Oral Antidiabetic Agents1

REVIEW ARTICLE
Drugs 2005; 65 (3): 385-411 0012-6667/05/0003-0385/$39.95/0 2005 Adis Data Information BV. All rights reserved.
Oral Antidiabetic Agents

Current Role in Type 2 Diabetes Mellitus
Andrew J. Krentz1 and Clifford J. Bailey2
1 2 Southampton University Hospitals NHS Trust, Southampton, UK Life and Health Sciences, Aston Pharmacy School, Aston University, Birmingham, UK
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386 1. Insulin Secretagogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390 1.1 Sulphonylureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390 1.1.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390 1.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391 1.1.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391 1.1.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 1.1.5 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 1.1.6 New Formulations of Sulphonylureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 1.2 Rapid-Acting Prandial Insulin Releasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 1.2.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 1.2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 1.2.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 1.2.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 1.2.5 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 2. -Glucosidase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 2.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 2.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 2.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 2.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 3. Insulin Sensitisers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 3.1 Biguanides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 3.1.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 3.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 3.1.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 3.1.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402 3.1.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 3.2 Thiazolidinediones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 3.2.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 3.2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 3.2.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405 3.2.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407 3.2.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407 4. Summary and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
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Abstract
Type 2 diabetes mellitus is a progressive and complex disorder that is difficult to treat effectively in the long term. The majority of patients are overweight or obese at diagnosis and will be unable to achieve or sustain near normoglycaemia without oral antidiabetic agents; a sizeable proportion of patients will eventually require insulin therapy to maintain long-term glycaemic control, either as monotherapy or in conjunction with oral antidiabetic therapy. The frequent need for escalating therapy is held to reflect progressive loss of islet -cell function, usually in the presence of obesity-related insulin resistance. Todays clinicians are presented with an extensive range of oral antidiabetic drugs for type 2 diabetes. The main classes are heterogeneous in their modes of action, safety profiles and tolerability. These main classes include agents that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (-glucosidase inhibitors) or improve insulin action (thiazolidinediones). The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated the benefits of intensified glycaemic control on microvascular complications in newly diagnosed patients with type 2 diabetes. However, the picture was less clearcut with regard to macrovascular disease, with neither sulphonylureas nor insulin significantly reducing cardiovascular events. The impact of oral antidiabetic agents on atherosclerosis beyond expected effects on glycaemic control is an increasingly important consideration. In the UKPDS, overweight and obese patients randomised to initial monotherapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with type 2 diabetes. Concern about cardiovascular safety of sulphonylureas has largely dissipated with generally reassuring results from clinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Study showed that intensive target-driven, multifactorial approach to management, based around a sulphonylurea, reduced the risk of both micro- and macrovascular complications in high-risk patients. Theoretical advantages of selectively targeting postprandial hyperglycaemia require confirmation in clinical trials of drugs with preferential effects on this facet of hyperglycaemia are currently in progress. The insulin-sensitising thiazolidinedione class of antidiabetic agents has potentially advantageous effects on multiple components of the metabolic syndrome; the results of clinical trials with cardiovascular endpoints are awaited. The selection of initial monotherapy is based on a clinical and biochemical assessment of the patient, safety considerations being paramount. In some circumstances, for example pregnancy or severe hepatic or renal impairment, insulin may be the treatment of choice when nonpharmacological measures prove inadequate. Insulin is also required for metabolic decompensation, that is, incipient or actual diabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certain comorbidities, for example presentation with myocardial infarction during other acute intercurrent illness, may make insulin the best option. Oral antidiabetic agents should be initiated at a low dose and titrated up according to glycaemic response, as judged by measurement of glycosylated
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haemoglobin (HbA1c) concentration, supplemented in some patients by self monitoring of capillary blood glucose. The average glucose-lowering effect of the major classes of oral antidiabetic agents is broadly similar (averaging a 12% reduction in HbA1c), -glucosidase inhibitors being rather less effective. Tailoring the treatment to the individual patient is an important principle. Doses are gradually titrated up according to response. However, the maximal glucose-lowering action for sulphonylureas is usually attained at appreciably lower doses (approximately 50%) than the manufacturers recommended daily maximum. Combinations of certain agents, for example a secretagogue plus a biguanide or a thiazolidinedione, are logical and widely used, and combination preparations are now available in some countries. While the benefits of metformin added to a sulphonylurea were initially less favourable in the UKPDS, longer-term data have allayed concern. When considering long-term therapy, issues such as tolerability and convenience are important additional considerations. Neither sulphonylureas nor biguanides are able to appreciably alter the rate of progression of hyperglycaemia in patients with type 2 diabetes. Preliminary data suggesting that thiazolidinediones may provide better long-term glycaemic stability are currently being tested in clinical trials; current evidence, while encouraging, is not conclusive. Delayed progression from glucose intolerance to type 2 diabetes in high-risk individuals with glucose intolerance has been demonstrated with troglitazone, metformin and acarbose. However, intensive lifestyle intervention can be more effective than drug therapy, at least in the setting of interventional clinical trials. No antidiabetic drugs are presently licensed for use in prediabetic individuals.
In 1998, the results of the randomised, multicentre UKPDS (United Kingdom Prospective Diabetes Study)[1] provided firm evidence of the importance of long-term glycaemic control in middle-aged patients with newly diagnosed type 2 diabetes mellitus. Compared with dietary manipulation alone, intensified therapy in the form of oral antidiabetic agents or insulin significantly reduced the development of microvascular complications (table I).[1] This knowledge drives current clinical practice, in which treatment is directed to the attainment of near-normoglycaemia, i.e. glycosylated haemoglobin (HbA1c) concentrations of 6.57.0%.[2-4] While such targets may be perceived as being unrealistic for many perhaps most patients, there is a broad consensus that chronic hyperglycaemia should be managed as well as is possible, weighing safety and quality-of-life considerations on an individual basis. It is important to bear in mind that glycaemic control is just one aspect of an overall
management plan that encompasses effective treatment of hypertension and dyslipidaemia;[2-6] both are commonly encountered in patients with type 2
Table I. Summary of main results of UKPDS (United Kingdom Prospective Diabetes Study) glycaemic control study.[1] Relative risk (RR) reductions in clinical endpoints for patients randomised to intensive (i.e. sulphonylurea or insulin) vs conventional therapy (i.e. diet) Endpoints RR for intensive therapy 0.88 0.75 Confidence intervala Log-rank p-value
Aggregate endpointsb Diabetes-related endpoints Microvascular complications Single endpoints Sudden death Retinal photocoagulation Cataract extraction a b 0.54 0.71 0.76 0.24, 1.21 0.53, 0.96 0.53, 1.08 0.047 0.0031 0.046 0.79, 0.99 0.60, 0.93 0.029 0.0099
95% Confidence interval for aggregate endpoints; 99% confidence interval for single endpoints. As defined and ascertained in UKPDS 33.[1]
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Table II. Main results for intensive (n = 80) vs conventional (n = 80) treatment of patients with type 2 diabetes mellitus and microalbuminuria. Mean follow-up was 7.8 years[8] Outcomes Composite endpoint nephropathy retinopathy Intensive (%) 24 24 52 Conventional (%) 44 47 71 Adjusted HR (95% CI) 0.47 (0.22, 0.74) 61% (13, 83) 58% (14, 79) 63% (21, 82) RRR (95% CI) NNT (95% CI) 5 (3, 19) 4 (3, 14) 5 (3, 35) 4 (2, 9)
autonomic neuropathy 36 64 HR = hazard ratio; NNT = number needed to treat; RRR = relative risk reduction.
diabetes and are regarded as important modifiable risk factors for atherosclerosis, the principal cause of premature mortality. Thus, a combined multifactorial therapeutic approach is required to maximise the impact of lifestyle and drug therapy on chronic micro- and macrovascular complications. Since management of chronic vascular and neuropathic complications accounts for the majority of health service spending for diabetes, such an approach is likely to be cost effective.[7] The Steno-2 Study,[8] which embraced such a multifactorial approach to treatment, demonstrated impressive reductions in vascular complications. In this randomised study of only 160 patients with type 2 diabetes and microalbuminuria, half of the patients received intensive target-driven therapy based in a hospital clinic and the remaining patients were cared for in primary care according to national guidelines. The main results of the study are presented in table II. While providing evidence for effectiveness, the translation of this approach to large numbers of patients in already stretched healthcare systems presents an additional challenge. Insulin resistance and defective insulin secretion are regarded as cardinal metabolic features of type 2 diabetes, subtle abnormalities of both being evident even at the earliest stages of glucose intolerance. While insulin resistance is highly prevalent on a global basis closely linked to obesity and physical inactivity near-normal glucose tolerance can be maintained as long as increased insulin secretion is sufficient to counter the elevated requirements imposed by insulin resistance.[4] Management of the asymptomatic or mildly symptomatic patient with newly diagnosed type 2 diabetes starts with one-toone advice and/or group education about the potential benefits of dietary modifications and, if feasible,
physical activity. The objective is always to improve metabolic control through reductions in bodyweight obesity being present in the majority of patients and other lifestyle measures that help improve insulin sensitivity. However, it is recognised that even if diet and exercise advice is successfully implemented, the majority of patients will require pharmacological therapy in the medium- to long term. Thus, only 25% of patients in UKPDS maintained a HbA1c level <7.0% after 9 years without oral agents or insulin. Not only was drug therapy usually required, the need for escalating polypharmacy in the pursuit of glycaemic targets was also amply demonstrated.[9] Continuing loss of function of islet cells is held to be the major determinant of the slowly progressive hyperglycaemia that characterises type 2 diabetes,[1] although other factors such as weight gain and/or failure of compliance with dietary prescriptions may also contribute. However, reiteration of lifestyle advice continues to be important even when pharmacotherapy has been initiated, avoidance of further weight gain being an important longterm objective. The selection of initial pharmacotherapy is based on a detailed consideration of the clinical and biochemical characteristics of the patient. Safety considerations must always be carefully considered since few, if any, antidiabetic agents are completely devoid of risk; some are appreciably more hazardous than others in certain clinical scenarios (see section 4). An assessment of the biochemical phenotype of the patient is required. However, in practice it can be difficult to judge whether insulin resistance or insulin deficiency is the dominant defect. As a rule, although it should be stressed, not invariably, younger patients at near-normal bodyweight are more likely to have greater insulin deficiency than
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obese, sedentary middle-aged patients. Failure to respond rapidly (i.e. within a week or two) to an oral agent in a patient thought to be complying with the dietary advice usually signals the need for early use of insulin. If a partial response is observed, dose escalation is followed by step-wise addition of complementary drugs (figure 1). Insulin is usually reserved for patients: (i) who fail to respond adequately to a combination of oral agents; (ii) in whom control deteriorates despite logical and adequate drug combinations; or (iii) for whom safety and efficacy considerations favour its use as the drug of choice, for example during pregnancy, or in patients with severe hepatic or renal impairment.[10] Several classes of oral antidiabetic agents are currently available, the range of options having enjoyed a welcome expansion in recent years. However, the evidence base and clinical experience vary considerably not only between classes but also between drugs drawn from the same class. As a result, prescribing decisions often appear to be made on rather subjective grounds, such as familiarity with a particular drug; this practice may help to explain notable regional differences in prescribing. In the remainder of this article we focus on treatment of hyperglycaemia in patients with type 2
Aim
diabetes. We consider both well established drugs and recent additions to the armamentarium. For each class of agents we present an outline of the mode of action, pharmacokinetics, indications and contraindications, efficacy, safety and tolerability, current place in management and future prospects, including role in prevention of type 2 diabetes. We have grouped the drugs according to their principal mode of action: (i) those that increase insulin secretion (insulin secretagogues); (ii) drugs delaying the rate of digestion and absorption of carbohydrates (glucosidase inhibitors); and (iii) those with direct effects on insulin-responsive tissues (insulin-sensitising agents). This sequence should not be taken to imply a hierarchy in terms of efficacy or merit. The recognition that type 2 diabetes is usually a progressive disease implies that drug dosages will need to be increased or therapy moved to another stage in the treatment algorithm.[2,4] While this article primarily reflects current practice in the UK, we have endeavoured to provide a review that acknowledges important differences in prescribing in other countries. A word about monitoring: assessing the response to antidiabetic therapy involves periodic generally 3- to 6-monthly measurement of HbA1c. This approach, which is
Procedure
Diagnosis
Diet, exercise, weight control and health education
Relieve symptoms, improve glycaemic control, enhance quality of life
Oral agent monotherapy: metformin, sulphonylurea, meglitinide, thiazolidinedione1, acarbose
Move to next stage if there is inadequate control of glycaemia or inadequate relief of symptoms
Oral agent combination therapy (using two different classes)
Insulin or insulin plus an oral agent Fig. 1. An algorithm for the treatment of type 2 diabetes mellitus. The progressive hyperglycaemia in type 2 diabetes requires a steppedcare approach with treatment being modified and added over time. Rapid progression to the next stage is recommended if the glycaemic target is not achieved. Late introduction of combinations of oral antidiabetic agents is often a prelude to insulin treatment. 1 Note that in Europe, thiazolidinediones and nateglinide have limited licenses. The -glucosidase inhibitor miglitol is also available in some countries (reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press).
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recommended in the UK, can be usefully complemented by self measurement of capillary blood glucose in selected, empowered patients and in particular clinical scenarios, for example in patients in whom iatrogenic hypoglycaemia is a concern. 1. Insulin Secretagogues
1.1 Sulphonylureas
Sulphonylureas have been extensively used for the treatment of type 2 diabetes for nearly 50 years. They lower blood glucose concentrations primarily by stimulating insulin secretion from the cells of the pancreatic islets. By the 1960s several sulphonylureas were available, including tolbutamide, acetohexamide, tolazamide and chlorpropamide, offering a range of pharmacokinetic options. However, doubts about safety were raised in the 1970s. A large US multicentre trial of antidiabetic therapy, the UGDP (University Group Diabetes Program)[11] reported apparent detrimental cardiovascular effects of tolbutamide. The UGDP was heavily criticised for perceived methodological failings and its findings were far from being universally accepted. Subsequent observational and randomised clinical studies using sulphonylureas have provided mixed evidence, but a review of the available literature provides little in the way of convincing evidence of cardiovascular toxicity.[12] Indeed, some studies have reported a decreased incidence of cardiovascular events in subjects with lesser degrees of glucose intolerance who received sulphonylureas.[12] The UKPDS investigators did not find any increase in risk of myocardial infarction among patients treated with sulphonylureas compared with patients randomised to insulin as monotherapy.[1] The Steno-2 Study,[8] has already been mentioned. A succession of more potent so-called secondgeneration sulphonylureas emerged in the 1970s and 1980s, for example glibenclamide (glyburide), gliclazide and glipizide. The latest, glimepiride, was introduced in the late 1990s.[13] Glimepiride is a once-daily drug for which claims have been made that it might offer advantages over other sulpho 2005 Adis Data Information BV. All rights reserved.
nylureas with respect to the risks of weight gain and hypoglycaemia. Compared with older sulphonylureas, glimepiride is relatively expensive and clinical outcome data are not available, as they are for the agents used in the UKPDS. The clinical relevance of theoretical, but much debated, effects of glimepiride on ischaemic preconditioning whereby a brief episode of ischaemia protects the myocardium against the detrimental effects of subsequent and more severe interruption of perfusion remain uncertain. The issues of the importance of ischaemic preconditioning and the possible influence of different sulphonylureas continue to be debated (see section 1.1.5).[14]
1.1.1 Mode of Action
Sulphonylureas have direct effects on the insulinproducing islet cells. The drugs bind to the -cell sulphonylurea receptor (SUR)-1, part of a transmembrane complex with adenosine 5-triphosphatesensitive Kir 6.2 potassium channels (KATP channels).[14,15] Binding of the sulphonylurea closes these KATP channels; this reduces cellular potassium efflux favouring membrane depolarisation. In turn, depolarisation opens voltage-dependent calcium channels, resulting in an influx of calcium that activates calcium-dependent proteins that control the release of insulin (figure 2). When sulphonylureas interact with SUR1 in the -cell plasma membrane they cause prompt release of pre-formed insulin granules adjacent to the plasma membrane the socalled first phase of insulin release.[16] Sulphonylureas also increase the extended (second phase) of insulin release that begins approximately 10 minutes later as insulin granules are translocated to the membrane from within the cell.[17] The protracted stimulation of the second phase of insulin release involves the secretion of newly formed insulin granules. The increased release of insulin continues while there is ongoing drug stimulation, provided the cells are fully functional. Sulphonylureas can cause hypoglycaemia since insulin release is initiated even when glucose concentrations are below the normal threshold for glucose-stimulated insulin release (approximately 5 mmol/L).
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Glucose GLUT2 Succinate esters Glucokinase Sulphonylureas Repaglinide Nateglinide
Glucose metabolism
ATP
R1 SU .2 6 Kir K ATP el nn cha
Proinsulin biosynthesis Ca2+-sensitive proteins
Depo
larisa
tion
PKA
Ca2+ channel
rgic ene Adr ptors rece
cAMP Insulin
2-adrenoceptor antagonists
c Re
ep
to
rs
GLP-1 Exenatide
Exocytosis PDE inhibitors Insulin
Fig. 2. The insulin-releasing effect of sulphonylureas and other agents on the pancreatic islet cell. Sulphonylureas bind to the sulphonylurea receptor (SUR)-1 located within the plasma membrane. This closes Kir 6.2 potassium channels which reduces potassium efflux, depolarises the cell and opens voltage-dependent calcium influx channels. Raised intracellular calcium brings about insulin release. According to the stimulus-secretion model, metabolism of glucose generates adenosine 5-triphosphate (ATP) leading to closure of potassium channels, permitting the normal cell to link insulin secretion closely to glucose concentration. Sulphonylureas may also enhance nutrient-stimulated insulin secretion by other actions on the cell. Other secretagogues, e.g. repaglinide, nateglinide, also stimulate insulin secretion via the SUR-Kir 6.2 complex. Other agents, e.g. phosphodiesterase (PDE) inhibitors, glucagon-like peptide (GLP)-1 (736 amide), act via cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) to promote proinsulin synthesis (reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press). GLUT2 = glucose transporter-2.
1.1.2 Pharmacokinetics
The principal distinguishing feature between different sulphonylureas relates to their pharmacokinetic characteristics (table III). Duration of action varies from <12 hours for tolbutamide to >24 hours for chlorpropamide because of differences in (i) rates of metabolism; (ii) activity of metabolites; and (iii) rates of elimination.[18] These properties have important implications for the risk of hypoglycaemia associated with various sulphonylureas, an issue that is further complicated by retarded release preparations of some compounds. All sulphonylureas are well absorbed and most reach peak plasma concentration in 24 hours. They are metabolised in the
liver, although metabolites and their routes of elimination vary considerably between compounds. Since all sulphonylureas are highly bound to plasma proteins they have the potential to interact with other drugs sharing this binding, for example salicylates, sulphonamides and warfarin; displacement from circulating proteins has been implicated in cases of severe sulphonylurea-induced hypoglycaemia (table IV).
1.1.3 Indications and Contraindications
Sulphonylureas remain a popular choice as firstline oral therapy for patients with type 2 diabetes who have not achieved or maintained adequate glycaemic control using nonpharmacological measures.
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Table III. Pharmacokinetic properties of sulphonylureas[19] Sulphonylureas First generation Chlorpropamideb Tolbutamidec Second generation Glibenclamide (glyburide) Glimepiride Glipizide Gliquidone Gliclazide a b c d 2.515 16 2.520 15180 40320d Intermediate to long Intermediate Short to intermediate Short to intermediate Intermediate Active Active Inactive Inactive Inactive Bile 50% Urine 80% Urine 70% Bile 95% Urine 65% 100500 5002000 Long Short Active Inactive Urine >90% Urine 100% Daily dosage (mg) Duration of actiona Activity of metabolites Main route of elimination
Long >24h; intermediate 1224h; short <12h. No longer available in the UK. Should be taken immediately before meals. Modified (extended)-release preparation, Diamicron MR dose range 30120mg.
Customarily they are preferred for patients who are not overweight since weight gain is usually promoted by their use. Sulphonylureas can be used in combination with agents from other classes of antidiabetic agents, with the exception of other insulin secretagogues. Daytime sulphonylurea treatment may be used in combination with bedtime insulin, and can reduce insulin doses by up to 50%. This is an increasingly accepted practice, albeit one that lacks firm evidence of long-term advantages over insulin monotherapy.[20] As mentioned earlier, continued gradual loss of -cell function is to be expected in most patients; this requires escalating insulin doses with increasing duration of diabetes. Sulphonylureas should be introduced at a low dose, usually the lowest recommended by the manufacturer, the blood glucose response being carefully observed over the first few weeks; self-monitoring of blood glucose by the patient may be helpful and, as mentioned earlier, is recommended where there are concerns about the potential consequences of hypoglycaemia, for example in the vulnerable elderly patient. In general, and intuitively, patients who have achieved less marked degrees of fasting hyperglycaemia after a trial of diet and exercise are more likely to develop hypoglycaemia than those with more marked hyperglycaemia. The dosage is increased at intervals of 24 weeks until the glycaemic target is, hopefully, achieved. If hypoglycaemia
develops (see section 1.1.5), or if a dosage increment produces no further improvement in glycaemic control, it is advisable to return to the previous dose. Hypoglycaemia, whether actual or, more commonly, perceived as a risk by either the patient or clinician, is the principal limitation to rapid dose escalation of sulphonylureas. The latter point notwithstanding, it should be borne in mind that the maximal blood glucose-lowering effect is usually achieved at doses below the maximum recommended by the manufacturer. This is probably a reflection of the fact that maximum stimulation of insulin secretion has already been attained since -cell function is significantly impaired. Improved -cell capacity resulting from alleviation of glucose toxicity may contribute to the risk of hypoglycaemia in some patients. Long-term glycaemic control should
Table IV. Drugs that can potentiate the anti-hyperglycaemic effect of sulphonylureas Mechanism Displacement from plasma proteins Examples Salicylates, sulphonamides, warfarin, phenylbutazone, fibric acid derivatives
Decreased hepatic metabolism Warfarin, monoamine oxidase inhibitors, chloramphenicol, phenylbutazone Decreased renal excretion Salicylates, probenecid, allopurinol
Intrinsic hypoglycaemic activity Salicylates, alcohol (ethanol), monoamine oxidase inhibitors
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be monitored by periodic measurement of HbA1c (or fructosamine if HbA1c is not available).

1.1.4 Efficacy
The blood glucose-lowering efficacy of sulphonylureas has been evaluated in many retrospective and prospective studies, and from decades of collective worldwide clinical experience. When used as monotherapy in patients inadequately controlled by nonpharmacological measures, sulphonylureas can be expected to reduce fasting plasma glucose by an average of 24 mmol/L accompanied by a decrease in HbA1c of 12%.[4,19,21] However, individual responses are variable. Since the hypoglycaemic effect of sulphonylureas is attributable to increased insulin secretion, the effectiveness of these drugs is dependent on adequate -cell function. The aforementioned progressive -cell failure that determines the natural history of type 2 diabetes may require an increased dosage of sulphonylureas if glycaemic control deteriorates. Rapid and uncontrollable deterioration of glycaemic control during sulphonylurea therapy is sometimes termed secondary sulphonylurea failure. This phenomenon, which is something of a misnomer, occurs in approximately 510% of patients per annum with suggestions of differences in failure rates between some compounds.[21,22] The inability to maintain acceptable glycaemic control is common to all sulphonylureas and is held to reflect an advanced stage of -cell failure, that is, it is a reflection of disease progression rather than a true failure of therapy. Individuals who have greater degrees of -cell reserve usually respond well to sulphonylureas; early use of sulphonylureas as first-line monotherapy in these patients will produce better blood glucose lowering than late intervention in patients with severely compromised -cell function. The plasma insulin concentrations achieved during sulphonylurea therapy do not usually extend beyond the range observed in the general non-diabetic population (including those with impaired glucose tolerance), and suggestions that sulphonylureainduced hyperinsulinaemia might increase the risk of detrimental insulin-induced effects on the cardiovascular system remain unsubstantiated.[12] Sulpho 2005 Adis Data Information BV. All rights reserved.
nylurea therapy generally has modest effects on blood lipid profiles, although some studies have noted a small decrease in plasma triglyceride levels possibly linked to improved glycaemic control and minor increments in high-density lipoprotein (HDL)-cholesterol. When a sulphonylurea is used in combination with another antidiabetic agent, the glucose-lowering efficacy of the sulphonylurea is approximately additive to the effect of the other agent. Once again, response is crucially dependent on the presence of adequate -cell function. Early use of such combination therapy is indicated when optimal titration of a single agent does not achieve adequate glycaemic control. The combination of two different types of agents is more likely to achieve glycaemic targets, albeit for a variable period of time. If combination therapy is started at a stage when hyperglycaemia is already marked (after failure of monotherapy), then -cell depletion is likely to be advanced. Under these circumstances, oral combination therapy is likely to offer limited benefit and the need for an early move to insulin treatment is usually clear. Since there are occasional exceptions to this rule, a limited trial of combination oral therapy may be worthwhile. However, the temptation to procrastinate unduly on transferring the patient to insulin treatment should be firmly resisted, not least since some patients derive rapid symptomatic benefit from insulin therapy. Impending metabolic decompensation, with or without ketosis, mandates immediate insulin treatment; more severe degrees of decompensation, for example obtundation, dehydration, ketosis-associated vomiting, necessitates emergency hospitalisation for treatment with intravenous insulin, fluids and electrolytes.
1.1.5 Adverse Events
Hypoglycaemia, usually subclinical or minor but occasionally life threatening, is the most common and potentially most serious adverse effect of sulphonylurea therapy.[23] Patients receiving sulphonylureas should receive instruction on the recognition and prevention of hypoglycaemia and the prompt actions they must take should warning symptoms develop. Severe protracted hypoglyDrugs 2005; 65 (3)
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caemia is more likely with longer-acting sulphonylureas such as glibenclamide, with tolbutamide holding the lowest place in the hierarchy of risk (see also section 1.1.6). Individuals with irregular eating habits (see section 1.2.3) or excessive alcohol consumption are at higher risk of sulphonylurea-induced hypoglycaemia. As mentioned in section 1.1.3, hypoglycaemia is also more likely to occur in patients with satisfactory glycaemic control, as indicated by an HbA1c concentration within, or just above, the non-diabetic reference range. These patients should always be questioned directly about recent symptoms of hypoglycaemia, although their nonspecific nature can raise problems of over-diagnosis; self-monitoring of capillary blood glucose concentrations during suggestive episodes should help to clarify this issue, although uncertainties may not be completely dispelled. If there is continuing doubt, a temporary reduction in dose is usually indicated. Estimates of the incidence of mild hypoglycaemia, that is, not requiring assistance from another individual, are often based on symptoms which have not necessarily been confirmed by contemporaneous self-measurement of capillary blood glucose. In the UKPDS, for example, about 20% of sulphonylurea-treated patients reported one or more episodes suggestive of hypoglycaemia annually; other studies have suggested similar rates.[23] The timing of hypoglycaemia tends to reflect the pharmacokinetics of the sulphonylurea. Thus, glibenclamide has a propensity to cause inter-prandial hypoglycaemia whereas chlorpropamide tends to induce hypoglycaemia in the pre-breakfast period. More severe hypoglycaemia (i.e. requiring assistance) occurred in about 1% of sulphonylurea-treated patients annually in the UKPDS. In general, lower rates (approximately 0.22.5 episodes per 1000 patient-years) have been reported from adverse event reporting to regulatory authorities or from physician-completed questionnaires. The mortality risk from severe sulphonylurea-induced hypoglycaemia has been calculated to be 0.0140.033 per 1000 patient-years.[23] Predictably, longer-acting high-potency agents, such as glibenclamide, appear to carry the greater mortality risk. For comparison, the occurrence of severe hypoglycaemia induced in
patients receiving insulin therapy is orders of magnitude higher. However, this does not detract from the importance of sulphonylurea-induced hypoglycaemia. Minor recurrent hypoglycaemia should prompt a reassessment of the choice of agent and consideration of an alternative secretagogue, for example a rapid-acting insulin releaser (see section 1.2). The treatment schedule, the possibility of drug interactions (table IV) and relevant features of the patients lifestyle, such as diet, meal patterns and alcohol use, should be reviewed. Severe episodes of sulphonylurea-induced hypoglycaemia mandate immediate admission to hospital: treatment with a continuous intravenous infusion of dextrose may be required for several days. There is a tendency for hypoglycaemia to recur shortly after initial resuscitation with intravenous dextrose; the patient should not be prematurely discharged after emergency treatment. Where accumulation of chlorpropamide is suspected, renal elimination may be enhanced by forced alkaline diuresis. The vasodilator diazoxide and the somatostatin analogue octreotide[24] have been used successfully to reversibly inhibit insulin secretion in severe sulphonylurea-induced hypoglycaemia, thereby reducing intravenous dextrose requirements. These drugs should be regarded as potentially useful adjuncts to intravenous glucose in some patients; octreotide avoids the adverse haemodynamic effects of diazoxide, an obsolete antihypertensive agent that may pose a hazard in the elderly patient with compromised cardiovascular reflexes. Other adverse events of sulphonylureas include uncommon sensitivity reactions usually cutaneous that are usually transient; erythema multiforme is rare. Fever, jaundice and blood dyscrasias are very rare; some sulphonylureas can reportedly precipitate acute porphyria in predisposed individuals. In its heyday, chlorpropamide was notorious for causing unpleasant facial flushing after consuming small quantities of alcohol; photosensitivity has also been reported. Chlorpropamide could also increase renal sensitivity to antidiuretic hormone, occasionally causing water retention with hyponatraemia. In contrast, glibenclamide is credited with a mild diuretic action. Weight gain is regarded as a class effect of
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sulphonylurea therapy, typically amounting to 14kg and stabilising after about 6 months. This weight gain, which is always unwelcome, is thought to reflect the anabolic effects of increased plasma insulin concentrations; some studies have suggested that reduced loss of calories as glucose in the urine may account for the majority of the weight gain.[19,21] The saga of the questionable cardiovascular safety of the sulphonylureas was given a nudge by the discovery that cardiac muscle and vascular smooth muscle express isoforms of the SUR2A and SUR2B. Sulphonylureas that contain a benzamido group (glibenclamide, glipizide, glimepiride) can bind to SUR2A and SUR2B,[15] whereas those without (e.g. tolbutamide, chlorpropamide and gliclazide) show very little interaction with the cardiac and vascular SUR receptors. The effects of the KATP channel opener nicorandil (an anti-anginal drug with cardioprotective properties) are blocked by sulphonylureas that have a benzamido group.[15] The clinical implications of these observations remain to be determined. Although very high concentrations of sulphonylureas can cause contraction of cardiac and vascular muscle, this is regarded as being unlikely to be clinically significant effect at therapeutic drug concentrations. Nonetheless, on the basis of adverse clinical experiences in high-risk patients, some high profile authorities continue to advocate that sulphonylurea use be kept to a minimum in patients with overt coronary artery disease.[25]
1.1.6 New Formulations of Sulphonylureas
held to be equivalent to 80mg of unmodified gliclazide. In a recent 6-month comparative multicentre study, gliclazide MR was associated with approximately 50% reduction in episodes of minor hypoglycaemia compared with glimepiride, at similar levels of glycaemic control; no episodes of severe hypoglycaemia were observed with either agent in this study.[26]
1.2 Rapid-Acting Prandial Insulin Releasers
Alterations to the formulation of some sulphonylureas have been undertaken to modify the duration of action.[4] For example, a micronised formulation of glibenclamide is available in the US that increases the rate of gastrointestinal absorption, thereby enabling an earlier onset of action. A longeracting (extended release) formulation of glipizide has also been introduced. A new (modified release [MR]) formulation of gliclazide was launched in some countries in 2002. This formulation has been designed to produce an initially rapid, followed by steady release of the drug to enable once-daily dosage. For the MR formulation of gliclazide, 30mg is
Under experimental conditions the first phase of glucose-stimulated insulin secretion is diminished early in the natural history of type 2 diabetes. The prompt physiological rise in plasma insulin in response to meals is attenuated and its peak delayed. An initial surge of insulin release appears to be particularly important for effective postprandial suppression of hepatic glucose production; failure to suppress endogenous glucose production exacerbates postprandial hyperglycaemia. Because postprandial hyperglycaemia contributes to elevated HbA1c levels it is a logical therapeutic target. Rapidacting prandial insulin releasers are available that stimulate rapid, but short-lived, insulin secretion.[27,28] These agents are taken orally immediately before a meal. Derivatives of meglitinide, such as repaglinide and the phenylalanine derivative nateglinide, are promoted as prandial glucose regulators; in fact, fasting hyperglycaemia is also improved to a lesser extent, particularly with repaglinide. Clinical experience with these agents remains limited in most countries; these drugs are appreciably more expensive than most sulphonylureas, the latter also having the reassurance of outcome data from the UKPDS.
Benzamido prandial insulin releasers bind to the SUR1 in the plasma membrane of the cell at a site distinct from the sulphonylurea binding site (figure 2). Since the KATP channel is closed when either the benzamido binding site or the sulphonylurea binding site on the SUR1 is bound with its respective agonist, there is no advantage in giving a prandial insulin releaser in addition to a sulphonylurea. However, drugs are also in development that promote Drugs 2005; 65 (3)
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cell proinsulin synthesis and act via signalling pathways distinct from the KATP channel (figure 2). The short half-life of repaglinide results in enhancement of the first-phase and early second-phase of insulin secretion that is less sustained than that observed with sulphonylureas.[27-29] Theoretical benefits on cardiovascular outcomes from preferentially targeting the postprandial period remain to be confirmed.[28,29] It is unclear whether postprandial hyperglycaemia per se is detrimental to the vascular endothelium or whether closely associated metabolic disturbances, for example dyslipidaemia, are responsible. Thus, the mechanism of the association between post-challenge hyperglycaemia and mortality observed in the multicentre DECODE (Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe) study is uncertain.[30] Randomised trials that are currently in progress should help clarify this issue.
Repaglinide is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations achieved in about 1 hour.[27] The drug is rapidly metabolised in the liver to inactive metabolites, which are mainly excreted in bile. When taken about 15 minutes before a meal, repaglinide produces a prompt insulin-releasing effect, which is limited to a period of about 3 hours, roughly coinciding with the duration of meal digestion. Nateglinide has a slightly faster onset and shorter duration of action, its binding to target receptors lasting only seconds. A 60mg dose of nateglinide taken 20 minutes before an intravenous glucose tolerance test restored first-phase insulin release and lowered glucose concentrations.[28,29]
daily dosages is a potential disincentive. Repaglinide should ideally be taken about 1530 minutes before a meal. Starting with a low dose, for example 0.5mg before each main meal, the effect on glycaemic control is monitored and the dosage titrated up every 2 weeks to a maximum of 4mg before each main meal; if a meal is not consumed the corresponding dose of repaglinide should be omitted. If glycaemic targets are not met, consider early introduction of combination therapy (e.g. with metformin). Unlike some sulphonylureas and metformin, repaglinide is suitable for patients with moderate renal impairment, although careful upward dose titration and close monitoring is still recommended. In contrast with the US, the UK license for nateglinide currently restricts use to combination therapy with metformin in patients who do not achieve glycaemic targets with the latter drug as monotherapy.[29] In the US, nateglinide may also be used as monotherapy or combined with a thiazolidinedione. Nateglinide should be used with caution in patients with hepatic disease.
1.2.4 Efficacy
Repaglinide (0.54mg taken about 1530 minutes before meals) results in dose-dependent increases in insulin secretion with reduced postprandial hyperglycaemia; a lesser reduction in fasting hyperglycaemia is also observed. Overall reductions in HbA1c are similar in magnitude to those observed with sulphonylureas, that is 12%. Combined with metformin, nateglinide reduces HbA1c by up to 1.5%.[28,29]
1.2.5 Adverse Events
Repaglinide may be used as monotherapy in patients inadequately controlled by nonpharmacological measures. Suitable candidates for rapid-acting insulin releasers include individuals with irregular lifestyles wherein meals are unpredictable or missed. The lower risk of hypoglycaemia associated with its use makes repaglinide an attractive option for some elderly patients, particularly if other agents are contraindicated. However, the need for multiple
The overall incidence of hypoglycaemic episodes is lower with repaglinide than with sulphonyureas. Sensitivity reactions, usually transient, can occur. Increased plasma levels of repaglinide have been reported when co-administered with gemfibrozil. A small increase in bodyweight can be expected in patients starting repaglinide as initial monotherapy, but there may be little change in weight among patients switched from a sulphonylurea. Nateglinide appears to have little effect on bodyweight when combined with metformin.[29]
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Intestinal lumen
Brush border
Starch -Amylase Sucrose Maltose maltotriose dextrins -Glucosidase inhibitor (acarbose, miglitol, voglibose) -Glucosidase enzymes
Enterocyte Microvillus Villus
Fig. 3. -Glucosidase inhibitors (e.g. acarbose) competitively inhibit the activity of -glucosidase enzymes in the brush border of small intestinal enterocytes (reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press).
2. -Glucosidase Inhibitors Inhibitors of intestinal -glucosidase enzymes retard the rate of carbohydrate digestion, thereby providing an alternative means to reduce postprandial hyperglycaemia.[31] Acarbose, the first glucosidase inhibitor to be marketed, was introduced in the early 1990s. Recently, two additional agents, miglitol and voglibose, have been introduced in some countries.[4] The -glucosidase inhibitors do not cause weight gain, can reduce postprandial hyperinsulinaemia and have lowered plasma triglyceride concentrations in some studies.[31] Their good safety record is a further advantage, but limited gastrointestinal tolerability has substantially limited their use. The relatively high cost of -glucosidase inhibitors is another consideration that has influenced prescribing. In the UK, acarbose use remains low.
2.1 Mode of Action
carbohydrate digestion until further along the intestinal tract, in turn causing glucose absorption to be delayed. The -glucosidase inhibitors should be taken with meals containing digestible carbohydrates, not monosaccharides; these drugs generally do not significantly affect the absorption of glucose. Since -glucosidase inhibitors move glucose absorption more distally along the intestinal tract they alter glucose-dependent release of intestinal hormones that enhance nutrient-induced insulin secretion. Release of gastric inhibitory polypeptide, which occurs mainly from the jejunal mucosa, may be reduced by -glucosidase inhibitors, whereas glucagon-like peptide-1 (736 amide) secretion (mostly from the ileal mucosa) is increased. Overall, -glucosidase inhibitors reduce postprandial insulin concentrations through the attenuated rise in postprandial glucose levels.[31]
2.2 Pharmacokinetics
The -glucosidase inhibitors competitively inhibit the activity of -glucosidase enzymes in the brush border of enterocytes lining the intestinal villi (figure 3). High affinity binding prevents these enzymes from cleaving their normal disaccharide and oligosaccharide substrates into monosaccharides prior to absorption. This defers the completion of
Acarbose is absorbed only to a trivial degree (<2%).[31] The drug is degraded by amylases in the small intestine and by intestinal bacteria; some of these degradation products are systemically absorbed, subsequently to be eliminated in the urine over about 24 hours.
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2.3 Indications and Contraindications
An -glucosidase inhibitor may be used as monotherapy for patients with type 2 diabetes that is inadequately controlled by nonpharmacological measures. Because -glucosidase inhibitors target postprandial hyperglycaemia, they can be a useful first-line treatment in patients who have a combination of only slightly raised basal glucose concentrations and more marked postprandial hyperglycaemia. A recent multicentre clinical trial (STOPNIDDM [Study TO Prevent NonInsulin-Dependent Diabetes Mellitus]) confirmed the utility of acarbose in preventing the transition from impaired glucose tolerance to diabetes[32] (see section 2.4). Acarbose can be used in combination with other antidiabetic agents. When starting therapy with an -glucosidase inhibitor it is said to be important to ensure that the patient is taking a diet rich in complex carbohydrates, as opposed to simple sugars. Acarbose should be taken with meals, starting with a low dose, for example 50 mg/day, and slowly titrating up over several weeks. Monitoring of glycaemic control, particularly postprandially, may be helpful. The postprandial action of these agents would not be expected to induce hypoglycaemia, at least when they are used as monotherapy. The maximum dosage of -glucosidase inhibitors may be limited by gastrointestinal symptoms; this is certainly our experience with acarbose (see section 2.5). Intuitively, patients experiencing gastrointestinal adverse effects with metformin may not be the best candidates in whom to add an -glucosidase inhibitor. A history of chronic intestinal disease serves as a largely theoretical contraindication to acarbose and other agents in this class. High dosages of acarbose can occasionally increase liver enzyme concentrations, and it is recommended that transaminase concentrations are measured at intervals in patients receiving the maximum dosage (200mg three times daily in the UK, a dosage rarely attained in practice for the aforementioned reasons). If liver enzymes are raised, the dosage of acarbose should be reduced to a level at which normal enzyme concentrations are re-established. Alternative causes of hepatic dysfunction should be considered. Pregnancy and
breast-feeding are traditionally regarded to be contraindications for all oral antidiabetic drugs, mainly because of a lack of safety data rather than evidence of detrimental effects.
2.4 Efficacy
An -glucosidase inhibitor can reduce peak concentrations of blood glucose and reduce interprandial troughs. Used as monotherapy to patients who comply appropriately with dietary advice, an glucosidase inhibitor will typically reduce postprandial glucose concentrations by 14 mmol/L. The incremental area under the postprandial plasma glucose curve can be more than halved in some individuals. There seems to be a carry-over effect that may produce a reduction in basal glycaemia up to 1 mmol/L. The decrease in HbA1c is usually about 0.51.0%, provided that a high dose of the drug is tolerated and dietary compliance is maintained.[33] There may be a trivial alteration in the gastrointestinal absorption of other oral antidiabetic agents when used in combination therapy. In general, the extra benefit to glycaemic control achieved by addition of an -glucosidase inhibitor to another antidiabetic agent is additive. In the recently published multicentre STOP-NIDDM trial acarbose reduced the risk of progression from impaired glucose tolerance to type 2 diabetes (relative hazard 0.75; 95% CI 0.63, 0.90; p = 0.0015).[32] This study randomised 1429 patients with impaired glucose tolerance to acarbose 100mg three times daily or placebo, of whom data were available for a modified intention-to-treat analysis in 1368 patients. Glucose tolerance was determined using a 75g oral glucose tolerance test. Intriguingly, new cases of hypertension and major cardiac events, including overt and clinically silent myocardial infarction, were also reduced by acarbose therapy.[34] The latter were not primary endpoints of the study, a limitation acknowledged by the investigators.[34] The results of ongoing trials using acarbose and other agents in this class are awaited.[35]
2.5 Adverse Effects
The most common problems with -glucosidase inhibitors are gastrointestinal adverse effects. In the
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STOP-NIDDM trial 31% of acarbose-treated patients compared with 19% on placebo discontinued treatment early.[32] If the dosage is too high (relative to the amount of complex carbohydrate in the meal), undigested oligosaccharides pass into the large bowel.[23] Carbohydrates fermented by the flora of the large bowel cause flatulence, abdominal discomfort and sometimes diarrhoea. This is most likely to occur during the initial titration of the drug and can sometimes be minimised by slow titration and by ensuring dietary compliance with meals rich in complex carbohydrate. In some patients the gastrointestinal symptoms may gradually subside with time, suggesting an adaptive response within the gastrointestinal tract. Hypoglycaemia is only likely to be encountered when an -glucosidase inhibitor is used in combination with a sulphonylurea or insulin.[23] No clinically significant drug interations have been reported. However, agents affecting gut motility can potentially influence the efficacy and gastrointestinal effects of acarbose; cholestyramine may increase the glucose-lowering effect of acarbose. 3. Insulin Sensitisers Insulin resistance is a prominent metabolic defect in most patients with type 2 diabetes.[36,37] Defective insulin action is not confined to glucose metabolism, subtle defects also being demonstrable in the regulation of other aspects of intermediary metabolism (e.g. lipolysis), using appropriate investigative techniques. Many cross-sectional and prospective studies have implicated insulin resistance in the pathogenesis of type 2 diabetes and the related metabolic syndrome of cardiovascular risk.[38] Therefore, defective insulin action at target tissue level is an attractive therapeutic target in type 2 diabetes.[39] The biguanides and, in particular, the thiazolidinediones act directly against insulin resistance, and so are regarded as insulin sensitising drugs.
3.1 Biguanides
guanidine derivatives in the 1920s. These early antidiabetic agents were all but forgotten as insulin became widely available and it was not until the late 1950s that three antidiabetic biguanides were reported: metformin, phenformin and buformin. Phenformin was withdrawn in many countries in the 1970s because of a high incidence of lactic acidosis; buformin received limited use in a few countries, leaving metformin as the main biguanide on a global basis. Metformin is the only biguanide available in the UK and, since 1995, the US.[23,40] Extensive clinical experience with metformin has been complemented by favourable results from the UKPDS. Metformin also enjoys the accolade of being among the least expensive of the oral antidiabetic agents.
Metformin has a variety of metabolic effects, some of which may confer clinical benefits that extend beyond glucose lowering (table V). However, the molecular mechanisms of metformin have yet to be fully identified. At the cellular level, metformin improves insulin sensitivity to some extent, an action mediated via post-receptor signalling pathways for insulin.[41,42] Recent data have suggested that adenosine 5-monophosphate-activated protein
Table V. Metabolic and vascular effects of metformin Anti-hyperglycaemic action suppresses hepatic glucose output increases insulin-mediated glucose utilisation decreases fatty acid oxidation increases splanchnic glucose turnover Weight stabilisation or reduction Improves lipid profile reduces hypertriglyceridaemia lowers plasma fatty acids and LDL-cholesterol; raises HDLcholesterol in some patients No risk of serious hypoglycaemia Counters insulin resistance decreases endogenous or exogenous insulin requirements reduces basal plasma insulin concentrations Vascular effects increased fibrinolysis decreases PAI-1 levels improved endothelial function HDL = high-density lipoprotein; LDL = low-density lipoprotein; PAI-1 = plasminogen activator inhibitor-1.
The finding that Galega officinalis (goats rue or French lilac), historically used as a traditional treatment for diabetes in Europe, was rich in guanidine led to the introduction of several glucose-lowering
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Metformin
Intestine Anaerobic glucose metabolism Glucose uptake and oxidation
Fat
Lactate
Fatty acids
Glyconeogenesis Glycogenesis Oxidation of FA
Glucose uptake and oxidation Glycogenesis Oxidation of FA
Liver
Muscle
Hepatic glucose production
Insulin-mediated glucose disposal
Blood glucose concentration Fig. 4. Actions of metformin. Inhibition of hepatic glucose production is regarded as the principal mechanism through which metformin lowers blood glucose (reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press). FA = fatty acids; indicates increase; indicates decrease.
kinase (AMPK) is a possible intracellular target of metformin.[43] Through phosphorylation of key proteins, AMPK acts as a regulator of glucose and lipid metabolism and cellular energy regulation.[44] Since metformin lowers blood glucose concentrations without causing overt hypoglycaemia it is most appropriately classed as an anti-hyperglycaemic as distinct from hypoglycaemic agent. The clinical efficacy of metformin in patients with type 2 diabetes requires the presence of insulin. The drug does not stimulate insulin release and a small decrease in fasting insulin concentrations is typically observed in patients with hyperinsulinaemia.[21] The predomi 2005 Adis Data Information BV. All rights reserved.
nant glucose-lowering mechanism of action of metformin is to reduce excessive rates of hepatic glucose production. Metformin reduces gluconeogenesis by increasing hepatic sensitivity to insulin (figure 4) and decreasing the hepatic extraction of certain gluconeogenic substrates (e.g. lactate). Hepatic glycogenolysis is also decreased by metformin. Insulin-stimulated glucose uptake in skeletal muscle is enhanced by metformin. This involves an increase in the movement of insulin-sensitive glucose transporter molecules to the cell membrane; an increase in the activity of the enzyme glycogen synthase promotes synthesis of glycogen. Metformin also
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acts in an insulin-independent manner to suppress oxidation of fatty acids and to reduce triglyceride levels in patients with hypertriglyceridaemia.[19] This reduces the energy supply for hepatic gluconeogenesis and has favourable effects on the glucose-fatty acid (Randle) cycle (in which fatty acids are held to compete with glucose as a cellular energy source).[37] Glucose metabolism in the splanchnic bed is increased by metformin through insulin-independent mechanisms. This may contribute to the blood glucose-lowering effect of the drug, and in turn may help to prevent gains in bodyweight. Collectively, the cellular effects of metformin serve to counter insulin resistance and to reduce the putative toxic metabolic effects of hyperglycaemia (glucose toxicity) and fatty acids (lipotoxicity) in type 2 diabetes.
other class of oral antidiabetic agent or with insulin. The drug is contraindicated in patients with impaired renal function (i.e. serum creatinine >120130 mol/L, depending on lean body mass), as a precaution against drug accumulation. Cardiac or respiratory insufficiency, or any other condition predisposing to hypoxia or reduced perfusion (e.g. hypotension, septicaemia) are further contraindications, as well as liver disease, alcohol abuse and a history of metabolic acidosis. Metformin can be used in the elderly, provided that renal insufficiency and other exclusions are not present. A difficulty in practice is that significant renal dysfunction may be present without the aforementioned elevation of serum creatinine. The improvement in insulin sensitivity can cause ovulation to resume in cases of anovulatory polycystic ovary syndrome (PCOS) [an unlicensed application of the drug in the absence of diabetes].[45] Metformin should be taken with meals or immediately before meals to minimise possible gastrointestinal adverse effects. Treatment should be started with 500 or 850mg once daily, or 500mg twice daily (one tablet with the morning and evening meals). The dosage is increased slowly one tablet at a time at intervals of about 2 weeks until the target level of glycaemic control is attained. If the target is not attained and an additional dose produces no greater effect, return to the previous dose and, in the case of monotherapy, consider combination therapy by adding in another agent (e.g. a sulphonylurea, prandial insulin releaser or thiazolidinedione). The maximal effective dosage appears to be about 2000 mg/day, given in divided doses with meals, the absolute maximum being 2550 or 3000 mg/day in different countries. Several single tablet combinations of a sulphonylurea (usually glibenclamide) with a biguanide (metformin or phenformin) have been available in some European countries and elsewhere for more than a decade. A slow-release formulation of metformin and a fixed-dose combination of metformin with glibenclamide is available in the US (Glucovance, Bristol-Myers Squibb Company,
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Metformin is a stable hydrophilic biguanide that is quickly absorbed and eliminated unchanged in the urine. It is imperative that metformin is only prescribed to patients with renal function that is sufficient to avoid accumulation of the drug. Renal clearance of metformin is achieved more by tubular secretion than glomerular filtration, the only significant drug interaction being competition with cimetidine, which can increase plasma metformin concentrations. There is little binding of metformin to plasma proteins. Metformin is not metabolised, and so does not interfere with the metabolism of coadministered drugs. Metformin is widely distributed, high concentrations being retained in the walls of the gastrointestinal tract; this provides a reservoir from which plasma concentrations are maintained. Nevertheless, peak plasma metformin concentrations are short-lived: in patients with normal renal function the plasma half-life (t1/2) for metformin is 25 hours, and almost 90% of an absorbed dosage is eliminated within 12 hours.[40]
Metformin is the therapy of choice for overweight and obese patients with type 2 diabetes.[42] It can be equally effective in normal weight patients. Metformin can also be used in combination with any
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Princeton, NJ, USA)1 and elsewhere (although not in the UK). A combined rosiglitazone/metformin (Avandamet, GlaxoSmithKline, Philadelphia, PA, USA) [see section 3.2] preparation is also available in some parts of the world. During long-term treatment with metformin it is advisable to check (e.g. annually) for the development of contraindications, particularly an elevated serum creatinine concentration (yearly measurement of creatinine clearance posing practical difficulties). Metformin can reduce gastrointestinal absorption of cyanocobalamin (vitamin B12). While anaemia is very rare, an annual haemoglobin measurement is prudent in patients at risk of nutritional deficiencies. It is advised to stop metformin treatment temporarily during use of intravenous radiographic contrast media, surgery and any other intercurrent situation in which the exclusion criteria could be invoked.[46] Substitution with insulin may be appropriate at such times. Metformin alone is unlikely to cause serious hypoglycaemia, but hypoglycaemia becomes an issue when metformin is used in combination with an insulin-releasing agent or insulin.
3.1.4 Efficacy
The long-term blood glucose-lowering efficacy of metformin is broadly similar to sulphonylureas. As monotherapy in patients who are not adequately controlled on nonpharmacological therapy, optimally titrated metformin therapy typically reduces fasting plasma glucose by 24 mmol/L, corresponding to a decrease in HbA1c by approximately 12%.[40] The effect is dependent upon the presence of some endogenous -cell function, and is largely independent of bodyweight, age and duration of diabetes. However, given the progressive nature of type 2 diabetes, re-assessment of dosage and consideration of additional therapy are required to maintain glycaemic control in the long term.[4,21] Metformin has several features that mark it out as a good choice for first-line monotherapy. The anti-hyperglycaemic action of metformin means that it is unlikely to cause severe hypoglycaemia. This may be explained in part because metformin does not stimulate insulin
1
secretion. Indeed, the reduction of basal insulin concentrations, notably in hyperinsulinaemic patients, should itself improve insulin sensitivity by relieving the insulin-induced downregulation of insulin receptor number and suppression of post-receptor insulin pathways.[35] Bodyweight tends to stabilise or decrease slightly during metformin therapy. Small improvements in the blood lipid profile may be observed in hyperlipidaemic patients; plasma concentrations of triglycerides, fatty acids and low-density lipoprotein (LDL)-cholesterol tend to fall, whereas cardioprotective HDL-cholesterol tends to rise. These effects appear to be independent of the antihyperglycaemic effect, although a lowering of triglyceride and free fatty acids is likely to help improve insulin sensitivity and benefit the glucose-fatty acid cycle. In the UKPDS, overweight patients who started oral antidiabetic therapy with metformin showed a statistically significant 39% reduced risk of myocardial infarction compared with conventional treatment (p = 0.01).[47] No clear relationship is evident between metformin dosage and decreased coronary artery events. This suggests that patients who can only tolerate a low dosage of metformin may benefit from continuing the drug, even when other agents have to be added to optimise glycaemic control. The decrease in myocardial infarction observed with metformin therapy in the UKPDS was not attributable to more effective lowering of HbA1c or major effects on classic cardiovascular risk factors such as plasma lipids. Consequently, other potentially vasoprotective effects of metformin have been invoked. Reported benefits of metformin on non-classic cardiovascular risk factors (table V) include increased fibrinolysis and a reduced concentration of the anti-thrombolytic factor plasminogen activator inhibitor-1 (PAI-1).[41,46] The mechanism of the cardioprotective effects of metformin remains uncertain. Detracting somewhat from this generally favourable view was evidence of an initially greater mortality when metformin was added to a sulphonylurea in a UKPDS substudy,[47] but longer-term follow-up has shown the benefits of metformin to be
The use of trade names is for product identification purposes only and does not imply endorsement.
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sustained.[48] The explanation may have been, at least in part, a spuriously low mortality rate in the comparator sulphonylurea monotherapy group.[47,49] The small number of events in this substudy adds to the uncertainty. Sulphonylurea plus metformin is a commonly used combination and it would be reassuring to have definitive safety data. Since each class as monotherapy appears safe from the cardiovascular perspective, alternative explanations have been postulated to explain similar findings seen in observational studies.[49] One plausible confounder might be greater cardiovascular risk attributable to more severe metabolic derangements in patients treated with the combination. Results from US trials and various large databases of follow-up with sulphonylurea plus metformin combination therapy have been reassuring.[21,49,50] Additional well designed comparative studies of appropriate statistical power would be required to quantify the risk to benefit equation for combination treatment with sulphonylurea plus metformin. However, recent results from the 5-year follow-up of UKPDS with no further attempt to continue in randomised groups show that the adverse impact of sulphonylurea plus metformin combination seen initially is no longer evident.[48] At this point, the aforementioned benefits observed on mortality and cardiovascular disease in overweight patients initially randomised to metformin monotherapy, while diminished, remained significant. Consistent with the action of metformin on insulin sensitivity, addition of metformin to patients receiving insulin therapy may necessitate a reduction of insulin dosage. Some patients also show an improvement in glycaemic control, although this is not always impressive. Metformin reduces the weight gain associated with insulin therapy and, by decreasing the insulin dosage, there may be a decrease in hypoglycaemic episodes. The regimen has usually involved once-daily bedtime long-acting (lente) insulin or twice-daily insulin suspension isophane with metformin at mealtimes. In the US Diabetes Prevention Program, metformin reduced the incidence of new cases of diabetes in overweight and obese patients with impaired glucose tolerance
by 33% overall. This compares with an intensive regimen of diet and exercise, which reduced the risk by 58%.[51] Younger, more obese individuals showed the most response to the preventive effects of metformin.
3.1.5 Adverse Effects
Abdominal discomfort and other gastrointestinal adverse effects, including diarrhoea, are encountered fairly commonly during the introduction of metformin. Symptoms may remit if the dose is reduced and re-titrated slowly, but about 10% of patients cannot tolerate the drug at any dose. The most serious feared adverse event associated with metformin is lactic acidosis; the occurrence is rare (about 0.03 cases per 1000 patient-years), but the mortality rate is high.[14,38] Since the background incidence of lactic acidosis amongst type 2 diabetic patients has not been established, it is possible that a proportion of cases that have been attributed to the drug were caused by other factors; this remains an area of controversy. Most cases of lactic acidosis in patients receiving metformin are due to inappropriate prescription of the drug.[23,40,46,52] The leading contraindication is renal insufficiency.[52] Metformin increases glycolysis to lactate, particularly in the splanchnic bed. The situation will be aggravated by any hypoxic condition or impaired liver function.[53] Hyperlactataemia occurs in cardiogenic shock and other illnesses that decrease tissue perfusion, and metformin is often only an incidental factor in these cases.[54] In the absence of reliable data to the contrary, metformin treatment should be stopped immediately in all cases of suspected or proven lactic acidosis, regardless of cause. Lactic acidosis is typically characterised by a raised blood lactate concentration (e.g. >5 mmol/L), decreased arterial pH and/ or bicarbonate concentration with an increased anion gap ([Na+] [Cl + HCO3] >15 mmol/L). Presenting symptoms are often nonspecific, but frequently include hyperventilation, malaise and abdominal discomfort. Treatment should be commenced immediately without waiting to determine whether metformin is a cause; bicarbonate remains the therapy of choice but evidence of its efficacy is scanty. The value of haemodialysis in removing accumulatDrugs 2005; 65 (3)
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ed metformin has been challenged by some authorities, but dialysis may nonetheless be helpful in optimising fluid and electrolyte balance during treatment with high-dose intravenous bicarbonates.[54]
3.2 Thiazolidinediones
Table VI. Metabolic effects of thiazolidinediones[55] Adipose tissue Glucose uptake Lipogenesis Muscle Glucose uptake Glucose oxidation Liver Gluconeogenesis Glycogenolysis Lipogenesis Glucose uptakea
Fatty acid uptake Glycolysis Pre-adipocyte Glycogenesisa differentiation a Inconsistent findings. indicates increase; indicates decrease.
Thiazolidinediones improve whole-body insulin sensitivity via multiple actions on gene regulation. These effects result from stimulation of a nuclear receptor peroxisome proliferator-activated receptor (PPAR), for which thiazolidinediones are potent synthetic agonists.[55] The antidiabetic activity of thiazolidinediones was described in the early 1980s, troglitazone being the first of the class to become available for clinical use. Troglitazone was introduced in the US in 1997, only to be withdrawn in 2000 because of cases of idiosyncratic hepatotoxicity resulting in fatalities. Troglitazone was available in the UK for only for a few weeks in 1997 before being withdrawn by its distributor as reports of hepatotoxicity accumulated in other countries. To date, two other thiazolidinediones, rosiglitazone and pioglitazone, have not shown the hepatotoxicity that led to the demise of troglitazone. Rosiglitazone and pioglitazone were introduced in the US in 1999 and in Europe in 2000.[56] Combination preparations (e.g. thiazolidinedione plus metformin) are also available.
Stimulation of PPAR is regarded as the principal mechanism through which thiazolidinediones enhance insulin sensitivity. PPAR is expressed at highest levels in adipose tissue, and less so in muscle and liver. PPAR operates in association with the retinoid X receptor. The resulting heterodimer binds to nuclear response elements, thereby modulating transcription of a range of insulin-sensitive genes, in the presence of necessary cofactors (figure 4).[55,57] Many of the genes activated or suppressed by thiazolidinediones are involved in lipid and carbohydrate metabolism (table VI). Stimulation of PPAR by a thiazolidinedione promotes differentiation of pre-adipocytes with accompanying lipogenesis, effects that promote or enhance the local effects of insulin. Thiazolidinediones increase
glucose uptake via glucose transporter-4 in skeletal muscle, and some reports indicate that rates of gluconeogenesis in the liver are reduced. Stimulation of lipogenesis via PPAR reduces circulating non-esterified fatty acid (NEFA) concentrations through cellular uptake and triglyceride synthesis (figure 5). The reduction in plasma NEFA concentrations is associated with increased glucose utilisation and reducing gluconeogenesis by reducing operation of the glucose-fatty acid cycle; reductions in ectopic lipid deposition in muscle and liver may contribute to the improvements on glucose metabolism. Thiazolidinediones also reduce the production and activity of the adipocyte-derived cytokine tumour necrosis factor (TNF)-.[55] The latter has been implicated in the development of impaired insulin action in muscle,[58] although the precise role of TNF in human states of insulin resistance remains unclear. Reductions in plasma insulin concentrations and lowering of circulating triglycerides are additional indirect mechanisms that may help to improve whole-body insulin sensitivity. Thiazolidinediones, like metformin, are anti-hyperglycaemic agents and require the presence of sufficient insulin to generate a significant blood glucose-lowering effect.
Rosiglitazone and pioglitazone are rapidly, and nearly completely absorbed (12 hours to peak concentration), although absorption is slightly delayed when taken with food. Both agents are extensively metabolised by the liver. Rosiglitazone is metabolised mainly to very weakly active metabolites with lesser activity that are excreted predominantly in the urine. The metabolites of pioglitazone are more active and excreted mainly in the bile. Metabolism of rosiglitazone is undertaken mainly by cytoDrugs 2005; 65 (3)
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chrome P450 (CYP) 2C8, which is not a widely activated isoform of CYP.[59] Thus, rosiglitazone does not interfere with the metabolism of other drugs. Pioglitazone is metabolised in part by CYP3A4 but, to date, no clinically significant reductions in plasma concentrations of other drugs (e.g. oral contraceptives) has been reported. Although both thiazolidinediones are almost completely bound to plasma proteins, their concentrations are low and have not been reported to interfere with other protein-bound drugs.
In the US, rosiglitazone and pioglitazone are available for use as monotherapy in non-obese and obese patients with type 2 diabetes in whom diabetes is not adequately controlled by nonpharmacological measures. They can also be used in combination with various other antidiabetic drugs and in combination with insulin. In Europe, rosiglitazone and pioglitazone can be used as monotherapy if the patient is contraindicated for or intolerant of metformin. Thiazolidinediones can be used in combination with metformin or a sulphonylurea. In Europe, combination with insulin remains a contraindication to
Thiazolidinedione Glucose
thiazolidinediones.[60] Substituting a thiazolidinedione for either a sulphonylurea or metformin in patients with inadequate glycaemic control is generally of limited value and risks a temporary deterioration in glycaemic control because of the slow onset of action of thiazolidinediones. Having been disappointed with this experience, some UK diabetologists have elected to use thiazolidinediones in combination with both a sulphonylurea and metformin.[60] The former strategy has met with variable success: some patients respond well, others show little response, requiring transfer to insulin. The combination of thiazolidinedione plus insulin can improve glycaemic control while reducing insulin dosages in obese patients, although peripheral oedema has been reported.[61] The main cautions to using thiazolidinediones are listed in table VII. Rosiglitazone and pioglitazone can cause fluid retention with increased plasma volume, a reduced haematocrit and a decrease in haemoglobin concentration. Therefore, the risk of oedema and anaemia should be taken into account, and in Europe, use of thiazolidinediones in patients with any evidence of congestive heart disease or
Fatty acids
GLUT-4
FATP
Glucose uptake and utilisation
aP2, acylCoA synthase
PPAR
RXR
Lipogenesis and adipocyte differentiation Hydrolysis of circulating triglycerides in chylomicrons and VLDL
Transcription of certain insulin-sensitive genes
Lipoprotein lipase
Adipocyte Fig. 5. Mechanism of action of a thiazolidinedione on an adipocyte (reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press). aP2 = adipocyte fatty acid binding protein; CoA = coenzyme A; FATP = fatty acid transporter protein; GLUT-4 = glucose transporter-4; PPAR = peroxisome proliferator-activated receptor-; RXR = retinoid X receptor; VLDL = very low-density lipoproteins; indicates increase.
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Table VII. Cautions in the use of thiazolidinediones Active liver disease This remains a contraindication to the use of thiazolidinediones even though neither rosiglitazone nor pioglitazone have been associated with troglitazone-like hepatotoxicity. In fact, the latter drugs are under investigation as a potential treatment for nonalcoholic steatohepatitis. In 2004, the US FDA recommendation for 2-monthly monitoring of biochemical liver function tests was relaxed. Instead, periodic biochemical monitoring is now left to the supervising clinicians discretion Heart failure The precise contraindications differ between countries. In Europe, current heart failure or a history of heart failure are contraindications to thiazolidinediones Insulin treatment Although rosiglitazone and pioglitazone are licensed in the US for use in combination with insulin, caution is required. Concerns about higher rates of heart failure underlie this concern. The European Agency for the Evaluation of Medicinal Products considers insulin therapy a contraindication to the use of thiazolidinediones Pregnancy and breast-feeding Thiazolidinediones are classified as pregnancy category C because of growth retardation in mid-to-late gestation in animal models. These drugs should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus Polycystic ovary syndrome Thiazolidinediones can cause ovulation to recommence in women with hyperandrogenism and chronic anovulation; risk of pregnancy
is some evidence for a modest blood pressure-lowering effect.[63] As a precautionary measure, liver function should be assessed by measuring serum ALT before starting therapy and subsequently at 2-monthly intervals (or, in the US, as judged necessary by the prescribing clinician) during the first year of treatment; thereafter, periodic monitoring of liver function is prudent. Pre-existing liver disease, the development of clinical hepatic dysfunction or elevated ALT levels >2.5 times the upper limit for the laboratory serve as contraindications to thiazolidinediones. However, as mentioned earlier, hepatotoxicity has not been a concern with either rosiglitazone or pioglitazone. Isolated cases of nonfatal hepatocellular damage have been reported; however, the issue is clouded by reports suggesting an intrinsically higher risk of liver failure in patients with type 2 diabetes. Nevertheless, precautionary monitoring of liver function remains advisable. When initiating therapy with rosiglitazone or pioglitazone, blood glucose monitoring and titration of drug dosage should be undertaken while bearing in mind that thiazolidinediones exert a slowly generated anti-hyperglycaemic effect that usually requires 23 months to reach maximum effect. According to the EU license, rosiglitazone can be given at a dosage of 4 mg/day in combination with a sulphonylurea, increasing to 8 mg/day (either once daily or in divided doses) in combination with metformin. Pioglitazone can be given as a once-daily dosage of 15mg, increasing to 30mg if necessary (maximum 45mg in the US and Europe). The therapeutic response varies markedly between patients and it can be difficult to predict those most likely to respond. If no effect is observed after 3 months it is appropriate to consider the patient as a nonresponder and to stop the treatment. Rosiglitazone and pioglitazone can be used in the elderly, provided there are no contraindications. Both drugs may be used in patients with mild-to-moderate renal impairment, although the potential for oedema is a concern. In women with anovulatory PCOS the improvement in insulin sensitivity may cause ovulation to resume during thiazolidinedione therapy. A combination
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heart failure is contraindicated. The choice of which patients to exclude on the basis of cardiac status varies between the product labelling sheets in the US and Europe. Consensus guidelines from the American Heart Association and the American Diabetes Association have recently been published.[62] Patients treated with a combination of insulin plus thiazolidinedione appear to be at highest risk of oedema, although the absolute rate of cardiac failure is low despite the fact the diabetes is a major risk factor for this complication.[62] The guidelines urge a cautious approach and careful clinical monitoring, especially for patients likely to be at higher risk of cardiac failure. The haemogloblin concentration should be checked before starting a thiazolidinedione, bearing in mind that reductions of up to 1 g/ dL in haemoglobin concentration may occur during therapy. No adverse effects on blood pressure have been noted with the thiazolidinediones, even with the increase in plasma volume; on the contrary, there
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preparation containing rosiglitazone plus metformin (Avandamet; combining rosiglitazone/metformin in strengths 1mg/500mg, 2mg/500mg, 4mg/500mg, 2mg/1000mg, although not all strengths are available in all countries).
3.2.4 Efficacy
Addition of rosiglitazone or pioglitazone to the treatment schedule of patients whose glycaemic control with a sulphonylurea or metformin is suboptimal has consistently resulted in significant reductions in HbA1c. As judged by the available literature, these agents have similar glucose-lowering effects, reducing HbA1c by around 0.51.5%.[64] However, the participants in these clinical trials had known diabetes of several years duration, the effects of thiazolidinediones being more apparent when -cell function is less impaired. While earlier use of thiazolidinediones may be advantageous, the longerterm picture requires clarification. Estimates of insulin sensitivity and -cell function (based on analysis of fasting glucose and insulin concentrations) have indicated that both defects can be improved by the addition of a thiazolidinedione.[64] The effects on plasma lipids and apoproteins have been the subject of debate. Rosiglitazone can cause a small rise in the total cholesterol concentration, which stabilises within about 3 months. This is accounted for by a rise in both the LDL-cholesterol and the HDL-cholesterol, leaving the LDL : HDL-cholesterol ratio and the total : HDL-cholesterol ratio little changed or slightly raised. Pioglitazone generally appears to have little effect on total cholesterol, and has been shown to reduce triglyceride concentrations in several studies. Both thiazolidinediones reduce the proportion of the smaller, more dense (more atherogenic) LDL particles.[64] To date, no prospective comparative studies of the two drugs have been reported and the clinical implications of these changes are uncertain.[63] Weight gain, similar in magnitude to sulphonylurea therapy (typically 14kg) and stabilising over 612 months, has been observed during thiazolidinedione therapy. There is some evidence that the distribution of body fat is altered such that visceral adipose depots are little changed or reduced, while
subcutaneous depots increase as new small, insulinsensitive adipocytes are formed. There are provisional data to suggest that thiazolidinediones exert a range of effects on aspects of the metabolic syndrome that might reduce the risk of atherosclerotic cardiovascular disease.[63,65] For example, thiazolidinediones have been reported to downregulate PAI-1 expression. Thiazolidinediones have also been reported to decrease urinary albumin excretion to a greater extent than expected for the improvement in glycaemic control and to reduce circulating markers of chronic low-grade inflammation. Preclinical studies suggesting that treatment of glucose-intolerant animals with a thiazolidinedione preserved -cell function have yet to be confirmed in human studies. In insulin-resistant women with a history of gestational diabetes at high risk of type 2 diabetes troglitazone reduced the incidence of newonset diabetes.[66] Whether thiazolidinediones will prove more effective than conventional antidiabetic agents in reducing the decline in -cell function in patients with established type 2 diabetes remains to be determined, although preliminary data in patients who respond to the drugs have been encouraging.[67] Also of considerable interest are the clinical implications of the aforementioned effects of thiazolidinediones on risk factors for cardiovascular disease. These effects, allied to direct anti-atherogenic actions reported in animal studies, are presently being studied in clinical trials with cardiovascular endpoints.[68]
3.2.5 Adverse Effects
Rosiglitazone and pioglitazone are generally well tolerated. As noted in section 3.2.3, caution is advised in heart disease; in the UK this includes a history of cardiac failure, oedema, anaemia and liver function requiring intermittent monitoring in accordance with the package labelling. If contraindications arise during treatment, monitoring should be intensified and, if necessary, treatment discontinued. Hypoglycaemia may occur several weeks after adding a thiazolidinedione to a sulphonylurea; selfmonitoring of blood glucose can be helpful in identifying the point at which the dosage of the sulphonylurea should be reduced. Since PPAR is expressed
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by many tissues, albeit at a low level, we must await the verdict of time for any unforeseen effects of long-term stimulation with thiazolidinediones. For example, PPAR activation in macrophages can reduce the production of some inflammatory cytokines and might increase transformation of monocytes to macrophages in the vascular wall. Stimulation of PPAR in colon cells has been variously reported to increase and decrease division and differentiation of these cells in different animals and cell models;[69] thus, familial polyposis coli is a contraindication to thiazolidinediones on theoretical grounds. 4. Summary and Conclusion The management of patients with type 2 diabetes has been given a firm evidence base in recent years through the results of randomised clinical trials, notably the UKPDS. An improved understanding of the pathogenesis and natural history of this complex metabolic disorder has facilitated the application of new therapeutic agents. Attainment and maintenance of near-normal glycaemic control, while minimising the risk of iatrogenic hypoglycaemia, is a central long-term objective of therapy; however, this is often difficult to achieve in practice. The following general principles should be applied while using oral antidiabetic drugs. Antidiabetic drug therapy must be considered carefully within the context of the overall care plan. This includes an assessment of which agent is most likely to achieve the therapeutic goals of the care plan, taking account of the accompanying medical and lifestyle circumstances and commitments of the patient. Always check for contraindications. For some classes of agents, e.g. sulphonylureas, duration of action and route of elimination will be important considerations if hypoglycaemia is likely, or if renal or liver disease raises concerns. Shorter-acting preparations are preferred for those at risk of hypoglycaemia and in the elderly. Start with the lowest recommended dose and monitor response taking the mode of action into account. Sulphonylureas generally produce a rap 2005 Adis Data Information BV. All rights reserved.
id improvement in glycaemic control (within days), whereas the maximal response to thiazolidinediones may take several weeks to become apparent. Maximal glucose-lowering effects are usually obtained at doses lower than the manufacturers recommendations, e.g. 510 mg/day for glibenclamide.
If the glycaemic target is not achieved consider adding another class of agent at an early stage. Undertake the same evaluation and titration procedure for the second agent. If a combination of two oral agents does not give adequate control, there may be some patients who will benefit from addition of a third differently acting oral therapy. Compliance generally deteriorates as the daily number of doses increases. Inability to achieve adequate glycaemic control with a logical combination of oral therapies is likely to indicate that the natural history of the disease has progressed to a state of severe -cell failure. In this situation it is usually necessary to switch to insulin therapy. Similarly, failure to respond to an oral agent (so-called primary failure) or loss of control (secondary failure) usually reflects a severe degree of insulin deficiency and early need for insulin. All oral antidiabetic agents are contraindicated in type 1 diabetes and in major metabolic decompensation. Insulin may be required temporarily during intercurrent severe illness.
Clinicians have a greater range of antidiabetic treatments to choose from than ever, but this has brought a new level of complexity to management. In addition, polypharmacy has become the norm for many patients with type 2 diabetes in recognition of the importance of treating hypertension and dyslipidaemia, both commonly encountered and modifiable cardiovascular risk factors. The main classes of oral antidiabetic drugs are broadly similar in their glucose-lowering capacity, at least in the short- to medium term.[70] Accordingly, the most appropriate therapy should be selected according to the clinical and biochemical characteristics of the patient, safety considerations always being a major consideration. The UKPDS has influenced prescribing in the UK
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since its publication (table VIII), with metformin now being the most commonly prescribed oral antidiabetic drug. Not only did metformin reduce the risk of myocardial infarction and all-cause mortality in the UKPDS, it has the added advantages of decades of clinical experience and it is inexpensive and weight-neutral (table V). On theoretical grounds, the thiazolidinediones appear promising, particularly with respect to possible preservation of -cell function and the potential for cardiovascular disease prevention. However, these agents have perhaps not entirely fulfilled early expectations of success, at least if judged in terms of their glucose-lowering abilities, which are no better than the conventional drugs. Part of this shortfall may be attributable to the complexity and heteroTable VIII. Relative costs and frequency of prescriptions for oral antidiabetic drugs in the UK[71,72]a Drug Relatively inexpensive Biguanides Sulphonylureasc Moderate -Glucosidase inhibitors Sulphonylureasc Relatively expensive Rapid-acting prandial insulin releasers Thiazolidinediones a Repaglinide, nateglinide Rosiglitazone, pioglitazone Only acarbose in UK Only metforminb in UK Frequency of prescriptions
This classification attempts to take average effective maintenance dosages into account and may be regarded as an approximate guide to relative UK Drug Tariff prices. Use of metformin has increased in recent years, this drug now being the most widely prescribed oral antidiabetic agent in the UK (49%); sulphonylureas lie close behind, gliclazide being the most popular agent accounting for 31% of spending on oral antidiabetic agents. Thiazolidinediones account for only 5% of all prescriptions but for 32% of the cost of all oral antidiabetic agents in the UK; these figures predate the 2003 license amendment permitting limited prescription of thiazolidinediones as monotherapy in selected patients. Acarbose, the only -glucosidase inhibitor in the UK, and the rapid-acting prandial insulin releasers repaglinide and nateglinide account for a small percentage (<5%) of prescribing or oral antidiabetic agents. In the UK the least expensive sulphonylureas are generic tolbutamide and glibenclamide. At the maximum recommended doses there is approximately a 5-fold difference between the least and most expensive sulphonylureas.
geneity of type 2 diabetes, any single therapeutic approach inevitably being of limited value. The thiazolidinediones are appreciably more expensive than metformin and sulphonylureas, which may contribute to their lesser use in many countries. Recent evidence suggesting that these agents may preserve -cell function suggests a unique property that might usefully be exploited.[66] If the putative anti-atherogenic benefits of the thiazolidinediones are confirmed this might dramatically alter the application of these agents in clinical medicine. Some authorities argue the case for early use of insulin-sensitising agents in combination therapy.[73] The realisation that the majority of type 2 diabetic patients will require a combination of differently acting oral antidiabetic agents to achieve and maintain glycaemic control in the long term has expanded interest in single tablet combinations. For patients with newly diagnosed type 2 diabetes it seems logical to introduce effective and safe pharmacological agents at an early stage, when responses to drug treatment are likely to be optimal. Identifying individuals with asymptomatic glucose intolerance would permit the early application of lifestyle measures; this might be followed by pharmacological intervention with metformin or acarbose. Further studies are required to clarify this issue as none of the currently available drug is licensed for use in prediabetic individuals. The emerging epidemic of type 2 diabetes in younger adults and children[74] poses particular challenges for clinicians all too aware of the limitations of current therapeutic options. The lifetime risk of vascular complications will be high in these individuals and nonadherence to therapy may be an even greater issue than in adults. In addition, despite exceptions,[75] lingering concerns over cardiovascular safety of sulphonylureas are largely dissipated by accumulating data. Until more data emerge, a cautious approach to the use of new drugs in young patients seems prudent. Acknowledgements
No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this review.
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46. Howlett HCS, Bailey CJ. A risk-benefit assessment of metformin in type 2 diabetes mellitus. In: Krentz AJ, editor. Drug treatment of type 2 diabetes. Auckland: Adis Books, 2000: 61-76 47. UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854-65 48. The Oxford Centre for Diabetes, Endocrinology and Metabolism: Diabetes Trials Unit. UK Prospective Diabetes Study [online]. Available from URL: http://www.dtu.ox.ac.uk/ ukpds/index.html [Accessed 2004 Nov 23] 49. Hermann LS, Lindberg G, Lindblad U, et al. Efficacy, effectiveness and safety of sulphonylurea-metformin combination therapy in patients with type 2 diabetes. Diabetes Obes Metab 2002; 4: 296-304 50. Johnson JA, Majumdar SR, Simpson SH, et al. Decreased mortality associated with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care 2002; 25: 2244-8 51. Diabetes Prevention Program Research Group. Reduction of the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403 52. Sulkin T, Bosman D, Krentz AJ. Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 1997; 20: 925-8 53. Holt HB, Krentz AJ. Metabolic emergencies in type 2 diabetes. In: Goldstein B, M uller-Wieland D, editors. Textbook of type 2 diabetes. London: Martin Dunitz, 2003: 183-98 54. Lalau J-D, Race J-M. Metformin and lactic acidosis in diabetic humans. Diabetes Obes Metab 2000; 2: 131-7 55. Day C. Thiazolidinediones: a new class of antidiabetic drugs. Diabetic Med 1999; 16: 1-14 56. Krentz AJ, Bailey CJ, Melander A. Thiazolidinediones for type 2 diabetes. BMJ 2000; 321: 252-3 57. Rosen ED, Spiegelman BM. PPAR-: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 2001; 276: 37731-4 58. Fasshauer M, Paschke R. Regulation of adipocytokines and insulin resistance. Diabetologia 2003; 46: 1594-1603 59. Baldwin SJ, Clarke SE, Chenery RJ. Characterisation of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol 1999; 48: 424-32 60. Bailey CJ, Day C, Krentz AJ. Nice timing for glitazones. Br J Diabetes Vasc Dis 2003; 3: 366-7 61. Buch HN, Baskar V, Barton DM, et al. Combination of insulin and thiazolidinedione therapy in massively obese patients with type 2 diabetes. Diabetic Med 2002; 19: 572-4
62. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and the American Diabetes Association. Circulation 2003; 108: 2941-8 63. Parulkar AA, Pendergrass ML, Granda-Ayala R, et al. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med 2001; 134: 61-71 64. Yki-J arvinen H. Thiazolidinedions. N Engl J Med 2004; 351: 1106-18 65. Marten FMAC, Visseren FLJ, Lemay J, et al. Metabolic and additional vascular effects of thiazolidinediones. Drugs 2002; 62 (10): 1463-80 66. Buchanan TA, Xiang AH, Peters RK, 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: 2796-803 67. Bell DSH. B-cell rejuvenation with thiazolidinediones. Am J Med 2003; 115 (8A): 20-23S 68. Roberts AW, Thomas A, Rees A, et al. Peroxisome proliferator activated receptor- agonists in atherosclerosis: current evidence and future directions. Curr Opin Lipidol 2003; 14: 567-73 69. Schoonjans K, Auwerx J. Thiazolidinediones: an update. Lancet 2000; 355: 1008-10 70. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA 2002; 287: 360-72 71. Kendall H. Trends in prescribing of drugs used to treat diabetes. Prescriber 2003; 14 (24): 38-9 72. Cuthbertson D, Leese G. Managing type 2 diabetes: oral antidiabetic drugs. Prescriber 2003; 14 (13): 47-53 73. Bell DSH. Type 2 diabetes mellitus: what is the optimal treatment regimen? Am J Med 2004; 116 (5A): 23S-9S 74. Kaufman FR. Type 2 diabetes mellitus in children and youth: a new epidemic. J Pediatr Endocrinol Metab 2002; 15 Suppl. 2: 737-44 75. Huizar JF, Gonzalez LA, Alderman J, et al. Sulfonylureas attenuate electrocardiographic ST-segment elevation during a myocardial infarction. J Am Coll Cardiol 2003; 42: 1017-21
Correspondence and offprints: Dr Andrew J. Krentz, Mailpoint 47, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. E-mail: a.j.krentz@soton.ac.uk
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Oral Antidiabetic Agents

Krentz & Bailey

2005 Adis Data Information BV. All rights reserved.

Oral Antidiabetic Agents

Drugs 2005; 65 (3)

Krentz & Bailey

Oral Antidiabetic Agents

Diet, exercise, weight control and health education

Relieve symptoms, improve glycaemic control, enhance quality of life

Oral agent monotherapy: metformin, sulphonylurea, meglitinide, thiazolidinedione1, acarbose

Oral agent combination therapy (using two different classes)

2005 Adis Data Information BV. All rights reserved.

Drugs 2005; 65 (3)

Krentz & Bailey

Oral Antidiabetic Agents

Glucose GLUT2 Succinate esters Glucokinase Sulphonylureas Repaglinide Nateglinide

R1 SU .2 6 Kir K ATP el nn cha

Proinsulin biosynthesis Ca2+-sensitive proteins

rgic ene Adr ptors rece

Exocytosis PDE inhibitors Insulin

Krentz & Bailey

Intrinsic hypoglycaemic activity Salicylates, alcohol (ethanol), monoamine oxidase inhibitors

Drugs 2005; 65 (3)

Oral Antidiabetic Agents

be monitored by periodic measurement of HbA1c (or fructosamine if HbA1c is not available).

Krentz & Bailey

Oral Antidiabetic Agents

Krentz & Bailey

Oral Antidiabetic Agents

Enterocyte Microvillus Villus

Krentz & Bailey

2.3 Indications and Contraindications

Oral Antidiabetic Agents

Drugs 2005; 65 (3)

Krentz & Bailey

Intestine Anaerobic glucose metabolism Glucose uptake and oxidation

Glyconeogenesis Glycogenesis Oxidation of FA

Glucose uptake and oxidation Glycogenesis Oxidation of FA

Hepatic glucose production

Insulin-mediated glucose disposal

Oral Antidiabetic Agents

Krentz & Bailey

2005 Adis Data Information BV. All rights reserved.

Drugs 2005; 65 (3)

Oral Antidiabetic Agents

Krentz & Bailey

Oral Antidiabetic Agents

Glucose uptake and utilisation

aP2, acylCoA synthase

Transcription of certain insulin-sensitive genes

2005 Adis Data Information BV. All rights reserved.

Drugs 2005; 65 (3)

Krentz & Bailey

Oral Antidiabetic Agents

Krentz & Bailey

Oral Antidiabetic Agents

2005 Adis Data Information BV. All rights reserved.

Drugs 2005; 65 (3)

Krentz & Bailey

2005 Adis Data Information BV. All rights reserved.

Drugs 2005; 65 (3)

Oral Antidiabetic Agents

2005 Adis Data Information BV. All rights reserved.