnicity.

The incidence of T2DM in white Europeans is relatively low compared with Asian/Pacific Islanders.

z Lack of exercise has a significant impact on the risk of developing T2DM. z Individuals with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) are at an increased risk of developing T2DM. z Regardless of the classification, all complications of T2DM are a consequence of chronic hyperglycaemia and the other metabolic and haemodynamic abnormalities that accompany this disease such as central obesity, dyslipidaemia and hypertension. z Elevated glucose levels result in the non-enzymatic formation of glycated proteins and, ultimately, advanced glycosylated end products (AGEs), the accumulation of sorbitol and fructose, increased hexosamine pathway flux and the activation of protein kinase C.

This over-abundance of sugars causes oxidative and osmotic stress.

z The cells particularly affected by hyperglycaemia are capillary endothelial cells throughout the body, mesangial cells in the renal glomerulus and neurons and Schwann cells in the autonomic and peripheral nerves.

These cell types above are unable to reduce their uptake of glucose when they are exposed to hyperglycaemic conditions.

z The microvascular complications are retinopathy, nephropathy and neuropathy. z Macrovascular complications include stroke, transient ischaemic attacks, coronary artery disease, myocardial infarction, hypertension and peripheral vascular disease.

◦ ◦

As varied as these may seem, they are all a consequence of hyperglycaemia-induced damage to the endothelium of blood vessels, most notably the arteries. Data suggest that cardiovascular disease accounts for the largest proportion of all diabetes-related healthcare expenditure.

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References:
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. The American Association of Clinical Endocrinologists Medical Guidelines for the Management of Diabetes Mellitus: the AACE system of intensive diabetes selfmanagement--2000 update. Endocr Pract 2000;6(1):43-84. Matthaei S, Stumvoll M, Kellerer M, Haring HU. Pathophysiology and pharmacological treatment of insulin resistance. Endocrine reviews 2000;21(6):585-618. Wajchenberg BL. beta-cell failure in diabetes and preservation by clinical treatment. Endocrine reviews 2007;28(2):187-218. WHO. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: WHO, 2006. ADA. Standards of medical care in diabetes--2010. Diabetes care 2010;33 Suppl 1: S11-61. Nathan DM, Davidson MB, DeFronzo RA, Heine RJ, Henry RR, Pratley R, et al. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes care 2007;30(3):753-9. Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes care 2003;26(11):3160-7. Mellitus ECotDaCoD. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes care 1997;20(7):1183-97. Jung CY, Lee W. Glucose transporters and insulin action: some insights into diabetes management. Archives of pharmacal research 1999;22(4):329-34. Shepherd PR, Kahn BB. Glucose transporters and insulin action--implications for insulin resistance and diabetes mellitus. The New England journal of medicine 1999;341(4):248-57. Benardot D. Advanced Sports Nutrition. Champaign: Human Kinetics, 2006. Nussey S, Whitehead S. The Endocrine Pancreas Endocrinology: an integrated approach. Oxford: BIOS Scientific Publishers Ltd 2001. Ratnayake WM, Galli C. Fat and fatty acid terminology, methods of analysis and fat digestion and metabolism: a background review paper. Annals of nutrition & metabolism 2009;55(1-3):8-43. Williams G, Pickup JC. Handbook of Diabetes, 3rd Edition: Wiley-Blackwell, 2004. DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988;37(6):667-87. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. The Medical clinics of North America 2004;88(4):787-835, ix. Olatunbosun S, Dagogo-Jack S. Insulin resistance: eMedicine, WebMD, 2009. Rhodes CJ, White MF. Molecular insights into insulin action and secretion. European journal of clinical investigation 2002;32 Suppl 3:3-13. Youssef W, McCullough AJ. Diabetes mellitus, obesity, and hepatic steatosis. Seminars in gastrointestinal disease 2002;13(1):17-30. Wellcome Trust. How does obesity cause ill-health?: Wellcome Trust, 2009. FEND. Diabetes. The policy puzzle: Is Europe making progress. , 2008. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52(1): 102-10. Drews G, Krippeit-Drews P, Dufer M. Oxidative stress and beta-cell dysfunction. Pflugers Arch 2010;460(4):703-18. Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. European journal of clinical investigation 2002;32 Suppl 3:14-23. Kaiser N, Leibowitz G, Nesher R. Glucotoxicity and beta-cell failure in type 2 diabetes mellitus. J Pediatr Endocrinol Metab 2003;16(1):5-22. International Diabetes Federation. IDF Diabetes Atlas, 4th edition, 2009. Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis. Diabetes care 1992;15(7):815-9. Votey S, Peters A. Diabetes, Type 2 - A Review: Web MD, 2010. Hewitt Associates LLC. Trends in HR and Employee Benefits: Chronic disease analysis diabetes trends, 2009.

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30. Jonsson B. Revealing the cost of Type II diabetes in Europe. Diabetologia 2002; 45(7):S5-12. 31. Narayan KM, Zhang P, Williams D, Engelgau M, Imperatore G, Kanaya A, et al. How should developing countries manage diabetes? CMAJ 2006;175(7):733. 32. ADA. Economic costs of diabetes in the U.S. In 2007. Diabetes care 2008;31(3): 596-615. 33. Diabetes UK. The cost of diabetes 2008. 34. Diabetes UK. Cost of diabetes to the NHS rising rapidly, 2010. 35. Ramachandran A, Ramachandran S, Snehalatha C, Augustine C, Murugesan N, Viswanathan V, et al. Increasing expenditure on health care incurred by diabetic subjects in a developing country: a study from India. Diabetes care 2007;30(2):252-6. 36. Feinberg AP. Epigenetics at the epicenter of modern medicine. JAMA 2008;299(11): 1345-50. 37. WHO. Genetics and Diabetes: WHO, 2009. 38. Yi F, Brubaker PL, Jin T. TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. The Journal of biological chemistry 2005;280(2):1457-64. 39. Maskarinec G, Grandinetti A, Matsuura G, Sharma S, Mau M, Henderson BE, et al. Diabetes prevalence and body mass index differ by ethnicity: the Multiethnic Cohort. Ethnicity & disease 2009;19(1):49-55. 40. Joint Health Surveys Unit. Health Survey for England 2006: Cardiovascular disease and risk factors. Leeds: The Information Centre, 2008. 41. International Diabetes Federation. IDF Diabetes Atlas, 2nd edition, 2003. 42. Liese AD, D’Agostino RB, Jr., Hamman RF, Kilgo PD, Lawrence JM, Liu LL, et al. The burden of diabetes mellitus among US youth: prevalence estimates from the SEARCH for Diabetes in Youth Study. Pediatrics 2006;118(4):1510-8. 43. Hannon TS, Rao G, Arslanian SA. Childhood obesity and type 2 diabetes mellitus. Pediatrics 2005;116(2):473-80. 44. Manson JE, Nathan DM, Krolewski AS, Stampfer MJ, Willett WC, Hennekens CH. A prospective study of exercise and incidence of diabetes among US male physicians. JAMA 1992;268(1):63-7. 45. Koppes LL, Dekker JM, Hendriks HF, Bouter LM, Heine RJ. Moderate alcohol consumption lowers the risk of type 2 diabetes: a meta-analysis of prospective observational studies. Diabetes care 2005;28(3):719-25. 46. Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ (Clinical research ed 1999;319(7224):1523-8. 47. Kato I, Kiyohara Y, Kubo M, Tanizaki Y, Arima H, Iwamoto H, et al. Insulin-mediated effects of alcohol intake on serum lipid levels in a general population: the Hisayama Study. J Clin Epidemiol 2003;56(2):196-204. 48. Kiechl S, Willeit J, Poewe W, Egger G, Oberhollenzer F, Muggeo M, et al. Insulin sensitivity and regular alcohol consumption: large, prospective, cross sectional population study (Bruneck study). BMJ (Clinical research ed 1996;313(7064):1040-4. 49. Thadhani R, Camargo CA, Jr., Stampfer MJ, Curhan GC, Willett WC, Rimm EB. Prospective study of moderate alcohol consumption and risk of hypertension in young women. Archives of internal medicine 2002;162(5):569-74. 50. Wannamethee SG, Shaper AG. Alcohol, body weight, and weight gain in middleaged men. Am J Clin Nutr 2003;77(5):1312-7. 51. Imhof A, Froehlich M, Brenner H, Boeing H, Pepys MB, Koenig W. Effect of alcohol consumption on systemic markers of inflammation. Lancet 2001;357(9258):763-7. 52. Sierksma A, van der Gaag MS, Kluft C, Hendriks HF. Moderate alcohol consumption reduces plasma C-reactive protein and fibrinogen levels; a randomized, diet-controlled intervention study. Eur J Clin Nutr 2002;56(11):1130-6. 53. Epifano L, Di Vincenzo A, Fanelli C, Porcellati F, Perriello G, De Feo P, et al. Effect of cigarette smoking and of a transdermal nicotine delivery system on glucoregulation in type 2 diabetes mellitus. Eur J Clin Pharmacol 1992;43(3):257-63. 54. Eliasson B, Attvall S, Taskinen MR, Smith U. The insulin resistance syndrome in smokers is related to smoking habits. Arterioscler Thromb 1994;14(12):1946-50. 55. Manson JE, Ajani UA, Liu S, Nathan DM, Hennekens CH. A prospective study of cigarette smoking and the incidence of diabetes mellitus among US male physicians. The American journal of medicine 2000;109(7):538-42.

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56. Dabelea D, Snell-Bergeon JK, Hartsfield CL, Bischoff KJ, Hamman RF, McDuffie RS. Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM Screening Program. Diabetes care 2005;28(3):579-84. 57. Rebarber A, Istwan NB, Russo-Stieglitz K, Cleary-Goldman J, Rhea DJ, Stanziano GJ, et al. Increased incidence of gestational diabetes in women receiving prophylactic 17alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery. Diabetes care 2007;30(9):2277-80. 58. Pinney SE, Simmons RA. Epigenetic mechanisms in the development of type 2 diabetes. Trends Endocrinol Metab 2010;21(4):223-9. 59. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. The Journal of clinical endocrinology and metabolism 1999;84(1):165-9. 60. Fowler M. Macrovascular and microvascular complications in type 2 diabetes patients. Clinical Diabetes 2008;26(2):77-82. 61. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005;54(6):1615-25. 62. Gerich JE. Clinical significance, pathogenesis, and management of postprandial hyperglycemia. Archives of internal medicine 2003;163(11):1306-16. 63. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414(6865):813-20. 64. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, et al. Retinopathy in diabetes. Diabetes care 2004;27 Suppl 1:S84-7. 65. Jawa A, Kcomt J, Fonseca VA. Diabetic nephropathy and retinopathy. The Medical clinics of North America 2004;88(4):1001-36, xi. 66. Koro CE, et al. Antidiabetic medication use and prevalence of chronic kidney disease among patients with type 2 diabetes mellitus in the United States. Clin. Therapeutics 2009;31(11):2608-17. 67. ADA. Standards of medical care in diabetes--2009. Diabetes care 2009;32 Suppl 1: S13-61. 68. Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia 2000;43(8):957-73. 69. Karvestedt L, Martensson E, Grill V, Elofsson S, von Wendt G, Hamsten A, et al. The prevalence of peripheral neuropathy in a population-based study of patients with type 2 diabetes in Sweden. Journal of diabetes and its complications 2010. 70. Lauterbach S, Kostev K, Becker R. Characteristics of diabetic patients visiting a podiatry practice in Germany. J Wound Care 2010;19(4):140-44. 71. Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of diabetic peripheral neuropathy in the US. Diabetes care 2003;26(6):1790-5. 72. International Diabetes Federation. Time to Act: Diabetes and Foot Care: International Diabetes Federation, 2005. 73. Apelqvist J, Larsson J, Agardh CD. Long-term prognosis for diabetic patients with foot ulcers. Journal of internal medicine 1993;233(6):485-91. 74. Faglia E, Favales F, Morabito A. New ulceration, new major amputation, and survival rates in diabetic subjects hospitalized for foot ulceration from 1990 to 1993: a 6.5-year follow-up. Diabetes care 2001;24(1):78-83. 75. Jeffcoate WJ, Chipchase SY, Ince P, Game FL. Assessing the outcome of the management of diabetic foot ulcers using ulcer-related and person-related measures. Diabetes care 2006;29(8):1784-7. 76. Moulik PK, Mtonga R, Gill GV. Amputation and mortality in new-onset diabetic foot ulcers stratified by etiology. Diabetes care 2003;26(2):491-4. 77. Naschitz JE, Lenger R. Why traumatic leg amputees are at increased risk for cardio vascular diseases. QJM 2008;101(4):251-9. 78. Resnick HE, Carter EA, Lindsay R, Henly SJ, Ness FK, Welty TK, et al. Relation of lowerextremity amputation to all-cause and cardiovascular disease mortality in American Indians: the Strong Heart Study. Diabetes care 2004;27(6):1286-93. 79. Schofield CJ, Libby G, Brennan GM, MacAlpine RR, Morris AD, Leese GP. Mortality and hospitalization in patients after amputation: a comparison between patients with and without diabetes. Diabetes care 2006;29(10):2252-6. 80. Prompers L, Huijberts M, Schaper N, Apelqvist J, Bakker K, Edmonds M, et al. Resource utilisation and costs associated with the treatment of diabetic foot ulcers. Prospective data from the Eurodiale Study. Diabetologia 2008;51(10):1826-34.

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81. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002;287(19):2570-81. 82. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. The New England journal of medicine 1998;339(4):229-34. 83. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. The New England journal of medicine 2003;348(5):383-93. 84. Laakso M. Cardiovascular disease in type 2 diabetes: challenge for treatment and prevention. J Intern Med 2001;249(3):225-35. 85. Hogan P, Dall T, Nikolov P. Economic costs of diabetes in the US in 2002. Diabetes care 2003;26(3):917-32. 86. Paterson AD, Rutledge BN, Cleary PA, Lachin JM, Crow RS. The effect of intensive diabetes treatment on resting heart rate in type 1 diabetes: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Diabetes care 2007;30(8):2107-12. 87. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W, Jr., et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995;92(5):1355-74.

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2. The Kidneys and Diabetes – Dealing with Hypoglycaemia

Professor Per Henrik Groop
University of Helsinki Folkhälsan Research Centre Helsinki, Finland

Dr Merlin Thomas

Danielle Alberti Memorial Centre for Diabetic Complications Baker Medical Research Institute Melbourne, Australia

Hypoglycaemia is the most frequent complication of diabetes management, affecting up to one quarter of all patients with type 2 diabetes, at least once a year.1 Although permanent damage or mortality due to hypoglycaemia is uncommon, even minor hypoglycaemic events can have a major effect on diabetes management. Hypoglycaemia (or a “hypo”) is cited as the most important (and feared) complication of diabetes by patients themselves, more important than kidney failure or heart disease. Hypoglycaemia is often the most important barrier to good glucose control, as attempts to avoid it result in therapeutic inertia and (reluctant) tolerance of higher glucose levels.2 Although the kidney is primarily regarded as an excretory organ, it also plays an important role in glucose homoeostasis. Impaired kidney function is associated with abnormal glucose metabolism, including decreased sensitivity to insulin, inadequate insulin secretion, and altered gluconeogenesis. Kidney disease also directly or indirectly alters the pharmacokinetics and pharmacodynamics of all agents used to treat type 2 diabetes.3 Combined, these contribute to an increased incidence and severity of hypoglycaemic episodes (Figure 1). This chapter will examine some of the reasons for this association, and the opportunities to reduce the risk of hypoglycaemic events in patients with chronic kidney disease (CKD).

Figure 1. Factors that contribute to the increased incidence of hypoglycaemia in diabetic patients with chronic kidney disease.

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Epidemiology and impact of hypoglycaemia in type 2 diabetes and CKD
In patients with advanced type 2 diabetes, such as those with CKD, the incidence and severity of hypoglycaemia are high. Severe hypoglycaemia (requiring medical attention) probably occurs at a rate of about 50 episodes per 100 patient-years. These rates are at least 5-10 fold higher than observed in diabetic patients without CKD. Mild and/ or asymptomatic hypoglycaemic events are even more common, and possibly ubiquitous. Data from small studies using continuous glucose monitoring in diabetic patients on dialysis reveal a glimpse of the size of the potential problem. For example, in a recent study of nine diabetic patients undergoing haemodialysis, ten hypoglycaemic events were seen in five subjects over a two-day monitoring period.4 Only three episodes were associated with symptoms and confirmed by capillary blood glucose tests.4 Individuals experiencing hypoglycaemia have an increased risk of adverse outcomes. This is not simply severe symptomatic events or deaths due to neuroglycopaenia. In fact, all-cause mortality is increased in those with a higher incidence of hypoglycaemia.5 It is possible that hypoglycaemia is simply a marker of vulnerability to such events. However, some data suggest that hypoglycaemia may directly contribute to adverse outcomes. For example, the surge of sympathetic activity and a release of catecholamines associated with hypoglycaemia has been associated with cardiovascular events, arrhythmia6 and sudden death.7

Renal gluconeogenesis
Although the liver is generally regarded as the seat of gluconeogenesis, healthy kidneys also synthesise and release significant quantities of glucose into the circulation 8, the loss of which also contributes to hypoglycaemia in patients with CKD. Following overnight fasting, approximately half of all glucose released comes from gluconeogenesis, with the other half coming from hepatic glycogenolysis (Figure 2).8 The liver and the kidney are the only two organs capable of gluconeogenesis in the human body. The liver is the major contributor to gluconeogenesis in healthy individuals (~60% of all gluconeogenesis following overnight fasting). However, glucose levels are maintained even in the absence of liver tissue (e.g. after removal of the liver in individuals undergoing liver transplantation), with overall endogenous glucose release only falling by less than 50%. It is now thought that hormonally regulated gluconeogenesis in the renal cortex accounts for ~20% of all glucose produced following overnight fasting (40% of all gluconeogenic sugar).9, 10

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Figure 2. Major sites of glucose production in response to overnight fasting

The kidneys also play an important role in the counter-regulatory response to hypoglycaemia, with both increased renal gluconeogenesis and, to a lesser extent, decreased glucose uptake, acting to maintain glucose circulating levels.11 The contribution of renal gluconeogenesis to total gluconeogenesis is also substantially greater in hypoglycaemia, with up to a third of all glucose produced coming from the kidneys.12 Furthermore, in patients with type 2 diabetes, in whom hepatic glycogen stores are depleted or glycogenolysis pharmacologically inhibited, a renal counter-regulatory response may be even more pivotal.

Kidney function and insulin kinetics
The production of insulin by the pancreas in response to feeding facilitates the uptake of glucose into the liver, fat and skeletal muscle to maintain euglycaemia post-prandially in healthy individuals. During fasting, insulin production is suppressed; triggering the release of glucose to ensure the brain receives the constant supply of glucose that it requires to function normally. A similar balance can be approximated with pharmacotherapy in patients with type 2 diabetes using exogenous insulin, sensitizers or secretogogues to achieve and sustain glucose control.

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Renal function significantly affects this balance. Degradation of insulin by liver and skeletal muscle is reduced in patients with CKD.13 At the same time, renal insulin handling is altered. Approximately 25% of the insulin secreted by beta cells is removed by healthy kidneys, equating to 6-8 units per day.13, 14 The kidneys, due to bypassing of the portal circulation and first-pass clearance by the liver, clear a much larger proportion of injected insulin - over half in some studies.13, 14 As a peptide of ~6 kDA in size, insulin is freely filtered at the glomerulus. Some insulin is also extracted from peri-tubular capillaries and secreted into the urine, possibly via insulin receptor-dependent transport.15 In the healthy kidney, >98% of filtered/secreted insulin is then reabsorbed and degraded.16 While peri-tubular insulin uptake increases as renal function declines to maintain renal insulin clearance, tubular injury in the diabetic kidney combined with a falling estimated glomerular filtration rate (eGFR) ultimately means that intact insulin is often found in the urine and, ultimately, the urinary insulin clearance approaches that of the (low) glomerular filtration rate. As a consequence, the circulating half-life of insulin is significantly modified in patients with CKD, especially when eGFR falls to below 30 ml/min/1.73m2.13 Indeed, the insulin halflife has been proposed as a valid test of kidney function.17 This prolonged insulin half-life significantly increases the risk of hypoglycaemia in patients with CKD as the glucose lowering effects of insulin and secretogogues carryover beyond the immediate post-prandial period. The effect of renal impairment on insulin kinetics appears similar for both short- and long-acting insulin, as well as agents that stimulate endogenous insulin production. As a result, some authors have recommended avoiding long-acting insulin preparations in patients with advanced renal failure to reduce the risk of hypoglycaemia.18 However, other studies support the use of long-acting insulin in this setting.13 The most important thing appears to be close monitoring and individualisation of diabetes care and glucose control targets in patients with CKD. This always involves reduced insulin doses. In general, those with an eGFR 30-45 ml/min/1.73m2 need 10% less insulin, those 15-30 ml/min/1.73m2 need 25% less insulin, and those with <15 ml/min/1.73m2 need about half their requirement when they have an eGFR >60 ml/min/1.73m2. Although insulin sensitisers such as metformin and the glitazones are not traditionally associated with hypoglycaemia, because of the prolonged actions of insulin in CKD, the incidence and severity of hypoglycaemia can also be increased by these drugs in this setting.

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The effect of kidney function on sulphonylurea (SU) antidiabetics
Sulphonylurea (SU) agents are widely used in the management of patients with type 2 diabetes, to directly stimulate the release of insulin from the beta cells of the pancreas. Hypoglycaemia is the most common complication of SU agents, occurring when insulin stimulation is not matched with food intake in those with irregular eating habits or medication compliance. Some SU agents are directly eliminated by the kidneys, or are metabolised in the liver to a variety of active compounds, which are then excreted by the kidneys. As a result, first generation sulphonylurea drugs, including tolazamide, acetohexamide and chlorpropamide 19, and glibenclamide (glyburide), a second-generation sulphonylurea with an active metabolite 20, are more likely to cause hypoglycaemia in individuals with renal impairment, and should not be used in this setting. By contrast, SU drugs with inactive metabolites including tolbutamide, glipizide, gliclazide and gliquidone are less likely to cause hypoglycaemia, although, as noted above, in patients with CKD, the half-life of endogenous insulin is prolonged. Consequently, SU-induced hypoglycaemia is also more common in those with impaired kidney function, regardless of the SU agent or formulation. All SUs should be used cautiously and with a dose reduction in patients with a reduced eGFR.3

Kidney Function and Metformin
One largely unheralded reason for an increased incidence of hypoglycaemia in diabetic patients with CKD, is the fact that the most widely used oral anti-diabetic agent, metformin, is often stopped and replaced with agents including insulin and secretagogues that are more likely to induce hypoglycaemia, weight gain and other side effects. By contrast, hypoglycaemia is generally not observed with metformin used as monotherapy, which acts as an insulin sensitiser to lower glucose levels by reducing hepatic production of glucose and slowing the absorption of glucose from a meal. The rationale for stopping metformin and substituting drugs with a potentially worse side effect profile is problematic.21, 22 Certainly, the excretion of biguanides such as metformin and phenformin is largely dependent on renal clearance, by both glomerular ultrafiltration and tubular secretion. Consequently, in patients with renal impairment, plasma concentrations may be significantly elevated and the drug may accumulate. This accumulation of phenformin has been associated with an increased risk of lactic acidosis, although data regarding the risk associated with metformin in CKD are less clear and largely anecdotal. When taken in an overdose, metformin can cause lactic acidosis, implying that significant drug ac-

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cumulation in renal disease, in theory, could cause the same phenomenon. However, even in those with CKD, lactic acidosis is a very rare event.21, 22 While stopping metformin in patients with CKD would eliminate this risk, it seems more prudent to reduce metformin dosing by one third in patients with eGFR between 30-45 ml/min/1.73m2.3 In some patients with stable renal impairment and an eGFR of 15-30 ml/min/1.73m2 metformin can also be safely used, at approximately half the normal dose. However, caution should be exercised in patients with unstable renal function, and those with co-morbid heart failure, alcoholism or liver disease, and the drug should be stopped 2–3 days prior to surgery or any procedure using iodinated radiographic contrast media, as a sudden decline in renal function can lead to drug accumulation in a hypoxic setting where lactate production may be already increased.3

The effects of kidney function on counter-regulatory response to hypoglycaemia
Falling blood glucose levels trigger the activation of a range of counter-regulatory responses, that contribute to both the symptomatology of the event as well as its reversal.23 The key regulators of this response include increased secretion of glucagon, growth hormone and cortisol as well as adrenergic activation. Each of these may be substantially abnormal in patients with advanced diabetes, and especially those with CKD.24 The effects of autonomic nervous system dysfunction associated with advanced diabetes on catecholamine release in response to hypoglycaemia are well known, contributing to both defective glucose counter-regulation and hypoglycaemia unawareness. Many patients also take sympathetic blocking medications, which impair counterregulatory glycogenolysis by the liver, although the risk is lower with selective beta-blockers than non-selective agents.25 Even in the absence of autonomic neuropathy, many patients with type 2 diabetes show attenuated glucagon, growth hormone, and cortisol responses to hypoglycaemia. In particular, insulin-dependent patients with type 2 diabetes, who represent the majority of those with advanced CKD, have extremely impaired glucagon response to hypoglycaemia when compared to controls and those with type 2 diabetes treated with oral hypoglycaemics, reflecting the more advanced pancreatic damage observed in these patients. In addition, elevated insulin concentrations in CKD, due to impaired renal clearance, inhibit glucagon release in response to low blood glucose. Rather than prevent hypoglycaemia, growth hormone and cortisol are “slow-acting” hormones that act to limit its severity and duration. Again, both these pathways are abnormal in patients with CKD, with dysfunction correlating with the severity of renal impairment.

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Parathyroid hormone (PTH) and glucose control
The metabolic actions of PTH extend beyond calcium homeostasis. Parathyroid hormone-related protein is produced by the pancreatic islet, where it acts to suppress insulin release from the beta cells. Secondary hyperparathyroidism acts to suppress insulin release in patients with CKD. Suppression of PTH levels with vitamin D supplementation or surgical removal of the glands, results in significant improvement in insulin release, and with it, an increased risk of hypoglycaemia in patients with CKD following such interventions.26, 27

Specific situations: hypoglycaemia on haemodialysis
Haemodialysis is the most common modality for renal replacement therapy in patients with type 2 diabetes and end stage renal disease (ESRD). Haemodialysis clears the blood of toxins via diffusion across a semi-permeable membrane and ultrafiltration, maintained by altering the pressure in the dialysate compartment that allows free water and some dissolved solutes to move across the membrane along a created pressure gradient. This has the potential to alter glucose homeostasis in a number of ways: Firstly, insulin resistance associated with uraemic toxicity can be substantially alleviated by dialysis.13 This means that when starting haemodialysis in diabetic patients there can be a dramatic improvement in peripheral insulin sensitivity, which alongside increased physical activity and a persisting prolonged insulin half-life can lead to an increased risk of hypoglycaemia in the days and weeks after starting dialysis. Insulin requirement should therefore be closely monitored after starting dialysis in patients with type 2 diabetes, as doses will need to be rapidly adjusted, sometimes to less than half of what was previously needed. Secondly, haemodialysis with a sodium bicarbonate buffer can lead to a loss of serum glucose in the dialysate effluent. In order to get around the problem of hypoglycaemia, it is common practice to add glucose to the dialysate, especially for diabetic patients on insulin. Certainly, less hypoglycaemia occurs when using a dialysate containing glucose compared to a glucose-free dialysate.28 Hypoglycaemia is further reduced when using 11 mM as opposed to 5.5 mmol/l of glucose.29 Blood pressures may be modestly lower with glucose in the dialysate, possibly due to suppression of counter-regulatory sympathetic drive.30 In addition, inter-dialytic weight gain, hypertriglyceridaemia and increased oxidative stress can also result from a high glucose dialysate. Some authors also suggest that the risk of post-dialysis hypoglycaemia is increased by a glucose-containing dialysate (by stimulating insulin then withdrawing dialysate glucose). The long-term balance of benefits of 35

risk remains to be determined. However, given the short survival of patients with diabetes on haemodialysis, such short-term gains appear to have primacy. ESRD is associated with an increased prevalence of protein-calorie malnutrition, reflected in reduced serum albumin concentrations and diminished hepatic glycogen stores. Institution of dialysis can have additional effects on protein and energy balance, including the loss of free amino acids, peptides and small proteins in the dialysate, especially with high flux dialysers. The net result of this can be to attenuate the counter-regulatory response to hypoglycaemia. Adding glucose to the dialysate can also reduce this effect by suppressing gluconeogenesis and catabolism. Another technique widely used to avoid hypoglycaemia on dialysis is to provide a meal to patients during the dialysis procedure. In theory, this can provide the glucose reserve to balance losses during and subsequent to dialysis. However, in practice, patients with advanced diabetes have significant gastroparesis 31, meaning that the effect of the meal is often manifested after dialysis. Moreover, dilation of the splanchnic bed following a meal can drop the blood pressure during dialysis.32 This has led some units to deliberately not feed during dialysis. However, feeding afterwards may also be problematic when plasma volumes are at their lowest and patients are attempting to mobilise to get home or return to their ward. Moreover, glucose control during dialysis (achieved by a glucose-containing dialysate that stimulates insulin release), if unmatched by food intake, subsequently and in the setting of an impaired counter-regulatory response, leads to a significant risk of hypoglycaemia that is greatest 2-6 hours after dialysis. Indeed, this post-dialysis period may be the most dangerous for patients with diabetes on dialysis. Finally, changes in the cytoplasmic pH of erythrocytes when using high bicarbonate dialysate, can result in the increased uptake of glucose into red cells, as intracellular acidosis stimulates the consumption of glucose by anaerobic metabolism.33 One of the major difficulties of hypoglycaemia on dialysis is that few patients are aware of low glucose levels, due to blunting of the counterregulator response in advanced disease (detailed above) and/or the use of sympathetic blockade. Symptoms are often attributed to dialysis disequilibrium or co-morbid disease. While hypoglycaemia should be suspected in any diabetic patient with CKD who exhibits any change in mental status, its prevention ultimately relies on frequent and careful glucose determinations. It is also important to remember that testing from an extracorporeal line is problematic because of recirculation.

36

Specific situations: peritoneal dialysis
Peritoneal dialysis uses the patient’s peritoneal membrane to exchange fluids and dissolved substances. The dialysis fluid typically contains a high concentration of glucose to ensure hyper-osmolality and hence continuous ultrafiltration. This potentially exposes patients to a significant glucose load that can cause difficulties for some patients with type 2 diabetes. Although the risk of hypoglycaemia might appear to be diminished (as a result of continuous glucose availability), in practice, attempts to match this glucose load with insulin, delivered into the dialysate or subcutaneously, can sometimes lead to more brittle control, especially initially. In general, patients on peritoneal dialysis need 2-3 times the insulin they received before starting it, coordinated with the strength of the bags as well as the dwell time. Intra-peritoneal insulin has a number of advantages including a reduced frequency of hypoglycaemic episodes.34 The recent development of glucose-free dialysate fluids can modify the risk of hypoglycaemia in some patients with diabetes. Although insulin requirements are much lower, and some studies have suggested reduced glucose variability, monitoring of glucose levels may be confounded by the icodextrin used in the place of glucose as the primary osmotic agent, which may give false glucose readings in some patients.35

Preventing hypoglycaemia in the clinic
In most cases, adjusting behaviours, the dose or timing of medications and/or the targets of treatment can prevent recurrent hypoglycaemic events. Selecting foods that meet individual glucose requirements can also be useful. For example, low GI foods and products, such as uncooked cornstarch, that ensure the slow delivery of glucose are helpful to prevent lows during the night or after meals (post-prandial hypoglycaemia). Sometimes having meals that provide more glucose up front may be important, particularly after dialysis and in those who are on fast-acting agents or insulin. Overeating or snacking to prevent hypoglycaemia is never a sustainable solution, and should be discouraged. Coordination of physical activity with medication doses and dialysis is also important. Because of the ever-present threat of hypoglycaemia, the rationale for attempting even modest glycaemic control in patients with CKD is somewhat precarious. It rests on the paradigm that maintaining glucose levels as close as possible to physiological levels will result in improved clinical outcomes. However, the evidence for this in diabetic patients with CKD remains largely anecdotal and inconclusive. Certainly, glycaemic control correlates closely with morbidity and mortality

37

in diabetic patients with advanced CKD and those on dialysis.36 However, such observational data cannot be used to prove that attempts to improve glycaemic control through anti-diabetic agents or other interventions will therefore result in better clinical outcomes. Indeed, recent studies in diabetic patients without CKD have failed to demonstrate mortality and cardiovascular benefits from better glycaemic control, even though HbA1c remains closely correlated with adverse outcomes in these cohorts.5 This does not mean that there is no point in any glucose control. Rather, that the utility for aggressive glycaemic control has probably passed and that other targets may be more appropriate for intensification. Poor glycaemic control remains a potent risk marker for those at increased absolute risk, in whom the absolute gain from intervention may therefore also be enhanced. Nonetheless, a modest degree of glucose control is probably still effective in reducing the risk of infection and cataracts, while choosing an individual target that reduces the risk of hypoglycaemia, especially in those with advanced age, irregular compliance or lifestyles. Patients that hope to maintain a driving license offer an additional challenge in balancing risk and mobility. Ultimately, careful individualisation of glucose management is the best recourse, which can never be reflected in guidelines or performance indices aimed at generic utility. As Sir William Osler once said, “If it were not for the great variability among individuals, medicine might as well be a science and not an art!”

38

References:
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycaemia in Type 2 diabetes. Diabet Med 2008;25(3):245-54. Leiter L, Yale, J-F, Chiasson, J-L, Harris, SB, Kleinstiver, P, Sauriol, L. Assessment of the impact of fear of hypoglycemic episodes on glycemic and hypoglycemic management. Can J Diabetes 2005;29:186-192. Snyder RW, Berns JS. Use of insulin and oral hypoglycemic medications in patients with diabetes mellitus and advanced kidney disease. Semin Dial 2004;17(5):365-70. Jung HS, Kim HI, Kim MJ, Yoon JW, Ahn HY, Cho YM, et al. Analysis of hemodialysisassociated hypoglycemia in patients with type 2 diabetes using a continuous glucose monitoring system. Diabetes Technol Ther 2010;12(10):801-7. Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010;363(15):1410-8. Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence. Diabetologia 2010;53(8):1552-61. Yakubovich N, Gerstein HC. Serious cardiovascular outcomes in diabetes: the role of hypoglycemia. Circulation 2011;123(3):342-8. Meyer C, Dostou JM, Gerich JE. Role of the human kidney in glucose counterregulation. Diabetes 1999;48(5):943-8. Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 2001;24(2):382-91. Cersosimo E, Garlick P, Ferretti J. Renal glucose production during insulin-induced hypoglycemia in humans. Diabetes 1999;48(2):261-6. Cersosimo E, Garlick P, Ferretti J. Renal substrate metabolism and gluconeogenesis during hypoglycemia in humans. Diabetes 2000;49(7):1186-93. Woerle HJ, Meyer C, Popa EM, Cryer PE, Gerich JE. Renal compensation for impaired hepatic glucose release during hypoglycemia in type 2 diabetes: further evidence for hepatorenal reciprocity. Diabetes 2003;52(6):1386-92. Mak RH. Impact of end-stage renal disease and dialysis on glycemic control. Semin Dial 2000;13(1):4-8. Rabkin R, Simon NM, Steiner S, Colwell JA. Effect of renal disease on renal uptake and excretion of insulin in man. N Engl J Med 1970;282(4):182-7. Petersen J, Kitaji J, Duckworth WC, Rabkin R. Fate of [125I]insulin removed from the peritubular circulation of isolated perfused rat kidney. Am J Physiol 1982;243(2): F126-32. Rubenstein AH, Mako ME, Horwitz DL. Insulin and the kidney. Nephron 1975;15(3-5): 306-26. Goll K, Lück, G. The insulin half-life as a kidney function test. Z Urol Nephrol 1975;68(12): 927-33. Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood glucose in diabetic patients with renal failure. Diabetes Metab 2000;26 Suppl 4:73-85. Harrower AD. Pharmacokinetics of oral antihyperglycaemic agents in patients with renal insufficiency. Clin Pharmacokinet 1996;31(2):111-9. Rydberg T, Jonsson A, Roder M, Melander A. Hypoglycemic activity of glyburide (glibenclamide) metabolites in humans. Diabetes Care 1994;17(9):1026-30. Nye HJ, Herrington WG. Metformin: The Safest Hypoglycaemic Agent in Chronic Kidney Disease? Nephron Clin Pract 2011;118(4):c380-c383. Preiss DJ, Sattar N. Metformin and lactic acidosis. Metformin: framed again? BMJ 2009;339:b5570. Tesfaye N, Seaquist ER. Neuroendocrine responses to hypoglycemia. Ann N Y Acad Sci 2010;1212:12-28. Arem R. Hypoglycemia associated with renal failure. Endocrinol Metab Clin North Am 1989;18(1):103-21. Kerr D. Drugs and alcohol. In: Frier B, Fisher B, editors. Hypoglycaemia and Diabetes. Clinical and Physiological Aspect. London: Edward Arnold; 1993:pp. 328–336. Mak RH, Bettinelli A, Turner C, Haycock GB, Chantler C. The influence of hyperparathyroidism on glucose metabolism in uremia. J Clin Endocrinol Metab 1985;60(2):229-33. Mak RH, Turner C, Haycock GB, Chantler C. Secondary hyperparathyroidism and glucose intolerance in children with uremia. Kidney Int Suppl 1983;16:S128-33.

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28. Jackson MA, Holland MR, Nicholas J, Lodwick R, Forster D, Macdonald IA. Hemodialysis-induced hypoglycemia in diabetic patients. Clin Nephrol 2000;54(1):30-4. 29. Simic-Ogrizovic S, Backus G, Mayer A, Vienken J, Djukanovic L, Kleophas W. The influence of different glucose concentrations in haemodialysis solutions on metabolism and blood pressure stability in diabetic patients. Int J Artif Organs 2001;24(12):863-9. 30. Sangill M, Pedersen EB. The effect of glucose added to the dialysis fluid on blood pressure, blood glucose, and quality of life in hemodialysis patients: a placebocontrolled crossover study. Am J Kidney Dis 2006;47(4):636-43. 31. Eisenberg B, Murata GH, Tzamaloukas AH, Zager PG, Avasthi PS. Gastroparesis in diabetics on chronic dialysis: clinical and laboratory associations and predictive features. Nephron 1995;70(3):296-300. 32. Barakat MM, Nawab ZM, Yu AW, Lau AH, Ing TS, Daugirdas JT. Hemodynamic effects of intradialytic food ingestion and the effects of caffeine. J Am Soc Nephrol 1993;3(11):1813-8. 33. Takahashi A, Kubota T, Shibahara N, Terasaki J, Kagitani M, Ueda H, et al. The mechanism of hypoglycemia caused by hemodialysis. Clin Nephrol 2004;62(5):362-8. 34. Duckworth W, Saudek C, Henry R. Why intraperitoneal delivery of insulin with implantable pump in NIDDM? Diabetes 1992;41:657-661. 35. Disse E, Thivolet, C. Hypoglycemic coma in a diabetic patient on peritoneal dialysis due to interference of icodextrin metabolites with capillary blood glucose measurements. Diabetes Care 2004;27(9):2279. 36. Oomichi T, Emoto M, Tabata T, Morioka T, Tsujimoto Y, Tahara H, et al. Impact of glycemic control on survival of diabetic patients on chronic regular hemodialysis: a 7-year observational study. Diabetes Care 2006;29(7):1496-500.

40

3. T2DM therapy in patients at risk of and with declining renal function

Professor Paola Fioretto

University of Padova Department of Medical and Surgical Sciences Padova, Italy

Chronic kidney disease and the T2DM patient
As we have seen in Chapter 2, declining kidney function is a significant problem in T2DM (affecting as much as 40% of patients 1, not only with regard to the long-term prognosis for the person with this condition, but also because of the implications for the therapeutic management of hyperglycaemia, the root cause, via different pathogenetic pathways, of diabetic chronic complications. As an example of how renal impairment impacts T2DM management, we only need to look at the incidence of hypoglycaemia among T2DM patients who also have some degree of chronic kidney disease (CKD). These patients are at a 240% higher risk of hypoglycaemia compared with those patients with normal renal function.2 That is a huge difference and one that undoubtedly changes the attitudes of the patients towards their medication and makes clinicians think twice before prescribing certain anti-diabetic agents. The main reason for this huge increase in the risk of hypoglycaemia is the fact that the kidneys play a pivotal role in the clearance and degradation of insulin, as well as several oral agents. The kidney clears insulin via two distinct routes. The first route entails glomerular filtration, while the second involves diffusion from the peritubular capillaries.3 With renal clearance impaired, the half-life of insulin is prolonged via a number of mechanisms and there is a concomitant decrease in the insulin requirement of the T2DM patient.3 This relationship between kidney function and the clearance of insulin means that hypoglycaemia in T2DM patients with CKD is a particular hazard where any compounds that stimulate the production of insulin are being used; notably the secretagogues (see below). For example, around 74% of sulphonylurea (SU) -induced severe hypoglycaemic events occur in patients with declining renal function.4 Regardless of these risks, the recent Kidney Disease Outcome Quality Initiative (KDOQI) clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease maintain that target HbA1c levels should be <7% irrespective of the presence or absence of CKD. The rationale for this seemingly strict guidance is that hyperglycaemia is the fundamental cause of vascular organ complications, including kidney disease.5 Furthermore, intensive treatment of hyperglycaemia is the most effective approach to prevent diabetic 41

nephropathy and, along with hypertensive therapy, to slow the progression of established kidney disease.5 For example, further analyses of the ADVANCE trial data published in 2009 showed that tight glycaemic control reduces the risk of new or worsening nephropathy (Figure 1).6 These effects are additive to those of blood pressure levels, without evidence of interaction.

Figure 1. Tight glycaemic control reduces new or worsening nephropathy (Adapted from Zoungas et al 2009).6

In addition, data suggests that achieving and maintaining target HbA1c levels may improve survival and slow and/or prevent complications in people with T2DM and kidney failure who are on dialysis. In a study by Kalantar-Zadeh et al., higher HbA1c values were associated with a higher risk of mortality after adjusting for potential confounders.7 The take home message is that tight glycaemic control is imperative for people with T2DM, including those who also have concomitant renal impairment. These recommendations leave the management of T2DM in something of a quandary because the first and second line therapies, namely metformin and SUs, are either contraindicated in renal impairment or have to be used with caution due to the risk of complications (e.g. hypoglycaemia). So, in view of this paradox, what can clinicians on the ground do? Should they go on using the established therapies and put the patient at risk of complications, or look at the emerging anti-diabetic therapies that can be used safely in T2DM patients with renal impairment thanks to their non-renal route of elimination? Chapter 4 looks at these emerging therapies in greater detail, while the remainder of this chapter reviews the impact of kidney disease on glycaemic control as well as a brief overview of the current T2DM therapies and their limitations, specifically in patients with renal impairment. 42

Kidney disease and implications for monitoring glycaemic control
HbA1c is the gold standard for determining glycaemic control in people with T2DM. However, there is concern that this measure may be affected by the degree of kidney dysfunction or the haematological complications of kidney disease (e.g. iron deficiency, haemolysis, shorter red blood cell lifespan, or acidosis).8 One small study compared correlations between HbA1c measurements and blood glucose in patients with moderate to severe kidney disease who did not require dialysis to those of patients without kidney disease. The study found no difference in the magnitude of the correlations between HbA1c and blood glucose between these patient groups.9 Therefore, HbA1c is as effective as an indicator of glycaemic control in patients with and without kidney disease. These data are strongly supportive of applying a target HbA1c level of <7.0% to patients not requiring dialysis but who have kidney disease.5 10 The correlation between HbA1c and blood glucose in haemodialysis patients is unclear and results from relevant studies are conflicting. Consequently, T2DM patients receiving dialysis are worthy of special consideration. One study concluded that HbA1c was an underestimate of glycaemic control in dialysis patients.9 On the other hand, a second study concluded that HbA1c measures >7.5% were likely to be an overestimate of glycaemic control.11 There is no evidence that haemodialysis treatment acutely changes the HbA1c measure.12 Further studies are needed to clarify the interpretation of HbA1c in patients receiving dialysis. Lower HbA1c has been associated with lower mortality risk in patients receiving haemodialysis.7 13 In view of these data, the current recommendations are also to aim for an HbA1c <7.0% in T2DM patients who are on dialysis.5 10

Current T2DM treatments and how they should be used in patients with declining renal function
In this section, we briefly review the mode of action and the key clinical characteristics of the various medications used in the management of T2DM. In particular, we consider how declining renal function in patients with T2DM influences the use of each of these medications (summarised in Table 1). Insulin therapy will not be discussed, although it is well known that the insulin dose needs to be reduced in patients with CKD, given that insulin is metabolised by the kidney. Thus, patients with CKD on insulin are at higher risk of hypoglycaemia and frequent blood glucose monitoring is necessary.

43

Secretagogues Sulphonylureas (SUs) SUs are a mainstay in T2DM treatment. They trigger insulin release by binding to ATP-dependent potassium channels on pancreatic β-cells (Figure 2).14 15 They are administered orally, once, twice or three times a day shortly before a meal.14 15 This class of antidiabetics is divided into first, second and third generation types; however the first generation SUs (e.g. chloropropamide and tolbutamide) are rarely used today.14 15 The second and third generation SUs (e.g. glibenclamide, gliclazide, glipizide and glimepiride) are more commonly prescribed, as they offer improved efficacy and tolerability.14 15 SUs are widely used to treat T2DM and are often combined with metformin alone or, more rarely, metformin and a thiazolidinedione (TZD), especially in those patients where metformin alone fails to provide adequate glycaemic control.14 15 Typical adverse events associated with the use of SUs include hypoglycaemia, weight gain, nausea, vomiting, diarrhoea, constipation, loss of appetite, abdominal pain, bloating, indigestion, liver function problems, blood disorders, allergic skin reactions, etc.14 15 The clearance of any SU and its metabolites is highly dependent on kidney function, and severe prolonged episodes of hypoglycaemia as a result of SU use have been described in dialysis patients.16 In patients with Stage 3–5 CKD, first-generation SUs should be avoided (Table 1). Of the newer generation SUs, glipizide is recommended because it is metabolised into inactive metabolites by the liver and then excreted by the kidney, and consequently there is a lower risk of hypoglycaemia (Table 1).5 Meglitinides Only two meglitinides are available (repaglinide and nateglinide) and they work in a similar way to SUs, except they bind to a different site on the ATP-dependent potassium channel (Figure 2). The net effect is an increase in insulin secretion, although they have a shorter duration of action than SUs.15 Meglitinides are taken orally up to three times a day with, or not longer than 30 minutes before, meals.15 They are often used in combination with metformin.15 Meglitinides are generally better tolerated than SUs and typical adverse events associated with these agents include hypo44

glycaemia, weight gain, allergic skin reactions, liver function problems, abdominal pain, nausea, diarrhoea, vomiting, constipation and visual disturbances.17 Repaglinide does not require a dose adjustment in T2DM patients with Stage 3-5 CKD or those who are on dialysis (Table 1).18 Indeed, the renal clearance of repaglinide is <10%. Nateglinide on the other hand should be avoided in Stage 3-5 CKD and in patients who are on dialysis (Table 1)18, since it is metabolised into active metabolites and could therefore expose patients with CKD to the risk of severe hypoglycaemia.

Figure 2. The mode of action of secretagogues (sulphonylureas and meglitinides).

45

Sensitisers Biguanides Metformin, the only biguanide currently available, is the gold-standard antidiabetic agent, and is typically the first-line drug therapy in T2DM patients when exercise or diet intervention have failed to achieve adequate glycaemic control.19 This compound decreases hepatic gluconeogenesis and increases the uptake of glucose by the peripheral tissues, especially the skeletal muscle (Figure 3).15 Metformin is widely used because of its effectiveness, good tolerability profile and low cost. It is commonly the basis for second- and third-line combination therapies.15 Taken up to three times a day, with or after a meal.19 Typical adverse events associated with the use of metformin include: nausea, vomiting, diarrhoea, abdominal pain, loss of appetite, (these often diminish after the initial stages of treatment), metallic taste, reduced absorption of vitamin B12, lactic acidosis, allergic skin reaction, general allergic reaction and liver function problems.19 Metformin does not exhibit the risk of hypoglycaemia associated with some of the other drug classes used to treat T2DM. However, special care must be taken when it is used in patients with CKD. There is an increased risk of lactic acidosis, even in patients with mild impairment of kidney function, which is likely due to the accumulation of the drug and its metabolites.20 Metformin is contraindicated in male patients with a serum creatinine >1.5 mg/dl and in female patients with serum creatinine >1.4 mg/dl (Table 1).5 This concept, however, has recently been challenged by some authors, who suggest its safe treatment option in patients with stable CKD.21

Figure 3. The mode of action of metformin.

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Thiazolidinediones (TZDs) The TZDs rosiglitazone and pioglitazone are currently available for the treatment of T2DM. The use of rosiglitazone in the treatment of T2DM has been marred by a meta-analysis, which demonstrated an increased risk of myocardial infarction (significant) and death from cardiovascular causes (borderline significance) in patients receiving this TZD.22 For these reasons, its use has been discontinued in Europe. TZDs bind to a peroxisome proliferator-activated receptor γ (PPAR γ) on the cell nucleus, eliciting a variety of effects, the net result of which is a decrease in insulin resistance allowing more glucose to enter the cells.15 TZDs are taken once or twice daily with or without food and they are often used in combination with metformin or metformin plus another antidiabetic drug, such as a SU.23 24 Typical adverse events include, weight gain oedema, heart failure, blood disorders, increase in blood lipids, increased appetite, increased risk of bone fractures (women), and visual disturbances.23 24 Of considerable interest is the suggestion that TZDs may prevent or slow the progression of kidney disease in people with T2DM independently of glycaemic control.25 Several small studies have reported a greater reduction in albuminuria in patients administered TZDs.8 However, there has been no evidence to support an independent association between TZD use and actual prevention of diabetic kidney disease. TZDs have been demonstrated to be effective without increasing the risk of hypoglycaemic episodes in patients with CKD, including those receiving dialysis,12 26 27 and in patients who require therapy for glycaemic control after a kidney transplant.28 As TZDs undergo hepatic metabolism, no adjustment in dosing is required in any stage of CKD, or for those patients on dialysis or who have had a kidney transplant (Table 1).8 One concern, however, of using TZDs in T2DM patients with renal impairment is that the risk of fluid retention and heart failure may be exacerbated8; thus they should be used with caution in patients with CKD. Nevertheless, fluid retention can be adequately controlled by diuretics. Alpha-glucosidase inhibitors (AGIs) Acarbose, miglitol and voglibose are the currently available AGIs. In contrast to the other anti-diabetic agents, AGIs have no effect on insulin secretion or sensitivity, as they are essentially non-systemic.15 These compounds inhibit enzymes in the small intestine that are responsible for breaking down carbohydrates into monosaccharides, thereby reducing the amount of monosaccharides, namely glucose that are transported through the intestinal wall into the bloodstream.15 AGIs are taken three times a day with the first mouthful of food.29 47

Due to their novel mode of action, the main adverse events associated with the use of AGIs are gastrointestinal in nature and include flatulence, diarrhoea, abdominal pain, nausea, vomiting and indigestion. Less commonly encountered adverse events include liver function problems, oedema, blood disorders and allergic skin reactions.29 With respect to their use in diabetic kidney disease, AGIs and their metabolites may result in hepatic damage; however, the relevant mechanisms have not been elucidated.30 For this reason, this drug class is not recommended for patients with a serum creatinine >2 mg/dl (Table 1).5 GLP-1 mimetics - exenatide Exenatide is the only GLP-1 mimetic. This product is a synthetic version of a hormone found in the venom of the gila monster lizard.31 Exenatide binds to the same cellular receptor as GLP-1 and therefore elicits the same effects, i.e. stimulation of insulin production and release from the pancreatic β-cells thereby enhancing glucose uptake by the tissues.31 Exenatide is administered twice daily by subcutaneous injection into the skin of the abdomen, thigh, or arm, any time within the 60-minute period before the first and last meals of the day.32 Exenatide is effective in reducing HbA1c, without exposing the patient to the risk of hypoglycaemia, and is associated with sustained weight loss. Exenatide is only indicated for use in combination with metformin and/or a SU when these oral therapies fail to provide adequate glycaemic control.32 Exenatide adverse events are commonly gastrointestinal in nature, including nausea and vomiting. Pancreatitis, headache, and dizziness have also been encountered, but are rare.32 Exenatide is eliminated almost entirely by glomerular filtration with subsequent proteolytic degradation in the kidney. In a small study in patients with CKD, exenatide was well tolerated in patients with mildmoderate renal impairment (GFR>30 ml/min), but not in patients with end stage renal disease (ESRD). Thus the manufacturers recommend no dose adjustment in patients with Stage 1-2 CKD. In patients with Stage 3 CKD, dose escalation from 5µg to 10µg should proceed conservatively (Table 1).32 Finally, the manufacturers recommend that exenatide is not used in T2DM patients with Stage 4-5 CKD (GFR<30 ml/ min), or those patients on dialysis (Table 1).32

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GLP-1 analogues - liraglutide Liraglutide is the only human GLP-1 analogue currently available. It is produced by recombinant DNA technology in a species of yeast (Saccharomyces cerevisiae).33 The amino acids that form the backbone of liraglutide are genetically engineered to have a small fatty-acid chain, which renders the peptide more resistant to degradation by the DPP-4 enzyme, allowing it to act for longer in the body.34 Liraglutide has a good efficacy and tolerability profile, but currently it is only indicated for use in combination with metformin and/or a SU when these oral therapies fail to provide adequate glycaemic control.33 Liraglutide is administered once daily by subcutaneous injection into the abdomen, upper thigh or arm, at any time of the day, regardless of when meals are eaten.33 The adverse events associated with liraglutide are commonly gastrointestinal in nature, although hypoglycaemia, pancreatitis, headache, dizziness and thyroid problems have also been encountered, albeit rarely.33 Liraglutide is degraded by endogenous peptidase and does not have a renal clearance. A small study evaluated the pharmacokinetics, safety and tolerability in patients with a wide range of renal function, from normal to ESRD; there was no association between renal status and exposure to the active drug or side effects. Thus, no specific dose adjustment is needed in CKD. Nevertheless, it is not recommended for use in patients with stage 3 CKD or above, due to a lack of experience with this product in these patients (Table 1).33 Amylin analogues Pramlintide is the only amylin analogue available. It mimics the effects of the amylin produced by the pancreatic β-cells, namely, slowing gastric emptying and suppressing the secretion of glucagon, the hormone that opposes the effects of insulin.35 Because it is a hormone, pramlintide has to be administered via subcutaneous injection prior to meals.35 Common adverse events associated with the use of pramlintide include nausea, hypoglycaemia, vomiting, headache, abdominal pain, weight loss and fatigue.35 For those patients with a GFR of <20 ml/min/1.73 m2 no dose adjustment of pramlintide is required (Table 1). However, there is a lack of clinical experience in patients with more severe renal impairment; therefore pramlintide is not recommended in these patient populations (Table 1).5

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DPP-4 inhibitors These compounds are covered in greater detail in Chapter 4; suffice to say here that EU prescribing information for sitagliptin and vildagliptin recommends that these agents should not be used in patients with Stage 3-5 CKD (Table 1).36 37 Saxagliptin can be used in these patients, but a dose reduction is recommended (Table 1).38 In the EU, it is recommended that none of these compounds be used in dialysis patients.36-38 The equivalent information in the US recommends that sitagliptin, vildagliptin and saxagliptin can be used in Stage 3-5 CKD with the appropriate dose adjustment.39-41 Linagliptin, also covered in greater detail in Chapter 4, is the only compound in this class that is primarily excreted via bile and the gut, a characteristic that has important implications for the potential management of T2DM patients with declining renal function.

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Class
Avoid Avoid Avoid Avoid No dose adjustment Avoid Avoid No dose adjustment Avoid Avoid Hypoglycaemia Lactic acidosis Hypoglycaemia Hypoglycaemia Hypoglycaemia Hypoglycaemia Hypoglycaemia Hypoglycaemia

Drug

CKD

Dialysis

Complication

Stage 3–5

First-generation SU
2

Acetohexamide

Avoid

Chlorpropamide

GFR 50–70 ml/min/1.73 m2: ↓50%

GFR <50 ml/min/1.73 m : Avoid

Tolazamide

Avoid

Tolbutamide

Avoid

Second-generation SU

Glipizide

No dose adjustment

Glyburide

Avoid

Glimepiride

Low dose: 1 mg/day

Meglitinides

Repaglinide

No dose adjustment

Nateglinide

Initiate low dose: 60 mg

Biguanides

Metformin

Contraindicated:

Table 1. Recommendations for non-insulin hyperglycaemia drug therapy for patients with moderate to severe CKD. Most of the content based on KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease.5 For other sources refer to the table.

51
Avoid Avoid Avoid Not recommended Unknown
2

Male: SCr >1.5 mg/dl

Female: SCr >1.4 mg/dl No dose adjustment No dose adjustment Volume retention Volume retention Possible hepatic toxicity

TZDs

Pioglitazone

No dose adjustment

Rosiglitazone

No dose adjustment

α-Glucosidase inhibitors

Acarbose

SCr >2 mg/dl: Avoid

Miglitol

SCr >2 mg/dl: Avoid

Incretin mimetics/ analogues

Exenatide32

Conservative dose escalation in Stage 3 CKD

Liraglutide33

Not recommended

Amylin analogue

Pramlintide

No dose adjustment

GFR <20 ml/min/1.73 m : Unknown Not recommended Not recommended

DPP-4 inhibitors

Sitagliptin36

Not recommended

Vildagliptin37

Not recommended

Saxagliptin38

Dose reduced to 2.5 mg once daily (use with caution in Stage 4-5 CKD) Not recommended

Limitations of current therapies
The central aim of T2DM management is to maintain near to normal blood glucose levels accomplished via a daily regimen of diet, exercise and antidiabetic agents or insulin injections, without exposing the patients to the risk of hypoglycaemia and weight gain. Unfortunately, the very nature of the disease and the strict, daily regimen for its management are a perfect recipe for very poor compliance. Oral antidiabetic agents (OADs) are a cornerstone of T2DM treatment; however, these compounds fail to provide sustainable and sufficient glycaemic control. Large, long-term trials, such as UKPDS and ADOPT have demonstrated that the glycaemic lowering effect of T2DM treatments decreases with time.42 43 The UKPDS trial demonstrated that after three years of monotherapy with OADs, 50% of patients were adequately controlled. However, after nine years of monotherapy only a quarter of patients still maintained adequate glycaemic control.43 The underlying reason for OADs being unable to provide sustainable glycaemic control is a declining glycaemic response, which in turn is a consequence of differences in genotypes interacting with external environmental factors to produce an in-vivo milieu that varies from person to person thus influencing the effects of a medication.44 The differences between people with T2DM, both physiologic and genetic and how a greater understanding of these factors can lead to individualised treatments for patients are discussed in more detail in Chapter 5. For the purposes of this chapter and the limitations of current treatments, the variables that influence the individual response to OAD are as follows:45
z Duration of diabetes. z Baseline HbA1c (reflecting the severity of the disease). z Anti-diabetes treatment status (treatment naive vs. treatment non-naive). z The hyperglycaemic treatment strategy (initiation or combination therapy vs. up-titration of existing therapy).

A further limitation of current therapies is their ability to treat T2DM people with co-morbidities, most notably chronic kidney disease. As part of the overarching metabolic syndrome, T2DM and kidney disease are intimately linked and the progression of the latter is definitely dependent on how the former is managed. As we have seen, many of the widely used OADs are a very blunt instrument when it comes to managing blood glucose levels in T2DM patients with concomitant kidney disease. Many of these compounds are excreted renally and kidney disease potentiates their activity resulting in a variety of complications.

52

The future of managing T2DM patients with declining renal function
In view of the limitations of the current therapies when it comes to managing T2DM patients with declining renal function, there is a pressing need for antihyperglycaemic agents that can be used safely and without dose adjustment or additional drug-related monitoring in this patient population. We need to remember this is by no means a small proportion of the total T2DM population, so any new treatments that fulfil these criteria have the potential to benefit a huge number of people. There are a number of promising new treatment options for T2DM on the horizon and some of these belong to established OAD classes, yet they offer the advantage of being safe to use without dose reduction in patients with kidney disease. These new treatments and an increased accuracy in phenotyping the patient with T2DM will be instrumental in individualising the management of this chronic disease.

Chapter 3 Summary
z Declining renal function has a significant impact on the way that T2DM is managed. z T2DM patients with impaired renal function are at a 240% higher risk of hypoglycaemia compared with those patients with normal renal function. z The kidneys play a critical role in the clearance and degradation of insulin and most antidiabetic agents z This is particular problem with antidiabetic agents that stimulate the release of insulin. z KDOQI guidelines recommend a target HbA1c level of <7% regardless of whether a patient has renal impairment or is on dialysis. z HbA1c is accurate for monitoring blood glucose control, even in patients with declining renal function, although there are still concerns in dialysis patients. z The majority of drugs available to treat hyperglycaemia are affected by kidney function and therefore should be either avoided or used in reduced doses for patients with CKD. z Some new antidiabetics can be used safely in renal impairment and dialysis, as they are not eliminated by the kidneys. z Current therapies for T2DM have many limitations, especially when it comes to treating T2DM patients with comorbidities. z New therapies that lower blood glucose levels safely in patients with declining renal function have the potential to benefit a huge number of people.

53

References:
1. 2. 3. 4. 5. 6. Koro CE, et al. Antidiabetic medication use and prevalence of chronic kidney disease among patients with type 2 diabetes mellitus in the United States. Clin. Therapeutics 2009;31(11):2608-2617. Davis TM, Brown SG, Jacobs IG, Bulsara M, Bruce DG, Davis WA. Determinants of severe hypoglycemia complicating type 2 diabetes: the Fremantle diabetes study. J Clin Endocrinol Metab;95(5):2240-7. Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of insulin. Diabetologia 1984;27(3):351-7. Haneda M, Morikawa A. Which hypoglycaemic agents to use in type 2 diabetic subjects with CKD and how? Nephrol Dial Transplant 2009;24(2):338-41. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 2007;49(2 Suppl 2):S12-154. Zoungas S, de Galan BE, Ninomiya T, Grobbee D, Hamet P, Heller S, et al. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: New results from the ADVANCE trial. Diabetes Care 2009;32(11):2068-74. Kalantar-Zadeh K, Kopple JD, Regidor DL, Jing J, Shinaberger CS, Aronovitz J, et al. A1C and survival in maintenance hemodialysis patients. Diabetes Care 2007;30(5): 1049-55. Cavanaugh KL. Diabetes management issues for patients with chronic kidney disease. Clinical Diabetes 2007;25(3):90-97. Morgan L, Marenah CB, Jeffcoate WJ, Morgan AG. Glycated proteins as indices of glycaemic control in diabetic patients with chronic renal failure. Diabet Med 1996;13(6):514-9. ADA. Standards of medical care in diabetes. Diabetes Care 2011;34 Suppl 1:S11-61. Joy MS, Cefalu WT, Hogan SL, Nachman PH. Long-term glycemic control measurements in diabetic patients receiving hemodialysis. Am J Kidney Dis 2002;39(2):297-307. Thompson-Culkin K, Zussman B, Miller AK, Freed MI. Pharmacokinetics of rosiglitazone in patients with end-stage renal disease. J Int Med Res 2002;30(4):391-9. Morioka T, Emoto M, Tabata T, Shoji T, Tahara H, Kishimoto H, et al. Glycemic control is a predictor of survival for diabetic patients on hemodialysis. Diabetes Care 2001;24(5):909-13. Williams G, Pickup JC. Handbook of Diabetes, 3rd Edition: Wiley-Blackwell, 2004. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002;287(3):360-72. Krepinsky J, Ingram AJ, Clase CM. Prolonged sulfonylurea-induced hypoglycemia in diabetic patients with end-stage renal disease. Am J Kidney Dis 2000;35(3):500-5. Daiichi Sankyo. Prandin® Summary of Product Characteristics. 2009. ADA. Executive summary: Standards of medical care in diabetes--2010. Diabetes Care 2010;33 Suppl 1:S4-10. Merck Sharpe & Dohme Ltd. Glucophage® Summary of Product Characteristics. 2009. Davidson MB, Peters AL. An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med 1997;102(1):99-110. Nye HJ, Herrington WG. Metformin: The Safest Hypoglycaemic Agent in Chronic Kidney Disease? Nephron Clin Pract 2011;118(4):c380-c383. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356(24):2457-71. GlaxoSmithKline. Avandia® Summary of Product Characteristics. 2008. Takeda. Actos Summary of Product Characteristics. 2007. Sarafidis PA, Bakris GL. Protection of the kidney by thiazolidinediones: an assessment from bench to bedside. Kidney Int 2006;70(7):1223-33. Chapelsky MC, Thompson-Culkin K, Miller AK, Sack M, Blum R, Freed MI. Pharmaco-. kinetics of rosiglitazone in patients with varying degrees of renal insufficiency. J Clin Pharmacol 2003;43(3):252-9. Mohideen P, Bornemann M, Sugihara J, Genadio V, Sugihara V, Arakaki R. The metabolic effects of troglitazone in patients with diabetes and end-stage renal disease. Endocrine 2005;28(2):181-6.

7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

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28. Villanueva G, Baldwin D. Rosiglitazone therapy of posttransplant diabetes mellitus. Transplantation 2005;80(10):1402-5. 29. Bayer. Glucobay SPC. 2009. 30. Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood glucose in diabetic patients with renal failure. Diabetes Metab 2000;26 Suppl 4:73-85. 31. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26(10):2929-40. 32. Eli-Lilly. Byetta 5 micrograms solution for injection SPC. 2009. 33. NovoNordisk. Victoza 6 mg/ml solution for injection in pre-filled pen. 2009. 34. Raun K, von Voss P, Gotfredsen CF, Golozoubova V, Rolin B, Knudsen LB. Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. Diabetes 2007;56(1):8-15. 35. Jones MC. Therapies for diabetes: pramlintide and exenatide. Am Fam Physician 2007;75(12):1831-5. 36. Merck Sharpe & Dohme Ltd. Januvia® Summary of Product Characteristics. 2009. 37. Novartis Europharm Ltd. Galvus® Summary of Product Characteristics. 2009. 38. Bristol-Myers Squibb Pharmaceuticals Ltd and AstraZeneca EEIG. Onglyza® Summary of Product Characteristics. June, 2009. 39. Bristol-Myers Squibb Pharmaceuticals Ltd and AstraZeneca EEIG. Onglyza® Prescribing Information. 2010. 40. Merck Sharpe & Dohme Ltd. Januvia® US Prescribing Information. 2010. 41. Novartis Europharm Ltd. Galvus® Prescribing Information. 2010. 42. Goldstein BJ. Clinical translation of “a diabetes outcome progression trial”: ADOPT appropriate combination oral therapies in type 2 diabetes. J Clin Endocrinol Metab 2007;92(4):1226-8. 43. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359(15):1577-89. 44. Smith RJ, Nathan DM, Arslanian SA, Groop L, Rizza RA, Rotter JI. Individualizing therapies in type 2 diabetes mellitus based on patient characteristics: what we know and what we need to know. J Clin Endocrinol Metab 2010;95(4):1566-74. 45. Gavin JR, 3rd, Bohannon NJ. A review of the response to oral antidiabetes agents in patients with type 2 diabetes. Postgrad Med 2010;122(3):43-51.

55

4. DPP-4 inhibitors in general and linagliptin in particular as a new treatment option in T2DM

Professor Michael Nauck

Diabeteszentrum Bad Lauterberg Bad Lauterberg im Harz, Germany

Dr Thomas Hach

TA Metabolism Boehringer Ingelheim Pharma GmbH & Co. KG Ingelheim, Germany

The incretin effect
DPP-4 inhibition as a means of controlling blood sugar levels has attracted considerable attention in recent decades. In order to understand how DPP-4 inhibitors work, it is pertinent to briefly review the incretin hormones and the physiological phenomenon known as the incretin effect. Insulin and glucagon play a central role in blood sugar homeostasis; they are influenced by a group of gastrointestinal hormones – the incretins. More than a century ago it was suggested that a hormone produced by the gastrointestinal tract stimulated secretory activity in the pancreas.1 Building on these ideas it was later discovered that eating promotes a much greater degree of insulin secretion compared with simply infusing glucose into the circulation, thus bypassing the gut.1 This phenomenon was termed the incretin (the crude intestinal extract being named secretin, with excretin stimulating the exocrine portion of the pancreas, and incretin acting on the endocrine pancreas) effect and it has since become clear that it involves several hormones (incretin hormones) of which the most important are glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (glucose-dependent insulinotropic peptide or GIP).1 Both GLP-1 and GIP are similar to glucagon in terms of their amino acid sequence. The former is secreted primarily by L-cells, which occur most abundantly in the ileum, colon and rectum, but also, to a lesser degree, in the upper gastrointestinal (GI) tract while the latter is secreted by K-cells in the duodenum/upper jejunum. The incretin hormones, GLP-1 and GIP, are released throughout the day, with levels increasing several-fold in response to a meal (Figure 1).2 They act on the pancreas augmenting glucose-induced insulin secretion. GLP-1 also suppresses glucagon secretion (GIP tends to stimulate glucagon secretion).3 When blood glucose concentrations are normal or elevated, GLP-1 and GIP stimulate insulin production and release from pancreatic β-cells thereby enhancing glucose uptake by insulin-dependent tissues, effects that are complemented by the ability of GLP-1 to lower glucagon secretion from the pancreatic α-cells (Figure 1).2 Decreased glucagon levels, along with higher insulin levels, lead to reduced gluconeogenesis in the liver, thus lowering blood glucose levels in the fasting and fed states (Figure 1).2 56

Figure 1. The incretin hormones and glucose homeostasis. Adapted from Drucker, 2006.2

Incretin hormones stimulate insulin release from pancreatic β-cells in a glucose-dependent manner (i.e. the insulin release happens only when glucose concentrations are normal or elevated, as typically observed in response to glucose ingestion); therefore the glucose-lowering effect they elicit does not result in hypoglycaemia. There is even evidence to suggest that GLP-1 may stimulate increases in β-cell mass and function; attributes we’ll consider later in this chapter.4 5

The incretin effect and T2DM
Several abnormalities have been observed in the entero-insular axis in T2DM patients.6 These defects include:
z Reduced GLP-1 response to food (Figure 2).7 8 This has not been uniformly confirmed, the majority of studies showing unchanged GLP-1 secretion comparing T2DM patients and healthy control subjects (Figure 3).9 z A somewhat decreased potency of GLP-1 in stimulating the release of insulin (Figure 3).10 However, exogenous GLP can still lower glucose concentrations into the normal range in patients with T2DM. z An almost complete loss of insulin secretion in response to even high doses of GIP.11 12 z Suppression of glucagon secretion is impaired during oral glucose tolerance tests (OGTTs) as opposed to isoglycaemic intravenous glucose infusion.13 This is also true in healthy subjects,14 so it is not an abnormality in T2DM.

57

Figure 2. The reduced GLP-1 response to food in T2DM, compared with normal patients. The meal was started at time zero and finished in the 10- to 15-min period. Adapted from Toft-Nielsen, et al. 2001.7

Figure 3. Integrated responses of ‘total’ GLP to oral glucose or mixed meals based on individual studies (a) reporting integrated incremental ‘total’ GLP-1 responses in patients with T2DM and an appropriate control group (weight-matched, non-diabetic participants) and using non-specific assays that measured intact and DPP-4-degraded forms of GLP-1.9 (b) Meta-analysis of studies dealing with secretion and providing incremental responses of GLP-1 in healthy subjects and patients with T2DM after an oral glucose tolerance test and/or after a standardised mixed meal.

58

The DPP-4 enzyme
Discovered in 1967, the DPP-4 enzyme has attracted a great deal of interest because of its role in a number of important cellular processes, not least of all its function in blood sugar homeostasis. This enzyme occurs as a membrane bound form abundant in several body tissues (e.g. kidney, heart and liver) and a free form that circulates in the blood stream. It is classed as a glycoprotein and a serine exopeptidase that cleaves peptides with proline and alanine in the pen-ultimate N-terminal position in a diverse range of substrates, including regulatory peptides (e.g. GLP-1 and GIP), chemokines, neuropeptides, and vasoactive peptides.15 Especially intact GLP-1 (sequence [7-36 amide] or [7-37]) is avidly attacked and degraded (products [9-36 amide] or [9-37]). Even during a continuous intravenous infusion, only 15 % of GLP-1 remains in its intact, biologically active state.16 DPP-4 thus limits and terminates the biological activity of GLP-1 (and, to a lesser degree, GIP).

DPP-4 inhibitors
Background and mode of action The DPP-4 enzyme is very important in the incretin system as it rapidly inactivates the incretin hormones, GLP-1 and GIP, thereby regulating their effects (Figure 4).2 Following the discovery that GLP-1 and GIP are degraded various inhibitors of the DPP-4 enzyme were identified. These findings paved the way for a novel means of reducing blood glucose levels via modulation of the incretin effect; namely prolonging the effect of native GLP-1, the biological activity of which is limited by a half-life of less than 2 minutes.17 Inhibition of DPP-4 has been shown to increase endogenous GLP-1 levels by 2-to-3 fold, thereby improving insulin secretion, suppressing glucagon, and lowering blood sugar.

59

Figure 4. The mode of action of a DPP-4 inhibitor.

Administration Crucially, in terms of patient convenience, DPP-4 inhibitors are orally active. Furthermore, sitagliptin, saxagliptin, linagliptin and alogliptin only have to be taken once a day, while vildagliptin is taken twice a day. With many oral antidiabetic drugs (OADs), a dose-finding period is required at the initiation of therapy, in which the most appropriate dose for a particular patient is determined. With DPP-4 inhibitors, a dose-finding period is unnecessary due to the way in which they act, the speed with which they act and the fact that gastrointestinal disturbances, such as nausea and vomiting are not common problems. These characteristics of DPP-4 inhibitors make them suitable for use in combination regimens.18-21 Efficacy HbA1c lowering Currently, there are four DPP-4 inhibitors on the market: sitagliptin, vildagliptin, saxagliptin and linagliptin, while the arrival of alogliptin onto the market is imminent. All of these agents have a unique mechanism of action compared with the other OADs, namely their ability to potentiate the activity of GLP-1 and enhance insulin secretion in a glucosedependent manner.22 Numerous randomised controlled clinical trials have demonstrated that DPP-4 inhibitors can reduce HbA1c, fasting plasma glucose (FPG) and postprandial glucose (PPG) versus placebo. Tables 1–4 present some of the key information from the sitagliptin, vildagliptin, saxagliptin and alogliptin clinical trials. The efficacy of linagliptin is discussed in some detail later in this chapter. 60

Table 1. Summary of sitagliptin phase III clinical data. Monotherapy/ combination
Monotherapy23 Monotherapy
24

Total number of patients
555 743 521 741 1172 273 701 1091 1172 587 353 441 222 277

Duration (weeks)
12 12 18 24 52 18 24 24 52 104 24 24 24 18

Sitagliptin dose

Baseline HbA1c (%)
7.7 7.9 8.1 8.0 7.5 7.7 8.0 8.8 7.5 8.6 8.1 8.3 8.3 8.8

Change in HbA1c (%)
-0.39 to -0.56* -0.38 to -0.77* -0.48 to -0.60* -0.79 to -0.94* -0.67 -0.73 -0.65* -1−2.1 -0.67 -1.4 to -1.7 -0.70* -0.74* -0.89* -0.9

50 mg bid or 100 mg QD 5, 12.5, 25 or 50 mg BID 100 mg or 200 mb QD 100 mg or 200 mb QD 100 mg QD 100 mg QD 100 mg QD 100 mg QD 100 mg QD 100 mg QD 100 mg QD 100 mg QD 100 mg QD 100 mg QD

Monotherapy25 Monotherapy Monotherapy Metformin28 Metformin29
(initial combination study)
26 27

Metformin30

Metformin27
(initial combination study)

Metformin31

Thiazolidinedione (TZD)32 Sulphonylurea (SU)33 Metformin + SU
33

Metformin + TZD34

*Placebo-adjusted change. Note that the studies are different and therefore not comparable; doses may vary in different studies. Change in HbA1c shows change from baseline except when asterisk is shown. QD = once daily dosing; BID = twice daily dosing

Table 2. Summary of vildagliptin phase III clinical data. Monotherapy/ combination
Monotherapy35 Monotherapy
36

Total number of patients
37 98 354 632 786 131 544 576 107 2789 463 515

Duration (weeks)
4 12 24 24 24 52 24 24 52 52 24 24

Vildagliptin dose

Baseline HbA1c (%)
7.2 8.0 8.4 8.4 8.7 6.6 8.4 8.4 7.8 7.3 8.7 8.5

Change in HbA1c (%)
-0.38* -0.6* -0.5 to -0.9* -0.8 to -0.9 -1.1 -0.30 -0.7 to -1.1 -0.9 -1.1 -0.44 -0.8 to -1.1* -0.6 to -0.7*

50 mg BID 25 mg QD 50 mg QD, 50 mg BID or 100 QD 50 mg QD, 50 mg BID or 100 QD 50 mg BID 50 mg QD 50 mg QD or 50 BID 50 mg BID 50 mg QD 50 mg BID 50 mg QD or 50 BID 50 mg QD or 50 BID

Monotherapy37 Monotherapy38 Monotherapy39 Monotherapy40 Metformin41 Metformin42 Metformin Metformin TZD45 SU46
43 44

*Placebo-adjusted change. Note that the studies are different and therefore not comparable; doses may vary in different studies. Change in HbA1c shows change from baseline except when asterisk is shown. QD = once daily dosing; BID = twice daily dosing.

61

Table 3. Summary of saxagliptin phase III clinical data. Monotherapy/ Combination
Monotherapy47
(initial combination study)

Total number of patients
401 1306 743 743 858 801 1306 768 565

Duration (weeks)
24 24 24 102 52 18 76 24 24

Saxagliptin dose

Mean baseline HbA1c (%)
7.9 9.5 8.1 8.1 7.7 6.5–10 8.0–12.0 8.5 8.4

Change in HbA1c (%)
-0.46 -2.5 -0.69 -0.40 -0.74 -0.52* -1.55 to -2.33* -0.64* -0.94*

2.5 mg, 5 mg or 10 mg QD 5 mg or 10 mg QD 2.5 mg, 5 mg or 10 mg QD 2.5 mg, 5 mg or 10 mg QD 5 mg QD 5 mg QD 5 mg or 10 mg QD 2.5 mg or 5 mg QD 2.5 mg or 5 mg QD

Metformin48

Metformin49 Metformina 50 Metformin51 Metformin52
(initial combination study)

Metformin53 SU54 TZD55

*Change in HbA1c = Adjusted mean change from baseline at end of study. a = long term extension of previous study. Efficacy data refers to saxagliptin 5mg. Note that the studies are different and therefore not comparable. QD = once daily dosing.

Table 4. Summary of alogliptin phase III clinical data. Monotherapy/ Combination therapy
Monotherapy Metformin57 SU58 TZD59 TZD60
(initial combination study)
56

Total number of patients
329 527 500 493 655 803

Duration (weeks)
26 26 26 26 12 26 52

Alogliptin dose

Mean baseline HbA1c (%)
7.0-10.0 7.9 8.1 8.0 6.9-10.4 8.8 7.0-10.0

Change in HbA1c (%)
-0.56−0.59 -0.6 -0.38−0.52 -0.66−0.80 -0.91-0.97 -1.7 -0.70

12.5 mg or 25 mg QD 12.5 mg or 25 mg QD 12.5 mg or 25 mg QD 12.5 mg or 25 mg QD 12.5 mg or 25 mg QD 12.5 mg or 25 mg QD 25 mg QD

TZD61

Metformin + TZD

62

*Placebo-adjusted change. Note that the studies are different and therefore not comparable; doses may vary in different studies. Change in HbA1c shows change from baseline except when asterisk is shown. QD = once daily dosing.

Cardiovascular protection Long-term safety data for DPP-4 inhibitors are not yet available. However, there is evidence to suggest these agents may confer some degree of cardiovascular protection.63 64 Further data to support or refute this hypothesis is currently being collected in large, prospective studies.63 A number of meta-analyses have recently been published that investigate, in detail, the cardiovascular safety of OADs. Sitagliptin was not associated with an increased risk of major adverse cardiovascular events.65 Likewise, vildagliptin was not associated with an increased risk of adjudicated cardiovascular and cerebrovascular events, even in a patient population that included subjects at increased risk of these events.66

62

Preservation of β-cell function There is growing evidence that progressive β-cell dysfunction is crucial for the development and progression of T2DM,67 68 the exact nature of which is still not fully understood, although several β-cell “aggressors” have been identified (Figure 5).69 In patients with T2DM it has been observed there is a reduced islet number and/or diminished β-cell mass in the pancreas due to increased apoptosis and inadequate regeneration.70 β-cells are known to have a very low antioxidant capacity, which has the potential to render them vulnerable to oxidative stress by reactive oxygen and nitrogen species.71 This process is believed to be central in the impairment of β-cell function during the development of T2DM. 71 Although T2DM is associated with a progressive decline in β-cell function, it has been shown that certain pharmacological treatments, such as DPP-4 inhibitors, metformin and TZDs can ameliorate β-cell function.72-74 In-vivo studies, usually performed in young rodents, have demonstrated that DPP-4 inhibitors exhibit favourable actions on islet and β-cell mass, morphology, and survival.74 75 Since similar beneficial effects were not observed with sulphonylurea treatment, it is believed that the effects on insulin-secreting cells in these in-vivo studies are mediated through specific actions of the drug(s) directly on β-cells rather than by an improvement of the metabolic milieu.76

Figure 5: Proposed model for the interplay between “aggressors” of the beta-cell in the pathogenesis of T2DM.69

63

Safety and tolerability Besides their demonstrated efficacy in lowering blood glucose levels, DPP-4 inhibitors have proven to be safe and well tolerated, with an overall incidence of adverse events similar to placebo.19-21 The incidence of specific adverse events is not increased with DPP-4 inhibitor treatment compared with placebo, and the dropout rates from studies due to adverse events are low.77 In some studies, upper respiratory tract infection, nasopharyngitis and headache have been reported in patients treated with DPP-4 inhibitors; a truly enhanced frequency has not been established.77 Even though DPP-4 inhibitors appear to be generally well tolerated, the collective experience with these drugs in the clinical setting has been relatively short; therefore, long-term surveillance is critical for the detection of potential adverse events that may occur rarely or following long-term use.77 In addition to its role in blood sugar homeostasis, the DPP-4 enzyme may play a role in the immune system (CD26, a marker of activated T-lymphocytes, is identical to DPP-4) and perhaps also in tumour biology.78 79 Extensive animal toxicology studies with high doses and long duration, however, do not provide evidence to support the theory that DPP-4 inhibitors have the potential to cause or promote tumours. A recent analysis of the FDA adverse events reporting database has been much debated, with the preliminary conclusion that the findings of an elevated risk for acute pancreatitis and pancreatic carcinoma found in the case of sitagliptin80 contradict findings from other analyses, are in part biologically implausible, and most likely are the result of reporting bias. However, a final judgement cannot be made based on findings currently available, and results from larger and longer duration clinical trials and other methods of surveillance need to be waited for to allow firmer conclusions. Hypoglycaemia An important consideration in the tolerability of OAD therapy is hypoglycaemia; however, compared to some of the OADs on the market, DPP-4 inhibitors are associated with a low incidence of hypoglycaemia thanks to their novel mode of action.18 DPP-4 inhibitors avoid the risk of hypoglycaemia in two ways:
z GLP-1, the levels of which are increased by DPP-4 inhibition, suppresses glucagon release only at euglycaemia, but not at hypoglycaemic plasma glucose concentrations.81 z DPP-4 inhibitors may, in addition, enhance α-cell responsiveness to the suppressive effects of hyperglycaemia and the stimulatory effects of hypoglycaemia, as shown for vildagliptin.82

64

Even though DPP-4 inhibitor treatment by itself is associated with a minimal risk of hypoglycaemia, caution is required when they are added to agents, which themselves can cause hypoglycaemia, such as SUs or insulin. Recently updated prescribing information in the US recommends that when sitagliptin is used with insulinotropic agents, a lower dose of the latter may be required to reduce the risk of hypoglycaemia.83 If at all possible, this combination should be avoided. Weight gain Weight gain is another important concern in OAD therapy as some compounds, such as SUs, non-SU secretagogues and TZDs are associated with significant increases in weight.84 Clinical studies have demonstrated that DPP-4 inhibitors are body-weight neutral.77 Other safety issues Angioedema has been reported in patients receiving vildagliptin and concomitant ACE inhibitors. Also, there have been incidences of skin lesions with vildagliptin, including blistering and ulceration, in nonclinical toxicology studies.85 Vildagliptin has not been approved in the U.S. due to a lack of studies in patients with renal impairment. In addition, in those markets where vildagliptin is approved, liver function monitoring is recommended with vildagliptin at three-month intervals during the first year and periodically thereafter.21 With saxagliptin, a dose-related mean decrease in absolute lymphocyte count was observed during clinical development, but the clinical relevance of this is unknown.86 Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome.20 Pending approval and the appropriate dose reduction, sitagliptin and saxagliptin may be used in patients with renal impairment. Alogliptin has been withdrawn from the FDA approval process due to insufficient cardiovascular safety data, but it has been approved in Japan. Elimination and implications for renal impairment The DPP-4 inhibitors, sitagliptin, vildagliptin, saxagliptin and alogliptin are primarily excreted via the kidneys. This route of elimination has obvious implications for the use of these agents in patients with renal impairment. Consequently, the prescribing information for sitagliptin, vildagliptin and saxagliptin in the EU recommend these agents should not be used in patients with moderate or severe renal impairment.19-21 The equivalent information in the US recommends these agents can be used in patients with moderate and severe renal impairment with the appropriate dose adjustment.83 65

Guidelines DPP-4 inhibitors have become an important part of the T2DM treatment strategy, to the extent where a number of the relevant guidelines make specific recommendations concerning the use of these compounds in people with this condition (Table 5).
Table 5. Guidelines concerning the use of DPP-4 inhibitors in people with diabetes

Organisation
American Association of Clinical Endocrinologists (AACE)/American College of Endocrinologists (ACE) consensus statement (2009)87

Recommendations*
● For HbA1c between 6.5% and 7.5%, DPP-4 inhibitors are one of four alternatives in monotherapy ● When progressing to dual therapy, they can be used in combination with metformin or with TZD ● In triple therapy they are recommended for use in combination with metformin plus TZD, glinides or SU87

American Diabetes Association (ADA) (2008)88 Consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes ADA/EASD (2009)89

● No specific recommendations, but DPP-4 inhibitors are expected to be listed with the next update88 ● DPP-4 inhibitors not included, but the consensus statement emphasizes the following: o Achievement and maintenance of near normoglycaemia (HbA1c < 7.0%) o Initial therapy with lifestyle intervention and metformin o Rapid addition of medications, and transition to new regimens, when target glycaemic goals are not achieved or sustained o Early addition of insulin therapy in patients who do not meet target goals.89

UK Guidelines - NICE (2009)90

● A DPP-4 inhibitor instead of a SU as second-line therapy to first-line metformin should be considered when control of blood glucose remains or becomes inadequate (HbA1c ≥ 6.5%, or other higher level agreed with the individual) ● Also, a DPP-4 inhibitor should be considered to be added as second-line therapy to first-line SU monotherapy when control of blood glucose remains or becomes inadequate (HbA1c ≥ 6.5%, or other higher level agreed with the individual) and the person does not tolerate metformin, or metformin is contraindicated ● Consider adding sitagliptin as third-line therapy to first-line metformin and a second-line SU when control of blood glucose remains or becomes inadequate (HbA1c ≥ 7.5% or other higher level agreed with the individual) and insulin is unacceptable or inappropriate. ● A DPP-4 inhibitor may be preferable to a TZD if: o A further weight gain would cause or exacerbate significant problems associated with a high body weight, or o A TZD is contraindicated, or o The person has previously had a poor response to, or did not tolerate, a TZD.90

International Diabetes Federation (IDF) guidelines (2005)

● DPP-4 inhibitors are not mentioned, but may be included in future updates91

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Other incretin therapies
DPP-4 inhibitors are not the only incretin therapies available for the management of T2DM. Exenatide and liraglutide are two other drugs that act on the incretin system. Instead of impeding the degradation of native GLP-1, exenatide mimics GLP-1, whereas as liraglutide is an analogue of this incretin (both stimulate GLP-1 receptors and, thus, are GLP-1 receptor agonists). In this section we will compare and contrast these agents with the DPP-4 inhibitors. Exenatide is a peptide hormone and a synthetic version of exendin-4, a hormone found in the saliva of the venomous lizard, the Gila monster. This hormone is composed of 39 amino acids, of which >50% are the same as those found in human GLP-1.92 The actions this drug has on the body in terms of glucose homeostasis are very similar to GLP-1. However, unlike endogenous or human recombinant GLP-1, it is more resistant to being broken down by the DPP-4 enzyme because of its different molecular structure, thereby extending its duration of action in vivo.92 Liraglutide is a human GLP-1 analogue produced by recombinant DNA technology in a species of yeast (Saccharomyces cerevisiae). The linked amino acids that form the backbone of liraglutide are genetically engineered so that it bears a small fatty-acid chain, an addition to the hormone that renders it more resistant to degradation by the DPP-4 enzyme. This modification extends the half-life of liraglutide in the body.93

Differentiating DPP-4 inhibitors from GLP-1 mimetics and analogues
Administration Being peptides, both exenatide and liraglutide would be digested in the GI tract if they were swallowed as an oral formulation; therefore, they must be administered via subcutaneous injection into the abdomen, upper thigh or arm. Exenatide must be injected twice a day, whereas liraglutide only needs to be injected once a day.94 95 Oral administration of a drug is more convenient for the patient than an injection and this route of administration may be a barrier to using exenatide and liraglutide in patients with such preferences. Efficacy Both DPP-4 inhibitors and GLP-1 mimetics/analogues differ in their efficacy and adverse event profiles. In clinical trials exenatide treatment was shown to be safe and efficacious. This GLP-1 mimic significantly 67

reduced HbA1C by -0.4% to -0.86% and body weight by 1.6kg to 2.8kg depending on the dose and the study.96-98 A study has shown that liraglutide is superior to sitagliptin in terms of HbA1c reduction (-1.5% vs. -0.9%).99 In a head-to-head study, liraglutide also out-performed exenatide; reducing HbA1c by -1.12% compared with -0.79% for exenatide.100 With increasing interaction of GLP-1 or GLP-1 receptor agonists with GLP-1 receptors, as obtained with both GLP-1 analogues (high, pharmacological concentrations) and DPP-4 inhibitors (near-physiological concentrations, approximately 2-3 fold above placebo levels), there are significant effects on the pancreatic islets and the respective glucose homeostasis. Higher concentrations (which may not be reached with DPP-4 inhibitor therapy due to their mechanism of action) are needed to slow down gastric emptying and to reduce appetite – characteristics of exenatide and liraglutide. Significant weight loss is one of the major advantages of GLP-1 mimetic/analogue therapy. Safety and tolerability In terms of safety tolerability, exenatide and liraglutide appear to be generally well tolerated, although they are associated with gastrointestinal adverse events, such as nausea, diarrhoea and vomiting.101 Both, exenatide and liraglutide have been shown to be associated with improved cardiovascular disease risk factors.102 103 Exenatide should not be used in patients with severe renal impairment or end-stage renal disease and should be used with caution in patients with renal transplantation.94 Liraglutide should be used with caution in renal impairment due to limited experience in this patient population.95 Acute pancreatitis is a potential concern for all incretin-based therapies. There have been reports of acute pancreatitis in people treated with exenatide. Albeit rare, these prompted the regulatory bodies to release safety warnings regarding the use of this drug.94 It seems that acute pancreatitis is not limited to the GLP-1 mimetics. As of January 2010 88 cases of acute pancreatitis in patients taking sitagliptin had been reported to the FDA, prompting a revision of the package insert for this drug as well.104 The recent analysis of the FDA adverse events reporting database concludes that careful long-term monitoring of patients treated with GLP-1 mimetics or DPP-4 inhibitors is required.80

Linagliptin – key characteristics
Linagliptin is a forthcoming addition to the DPP-4 inhibitor class. This section looks at the key attributes of this drug, especially those that differentiate it from the other DPP-4 inhibitors.

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Pharmacology and pharmacokinetics The affinity of linagliptin for the DPP-4 enzyme is high, which results in a slow dissociation of this compound from its substrate. Compared with vildagliptin, linagliptin has a 10-fold slower dissociation/off-rate.105 The very low dissociation of linagliptin complements the potency of this drug, which is the highest in its class.105 Linagliptin has the highest selectivity for DPP-4 relative to DPP-8 and DPP-9 of all the DPP-4 inhibitors.106-110 Linagliptin is 10,000 times more selective for DPP-4 than it is for either DPP-8 or DPP-9. This has potential implications for the tolerability and long-term safety of linagliptin, since the specific functions of DPP-8 and DPP-9 have not yet been elucidated. A high selectivity for DPP-4 reduces the likelihood of possible adverse effects related to the inadvertent inhibition of DPP-8 and DPP-9.111 Early clinical studies involving healthy volunteers demonstrated that linagliptin is rapidly absorbed following oral administration of a 5 mg dose. Peak plasma concentrations were reached after 1.5 hours. As a consequence of the tight binding of linagliptin to its substrate it has a long terminal half-life of more than 100 hours, but this does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of 5 mg linagliptin are reached by the third dose.112 The co-administration of a high-fat meal with linagliptin had no clinically relevant effects on pharmacokinetics; therefore it may be administered with or without food. Perhaps the most salient of linagliptin’s pharmacokinetic characteristics is its primarily non-renal route of excretion. Renal excretion accounts for only 5% of the dose. One main metabolite was detected during the course of preclinical studies, but this was found to be pharmacologically inactive. With its primarily non-renal route of elimination linagliptin can be used in patients with any degree of renal or liver impairment or cardiac insufficiency. No warnings/precautions, dose adjustments and additional monitoring of renal or liver function are required in patients treated with linagliptin. Efficacy Linagliptin was tested in a large clinical trial program involving >6,500 patients in more than 40 countries. These randomised, controlled studies have shown that linagliptin reduces HbA1c in all stages of T2DM and in combination with all currently used treatment regimens. In addition, improvements in FPG, PPG and β-cell function have been demonstrated. Key information from these studies is summarised in Table 6. As monotherapy, linagliptin has been shown to provide a significant and clini69

cally meaningful treatment option for T2DM patients including those whose treatment options are limited due to renal impairment. As monotherapy and in combination with metformin and metformin and a SU, linagliptin was proven to be most efficacious in patients with higher baseline HbA1c values. In addition to significantly lowering HbA1c (Table 6), linagliptin as monotherapy also had favourable effects on FPG and 2h PPG. At 24 weeks these glycaemic parameters were reduced by -23 mg/dL (-1.3 mmol/L) and -58 mg/dL (-3.2 mmol/L), respectively versus placebo.113 As an add-on to metformin, linagliptin therapy significantly reduced HbA1c at 24 weeks (Table 6), and also yielded significant, placebocorrected reductions in mean FPG (-23 mg/dL, or -1.3 mmol/L) and 2h PPG (- 67 mg/dl).114 Likewise, triple therapy (metformin + SU + linagliptin) significantly reduced HbA1c (Table 6). The placebo-adjusted reduction in FPG with this triple therapy regimen was -13 mg/dL at 24 weeks.115 In initial combination therapy with a pioglitazone, linagliptin therapy significantly reduced HbA1c (Table 6).116
Table 6. Summary of linagliptin phase III clinical data Monotherapy/ Combination
Monotherapy
117

Total number of patients
561 503 701 1058 389

Duration (weeks)
12 24 24 24 24

Linagliptin dose

Mean baseline HbA1c (%)
8.01 8.09 7.0-10.0 7.5-11.0

Change in HbA1c (%)
-0.87 to -0.88 -0.69 -0.49 -0.62 -1.06

5 mg or 10 mg QD 5 mg QD 5 mg QD 5 mg QD 5 mg QD

Monotherapy118 Metformin119 Metformin and SU120 TZD121
QD = once daily dosing

Safety and tolerability The linagliptin studies conducted to date have demonstrated weight neutrality in mono- and combination therapies. Additionally, there was no increased risk of hypoglycaemia attributed to linagliptin use in monotherapy or combination therapy with metformin or pioglitazone. Like the other DPP-4 inhibitors, the overall incidence rate of adverse events reported for linagliptin was similar to placebo (55.0% versus 53.8%). Discontinuation of therapy due to adverse events was higher in patients who received placebo as compared to linagliptin 5 mg (3.6 % versus 2.3 %). The most frequently reported adverse event in the linagliptin clinical trial programme was hypoglycaemia because of those cases observed in the triple combination study (metformin + sulphonylurea + linagliptin). The incidence of hypoglycaemia in this study was 22.9% in the treatment arm compared with 14.8% in the placebo arm. None of these cases of hypoglycaemia was classified as severe. 70

What do these attributes mean for patients with T2DM? It is anticipated that the primarily non-renal route of elimination of linagliptin will allow this compound to be used in people with renal insufficiency without dose adjustments. This has potentially important implications for T2DM management in light of the fact that at least a third of people with diabetes have some degree of renal impairment and that many current T2DM treatments are contraindicated in patients with renal impairment.84 122 The high potency of linagliptin means that a low dose of linagliptin can be administered to T2DM patients in small tablets; features that are crucial to the good tolerability of a drug and the willingness of people with T2DM to take their medication as prescribed. Additionally, these attributes lend linagliptin to inclusion in fixed-dose combinations. The high selectivity of linagliptin for the DPP-4 enzyme rather than DPP-8 or DPP-9 is reassuring, in that no untoward off-target interactions are expected, helping to confer a placebo-like tolerability profile. As linagliptin binds tightly to the DPP-4 enzyme, a single dose taken at any time of the day is sufficient to provide a full 24 hours of glycaemic control.

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Chapter 4 Summary
z Eating promotes a much greater degree of insulin secretion compared with intravenous injection of glucose. This is the incretin effect, a physiological phenomenon mediated by the incretin hormones, notably glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). z Incretin hormones elicit an increase in glucose-dependent insulin secretion and suppress glucagon secretion as well as increasing sensitivity to insulin and glucose uptake in the peripheral tissues, independent of insulin secretion. z GLP-1 may stimulate increases in β-cell mass and function (animal and cell line studies). z In people with T2DM there are several defects in the incretin effect:

◦ ◦

Decreased potency of GLP-1 in stimulating the production and release of insulin. An almost complete loss of late-phase insulin secretion in response to GIP. Suppression of glucagon secretion is impaired during oral glucose tolerance tests (OGTTs) as opposed to isoglycaemic intravenous glucose infusion.

z DPP-4 inhibitors can enhance and prolong the effects of endogenous GLP-1 by inhibiting the enzyme that rapidly degrades this incretin hormone. z These DPP-4 inhibitors are orally active, do not require a dose-finding period and two of the three types currently available only have to be taken once a day. z DPP-4 inhibitors can significantly reduce HBA1c, FPG and PPG. There is also some evidence to suggest they may preserve β-cell function and provide some degree of cardiovascular protection. However, studies proving a lasting improvement in the course of diabetes progression still have to be initiated. z Generally, DPP-4 inhibitors have proven to be safe and well tolerated, with an overall incidence of adverse events similar to placebo.

◦ ◦ ◦

DPP-4 inhibitor treatment is associated with a low incidence of hypoglycaemia due to their glucose-dependent mode of action (as derived from studies with GLP-1). DPP-4 inhibitors are body-weight neutral. Specific issues with vildagliptin may be angioedema, skin lesions and elevation in liver enzymes (with uncertain impact on the spectrum of adverse events observed with clinical use). Saxagliptin has been associated with a minor decrease in absolute mean lymphocyte count, again with uncertain clinical significance. All the currently available DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin and alogliptin) are primarily excreted via the kidneys with implications for their use in people with renal impairment (dose reduction or avoidance of use in that particular population). The suspicion has been raised based on analyses from an adverse events reporting database located at the FDA that pancreatitis and pancreatic carcinoma may be observed more often with sitagliptin treatment, but this evidence is considered non-convincing due to the nature of this database and the high likelihood for reporting bias.

◦ ◦

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z Several guidelines make specific recommendations concerning the use of DPP-4 inhibitors. z Exenatide and liraglutide are injected incretin therapies.

◦ ◦ ◦ ◦

They are effective in reducing HbA1c as well as body weight.

They are generally well tolerated and the most common adverse events are gastrointestinal disturbances. Exenatide should not be used in patients with severe renal impairment or end-stage renal disease and liraglutide should only be used with caution in renal impairment. Acute pancreatitis is a potential concern for all incretin-based therapies, including DPP-4 inhibitors and GLP-1 mimetics/analogues.

z Linagliptin is a relatively new addition to the DPP-4 inhibitor market. It has the following characteristics:

◦ ◦ ◦ ◦ ◦ ◦ ◦

A very high affinity for its substrate and a high level of potency compared with the other compounds in its class. 10,000 times more selective for DPP-4 than it is for either DPP-8 or DPP-9. Rapidly absorbed and has a long terminal half-life of more than 100 hours. Administered as a single 5 mg tablet at any time of the day with or without food. Primarily excreted non-renally; therefore it can be used without dose adjustments or warnings in patients with renal impairment. In clinical trials, linagliptin alone or in combinations with other OADs has demonstrated its ability to improve HbA1c, FPG, PPG and β-cell function. Linagliptin is weight neutral and has proved to be well tolerated.

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42. Bolli G, Dotta F, Rochotte E, Cohen SE. Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes, obesity & metabolism 2008;10(1):82-90. 43. Ahren B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes care 2004;27(12):2874-80. 44. Ferrannini E, Fonseca V, Zinman B, Matthews D, Ahren B, Byiers S, et al. Fifty-twoweek efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes, obesity & metabolism 2009;11(2):157-66. 45. Garber AJ, Schweizer A, Baron MA, Rochotte E, Dejager S. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes, obesity & metabolism 2007;9(2):166-74. 46. Garber AJ, Foley JE, Banerji MA, Ebeling P, Gudbjornsdottir S, Camisasca RP, et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes, obesity & metabolism 2008; 10(11):1047-56. 47. Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Current medical research and opinion 2009;25(10):2401-11. 48. Jadzinsky M, Pfutzner A, Paz-Pacheco E, Xu Z, Allen E, Chen R. Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes, obesity & metabolism 2009;11(6):611-22. 49. DeFronzo RA, Hissa MN, Garber AJ, Luiz Gross J, Yuyan Duan R, Ravichandran S, et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes care 2009;32(9):1649-55. 50. DeFronzo RA, et al. Once-Daily Saxagliptin Added to Metformin Provides Sustained Glycemic Control and Is Well Tolerated Over 102 Weeks in Patients With Type 2 Diabetes. Diabetes care 2009;58 (Suppl 1):A147, Abstract 547. 51. Goke B, Gallwitz B, Eriksson J, Hellqvist A, Gause-Nilsson I. Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. International journal of clinical practice 2010;64(12):1619-31. 52. Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes/ metabolism research and reviews 2010;26(7):540-9. 53. Pfutzner A, Paz-Pacheco E, Allen E, Frederich R, Chen R, Investigators CV. Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks. Diabetes, obesity & metabolism 2011;13(6):567-76. 54. Chacra AR, et al. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial. The International Journal of Clinical Practice 2009;Published online - doi: 10.1111/j.1742-1241.2009.02143.x. 55. Hollander P, Li J, Allen E, Chen R. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. The Journal of clinical endocrinology and metabolism 2009;94(12):4810-9. 56. DeFronzo RA, Fleck PR, Wilson CA, Mekki Q. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes care 2008;31(12):2315-7. 57. Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q, Alogliptin Study G. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin mono therapy: a multicentre, randomised, double-blind, placebo-controlled study. International journal of clinical practice 2009;63(1):46-55. 58. Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q, Alogliptin Study G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes, obesity & metabolism 2009;11(2):167-76.

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59. Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q, Alogliptin Study G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Current medical research and opinion 2009;25(10):2361-71. 60. Kaku K, Itayasu T, Hiroi S, Hirayama M, Seino Y. Efficacy and safety of alogliptin added to pioglitazone in Japanese patients with type 2 diabetes: a randomized, doubleblind, placebo-controlled trial with an open-label long-term extension study. Diabetes, obesity & metabolism 2011;13(11):1028-35. 61. Rosenstock J, Inzucchi SE, Seufert J, Fleck PR, Wilson CA, Mekki Q. Initial combination therapy with alogliptin and pioglitazone in drug-naive patients with type 2 diabetes. Diabetes care 2010;33(11):2406-8. 62. Bosi E, Ellis GC, Wilson CA, Fleck PR. Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallelgroup study. Diabetes, obesity & metabolism 2011;13(12):1088-96. 63. Frederich R, Alexander JH, Fiedorek FT, Donovan M, Berglind N, Harris S, et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med;122(3):16-27. 64. Monami M, Iacomelli I, Marchionni N, Mannucci E. Dipeptydil peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis;20(4):224-35. 65. Williams-Herman D, Engel SS, Round E, Johnson J, Golm GT, Guo H, et al. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord;10:7. 66. Schweizer A, Dejager S, Foley JE, Couturier A, Ligueros-Saylan M, Kothny W. Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large Phase III type 2 diabetes population. Diabetes, obesity & metabolism;12(6):485-94. 67. Kahn SE. The relative contribution of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 2003;46:3-19. 68. Marchetti P, Dotta F, Lauro D, Purrello F. An overview of pancreatic beta-cell defects in human type 2 diabetes: implications for treatment. Regul Pept 2008;146(1-3):4-11. 69. Donath MY, Storling J, Maedler K, Mandrup-Poulsen T. Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J Mol Med 2003;81(8):455-70. 70. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52(1): 102-10. 71. Drews G, Krippeit-Drews P, Dufer M. Oxidative stress and beta-cell dysfunction. Pflugers Arch 2010;460(4):703-18. 72. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 2002;51(9): 2796-803. 73. Kitabchi AE, Temprosa M, Knowler WC, Kahn SE, Fowler SE, Haffner SM, et al. Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin. Diabetes 2005; 54(8):2404-14. 74. Pospisilik JA, Martin J, Doty T, Ehses JA, Pamir N, Lynn FC, et al. Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocininduced diabetic rats. Diabetes 2003;52(3):741-50. 75. Mu J, Woods J, Zhou YP, Roy RS, Li Z, Zycband E, et al. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes 2006;55(6):1695-704. 76. Marchetti P, Lupi R, Del Guerra S, Bugliani M, D’Aleo V, Occhipinti M, et al. Goals of treatment for type 2 diabetes: beta-cell preservation for glycemic control. Diabetes care 2009;32 Suppl 2:S178-83. 77. Ahren B. Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes. Expert opinion on emerging drugs 2008;13(4):593-607. 78. Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH. The role of CD26/ dipeptidyl peptidase IV in cancer. Front Biosci 2008;13:1634-45. 79. Masur K, Schwartz F, Entschladen F, Niggemann B, Zaenker KS. DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells. Regul Pept 2006;137(3):147-55.

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80. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 2011;141(1):150-6. 81. Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. The Journal of clinical endocrinology and metabolism 2002;87(3):1239-46. 82. Ahren B, Schweizer A, Dejager S, Dunning BE, Nilsson PM, Persson M, et al. Vildagliptin enhances islet responsiveness to both hyper- and hypoglycemia in patients with type 2 diabetes. The Journal of clinical endocrinology and metabolism 2009;94(4): 1236-43. 83. Merck Sharpe & Dohme Ltd. Januvia® US Prescribing Information. 2010. 84. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002;287(3):360-72. 85. Novartis Europharm Ltd. Galvus® Prescribing Information. 2010. 86. Bristol-Myers Squibb Pharmaceuticals Ltd and AstraZeneca EEIG. Onglyza® Prescribing Information. 2010. 87. Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract 2009;15(6):540-59. 88. ADA. Standards of medical care in diabetes--2009. Diabetes care 2009;32 Suppl 1: S13-61. 89. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes care 2009;32(1):193-203. 90. Sibal L, P.D. H. Management of type 2 diabetes: NICE guidelines. Clin Med 2009;9(4): 353-57. 91. International Diabetes Federation, Clinical guidelines taskforce. Global guideline for type 2 diabetes. Brussels: International Diabetes Federation, 2005. 92. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes care 2003;26(10):2929-40. 93. Raun K, von Voss P, Gotfredsen CF, Golozoubova V, Rolin B, Knudsen LB. Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. Diabetes 2007;56(1):8-15. 94. Eli-Lilly. Byetta 5 micrograms solution for injection SPC. 2009. 95. NovoNordisk. Victoza 6 mg/ml solution for injection in pre-filled pen. 2009. 96. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes care 2004;27(11):2628-35. 97. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes care 2005;28(5):1092-100. 98. Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes care 2005;28(5):1083-91. 99. Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, openlabel trial. Lancet;375(9724):1447-56. 100. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374(9683):39-47. 101. Holst JJ, Deacon CF, Vilsboll T, Krarup T, Madsbad S. Glucagon-like peptide-1, glucose homeostasis and diabetes. Trends Mol Med 2008;14(4):161-8. 102. Klonoff DC, Buse JB, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Current medical research and opinion 2008;24(1):275-86.

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103. Courreges JP, Vilsboll T, Zdravkovic M, Le-Thi T, Krarup T, Schmitz O, et al. Beneficial effects of once-daily liraglutide, a human glucagon-like peptide-1 analogue, on cardiovascular risk biomarkers in patients with Type 2 diabetes. Diabet Med 2008; 25(9):1129-31. 104. Olansky L. Do incretin-based therapies cause acute pancreatitis? J Diabetes Sci Technol 2010;4(1):228-29. 105. Thomas L, Eckhardt M, Langkopf E, Tadayyon M, Himmelsbach F, Mark M. (R)-8-(3amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazoli n-2-ylmethyl)-3,7dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. The Journal of pharmacology and experimental therapeutics 2008;325(1):175-82. 106. Biftu T, Feng D, Qian X, Liang GB, Kieczykowski G, Eiermann G, et al. (3R)-4-[(3R)-3Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoro ethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Bioorg Med Chem Lett 2007;17(1):49-52. 107. Brandt I, Joossens J, Chen X, Maes MB, Scharpe S, De Meester I, et al. Inhibition of dipeptidyl-peptidase IV catalyzed peptide truncation by Vildagliptin ((2S)-{[(3hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile). Biochem Pharmacol 2005;70(1):134-43. 108. Deacon CF, Holst JJ. Saxagliptin: a new dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. Advances in therapy 2009;26(5):488-99. 109. Feng J, Zhang Z, Wallace MB, Stafford JA, Kaldor SW, Kassel DB, et al. Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. Journal of medicinal chemistry 2007;50(10):2297-300. 110. Matsuyama-Yokono A, Tahara A, Nakano R, Someya Y, Nagase I, Hayakawa M, et al. ASP8497 is a novel selective and competitive dipeptidyl peptidase-IV inhibitor with antihyperglycemic activity. Biochem Pharmacol 2008;76(1):98-107. 111. Kirby M, Yu DM, O’Connor S, Gorrell MD. Inhibitor selectivity in the clinical application of dipeptidyl peptidase-4 inhibition. Clin Sci (Lond);118(1):31-41. 112. Heise T, Graefe-Mody EU, Huttner S, Ring A, Trommeshauser D, Dugi KA. Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes, obesity & metabolism 2009;11(8):786-94. 113. Baseline HbA1c: 8.0% linagliptin-treated group; 8.0% placebo group; Full analysis set (FAS), Last observation carried forward (LOCF). ADA 70th Scientific Sessions; 2010; Orlando, Florida, USA. 114. Baseline HbA1c: 8.09% linagliptin-treated group; 8.02% placebo group; full analysis set (FAS), Last observation carried forward (LOCF) ADA 70th Scientific Sessions; 2010; Orlando, Florida, USA. 115. Linagliptin monotherapy improves glycaemic control and measures of beta-cell function in Type 2 diabetes. ADA 70th Scientific Sessions; 2010; Orlando, Florida, USA. 116. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled Type 2 diabetes. ADA 70th Scientific Sessions; 2010; Orlando, Florida, USA. 117. Kawamori R, Inagaki N, Araki E, Watada H, Hayashi N, Horie Y, et al. Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: a randomized, placebo and active comparator-controlled, double-blind study. Diabetes, obesity & metabolism 2011. 118. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes, obesity & metabolism 2011;13(3):258-67. 119. Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes, obesity & metabolism 2011;13(1):65-74. 120. Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med 2011;28(11):1352-61.

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121. Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes, obesity & metabolism 2011;13(7):653-61. 122. Koro CE, et al. Antidiabetic medication use and prevalence of chronic kidney disease among patients with type 2 diabetes mellitus in the United States. Clin. Therapeutics 2009;31(11):2608-17. 123. Vollmer K, Holst JJ, Baller B et al (2008) Predictors of incretin concentrations in subjects with normal, impaired, and diabetic glucose tolerance. Diabetes 57:678–687. 124. Theodorakis MJ, Carlson O, Michopoulos S et al (2006) Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am J Physiol (Endocrinol Metab) 290:E 550–559. 125. Muscelli E, Mari A, Casolaro A et al (2008) Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes 57:1340–1348. 126. Vilsbøll T, Krarup T, Sonne J et al (2003) Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. J Clin Endocrinol Metab 88:2706–2713. 127. Ryskjaer J, Deacon CF, Carr RD et al (2006) Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbA1c levels, but is not acutely affected by food intake. Eur J Endocrinol 155:485–493. 128. Salinari S, Bertuzzi A, Asnaghi S, Guidone C, Manco M, Mingrone G (2009) First-phase insulin secretion restoration and differential response to glucose load depending on the route of administration in type 2 diabetic subjects after bariatric surgery. Diabetes Care 32:375–380. 129. Knop FK, Vilsboll T, Hojberg PV, et al. The insulinotropic effect of GIP is impaired in patients with chronic pancreatitis and secondary diabetes mellitus as compared to patients with chronic pancreatitis and normal glucose tolerance. Regul Pept 2007;144(1-3):123-130.

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5. The future of anti-diabetics in T2DM therapy

Professor Ele Ferrannini

Department of Internal Medicine University of Pisa School of Medicine Pisa, Italy

Dr Thomas Hach

TA Metabolism Boehringer Ingelheim Pharma GmbH & Co. KG Ingelheim, Germany

Unmet needs in T2DM therapy
As we have seen in Chapter 1, T2DM is a huge, global problem. Many treatments are available to tackle this chronic and potentially serious condition, but the fact is that, in many patients, long-term glycaemic control and adherence to therapies is far from optimal; limited by a lack of sustained efficacy, safety and tolerability issues and product label restrictions. These problems are compounded in those patients with comorbidities that interfere with diabetes therapy, such as renal impairment.

Beyond HbA1c in assessing treatment efficacy
Assessing the degree to which glycaemic control is achieved hinges on a number of parameters. If these targets are not met then glycaemia is considered to be uncontrolled. These targets are as follows:
z HbA1c: <7.0%1 z FPG: 3.9 – 7.2 mmol/L (70 – 130 mg/dl)2 z 2-hour postprandial blood glucose: <7.8 mmol/L (<140 mg/dl)3, 4 up to <10 mmol/L (<180 mg/dl)5

As these targets indicate whether glycaemia is controlled or not, they relate directly to the efficacy of any given therapy in lowering blood glucose levels in patients with T2DM. For this reason, the level of efficacy of any treatment will remain an important decision factor in choosing the most appropriate agent. HbA1c, as a proxy for efficacy, is the current gold standard in monitoring treatment and informing management decisions in people with diabetes.6 However, using this measure in isolation is not without its limitations.6 HbA1c reflects the mean blood glucose level during the preceding six to eight weeks, but this is true only for the population as a whole, not the individual patient.6 For assessing the efficacy of a given treatment in the future we should take a more holistic approach. It is known that about 33% of people diagnosed as having T2DM based on postprandial (PPG) hyperglycaemia have normal fasting plasma glucose (FPG).7 It has been shown that the deleterious effects of dysglycaemia – daily excursions in FPG and PPG – develop before diabetes is diagnosed.8 81

The degree to which FPG and PPG influence overall glycaemia is relatively complex, but we know that PPG contributes ~70% to the total glycaemic load in patients who are fairly well controlled (HbA1c <7.3%). In patients who are very poorly controlled (HbA1c >10.2) it is FPG that contributes around 70% to the total glycaemic load (Figure 1).7, 9 Furthermore, there is a Iinear relationship between the risk of CV death and the 2-hour oral glucose tolerance test (OGTT).7 These data suggest that all the parameters for assessing glycaemia (HbA1c, FPG, and PPG) should be considered in the management of T2DM.7 In assessing the efficacy of a T2DM therapy we should take into account not only its ability to lower HbA1c, but also its ability to normalise the blood glucose excursions that can occur during the day i.e. the spikes in FPG and PPG.10, 11

Figure 1. Relative contributions of PPG (dark blue) and FPG (light blue) to the overall diurnal hyperglycaemia over quintiles of HbA1c.9

Beyond glycaemic measures in assessing treatment efficacy
In addition to glycaemic parameters for assessing the efficacy of T2DM treatment, it is becoming increasingly clear that other parameters beyond glycaemic control are important. T2DM is a complex condition that is often part of a much broader metabolic syndrome that manifests itself with obesity, hypertension and dyslipidaemia. Also, the side effects associated with some treatments can have a negative impact on the patient’s quality of life.12

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In terms of dyslipidaemia it is known that pioglitazone is associated with improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size, whereas rosiglitazone is not.13 Rosiglitazone has since been associated with a number of adverse effects, but this example illustrates the point that the variation in efficacy of the various T2DM treatments, even those in the same therapeutic class, extends beyond simple glucose lowering. Obesity can complicate the management of diabetes by increasing insulin resistance and blood glucose concentrations as well as negatively impacting lipidaemia,14 but it is well known that some T2DM treatments, such as SUs, Glinides, and TZDs are associated with significant increases in weight.15 Impact on body weight and in turn lipidaemia will be increasingly recognised as an important measure of efficacy for new and emerging T2DM treatments. Some new therapies have demonstrated favourable characteristics with regard to body weight. For example, the DPP-4 inhibitors are weight neutral and the GLP-1 mimetics/analogues can reduce body weight significantly.16-20 Treatment adherence and the needs of the patient Intimately related to the clinical parameters of efficacy discussed above is the perennial problem of treatment adherence. The full benefits of a T2DM treatment are only gained if the patient takes the medications as prescribed. It has been generally acknowledged for years that non-adherence rates for chronic illness regimens and for lifestyle changes are ~ 50%.21 As a group, patients with diabetes find it difficult to adhere to their treatment regimens.22 Complex regimens One treatment-related factor that is known to influence adherence is regimen complexity. It is well known that people with diabetes have to take several medications every day for their T2DM and concurrent conditions.23 Given the fact that patients often have to take different medications, with different dosage frequencies, at different times of the day, it is hardly surprising that many of them are unable to follow treatment regimens closely.23 Simplifying treatment regimens using single pill formulations that can be taken at any time of the day can potentially help patients to adhere to their medication and consequently improve the clinical efficacy of T2DM treatments.21

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Tolerability issues Tolerability is another treatment-related issue that can seriously impact treatment adherence. T2DM treatment options offer a trade off between efficacy and tolerability due to product label restrictions and adverse effects, e.g. weight gain, hypoglycemia, injections, heart failure and GI problems.24, 25 Common side effects of current treatments (metformin, SUs, glinides, TZDs, insulin, α-glucosidase inhibitors and GLP-1 mimetics/analogues) are headache, nausea, GI disorders, weight gain and hypoglycaemia. These side effects are sometimes accompanied by subsequent, more severe complications, e.g. hypoglycaemia may influence cardiovascular events and dementia.26, 27 In view of these tolerability issues, the guidelines make specific recommendations regarding each class of T2DM treatment (Figure 2).

Figure 2. Traditional medications and their adverse effect considerations.28

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“Failure-based” treatment strategies
Several large, randomised trials have demonstrated that intensive treatment can improve outcomes in people with T2DM. For example, post-trial monitoring data from the UKPDS shows that patients who received intensive treatment during the study continue to have a significantly decreased risk of any diabetes-related endpoint over the long term; an effect that is known as “a legacy of improved outcomes” because early intensive treatment leaves a legacy of clinical benefits.29, 30 Controlling glycaemia more aggressively, instead of simply waiting for treatment failure aims to avoid the phenomenon known as ”metabolic memory”. This concept, which refers to diabetic vascular stresses persisting after glucose normalisation, has been supported by laboratory and clinical data.31, 32 The progressive nature of T2DM requires regular monitoring and adjustment of treatment, but all too often management strategies for this condition are ‘failure based’, in that there is a tendency to persist with monotherapy until blood glucose levels are no longer controlled.23 There appears to be inertia in primary care impeding the adoption of an aggressive, treat-to-target approach (i.e. early enforced normalization of blood glucose levels) even though the benefits of intensive management in the short- and long-term have been demonstrated by some long-term studies. An early switch to antidiabetic combination treatment that addresses the dual endocrine defects of insulin resistance and β-cell dysfunction, would deliver a markedly greater reduction in HbA1c for those patients who are struggling to meet their glycaemic targets.33

Predictability of treatment response and the need for individualised treatment
Currently, T2DM management is very much a ‘one treatment fits all’ affair.34 People with T2DM are generally treated in the same way regardless of underlying differences that may affect their therapeutic response.34 There is a huge variation in response, which makes it almost impossible to predict the treatment effect in any given patient.34 Differences in genotype interact with external environmental factors to produce an in-vivo milieu that varies from person to person thus impacting the effects of a medication.34 Analyses have shown that in the USA only 56% of patients diagnosed and treated for diabetes reach their glycaemic targets, whereas in Germany the figure is 48% (glycaemic target for both the USA and Germany is <7% HbA1c).35, 36 This failure in treatment leaves a substantial 85

population exposed to prolonged periods of damaging hyperglycaemia.34 There is now a consensus that further insight into the differences between people with T2DM, both physiologic and genetic, should not only help elucidate the pathogenesis of this disease, but lead to individualised treatments for patients that will improve glycaemic control, maximise individual benefit, minimise risk, reduce diabetes complications, and ultimately provide reductions in global health cost.34 The recent consensus published in the Journal of Clinical Endocrinology and Metabolism (Smith et al., 2010) makes a series of recommendations for increasing understanding of the heterogeneity of T2DM and achieving the goal of individualising therapy and improving treatment response (Table 1).34
Table 1. Recommendations for individualising therapies in T2DM based on patient characteristics.34

Recommendation
Extend analysis of existing data and data sources

Specific details
• There are already a plethora of data and data sources

that could be potentially valuable in individualising therapy; however, to date, these have been largely underutilised. provide important insights into the relative effectiveness of specific interventions in subgroups of patients with T2DM and advance our understanding of individualised therapy. cally collect data to address phenotypic and genetic heterogeneity measures.

• Pooled analyses or meta-analyses of such data may

Expand existing or develop new data registries

• All new and existing diabetes registries should systemati-

• Not only should these registries collect material for future

biomarker and genetic analysis, but registries should be designed to specifically address the heterogeneity of diabetes with hypotheses generated by examining existing data. by design, collect phenotypic information relevant to response to therapy.

Develop new clinical trials

• Future randomised studies of diabetes therapies should,

Develop new technologies

• Targeting therapy toward more appropriate subgroups of

patients will require increasingly accurate and efficient methods to measure markers for diabetes heterogeneity and heterogeneous response to treatment. tal issues that underlie the heterogeneous response to diabetes therapies.

Expand basic research

• Basic research is needed to explore numerous fundamen-

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Cardiovascular safety
Completed studies Numerous observational studies have shown a clear relationship between hyperglycaemia and cardiovascular (CV) disease. Because of the known increase in the risk of CV disease in T2DM and the emphasis on CV safety in the development of T2DM medications by regulatory authorities there is considerable interest in the degree to which T2DM treatments influence CV health.37 However, very little is known about the CV effects of newer T2DM treatments. Several large, long-term studies have investigated the CV safety of T2DM treatments, i.e. UKPDS, ACCORD, ADVANCE and VADT, all of which failed to show that intensive glucose control significantly reduces CV events.33, 38-40 Indeed, ACCORD was terminated early due to higher (non-significant) mortality in the intensive treatment group, which has led to the conclusion in some quarters that intensive glucose control not only has no effect on the risk of CV events, but can even be harmful in patients at high CV risk.38 It is possible to argue that in the UKPDS metformin was associated with an improvement in CV mortality (this is supported by recent meta-analyses – see the end of this chapter).41 This follow-up study of the tight glucose intervention in the UKPDS showed that intensive glucose control was associated with a significant reduction in the risk for myocardial infarction, diabetes-related deaths and all-cause mortality.41 This suggests that early, strict glucose control generates a legacy that is eventually translated into CV protection. Currently, this is nothing more than a hypothesis that requires testing.41 The PROACTIVE study showed that pioglitazone can reduce the risk of secondary macrovascular events in a high-risk patient population with T2DM and established macrovascular disease; however, the study failed on the primary composite endpoint and only demonstrated CV benefit on a secondary endpoint.42-45 The RECORD trial demonstrated that while the addition of rosiglitazone to glucose-lowering therapy did not increase the risk of overall mortality and morbidity, it did increase the risk of heart failure.46 In the STOPNIDDM trial, acarbose was associated with a CV benefit, however, this was a trial in IGT, not T2DM, and the number of observed CV events was very low.47 Whether early insulin treatment results in a beneficial effect on the CV system remains an open question,47 but one that the ORIGIN trial will attempt to answer, the first results of which are expected in 2012. The Steno-2 study demonstrated CV risk improvement, but this is a small study and the multi-factorial interventions make it impossible to attribute the observed effect to a single compound.48

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Definitive proof for CV protection afforded by T2DM treatment is scant to say the least, so much so that the spectre of increased CV risk due to T2DM treatment looms large in the minds of many experts. The results from these trials may relate to the particular drugs used rather than difference between intensive and conventional management. There have been many high profile cases concerning the use of some compounds and an associated increase in CV events with the most infamous being rosiglitazone and to a lesser extent the first generation SU, tolbutamide.49, 50 Naturally, these fears have placed the TZDs, as a class, under great scrutiny, but the fact remains that large trials and meta-analyses (i.e. PROactive, Nissen and Wolski’s meta-analyses and RECORD) do not provide definitive answers with regard to the CV safety of these compounds.42, 46, 50, 51 Prompted by these concerns, the FDA conducted a systematic review of epidemiologic studies of CV risk in patients treated with rosiglitazone or pioglitazone,52 the results of which are consistent with results of the same organisation’s meta-analyses of randomised clinical trials with these two TZDs.53 The salient point from these analyses is that it is highly likely that rosiglitazone therapy is associated with increased risk of adverse CV outcomes.53 Ongoing studies There are a number of ongoing trials investigating the CV outcomes associated with T2DM treatment. The driving force behind the relatively recent initiation of these large trials, often involving more than 10,000 patients, is the fact the regulatory bodies now require CV safety on all new and emerging T2DM treatments. These CV outcome trials are summarised in Table 2.

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Trial name
Dec 2008 – Dec 2014* 14,000 Assess the impact of sitagliptin as part of usual care vs. usual care without sitagliptin on primary composite CV endpoint (CV-related death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina requiring hospitalization) Time from randomization to the occurrence of the primary major adverse cardiac events, defined as a composite of CV death, nonfatal myocardial infarction and nonfatal stroke The composite endpoint of CV death, non-fatal myocardial infarction or non-fatal ischaemic stroke CV morbidity/mortality in people at high risk for vascular disease with either IFG, IGT, or early type 2 diabetes NCT00968708 NCT00790205

Aim

Start and end date

Patients enrolled

Primary outcome measures

Clinical Trial. gov identifier

TECOS54

To determine if including sitagliptin as part of usual care has any impact upon a composite CV endpoint

EXAMINE55 Sep 2009 – Dec 2014 5,400

To determine the CV outcomes of alogliptin, once daily, compared with placebo, in addition to standard of care, in subjects with T2DM and acute coronary syndrome May 2010 – May 2015 12,000

SAVOR- TIMI 5356

To determine if saxagliptin can reduce the risk of CV events when used alone or added to other diabetes medications Sep 2003 – Dec 2011 12,500

NCT01107886

ORIGIN57

Determine if insulin glargine-mediated normoglycaemia can reduce CV morbidity and/or mortality in people at high risk for vascular disease with either IFG, IGT or early T2DM Oct 2010 – Sep 2018 6,000

NCT00069784

CAROLINA58

NCT01243424

Table 2. Ongoing CV outcome studies investigating the CV safety of T2DM treatments

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Dec 2009 – Apr 2013 4,332 Dec 2010 – Aug 2014 4,000 Jun 2010 – Mar 2017 9,500 Aug 2010 – Jan 2016 8,754

Determine the long-term impact on CV morbidity and mortality, relevant efficacy parameters (e.g., glycaemic parameters) and safety (e.g., weight and hypoglycaemia) of treatment with linagliptin in patients with T2DM at elevated CV risk receiving usual care, and compare outcome against glimepiride

Time to first occurrence of any of the following components of the primary composite endpoint: CV death, non-fatal myocardial infarction, non-fatal stroke and hospitalisation for unstable angina pectoris Major adverse cardiovascular events, including CV death, nonfatal MI, and nonfatal stroke

CANVAS

Evaluate canagliflozin compared to placebo on CV events including CV death, heart attack, and stroke in patients with T2DM, whose diabetes is not well controlled at the beginning of the study and who have a history of CV events or have a high risk for CV events. Three sub-studies will compare the effectiveness of lowering blood glucose and assess the safety of canagliflozin relative to placebo in patients receiving specific commonly used diabetes agents.

NCT01032629

BI 10773 CV Outcome Event Trial in T2DM59

To investigate the safety of BI 10773 treatment in patients with T2DM and high CV risk

Time to the first occurrence of any of the following adjudicated components of the primary composite endpoint: CV death (including fatal stroke and fatal myocardial infarction, non-fatal MI and non-fatal stroke. Time to first confirmed CV event in the primary composite CV endpoint (CV-related death, nonfatal myocardial infarction (MI), or nonfatal stroke) Time from randomisation to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke (a composite CV outcome)

NCT01131676

EXSCEL60

Compare the impact of including exenatide once weekly as part of usual care vs. usual care without exenatide on major CV outcomes

NCT01144338

LEADER61

To determine the long term effect of liraglutide on CV events in subjects with T2DM

NCT01179048

Should the results of the above trials be overwhelmingly positive, they will prove that T2DM treatments can provide benefits beyond simply lowering blood glucose levels. The data will provide an insight into the cardiovascular safety and potential cardiovascular protection of the compounds being investigated. The results of these trials in conjunction with an increased knowledge of disease genetics and drug mode of actions could stimulate a reappraisal of T2DM management.

Emerging therapeutic classes
DPP-4 inhibitors DPP-4 inhibitors are oral anti-diabetics. They do not require an uptitration period, are weight neutral and are associated with significant improvements in glucose control in patients with T2DM by preventing the inactivation of the incretin hormone GLP-1, which stimulates glucosedependent insulin secretion and suppresses glucagon secretion.16 DPP-4 inhibitors are efficacious over a broad range of HbA1c levels. They have shown to be effective as both monotherapy and as add-on therapy to metformin, SUs, TZDs and insulin in subjects who lack adequate glycaemic control.16 In addition to their demonstrated efficacy as mono- and add-on therapy they are also generally safe and have a placebo-like tolerability profile.16 Long-term safety data for DPP-4 inhibitors is still lacking, although they are now included in the most recent US and European guidelines2, 62 There are concerns regarding the ubiquitous tissue expression (liver, lung, lymphocytes, etc) of the DPP enzymes, their role in tumour suppression and their interaction with other hormones besides GLP-1.63-67 To date there is nothing in the safety record of DPP-4 inhibitors to suggest these concerns have any clinical grounding Also, due to the way that sitagliptin, vildagliptin and saxagliptin are cleared from the body, their use is not recommended in patients with moderate to severe renal insufficiency and because they have not been studied in severe hepatic insufficiency their use is also not recommended in the these patients (vildagliptin should not be used in any type of hepatic impairment).68-70 Linagliptin on the other hand can be used without dose adjustment in all stages of renal impairment. Table 3 presents a ‘SWOT’ analysis of the DPP-4 inhibitors.

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Table 3. DPP-4 inhibitors – Strengths, Weaknesses, Opportunities and Threats.

Strengths
z

Weaknesses
z z

Potentiate the activity of GLP-1 and enhance glucose-dependent insulin secretion Associated with a low incidence of hypoglycaemia Weight neutral Significant body of data supporting their use in T2DM Orally active No titration period required Shown to be effective in mono- and combination therapy Placebo-like tolerability

Long-term data lacking Dose adjustment required or contraindicated in moderate or severe renal impairment (except linagliptin) Safety concerns with vildagliptin Price Not specifically included in all guidelines, but are included in the ADA/EASD consensus guidelines

z z z

z z z

z z z

z

Opportunities
z z

Threats
z

May confer some degree of cardio-protection T2DM management is moving beyond simple glycaemic parameters The position of many OADs is being eroded by safety concerns (e.g. SUs, TZDs) Patient-centric treatment is increasingly important Positive data from CV outcome studies

Possible safety issues related to long-term consequences of DPP-4 inhibition Possible safety issues related to inadvertent inhibition of DPP-8 and DPP-9 Negative data from CV outcome studies New compounds with novel modes of action

z

z

z z

z z

91

GLP-1 mimetics and analogues Exenatide and liraglutide are injected drugs that also act on the incretin system. Instead of impeding the degradation of native GLP-1 like DPP-4 inhibitors, exenatide mimics GLP-1, whereas as liraglutide is an analogue of this incretin. Both of these agents offer considerable reductions in blood glucose levels and body weight (see Chapter 4). In addition, exenatide has been shown to have favourable effects on lipidaemia.71 The drawbacks of GLP-1 mimetics/analogues include their need to be injected, gastrointestinal side effects and a potential link with acute pancreatitis. Table 4 presents a ‘SWOT’ analysis of these agents.
Table 4. GLP-1 mimetics/analogues – Strengths, Weaknesses, Opportunities and Threats.

Strengths
z

Weaknesses
z z

Supplement endogenous GLP-1 and enhance glucose-dependent insulin secretion Associated with a low incidence of hypoglycaemia Weight loss Significant body of data supporting their use in T2DM Shown to be effective in mono- and combination therapy Generally well tolerated Considerable improvements in lipidaemia (exenatide)

Long-term data lacking Should not be used in severe renal impairment or end stage renal disease (exenatide) Should be used with caution in renal impairment (liraglutide) Price Need to be injected Gastrointestinal side effects Not specifically included in all guidelines

z z z

z

z z z z

z

z z

Opportunities
z z z

Threats
z z z

May confer some degree of cardio-protection Effect of weight loss on CV risk factors T2DM management is moving beyond simple glycaemic parameters The position of many OADs is being eroded by safety concerns (e.g. SUs, TZDs) Patient-centric treatment is increasingly important Positive data from CV outcome studies

May cause pancreatitis Negative data from CV outcome studies New compounds with novel modes of action

z

z z

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SGLT-2 inhibitors In the kidneys, two transporter proteins, sodium-glucose co-transporter-1 (SGLT-1) and SGLT-2 are crucial in regulating the reuptake of sodium and glucose back into ultra-filtrated blood.72 Inhibiting SGLT-2 has been identified as a way of reducing glucose re-uptake and therefore reducing blood glucose levels. 72 No compounds in this class are currently available on the market. Dapagliflozin has filed for approval, while canagliflozin/empagliflozin are in Phase 3 development. Initial SGLT-2 inhibitor data shows there are no excessive losses of fluid, sodium, or potassium; very low risk of hypoglycaemia; significant reductions in HbA1c (~0.7%) modest weight loss (1 to 4 kg) and a lowering of systolic blood pressure (1 to 4 mmHg).7275 Potential drawbacks of SGLT-2 inhibition include a slight increase in urine volume and a tendency to increase urinary tract infections and genital mycosis. The latter drawback is thought to be due to the increased levels of glucose in the urine, which supports the growth of yeasts, etc.72 Table 5 presents a ‘SWOT’ analysis of the SGLT-2 inhibitors.
Table 5. SGLT-2 inhibitors – Strengths, Weaknesses, Opportunities and Threats.

Strengths
z z z z z z z

Weaknesses
z

Novel mode of action Orally active Insulin-independent mode of action Associated with modest weight loss Associated with a low incidence of hypoglycaemia Lower systolic blood pressure High selectivity – SGLT-2 not found in other tissues

Not yet supported by a large body of late phase clinical data Increase in urine volume Increase in urinary tract/genital infections No data on long-term inhibition of SGLT-2 SGLT-2 inhibition is an unknown quantity in T2DM management High selectivity – effects on other important disease management parameters may be limited

z z z z

z

Opportunities
z

Threats
z

T2DM management is moving beyond simple glycaemic parameters The position of many OADs is being eroded by safety concerns (e.g. SUs, TZDs) Patient-centric treatment is increasingly important

New compounds with novel modes of action emerging Long term consequences of higher glucose levels in the urine

z

z

z

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11β-HSD1 inhibitors This enzyme is responsible for the regeneration of cortisol from its inert form, cortisone (Figure 3). Inhibitors of 11β-HSD1 have reached Phase IIb clinical trials for the treatment of T2DM. These compounds act by decreasing the cortisol generated in liver and adipose tissue, thereby reducing tissue-specific gluconeogenesis and fatty acid metabolism.76 11β-HSD1 inhibitors are predicted to be at least weight neutral, if not leading to some weight loss. In addition, they should improve glycaemia without inducing hypoglycaemia.76 The concern of physiologists is that if you artificially reduce the level of circulating cortisol by means of the 11β-HSD1 pathway, you run the risk of adrenal gland compensation and activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the production of more cortisol.76 In this scenario, the adrenal glands might also simultaneously produce excess adrenal androgens, which, at high concentrations are associated with numerous negative effects. To date, these fears have not been borne out in animal studies where the complete deletion of the 11β-HSD1 gene in mice had, overall, inconclusively minimal effects on adrenal action.76 Harno and White (2010) conclude that 11β-HSD1 inhibition represent a compelling treatment strategy for T2DM.76 Table 6 presents a ‘SWOT’ analysis of the 11β-HSD1 inhibitors.

Figure 3. 11β-HSD1 and regeneration of cortisol. (a) Inactive cortisone is converted to (b) active cortisol by the enzyme 11β-HSD1.76

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Table 6. 11β-HSD1 inhibitors – Strengths, Weaknesses, Opportunities and Threats.

Strengths
z z z z

Weaknesses
z z

Novel mode of action Orally active Weight neutral and may even result in weight loss Should improve glycaemia without inducing hypoglycaemia Favourable effects on triglycerides and blood pressure

Still in the early stages of development Not yet supported by a large body of late phase clinical data No data on long-term inhibition of 11β-HSD1 11β-HSD1 inhibition is an unknown quantity in T2DM management Unknown how 11β-HSD1 inhibition could fit in combination therapy 11β-HSD1 also expressed in the CNS Concerns over adrenal gland compensation and activation of the hypothalamic-pituitary-adrenal (HPA) axis Concerns over excess production of adrenal androgens

z z

z

z

z z

z

Opportunities
z

Threats
z

T2DM management is moving beyond simple glycaemic parameters Coverage of all metabolic syndrome characteristics with one drug The position of many OADs is being eroded by safety concerns (e.g. SUs, TZDs) Some early concerns not borne out in initial human studies Pathway may attenuate progression of T2DM May improve CV risk factors

Unknown how 11β-HSD1 inhibition may affect lipidaemia in the long-term Emergence of other agents with a more familiar mode of action

z

z

z

z

z z

95

Glucagon antagonism Glucagon plays a central role in glucose homeostasis, namely by increasing hepatic glucose production and raising blood glucose levels. Blunting the effects of has long been considered a means of reducing hyperglycaemia in T2DM. There are two ways in which to limit the activity of glucagon. Firstly, immuno-neutralisers effectively reduce the amount of glucagon in the body, but the development of such compounds for use in humans has not progressed because of limitations imposed by the delivery methods necessary to achieve significant levels of exposure for the peptide agents.77 Secondly, and more promisingly, are small molecules that inhibit the glucagon receptor. Several examples of these are in early Phase 2 clinical development. They act by preventing glucagon binding to its receptor and triggering the increased production of glucose.78 Blocking the action of glucagon is predicted to be an effective means of controlling hepatic glucose production, thereby lowering fasting and postprandial hyperglycaemia in T2DM.77 Table 7 presents a ‘SWOT’ analysis of glucagon receptor antagonists.
Table 7. Glucagon receptor antagonists – Strengths, Weaknesses, Opportunities and Threats.

Strengths
z z z

Weaknesses
z z

Novel mode of action Orally active Offers the control of hepatic glucose production

Still in the early stages of development Not yet supported by a large body of late phase clinical data No data on long-term antagonism of glucagon receptors Glucagon receptor antagonists are an unknown quantity in T2DM management Unknown how glucagon receptor antagonists could fit in combination therapy Glucagon receptors widely expressed throughout the body

z

z

z

z

Opportunities
z

Threats
z

T2DM management is moving beyond simple glycaemic parameters The position of many OADs is being eroded by safety concerns (e.g. SUs, TZDs) Patient-centric treatment is increasingly important

Emergence of other agents with a more familiar mode of action

z

z

96

Interleukin-1β receptor antagonists Interleukin-1β is a proinflammatory cytokine that inhibits the function and promotes the apoptosis of pancreatic β-cells.79 β-cells producing this cytokine have been observed in pancreatic sections obtained from patients with T2DM. Depending on culture conditions, high glucose levels have been shown to increase β-cell production and the release of interleukin-1β, followed by functional impairment and apoptosis.79 Using an antagonist to prevent interleukin-1β from binding to its receptor protects human β-cells from glucose-induced functional impairment and apoptosis.80 This therapeutic approach has the potential to block the pathogenic progression of T2DM. Anakinra, a recombinant human interleukin-1–receptor antagonist, is currently in Phase 2 development. A recent study has demonstrated that HbA1c levels in T2DM patients treated with this compound for 13 weeks were 0.46% lower than in those treated with placebo.79 In addition, anakinra was associated with improved β-cell secretory function and reduced markers of systemic inflammation.79 In terms of safety, no cases of symptomatic hypoglycaemia or serious, drug related adverse events were observed during this study.79 Table 8 presents a ‘SWOT’ analysis of interleukin-1β receptor antagonists.
Table 8. Interleukin-1β receptor antagonists – Strengths, Weaknesses, Opportunities and Threats.

Strengths
z z z

Weaknesses
z z

Novel mode of action Orally active Impedes the pathogenic progression of T2DM

Still in the early stages of development Not yet supported by a large body of late phase clinical data No data on long-term antagonism of interleukin-1β receptor Interleukin-1β receptor antagonists are an unknown quantity in T2DM management Unknown how Interleukin-1β receptor antagonists could fit in combination therapy Interleukin-1β receptor widely expressed in the body

z

z

z

z

Opportunities
z

Threats
z

T2DM management is moving beyond simple glycaemic parameters The position of many OADs is being eroded by safety concerns (e.g. SUs, TZDs) Patient-centric treatment is increasingly important The only therapy that targets the pathogenesis of T2DM

Emergence of other agents with a more familiar mode of action Doubts over whether this drug target represents a viable, long-term treatment strategy

z

z

z z

97

Beyond glycaemic control
In this chapter we have already discussed the trials that have investigated the degree to which T2DM treatments influence CV risk. Fifty percent of people diabetes die from CV disease, primarily heart disease and stroke,81 so there’s intense interest in defining the degree to which specific drugs and combinations of drugs influence CV risk. Since the 1990s, the options for OAD treatment have increased markedly. The expanded selection has created a need for comparative data on the risks and benefits of anti-diabetic drugs, particularly in light of the greater cost of newer agents.82 A meta-analysis of forty clinical trials shows that metformin is associated with a 26% reduction in the relative risk of CV mortality compared with SUs, TZDs, glinides and placebo.82 A meta-analysis is only as good as the studies it includes and the authors of this particular analysis conclude: “larger, long-term studies taken to hard endpoints and better reporting of CV events in shortterm studies will be required to draw firm conclusions about major clinical benefits and risks related to OADs.”82 It is increasingly evident that controlling weight, hypertension and dyslipidaemia is tantamount to reducing CVD outcomes in patients with T2DM.83 Some emerging T2DM treatments, such as the SGLT-2 inhibitors, have been shown to reduce blood pressure and body weight (1–4 kg).73 As monotherapy or add-on to metformin over periods of 12–24 weeks, dapagliflozin at a dose of 10 mg/day reduced systolic blood pressure (3–5 mmHg) and diastolic blood pressure (~2 mmHg) with no apparent change in heart rate.74, 84, 85 These results are promising, but it remains to be seen if these agents can sustain this level of blood pressure reduction in the long term. Sustained improvements in glycaemia and one of the most important CV risk factors would represent a significant breakthrough in the management of T2DM. Furthermore, SGLT-2 inhibitors could offer a clinically meaningful treatment opportunity even in T1DM.86 Certain T2DM therapies have also demonstrated their ability in improving dyslipidaemia. A meta-analysis shows that metformin significantly reduces total and low-density lipoprotein (LDL) cholesterol, although these reductions are rather small.87 In a study in T2DM patients, pioglitazone improves levels of triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size.13 In 3-year open-label extension studies the incretin therapy exenatide was associated with a 12% decrease in triglycerides, a 6% decrease in LDL and 24% increase in HDL.71 It has been postulated that the weight loss/weight neutrality of incretin therapies contributes to lipid improvements.83 In a four week study the DPP-4 inhibitor vildagliptin was shown to improve postprandial plasma triglyceride levels.88 Large, long term studies are the only definitive way of elucidating the influence that T2DM treatments have on CV risk factors. 98

Intimately linked to T2DM and CV disease is obesity and this is another area where certain agents may offer significant benefits. It is well known that some compounds, such as SUs, non-SU secretagogues, insulin and TZDs are associated with significant increases in weight.15 However, the incretin therapies, with their novel mode of action, and several of the emerging therapies are weight neutral or associated with significant weight loss (reviewed in Chapter 4), which has implications for lipidaemia and patient quality of life. In addition to potential CV protection afforded by some drugs there is also intriguing evidence that certain T2DM treatments may even reduce the risk of developing cancer. A cohort study has demonstrated that metformin use reduces the risk of developing cancer by 37%, even after taking into account various factors such as age, blood sugar control, smoking and weight.89 The authors of this study conclude “a randomised trial is needed to assess whether metformin is protective in a population at high risk for cancer.”89 Treatments such as metformin reduce insulin resistance and it has been suggested that insulin resistance is associated with an increased risk of cancer.90 Correspondingly, it has been found that SUs are associated with a higher risk of cancer-related mortality than metformin.91 We are still largely in the dark with respect to the full range of effects associated with the use of T2DM treatments. The ongoing CV outcome studies outlined earlier in this chapter will go some way to defining the degree to which several of these treatments influence CV risk, but this may represent the tip of the physiological iceberg. The widely used medications used in the treatment of T2DM may have effects way beyond lowering glycaemia and improving the various risk factors of CV disease.

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Unmet needs and emerging risks/benefits shaping future trends in the use of T2DM treatments
There are certainly a number of important unmet needs in T2DM, but how will these shape the management of this condition? How will T2DM be managed in the next ten or even the next twenty years? Naturally, this is speculation, but we base it on the information we have reviewed above and in the previous chapters. We can be fairly certain that metformin will remain the gold standard antidiabetic treatment simply because of the long experience with the drug, its high level of efficacy, good tolerability profile, overall cost-effectiveness and possible benefits beyond simple glycaemic control (cardiovascular protection and reduced risk of cancer). In contrast we will very likely see a progressive move away from SUs, TZDs and glinides due to potential safety and tolerability issues. Future trends in the use of incretin therapies such as the DPP-4 inhibitors and the GLP-1 mimetics/analogues are more difficult to speculate on. Both are effective in improving glycaemia, but many questions still linger over this therapeutic approach. In part, these questions have been addressed by emerging DPP-4 inhibitors that possess high potency, high selectivity and non-renal elimination. The GLP-1 mimetics and analogues may become increasingly important because of their very high level of glycaemic efficacy and associated weight loss, although the need for subcutaneous injections will always be a significant barrier to their widespread use. With metformin as the gold standard the importance of combination therapy will also continue to rise as those people poorly controlled on metformin monotherapy are treated with combination regimens containing familiar OADs and those with novel modes of action that are still in development.92 The earlier use of combination therapy in T2DM will probably also increase over time.92 Furthermore, we can expect that treatment decisions in T2DM will increasingly hinge on a number of factors, rather than just the glycaemic lowering ability and tolerability profile of a drug.93, 94 Factors such as comorbidities (e.g. renal impairment), compliance and adherence, CV protection and cost-effectiveness will all be important in the more holistic management of T2DM.93, 94 A further likely trend is the increasing influence of patient organisations and other groups in driving the issue of patient-centric treatment, which has always been something of a neglected area in the management of chronic conditions. To improve the way in which individuals with T2DM are treated we may see a progressive move to tailored therapy that builds on advances in the understanding of the genetics of this disease as well as the various products of the drug development pipeline. 100

It is well established that obesity, reduced physical activity, and aging increase susceptibility to T2DM; however, many people exposed to these risk factors do not develop the disease.95 Recent genome studies have identified a number of genetic variants that explain some of the inter-individual variation in diabetes susceptibility.95 In addition to the genetic markers of T2DM there is also a growing body of evidence suggesting a role for epigenetic factors (heritable changes in gene function that occur without a change in the nucleotide sequence) in the complex interplay between genes and the environment (Figure 4).95 Environmental factors of considerable note include persistent organic pollutants (POPs), the presence of which have been shown to be related to the prevalence of diabetes (dose response relationship).96, 97 It has also been suggested that as people become more overweight, the retention and toxicity of POPs related to the risk of diabetes may increase.96, 97

Figure 4. The interplay between genetics, epigenetics and the environment in the development of T2DM.95

Understanding the underlying genetic and epigenetic defects in blood sugar homeostasis and how these interact with environmental factors (e.g. persistent organic pollutants) will help direct T2DM management, perhaps drawing on new therapies with novel modes of action that target specific defect(s).34, 95 Drug development is promising to deliver a range of therapies that will directly address a number of the unmet needs currently facing the management of T2DM. Compounds such as the SGLT-2 inhibitors promise to deliver significant improvements in blood glucose levels as well 101

as reducing body weight, blood pressure and major CV risk factors. Other agents in clinical development offer a variety of novel modes of action, some which even target the pathogenesis of T2DM. The arrival of new drugs onto the market is widely anticipated. However, the enthusiasm for using new therapies needs to be tempered with data that validates the safe and effective use of these agents in T2DM.

Chapter 5 Summary
z Glycaemic control should take into account FPG and PPG as well as HbA1c. z The effect of treatment on body weight, hypertension, lipidaemia and other CV risk factors is also very important. z Treatment adherence may be improved by better tolerability and reduced pill burden. z The importance of co-morbidities (e.g. renal impairment) are often neglected in treatment decisions. z T2DM treatment requires regular adjustment and a deliberate treat-to-target strategy. z Intensive management increases the cost of treatment, but can reduce the cost of complications considerably as well as increasing the time free of complications. z Debate continues regarding the effect of intensive versus conventional glucose control on the risk of CV events, although a number of large studies will shed more light on this subject. z Emerging treatments will be useful in addressing the unmet needs in T2DM management:

◦ ◦ ◦ ◦

Incretin therapies have been shown to have positive effects on lipidaemia. The SGLT-2 inhibitors can reduce weight and blood pressure – important CV risk factors. Incretin therapies are weight neutral or are associated with significant weight loss. Metformin appears to reduce the risk of cancer, while drugs that elicit an increase in circulating insulin levels (SUs, insulin) may have the opposite effect.

z Metformin will most likely remain the gold standard in T2DM management. z New treatments, such as those targeting the incretin system may become increasingly important, especially in combination therapy. z Advances in our understanding of the disease, its treatment and the needs of the patient will drive the individualisation of T2DM therapy.

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Type 2 diabetes mellitus (T2DM), a dysfunction in the metabolism of glucose, is a burgeoning public health problem, the growth of which shows no signs of abating. This book begins with a short introduction to the disease, which sets the scene for a more detailed consideration of some pressing issues; notably the importance of chronic kidney disease (CKD) in people with T2DM and the implications this co-morbidity has for the medicinal management of T2DM. Intensive research efforts are providing clinicians with a growing number of medicinal options for the management of T2DM. This book reviews some of these new and emerging therapies and what they mean for the management of T2DM in people who also have CKD.

ISBN 978-3-00-037347-3

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