Review
Pathophysiology and treatment of type 2 diabetes:
Lancet 2014; 383: 1068–83
Published Online
December 4, 2013
http://dx.doi.org/10.1016/
S0140-6736(13)62154-6
See Online/Comment
http://dx.doi.org/10.1016/
S2213-8587(13)70187-6
Division of Metabolism,
Endocrinology and Nutrition,
Department of Medicine,
VA Puget Sound Health Care
System, University of
Washington, Seattle, WA, USA
(Prof S E Kahn MB ChB);
Diabetes Division, Baker IDI
Heart and Diabetes Institute,
Melbourne, VIC, Australia
(Prof M E Cooper MB BS); and
Department of Clinical and
Experimental Medicine,
University of Pisa School of
Medicine, Pisa, Italy
(Prof S Del Prato MD)
Correspondence to:
Prof Steven E Kahn, VA Puget
Sound Health Care System,
Seattle, WA 98108, USA
skahn@uw.edu
1068
perspectives on the past, present, and future
Steven E Kahn, Mark E Cooper, Stefano Del Prato
Glucose metabolism is normally regulated by a feedback loop including islet β cells and insulin-sensitive tissues, in
which tissue sensitivity to insulin affects magnitude of β-cell response. If insulin resistance is present, β cells
maintain normal glucose tolerance by increasing insulin output. Only when β cells cannot release sufficient insulin
in the presence of insulin resistance do glucose concentrations rise. Although β-cell dysfunction has a clear genetic
component, environmental changes play an essential part. Modern research approaches have helped to establish the
important role that hexoses, aminoacids, and fatty acids have in insulin resistance and β-cell dysfunction, and the
potential role of changes in the microbiome. Several new approaches for treatment have been developed, but more
effective therapies to slow progressive loss of β-cell function are needed. Recent findings from clinical trials provide
important information about methods to prevent and treat type 2 diabetes and some of the adverse effects of these
interventions. However, additional long-term studies of drugs and bariatric surgery are needed to identify new ways
to prevent and treat type 2 diabetes and thereby reduce the harmful effects of this disease.
The epidemic of type 2 diabetes decreased uptake of glucose in muscle and adipose
The worldwide explosion of obesity has resulted in an tissue.5 Nowadays, some of these abnormalities are
ever-increasing prevalence of type 2 diabetes—a non- attributed to adiposity, especially adiposity within the
communicable disease that affects more than 370 million intra-abdominal cavity.6
people.1 Without concerted efforts to address the patho-
genesis and treatment of this syndrome, the harmful The present: the crucial role of β cells to glucose
macrovascular and microvascular outcomes of type 2 homoeostasis by feedback regulation
diabetes will remain a major burden for decades to The importance of insulin resistance and β-cell
come. In this Review we examine aspects of the patho- dysfunction to the pathogenesis of type 2 diabetes was
genesis and treatment of type 2 diabetes, and discuss debated for a long time; many thought that insulin
future needs if the most damaging result of obesity is to resistance was the main abnormality in type 2 diabetes,
be reversed. and that inability to secrete insulin was a late
manifestation.5 This notion changed with the finding that,
Pathogenesis of type 2 diabetes: from the past as with most endocrine systems in human beings, a
to the present and future feedback loop operates to ensure integration of glucose
The past: identification of β-cell dysfunction and homoeostasis and maintenance of glucose concentration
insulin resistance in a narrow range.7
Development of the insulin radioimmunoassay led to the This feedback loop relies on crosstalk between β cells
finding that patients with early-maturity-onset diabetes and insulin-sensitive tissues (figure 1). Insulin released
produced insulin and secreted this hormone in response in response to β-cell stimulation mediates uptake of
to nutrient ingestion.2 Subsequently, defects in the ability glucose, aminoacids, and fatty acids by insulin-sensitive
of islet β cells to respond to intravenous secretagogues tissues. In turn, these tissues feed back information to
(including glucose) were reported in these patients.3 islet cells about their need for insulin. The mediator of
Additionally, these patients did not respond well to this process has not been identified, but probably
insulin,4 and were thus deemed to be insulin insensitive. includes integration between the brain and humoral
This insulin insensitivity was shown to contribute to system. If insulin resistance is present, as often happens
increased production of glucose by the liver and in people with obesity, β cells increase insulin output to
maintain normal glucose tolerance. However, if β cells
are incapable of this task, plasma concentrations of
Search strategy and selection criteria glucose increase.
We searched PubMed and Google Scholar, mainly for original Although the distinction between impaired fasting
research articles published up to May, 2013, which focused on glucose and impaired glucose tolerance (sometimes
the pathophysiology and treatment of type 2 diabetes. The together referred to as prediabetes) and diabetes is
main search terms used were “pathophysiology”, “type 2 established by testing of 2 h glucose concentrations after
diabetes”, “prediabetes”, “β-cell”, “insulin resistance”, and fasting and a standardised load of oral glucose,8 these
“treatment”. We mostly identified full-text articles written in disturbances form a continuum in which the magnitude
English. We also searched ClinicalTrials.gov for information of reduction in β-cell function establishes the degree of
about ongoing clinical trials in type 2 diabetes. increase in plasma glucose. Insulin resistance is already
well established if impaired glucose tolerance is present;
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 Review

rises in glucose concentrations, even within the normal

range, are due to a continuous fall in β-cell function.9 A
Further progressive deterioration of β-cell function Insulin sensitive

accounts for the evolving natural history of the disease,

from impaired glucose tolerance to type 2 diabetes.10,11
Reduced β-cell function is already present in groups at
increased risk of diabetes (eg, first-degree relatives of
patients with diabetes,12 women with gestational
diabetes13 or polycystic ovary syndrome,14 and elderly
people15) and underlies progression to the disease.
Furthermore, β-cell function is heritable16 and is crucially
important to differences in glucose intolerance and rates
of type 2 diabetes between various racial and ethnic
groups.17
Despite advances in understanding of the importance Insulin response
of insulin resistance and β-cell dysfunction to the
pathogenesis of type 2 diabetes and high-risk states, the
B
disease process is clearly heterogeneous, and includes Insulin resistance
other pathogenic factors.

Genes, environment, and development of type 2 diabetes

Genes and the environment together are important
determinants of insulin resistance and β-cell dysfunction
(figure 2). Because changes in the gene pool cannot
account for the rapid increase in prevalence of type 2
diabetes in recent decades, environmental changes are
essential to understanding of the epidemic.
Advances in technology and analytical approaches have
identified genes linked with type 2 diabetes. With use of
candidate-gene approaches, PPARG was the first gene
identified.18 Subsequently, mostly with use of genome- Enhanced insulin response

wide association studies, more than 50 gene loci have

been linked with type 2 diabetes.19 Furthermore, 53 loci C
Insulin resistance
have been linked with concentrations of insulin and
glucose (however, not always with both fasting and 2 h
concentrations of glucose), of which 33 are also associated
with type 2 diabetes.19,20 Although some loci are associated
with obesity and insulin resistance, most are linked with
β-cell function.21 Gene products for most of these loci
have not been definitively identified. Together, these
genes do not explain much of the genetic basis of type 2
diabetes; the use of genotype risk scores only slightly
improves prediction of subsequent diabetes compared
with more frequently used clinical risk factors.22,23
Aside from obvious increases in caloric intake and
decreased energy expenditure, other environmental Diminished insulin response
factors seem to be important. Nutrient composition,
Figure 1: Feedback loop between islet β cells and insulin-sensitive tissues
specifically increased amounts of dietary fat (particularly (A) Insulin interacts in the liver to suppress glucose production, and in muscle
saturated fat), are important to development of obesity, and adipose tissue to stimulate uptake of glucose, aminoacids, and fatty acids.
insulin resistance, β-cell dysfunction, and glucose The amount of insulin released to maintain normal glucose homoeostasis is
established by prevailing insulin sensitivity. This feedback is probably mediated
intolerance.24 Furthermore, an ageing-associated
through neuronal and humoral mechanisms, but exact mediators are still not
reduction in the responsiveness of β cells to carbohydrate known. (B) When insulin resistance develops in insulin-sensitive tissues,
partly underlies the fall in glucose tolerance with ageing.25 feedback to β cells ensures that the cells increase insulin output to maintain
The in-utero environment, established partly by the normal glucose tolerance. (C) When β cells are incapable of increasing insulin
output in the presence of insulin resistance, the result is development of
mother’s body size, could produce epigenetic and gene-
increased glucose concentrations, which initially manifests as impaired glucose
expression changes that affect the risk of development of tolerance. Because β-cell dysfunction progresses, further elevations in glycaemia
obesity and type 2 diabetes for the offspring.26 Recent occur and diabetes is the eventual result.

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 Review
↓Energy expenditure Obesity
↑Caloric intake
Body β-cell
Nutrient composition Environment adiposity dysfunction
genes genes
? Environmental
chemicals
? Microbiome Type 2 diabetes
Figure 2: Role of genes and the environment in development of obesity and
type 2 diabetes
Interaction of genes that affect body adiposity with environmental factors results
in development of obesity and associated insulin resistance. However, only when
genes for abnormal β-cell function are present along with those for body adiposity
does interaction with the environment result in development of type 2 diabetes.
discussion has also focused on the role of environmental
chemicals in the epidemics of obesity and diabetes.27
Further delineation of the roles of reduced β-cell
numbers and α-cell dysfunction
The reduction of β-cell numbers in type 2 diabetes is well
known.28–31 The basis for this loss is multifactorial, and
includes glucolipotoxicity32 and amyloid deposition that
result in β-cell apoptosis through oxidative and
endoplasmic-reticulum stress.31 This loss is not
counterbalanced by replacement with new β cells,
because the human pancreas seems to be incapable of
renewing these cells after 30 years of age.33 Although a
reduction in β-cell mass occurs in type 2 diabetes, the
magnitude of this abnormality is clearly insufficient to
explain the degree of impairment in insulin release.
Whether the underlying defect in β-cell function is
important as an initiator of β-cell loss, and whether
increasing secretory demand on each individual β cell as
numbers decrease causes ongoing loss of β cells, remains
to be defined. Elucidation of the importance of β-cell
function compared with mass could have important
implications for development of approaches to preserve
β cells and help to maintain or improve glucose tolerance.
Although less well studied, dysregulated release of
glucagon by α cells, which manifests as increased
concentrations of fasting glucagon and failure to
adequately suppress glucagon release after meal
ingestion, contributes to the development of hyper-
glycaemia.34 Whether this dysregulation is a primary
change in α cells or is secondary to an abnormality in
β-cell function is not yet resolved. However, islet blood
flows from β cells to α cells and then to somatostatin-
producing δ cells;35 high concentrations of insulin
bathing α cells are capable of suppression of glucagon
release.36 Other β-cell products—eg, zinc, γ-amino-
butyric acid, or glutamate—might also regulate glucagon
release.36 Approaches that reduce glucagon release or
1070
impair its action to raise glucose concentrations could
represent additional therapeutic alternatives for type 2
diabetes.34
Important roles of the intestine and brain
The gastrointestinal tract produces various peptides, not
all of which directly modulate nutrient absorption.
Glucagon-like peptide 1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP), collectively known as
incretins, act on the pancreatic islet. GLP-1 is more
important, and acts both on β cells to enhance insulin
secretion and on α cells to suppress glucagon secretion.37
Plasma concentrations of GLP-1 generally do not differ
in individuals with normal glucose tolerance, impaired
glucose tolerance, or type 2 diabetes.38 Therefore, the
β-cell response to GLP-1 after meal ingestion has to
be deficient, as noted after intravenous administration
of GLP-1 under controlled conditions.39 This deficient
response is consistent with a model of global
deficiency in β-cell responsiveness to many secreta-
gogues (eg, sulfonylurea antidiabetics, aminoacids, and
β-adrenoreceptor agonists).40 Although GLP-1 acts
directly on α cells to suppress glucagon release, the effect
of this mechanism compared with modulation by β-cell
products is uncertain, both in healthy people and in
those with type 2 diabetes (in which glucagon is
inadequately suppressed during meals). Increased
concentrations of GLP-1 have been reported after
bariatric surgery, and are thought to account for many of
the beneficial effects of the intervention, particularly in
patients with type 2 diabetes.41 However, increased GLP-1
is not the only mechanism by which glucose lowering
can occur after this surgical procedure.41,42
Bile acids are also important in the regulation of
glucose metabolism. They are endogenous ligands of the
farnesoid X receptor, and activation of the receptor
results in release of the fibroblast growth factor (FGF) 19.43
Bile acids also activate G-protein-coupled bile-acid
receptor 1 located on intestinal L cells, leading to GLP-1
secretion.44 In human beings, infusion of bile acids
intraduodenally in a dose-dependent manner increases
plasma concentrations of FGF19, with smaller effects on
concentrations of GLP-1 and cholecystokinin.45 Because
FGF19 has insulin-like effects (it induces synthesis of
glycogen and proteins, and inhibits glucose production43)
the biliary system might have an underappreciated role
in modulation of glucose homoeostasis.
The intestinal microbiome also seems to be important
to the pathophysiology of type 2 diabetes.46 The
microbiome has about 100 times more genetic
information than has the human genome, together
comprising the human metagenome. Many products of
the microbiome provide functions beyond that of the
host genome, thereby serving an important role in
human physiology. These gut communities are thought
to play an important part in several conditions and
disorders (eg, obesity and type 2 diabetes), although
www.thelancet.com Vol 383 March 22, 2014

which bacterial species cause changes to human
metabolism is not clear.47 Findings from two studies that
used faecal samples suggested that functional changes in
the gut microbiome might be directly linked to
development of type 2 diabetes;48,49 however, metagenomic
markers differ between populations, suggesting that
their ability to predict development of diabetes will
probably vary.49 Findings from a recent proof-of-concept
study50 showed improvements in insulin sensitivity in
patients with metabolic syndrome 6 weeks after infusion
of intestinal microbiota from lean individuals. Lastly,
different gut flora might affect nutrient absorption,
because in human beings nutrient load can alter the
faecal bacterial community in a short time.51
The nervous system is another important regulator of
metabolic processes. Both sympathetic and para-
sympathetic nervous systems control glucose
metabolism, directly through neuronal input, and
indirectly through the circulation to affect release of
insulin and glucagon52 and production of hepatic
glucose.53 In human beings, the vagus is important in
regulation of islets, because severing of this nerve results
in impaired insulin secretion.54 The hypothalamus is an
important integrator, because its ablation in rats results
in dysregulation of β cells and development of
hyperinsulinaemia.55 This brain region also regulates
hepatic production of glucose through the actions of
insulin, glucose, and fatty acids.56–58 Insulin action at this
site is also essential in regulation of bodyweight, with
decreased activity leading to obesity.59 Inflammation-
induced neuronal injury occurs rapidly in rodents fed a
high-fat diet.60 Findings from imaging studies of obese
and lean people suggest that structural changes occur in
the hypothalamus, consistent with the occurrence of
gliosis in obesity.60 Finally, clock genes expressed in the
brain are important in establishment of circadian
rhythmicity and, together with sleep, have become a
focus of investigation because changes in diurnal
patterns and quality of sleep can have important effects
on metabolic processes.61,62
Systemic and islet inflammation
Obesity is often characterised by systemic inflammation,
and preclinical evidence links systemic inflammation to
β-cell dysfunction.63,64 Markers of systemic inflammation,
including C-reactive protein and its upstream regulator
interleukin 6, are cross-sectionally associated with insulin
sensitivity and β-cell function.65,66 Lifestyle change and
pharmacological drugs improve markers of inflam-
mation,66–68 and have been associated with improvements
in β-cell function in patients with type 2 diabetes.69,70
Direct effects of inflammation on β cells arise from
activation of the intraislet immune response.71 Glucose
and fatty acids increase production of interleukin 1β in
islets,72,73 and naturally occurring antagonists (particularly
interleukin 1 receptor antagonist) balance and regulate
the action of interleukin 1β in islets and other tissues.74
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Review
Circulating concentrations of interleukin 1β and
interleukin 1 receptor antagonist are increased in patients
with type 2 diabetes;75,76 lower concentrations at the time
of initiation of interleukin 1 receptor antagonist treatment
could predict maintenance of improved β-cell function
after intervention to reduce islet inflammation.70
Expansion of adipose tissue is associated with
accumulation of activated macrophages that express
several proinflammatory genes, including cytokines (eg,
tumour necrosis factor α) that locally impair insulin
signalling.77,78 A feed-forward process, in which activation
of transcription factors causes further production of
proinflammatory cytokines, also plays a part.79 When
production of these cytokines is sufficient, they are
released into the circulation where they can act at distant
sites (eg, the liver and skeletal muscle) to worsen insulin
resistance. A similar process can occur in the liver with
Kupffer cells (resident macrophages) and recruited
macrophages.80 Hypothalamic inflammation might also
contribute to central leptin resistance and weight gain.81
The future: genetics, epigenetics, and omics
Although understanding of the genetics of type 2 diabetes
has advanced rapidly, much remains unknown. How
genes interact with the environment to cause progressive
loss of β-cell function is unclear. Environmental factors
and hyperglycaemia could contribute to epigenetic
changes in DNA and histones, thereby modifying gene
expression in organs implicated in the pathogenesis and
progression of type 2 diabetes, including in β cells.82,83
Whether such changes contribute to the increased risk of
type 2 diabetes and the progression of disease will be of
interest. Finally, because only a small proportion of the
risk of type 2 diabetes can be attributed to identified
genetic loci, the search for rarer variants with approaches
such as exome sequencing might provide additional
insights and possible therapies.
The so-called omics (eg, metabolomics, lipidomics,
proteomics, genomics, and transcriptomics) are based
on the study of constituents of the cell or body in a
collective way. The findings made with use of these
approaches are being integrated to better understand the
pathophysiology of type 2 diabetes and the heterogeneity
of responses to different glucose-lowering therapies.
Findings from studies that used metabolomics and
lipidomics showed that increases in branched-chain and
aromatic aminoacids were associated with obesity and
type 2 diabetes.84,85 Furthermore, patients with high
concentrations of specific six-carbon sugars, aminoacids,
and fatty acids, and low concentrations of other
aminoacids and fatty acids, had an increased risk of
developing type 2 diabetes over a 7 year follow-up.86
Whether all or some of these substrate markers are
associated with genetic determinants, dietary factors, or
the actions of gut microbes has not been established.
In the long term, these new approaches should identify
additional genes and metabolic markers; profiles
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 Review

A have been unsuccessful because of adverse effects or

15 SGLT2 inhibitors negligible therapeutic efficacy, several are very well
Bromocriptine accepted and are used worldwide. The mode of action for
Colesevelam
most of these drugs has been reported (figure 3).
Classes of glucose-lowering drugs

DPP4 inhibitors
Inhaled insulin However, individual responses to these drugs can differ
10 Pramlintide greatly, probably as a result of the heterogeneous nature
GLP-1 receptor agonists
Glinides of the pathophysiology of type 2 diabetes. The
Thiazolidinedione antidiabetics appendix provides further discussion on drugs that have
Insulin analogues been widely available for more than a decade (eg,
5 α-glucosidase inhibitors
Human insulin sulfonylurea antidiabetics, biguanide antidiabetics,
Metformin α-glucosidase inhibitors, and peroxisome proliferator-
Animal insulin Sulfonylurea antidiabetics activated receptor γ agonists).
0
0 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010
Drugs with actions dependent on the gastro-
Year
intestinal tract
Drugs that mediate their effect through the gastro-
B Classic Less classic intestinal tract include α-glucosidase inhibitors that slow
Sulfonylurea antidiabetics Bromocriptine glucose absorption by delaying degradation of complex
Glinides
GLP-1 receptor agonists carbohydrates in the gastrointestinal tract;87 pramlintide,
DPP4 inhibitors which slows gastric emptying and thus delays glucose
Insulin
absorption;88 and the bile-acid-binding resin colesevelam,
which lowers cholesterol and modifies release of other
gastrointestinal peptides that can reduce plasma
concentrations of glucose.89
Incretin-related products are designed to mimic or
augment the action of GLP-1 and GIP, which are released
Lifestyle modification α-glucosidase inhibitors SGLT2 inhibitors
Metformin Pramlintide
by the intestine. GLP-1 receptor agonists are peptides
Thiazolidinedione antidiabetics Colesevelam with longer half-lives than GLP-1, whereas dipeptidyl
peptidase 4 (DPP4) inhibitors block the action of DPP4,
Figure 3: Drugs to treat type 2 diabetes which is responsible for rapid degradation of GLP-1 and
(A) The rate of introduction of new classes of drugs has accelerated during the past 20 years. Two classes (animal GIP.90 Improvement of the pharmacokinetics and
insulin and inhaled insulin; red) are essentially no longer available as therapeutics. (B) Different classes of drugs act
on different organ systems. Insulin is a replacement for the natural product of islet β cells. Classic organ systems
pharmacodynamics of incretin-based drugs is under
that have been targeted for decades comprise the pancreatic islet, liver, muscle, and adipose tissue. Non-classic investigation to reduce dosing and to improve glucose
targets have been focused on recently, and include the intestine, kidneys, and brain. DPP4=dipeptidyl peptidase 4. control.91 Although not completely understood, infusion
SGLT2=sodium–glucose co-transporter 2. GLP-1=glucagon-like peptide 1. of large doses of GLP-1 intravenously can normalise
glucose concentrations with less nausea or vomiting—
See Online for appendix obtained through these assessments could provide the adverse effects that can be dose limiting and prevent
level of detail needed to establish the mediator (or normalisation of glucose concentrations—than for
mediators) of the feedback loop that interconnects β cells subcutaneous administration.92,93 Whether new drugs
with insulin-sensitive tissues, and help to unravel the can further improve glucose lowering and reduce nausea
heterogeneity of the disease. Furthermore, these and vomiting remains unknown. In addition to the clear
assessments should complement and advance present effect of these drugs on improvement of glycaemia,
understanding of the best approaches to treat the incretin-related products might also have beneficial
dysregulated metabolic milieu in type 2 diabetes, which effects on the cardiovascular system,94,95 although
includes not only glucose but also fatty acids and findings from the first two of a series of intervention
aminoacids. studies showed a neutral effect.96,97 Incretin-related
medications have been purported to increase the risk of
Treatment of type 2 diabetes acute pancreatitis; this suggestion is based on findings
Oral and injectable drugs: present knowledge, lessons from studies that used the inherently biased
learned, and implications for the future pharmacovigilance and administrative databases.98–101
The increasing prevalence of type 2 diabetes has More recently, GLP-1 receptor agonists and DPP4
stimulated development of many new approaches to inhibitors have been postulated to cause malignant
safely treat hyperglycaemia (figure 3). The aim of these transformations in the pancreas. However, this
therapies is to reduce and maintain glucose suggestion was based on histological assessments of a
concentrations as close to normal for as long as possible very small number of samples from brain-dead organ
after diagnosis (panels 1, 2), and thereby prevent donors that were inadequately matched with controls for
development of complications. Although some therapies several crucial variables.102,103 Importantly, despite

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 Review

publicity received by this report, after a full assessment clinical investigation. These drugs effectively reduce
of the data the European Medicines Agency indicated plasma glucose, bodyweight, and blood pressure. However,
that they were insufficient to support any causal the increase in urinary glucose is associated with a five
association between these drugs and pancreatic cancer.104 times higher rate of genital mycotic infections, and a 40%
increase in infections of the lower urinary tract, compared
Inhibitors of sodium–glucose co-transporter 2 with active comparators;108 additionally, these drugs cause
The kidneys not only excrete and reabsorb glucose, but also unexplained, although slight, increases in LDL and HDL
produce glucose through gluconeogenesis.105 Generally, cholesterol.109 The increase in infections, and the potential
the quantity of glucose filtered does not exceed the kidneys’ effect on outcomes for cardiovascular disease (if
threshold to reabsorb it, and thus little appears in urine. unfavourable changes in LDL cholesterol outweigh
The finding that sodium–glucose co-transporter 2 (SGLT2) favourable changes in HDL cholesterol), might reduce
reabsorbed glucose from urine led to the development of acceptance of these drugs by patients and health-care
inhibitors of this transporter to increase urinary glucose providers. Long-term studies that are in progress (eg,
excretion.106,107 Two, dapagliflozin and canagliflozin, were ClinicalTrials.gov identifiers NCT01032629, NCT01131676,
recently introduced to market, and others are under and NCT01730534) will measure the cardiovascular safety
of this class of glucose-lowering drugs.
Panel 1: Oral drugs approved for treatment of
Drugs acting through the CNS
hyperglycaemia in type 2 diabetes*
Although the brain is crucial to the regulation of
Second-generation sulfonylurea antidiabetics glucose metabolism, development of approaches that
• Glibenclamide (also known as glyburide) act centrally to reduce glucose concentrations has been
• Gliclazide difficult. The dopamine-receptor agonist bromocriptine
• Glimepiride is the only approved drug to regulate glucose
• Glipizide metabolism that acts centrally, based on the notion that
it restores circadian rhythm.110 Circadian rhythm is
Biguanide antidiabetics
established partly by clock genes that are expressed
• Metformin
centrally and in peripheral tissues, and affects several
Peroxisome proliferator-activated receptor γ agonists organ systems associated with metabolism.61 Other
(thiazolidinedione antidiabetics) drugs that reduce glucose concentrations through
• Pioglitazone
• Rosiglitazone
Panel 2: Injectable drugs approved for treatment of
α-glucosidase inhibitors hyperglycaemia in type 2 diabetes*
• Acarbose
Islet amyloid polypeptide (amylin) analogues
• Miglitol
• Pramlintide
• Voglibose
GLP-1 receptor agonists
DPP4 inhibitors
• Exenatide
• Alogliptin
• Liraglutide
• Linagliptin
• Lixisenatide
• Saxagliptin
• Sitagliptin Rapid-acting and short-acting insulin
• Vildagliptin • Soluble insulin (also known as regular insulin)
• Insulin aspart
SGLT2 inhibitors
• Insulin glulisine
• Canagliflozin
• Insulin lispro
• Dapagliflozin
• Insulin zinc–amorphous (also known as insulin semilente)
Glinides
Intermediate-acting insulin
• Nateglinide
• Isophane insulin (also known as NPH insulin)
• Repaglinide
• Insulin zinc (also known as insulin lente)
Bile-acid-binding resins
Long-acting insulin
• Colesevelam
• Insulin zinc–crystalline (also known as insulin ultralente)
Dopamine-receptor agonists • Insulin detemir
• Bromocriptine • Insulin glargine
DPP4=dipeptidyl peptidase 4. SGLT2=sodium–glucose co-transporter 2. *Not all drugs GLP-1=glucagon-like peptide 1. NPH=neutral protamine Hagedorn. *Not all drugs
available in all countries. available in all countries.

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 Review
central actions often do so by reducing food intake and
bodyweight—eg, GLP-1 receptor agonists, which
effectively reduce bodyweight if they cross the blood–
brain barrier.90
Modified insulins
Insulin therapies have advanced substantially in recent
years, including discontinuation of animal forms and
introduction of human forms. Modification of insulin
has focused on changes to its pharmacokinetics, to
make its action either more rapid (to better simulate the
effect of insulin postprandially) or more prolonged, so
as to reduce the need for twice-daily administration and
create more flexibility with dosing.111 Whether these
goals are always beneficial is debated.112 Insulin degludec
(an insulin that forms soluble multihexamers on sub-
cutaneous injection) has a longer duration of action
than does insulin glargine, provides similar glucose
control with less nocturnal hypoglycaemia,113 and has
been approved in Europe and several other countries.
However, the US Food and Drug Administration raised
questions about the cardiovascular safety of insulin
degludec and requested a cardiac safety study before
reconsidering this insulin formulation for approval.
Another long-duration insulin in development is
insulin coupled with polyethylene glycol to delay
absorption and clearance.114 Concentrated formulations
of insulin (500 units per mL) are effective in a small
number of very insulin-resistant patients;115 the
effectiveness of this insulin when dosed two or three
times a day is under investigation in a large trial
(NCT01774968). Other areas of research interest include
formulation of insulin for delivery by other routes and
to reduce the risk of hypoglycaemia. Although inhaled
insulin was expected to be revolutionary, difficulties in
the development of practical delivery devices and a
possible increased risk of lung carcinoma mostly ended
the pursuit of such an approach.116 Oral formulations
are also challenging, because of the need to avoid
destruction of insulin by intestinal secretions and
simultaneously deliver a predictable amount of insulin
to plasma from the intestinal tract.117 With the
emergence of treatment approaches that aggressively
reduce glucose concentrations, so-called smart insulins
are being developed that are dependent on ambient
glucose concentration. These insulin formulations
become active when glucose concentrations are raised;
increased glucose competes with glycosylated insulin
for binding to a lectin, thereby freeing insulin—an
effect that would not occur if glucose concentrations
were below normal.118 This technology is under-
developed, but could provide an interesting alternative
if successful in clinical development. Insulin molecules
that are modified for liver selectivity are also under
investigation; in human beings, they provided improved
glycaemic control with fewer adverse effects,
particularly hypoglycaemia.119
1074
Future developments in mostly untested areas
Because available treatments at present do not easily
achieve and maintain normal concentrations of glu-
cose as β-cell function progressively decreases, new
approaches are being developed (table 1), which represent
mostly untested mechanisms.
Treatment and prevention: goals and outcomes
of clinical trials
The present situation
In 1998, investigators of the landmark UKPDS trial143
reported that improved glucose control (mainly with
sulfonylurea antidiabetics and insulin) reduced
microvascular complications in recently diagnosed
patients with type 2 diabetes. The primary analysis did
not show a clear benefit for macrovascular disease, and
thus four large intervention studies were designed to
examine the effect of more intensive lowering of glucose
for cardiovascular outcomes.
Insulin was a major component of the glucose-lowering
interventions used in the ACCORD,144 VADT,145 and
ORIGIN146 trials, whereas the ADVANCE study147 used a
regimen based on the sulfonylurea antidiabetic gliclazide.
Intensive glucose lowering did not reduce cardiovascular
events in any of these studies, and indeed in susceptible
patients might have been harmful. Analyses from
ACCORD suggested that the patients who were at greatest
risk of an adverse outcome from aggressive glucose
lowering had a long duration of diabetes, poor glucose
control at time of commencement of intensive insulin
therapy, and did not have an immediate glucose-lowering
response.148 Similar to findings from UKPDS, findings
from ACCORD showed that improved glucose control
reduced microvascular complications;149 however, these
positive findings need to be balanced against the potential
harmful effects of intensified therapy on cardiovascular
outcomes. A similar microvascular benefit was shown by
findings from ADVANCE, with the magnitude of effect
related to the degree of glucose control, and affecting
mostly renal outcomes (essentially as a result of reductions
in microalbuminuria).147 Findings from ORIGIN showed
no evidence of an increased risk of cancer for insulin
glargine,146 despite suggestions from findings of
pharmacovigilance studies that insulin could promote
cancer.150 These findings of no effect of insulin therapy on
cancer is consistent with a report that serum samples
from patients with type 2 diabetes, treated with insulin
glargine, activated insulin receptors A and B similarly to
isophane insulin (also known as neutral protamine
Hagedorn insulin), and did not increase signalling
through the IGF-1 receptor.151 Thus, on the basis of five
separate studies, present approaches to intensify glucose
control are valuable to reduce microvascular complications
but are not effective to reduce cardiovascular events, and
are possibly even harmful in patients with advanced type 2
diabetes. Similar conclusions were reached by investi-
gators of two meta-analyses that included these and other
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 Review

Goal Comments
FFAR1 (also known as GPR40) Increase β-cell secretory function Activated by medium-chain to long-chain fatty acids; TAK-875 first FFAR1 agonist in phase 3 clinical trials120
GPR119 Increase β-cell secretory function Receptor located in β cells and intestine; activation in intestine results in increased release of incretin121
Liver-derived proteins, including Increase β-cell mass Two recently discovered proteins increase β-cell mass in animal models;122,123 whether targeting of β-cell mass will
betatrophin adequately increase insulin production and secretion is unclear
FOXO1 Increase β-cell mass Decreased production of Foxo1 results in β-cell dedifferentiation in mouse models, with some β cells becoming α cells;124
redifferentiation can result in cells capable of producing and secreting insulin
Glucagon-receptor antagonists Decrease effect of glucagon Blocking of glucagon action reduces glucose concentrations and results in compensatory α-cell hyperplasia and increased
and glucagon antibodies plasma concentrations of glucagon;125 associated with dyslipidaemia
Oxyntomodulin Decrease effect of glucagon Product of the proglucagon gene GCG; agonist of both glucagon and GLP-1 receptors; induces weight loss in human
beings by reduction of food intake and increasing of energy expenditure126
Glucokinase Reduce hepatic production of In addition to reduction of glucose production, targeting of glucokinase would increase insulin secretion because of the
glucose crucial role of the enzyme in the β cell; human studies show favourable effects on glucose lowering with increased
hypoglycaemia, but glucose-lowering effects not maintained beyond a few months127
Glucose-6-phosphatase, fructose- Reduce hepatic production of Goal is to decrease glycogenolysis and gluconeogenesis;128 targeting can cause unwanted triglyceride accumulation in the
1,6-bisphosphatase, and glycogen glucose liver128
phosphorylase
CPT1A (also known as CPT-1) Reduce hepatic production of Blocking of CPT1A inhibits fatty-acid oxidation, and selective inhibition in the liver should decrease gluconeogenesis;
glucose teglicar chronically reduces hepatic production of glucose without changing peripheral glucose uptake, but increases
hepatic triglyceride129
AMP kinase Increase insulin action Chemical activators include thienoperydones, D-xylose and lipophilic D-xylose derivatives, cilostazol, phytoestrogens,
momordicosides, capsaicinoids, furanothiazolidine, and AICAR; structurally unrelated compounds include chromium
pibolinate, α-lipoic acid, kainic acid, cannabanoids, long-chain fatty acids, reactive oxygen species, leptin, ghrelin, and
interleukin 6
SIRT1 Increase insulin action Activation of SIRT1 downregulates the nuclear transcription factor P53, represses PPARγ, and complexes with PPARγ
coactivator 1α and HNF4α; activation increases insulin sensitivity and insulin secretion in rodents;130 caloric restriction
specifically regulates tissue concentrations of SIRT1 (increase in white adipose tissue, muscle, and pancreas; decrease in
liver130); prototype drug is resveratrol, which is a natural product in grapes; in-vitro data conflict as to whether SIRT1 acts
as an oncogene or tumour suppressor130
PTPN1 (also known as PTP1B) Increase insulin action Inhibition of PTPN1 is a potential treatment for type 2 diabetes and other insulin-resistance-associated disorders; inhibition
improves insulin sensitivity and reduces bodyweight, total cholesterol, and triglycerides in mice fed a high-fat diet131
FGF21 Increase insulin action Abundantly expressed in white adipose tissue, liver, and pancreas;132 in liver, produces a profile similar to that of fasting
by inducing gluconeogenesis, fatty-acid oxidation, and ketogenesis by inducing PPARγ coactivator 1α;132 in human
beings, FGF21 concentrations increase with prolonged fasting and are increased in overweight individuals with features
of metabolic syndrome;132 administration of a new FGF21 variant to diabetic rhesus monkeys reduced bodyweight,
glucose, insulin, LDL cholesterol, triglycerides, and leptin and increased HDL cholesterol and adiponectin133
IKKβ–NFκB pathway Decrease cellular inflammation In studies of patients with type 2 diabetes, using salsalate as an inhibitor reduced haemoglobin A1c by 0·37% during
48 weeks of treatment;134 urinary albumin excretion increases with therapy which reverses with withdrawal of treatment134
Interleukin 1β receptor antagonists Decrease cellular inflammation Main target is intraislet immune response resulting in interleukin 1β production;71 studies in human beings have been
and interleukin 1β antibodies mixed, with modest effects to reduce haemoglobin A1c135
HSD11B1 (also known as Reduce cortisol production Enzyme generates cortisol from its inactive form cortisone;136 enzyme implicated in visceral obesity and metabolic
11β-HSD1) syndrome137 with increased enzyme activity in adipose tissue in obese and insulin-resistant people;138,139 inhibitors have
shown a small effect on glucose lowering140
Glucagon and GLP-1 Coagonist therapy Principle is to combine two peptides with different effects;141 increased energy expenditure with GLP-1 ameliorated the
effects of glucagon to increase concentrations of glucose142

NFκB=nuclear factor κ-light chain-enhancer of activated B cells. PPARγ=peroxisome proliferator-activated receptor γ. GLP-1=glucagon-like peptide 1.

Table 1: Selected therapeutic targets of largely untested mechanisms for type 2 diabetes

studies.152,153 These differences in cardiovascular outcomes
emphasise the need for individualised targets for glucose
control, as recommended in a position statement by the
American Diabetes Association and the European
Association for the Study of Diabetes on treatment of
type 2 diabetes.154 Addressing of concomitant cardio-
vascular risk factors (eg, LDL cholesterol and blood
pressure) could be more effective, and is consistent with
the multifactorial approach used in the Steno 2 study,155
findings from which showed a reduction in both cardio-
vascular and microvascular events that was sustained even
after cessation of regimens to reduce glucose, blood
pressure, and lipids.
Because lifestyle changes to reduce bodyweight have
always been an important therapy for type 2 diabetes,
investigators of Look AHEAD trial156 examined the effect
of weight reduction (achieved by an intensive lifestyle
intervention) on cardiovascular events. Despite
differential weight loss for more than 10 years and
improvements in many cardiovascular risk factors
(including blood pressure and lipids), lifestyle change did
not reduce cardiovascular events compared with diabetes
support and education (control group). This finding
might have been because large proportions of participants
in both groups received medical treatment for these risk
factors. However, participants in the group receiving

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 Review
intensive lifestyle intervention who had a history of a
cardiovascular event at baseline had a tendency for an
increased risk of a subsequent cardiovascular event;156 a
similar finding was reported in ACCORD.144 Several other
findings from Look AHEAD are worthy of comment.
First, participants in the weight-loss group were more
likely to achieve either partial or complete remission of
diabetes,157 had better glucose control needing fewer
glucose-lowering drugs (including insulin), and were
more likely to achieve a glycated haemoglobin A1c
measurement of less than 7% (53 mmol/mol) than were
those in the control group.158 However, despite weight loss
and addition of drugs, patients in the treatment group
had similar progression of diabetes to that of the control
group—ie, with continuous increases in glycated
haemoglobin A1c.156 Second, lifestyle change slowed
progression of nephropathy. Third, other health outcomes
associated with better quality of life—eg, sleep apnoea159
and mobility160—improved. Thus, intensive lifestyle
change in patients with type 2 diabetes has benefits, but
unfortunately not for cardiovascular outcomes, which
remain the major cause of premature mortality in type 2
diabetes.
In view of the fact that type 2 diabetes is a progressive
disease due to advancing β-cell dysfunction, can new
drugs slow loss of β-cell function to provide durable
glucose control? In the ADOPT study,161 recently diagnosed
and previously untreated patients were given 4 years of
monotherapy with glibenclamide, metformin, or
rosiglitazone. Glibenclamide produced the largest initial
reduction in glycaemia, but provided poorest maintenance
of overall glucose control. Whereas the onset of glucose
lowering with the other two drugs was slower than for
glibenclamide, it was most sustained with rosiglitazone,
with intermediate maintenance of glucose control with
metformin, which was mostly related to effect on β-cell
function.11,161 Whether recently introduced drugs will
maintain glucose control over the long term remains to be
established. Limited data from a few patients suggest that
incretin-based therapies, which are purported to improve
β-cell health, could have such a benefit.162
Strategies to slow disease progression have also
focused on people with impaired glucose tolerance or
impaired fasting glucose because of their high risk of
development of type 2 diabetes. Several studies have
examined the ability of lifestyle modification and drugs
to slow progression to diabetes (table 2). Findings from
these trials have nearly all shown a benefit, with lifestyle
modifications being more efficacious than any drug, with
the exception of the thiazolidinedione antidiabetics.163–175
Findings from prolonged follow-up showed that in some
instances the benefit of treatment was retained for
10 years or more,176–178 and could reduce risk of
development of severe retinopathy.179 In the DPP study,180
restoration of individuals to normal fasting and 2 h
glucose concentrations only once during the intervention
phase was associated with a reduced rate of subsequent
1076
diabetes, mostly as a result of improved β-cell function. A
question that has largely gone unanswered is whether
the interventions actually alter the natural history of the
disease, or simply mask the development of diabetes as a
result of earlier commencement of treatment.181 Only
reports of the effects of troglitazone in DPP172 and insulin
glargine in ORIGIN146 suggest a residual benefit after
prolonged withdrawal of the intervention. However,
despite good rationale for approval of interventions to
delay the onset of diabetes,182 no drug has yet received
official sanction as a preventive treatment.
Finally, whereas type 2 diabetes mostly affects adults,
sadly it is now emerging in youth. The pathogenesis of
the syndrome in children is also crucially established by
loss of β-cell function, with the degree of residual β-cell
function determining glucose control in recently
diagnosed patients.183 The TODAY study184 examined the
effect of lifestyle and drugs in a young cohort with
diabetes duration of less than a year, and found glycaemia
to be best managed by the combination of rosiglitazone
and metformin, with the addition of lifestyle to metformin
being no better than metformin alone. The disease’s
course in young people seems to be more aggressive than
in adults, with the differential effect of interventions
being the result of a greater improvement in β-cell
function.183 Further analyses from TODAY showed that in
young people with type 2 diabetes, dyslipidaemia185 and
hypertension186 are common and worsen over time. Both
microalbuminuria and retinopathy increase with diabetes
duration, and severity is related to glycaemic control.186,187
These findings provide much-needed insights, and will
certainly give rise to additional investigations into better
treatments for type 2 diabetes in youth. Hopefully, good
alternatives will be found, because the very high morbidity
in young people has major implications for their quality
of life as the duration of disease lengthens and
complications develop.
What does the future hold?
Several of these studies are following up participants for
outcomes relevant to type 2 diabetes. In DPP, conversion
from impaired glucose tolerance to diabetes has been
diagnosed within 6 months; findings from this study will
provide a better understanding of the natural history of
microvascular and macrovascular complications, and help
to establish whether some of these complications (eg,
retinopathy) develop before the onset of diagnostic
hyperglycaemia. In both DPP and Look AHEAD,
assessment of the decrease in longitudinal cognitive
function will provide insight into this underappreciated
adverse outcome of hyperglycaemia. Passive follow-up of
participants from ORIGIN, ADVANCE, and TODAY will
inform as to whether improved glucose control provides
any beneficial legacy (so-called metabolic memory) on
vascular disease, as was suggested initially by findings
from the follow-up of patients with type 1 diabetes in the
DCCT study,188 and subsequently from the follow-up of
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 Review

Study groups and number of Average duration Incidence of diabetes in Relative risk p value Notes
partipants of follow-up control or placebo group reduction
(years) (per 100 person-years) (%)
Lifestyle
Da Qing163 Control (133), diet (130), exercise 6·0 15·7 31% (control all <0·05 Randomisation by clinic and not
(141), diet and exercise (126) vs diet); 46% by individual
(control vs
exercise); 42%
(control vs
diet and
exercise)
Finnish Diabetes Prevention Study164 Control (257), lifestyle (265) 3·2 5·8 58% <0·001 ··
US Diabetes Prevention Program165 Placebo (1082), lifestyle (1079) 2·8 11·0 58% <0·001 ··
Indian Diabetes Prevention Control (136), lifestyle (133) 2·5 18·3 28·5% 0·018 ··
Programme166
Medication
US Diabetes Prevention Program165 Placebo (1082), metformin (1073) 2·8 11·0 31% <0·001 ··
Indian Diabetes Prevention Control (136), metformin (133) 2·5 18·3 26·4% 0·029 ··
Programme166
Nepi Antidiabetes Study167 Placebo (138), glimepiride (136) 3·7 14·8 25·5% 0·072 ··
STOP-NIDDM168 Placebo (715), acarbose (714) 3·3 12·4 25% 0·0015 ··
XENDOS169 Placebo (344), orlistat (350) 4·0 7·2 45% 0·0024 Only participants with impaired
glucose tolerance from the study
presented
NAVIGATOR170 Placebo (4661), nateglinide (4645) 5·0 7·2 −7% NS ··
ORIGIN146 Control (719), insulin glargine (737) 6·2 5·0 28% 0·006 Only participants with impaired
glucose tolerance from the study
presented; 100 days after
stopping therapy, risk reduction
with insulin glargine was 20%
TRIPOD171 Placebo (122), troglitazone (114) 3·6 12·1 55% <0·01 Study discontinued prematurely
because of withdrawal of
troglitazone from the market
US Diabetes Prevention Program172 Placebo (582), troglitazone (585) 0·9 12·0 75% <0·001 Troglitazone discontinued
prematurely because of hepatic
adverse events including a death
DREAM173 Placebo (2634), rosiglitazone (2365) 3·0 8·3 62% <0·001 ··
ACT NOW174 Placebo (299), pioglitazone (303) 2·4 7·6 72% <0·001 ··
Combination therapy
Indian Diabetes Prevention Control (136), lifestyle plus 2·5 18·3 28·2% 0·022 ··
Programme166 metformin (129)
CANOE175 Placebo (104), lifestyle plus 3·9 10·1 66% <0·001 ··
rosiglitazone (103)

When not available, incidence rates were calculated from the proportion of individuals who had reached the primary outcome divided by the average duration of follow-up. NS=not significant.

Table 2: Results of intervention studies to prevent development of type 2 diabetes in people with impaired glucose tolerance

UKPDS.189 Because improved glucose control reduces
microvascular complications, and greater progression of
retinopathy is associated with increased cardiovascular
disease,190 a beneficial effect on cardiovascular outcomes
might also be observed in these studies.
Cardiovascular safety of glucose-lowering drugs has
become an essential requirement for their registration,191
and large studies of incretin-based therapies (NCT00790205,
NCT00968708, NCT01107886, NCT01144338, NCT01147250,
NCT01179048, NCT01243424, and NCT01394952) and
SGLT2 inhibitors (NCT01032629, NCT01131676, and
NCT01730534) are underway. The results of the SAVOR-
TIMI 53 (NCT01107886) and EXAMINE (NCT00968708)
studies were recently reported, and showed no increased
risk of cardiovascular events with the DPP4 inhibitors
saxagliptin96 and alogliptin.97 Collectively, the studies
examining GLP-1 receptor agonists and DPP4 inhibitors
will also provide an unbiased assessment of the possible
increased risk of acute pancreatitis and malignant
transformation in the pancreas with these drugs. Although
the number of pancreas-related events in SAVOR-TIMI 53
and EXAMINE were too small to be definitive, there was no
evidence for a marked excess of such events with either
drug. One of these long-term studies (NCT01243424)
directly compares a DPP4 inhibitor to glimepiride, and will
provide insight into whether sulfonylurea antidiabetics

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 Review
confer an increased risk of cardiac events, a question raised
by findings from the University Group Diabetes Program
more than 40  years ago.192,193 Furthermore, these studies
should provide information about whether incretin-based
drugs actually protect against cardiovascular disease, as
suggested by findings from meta-analyses of phase 2
and 3 studies.194,195 Finally, although not designed specifically
to do so, these studies will provide clues as to whether
incretin-based therapies and SGLT2 inhibitors provide
more durable glucose control.
What else is needed? Although present treatment
algorithms are less prescriptive than were earlier
algorithms, and advocate a more personalised approach to
the choice of drugs and treatment targets for type 2
diabetes,154 an important question that still remains is
what drug to add after metformin. Present treatment
algorithms are based mostly on studies done by
pharmaceutical companies, which typically do not
compare more than two drugs and are short term. The
GRADE trial196 will compare head-to-head the effect on
metabolic control of the sulfonylurea antidiabetic
glimepiride, the DPP4 inhibitor sitagliptin, the GLP-1
analogue liraglutide, and basal insulin glargine when
added to metformin, for up to 7 years of intervention. It
will also examine adverse effects, effect on cardiovascular
risk factors, quality of life, tolerability, cost-effectiveness,
and phenotypic characteristics associated with response to
or failure of the four different drug combinations. This
outcome, along with genotyping of participants, should
also provide insight into possible subtypes of the disease
and a more accurate, pathogenesis-based approach to
individualised treatment. However, GRADE will not
address whether initiation of therapy with a combination
of drugs is more beneficial than the more traditional
stepwise approach.
Because present treatment approaches do not prevent
or slow the loss of β-cell function, alternative approaches
are urgently needed. RISE (NCT01779362, NCT01779375,
and NCT01763346)197 is a feasibility study employing
three different protocols to assess the effect on β-cell
function of medical and surgical approaches in adults
and children with impaired glucose tolerance or recently
diagnosed diabetes. The drug protocols in adults and
children will last 12 months, with advanced testing of
insulin sensitivity and β-cell function at baseline, at the
end of active treatment, and after a 3 month washout. In
adults, metformin alone, insulin glargine followed by
metformin, and liraglutide plus metformin will be
compared with placebo (NCT01779362), whereas in the
children the former two regimens will be tested
(NCT01779375). The surgical protocol in adults will
compare using the same outcomes the effect of weight
loss from laparoscopic banding with metformin alone
during 24 months of follow-up (NCT01763346).
Surgical procedures aimed at reduction of weight have
been postulated to have benefits beyond simple weight
loss and glucose control, and include reduced
1078
cardiovascular events and mortality.198–200 However, these
hypotheses are based on results from the SOS study,198–200
in which participants were not randomised and the
control group was contemporaneously matched, only
received conventional treatment, and differed by several
characteristics at baseline. Thus, appropriately controlled
studies comparing surgical and non-surgical inter-
ventions to produce weight loss are needed. Furthermore,
long-term studies of the effect of so-called metabolic
surgery, which focuses mainly on correction of metabolic
abnormalities rather than weight loss (as does bariatric
surgery),201 are needed to establish whether the
progression of diabetes can be slowed or halted and
whether adverse events as a result of the surgery reduce
its usefulness. Clarification of the differential long-term
positive and negative effects of simple restriction with
banding versus the more complex bypass procedures
would also be helpful.201
Conclusions
In 1984, Asmal and Marble202 wrote that “despite the
availability of oral hypoglycaemic drugs for nearly
30  years, their precise mode of action and role in the
management of diabetes mellitus remains poorly
defined and controversial”. Nearly 30 years after that
statement, doctors and researchers still have a great deal
to learn about the pathogenesis of type 2 diabetes and
how best to use the therapies available, although great
progress has been made in clarification of their modes
of action. The next 30 years will hopefully provide the
knowledge and approaches needed to reduce the global
harm of type 2 diabetes, not only through management
of the disorder more effectively with a combination of
non-pharmacological and pharmacological approaches,
but also through prevention of the disease and
identification of new strategies to directly target its
complications.
Contributors
SEK did the initial literature review and wrote first draft of this Review.
MEC and SDP provided critical review and redrafting of the text and
figures, and assisted with additional literature review.
Conflicts of interest
SEK has received honoraria for advisory work and lectures from
Boehringer Ingelheim, Bristol-Myers Squibb, Elcelyx, Eli Lilly,
Genentech (Roche), GlaxoSmithKline, Intarcia, Janssen, Merck, Novo
Nordisk, Receptos, and Takeda. MEC has received honoraria for advisory
work and lectures from AbbVie, AstraZeneca, Bayer, Boehringer
Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Novo Nordisk, and
Takeda. SDP has received honoraria for advisory work and lectures from
AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly,
GlaxoSmithKline, Intarcia, Janssen, Merck Sharpe and Dohme, Novartis,
Novo Nordisk, Roche Diagnostics, Sanofi-Aventis, and Takeda; and
research support from Bristol-Myers Squibb, Merck Sharpe and Dohme,
Novartis, and Novo Nordisk.
Acknowledgments
SEK is supported partly by the US Department of Veterans Affairs and
NIH grant DK-017047. MEC is supported by an Australia Fellowship
from the National Health and Medical Research Council of Australia.
SDP was supported by grant 2010YK7Z5K_006 from the Italian Ministry
of Education and Research.
www.thelancet.com Vol 383 March 22, 2014

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