The British Journal of Diabetes & Vascular Disease

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Review: Inhibition of dipeptidyl peptidase-4 with vildagliptin: a potential new treatment for type 2 diabetes
Richard E Pratley, Afshin Salsali and Glenn Matfin British Journal of Diabetes & Vascular Disease 2006 6: 150 DOI: 10.1177/14746514060060040201 The online version of this article can be found at: http://dvd.sagepub.com/content/6/4/150

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Inhibition of dipeptidyl peptidase-4 with vildagliptin: a potential new treatment for type 2 diabetes
RICHARD E PRATLEY,1 AFSHIN SALSALI,1 GLENN MATFIN2
Abstract Introduction
Diabetes mellitus currently affects more than 170 million people worldwide and its prevalence is increasing dramatically.1 By 2025, the number of affected individuals is expected to exceed 330 million, globally.1 The chronic microvascular and macrovascular complications of diabetes associated with poor glycaemic control account for much of the morbidity, mortality and economic costs associated with the disease. Although substantial evidence indicates that good glycaemic control can lower the risk for microvascular complications (and probably macrovascular disease as well), most patients are not treated to recommended glycaemic goals.2-5 In the recent US National Health and Nutrition Examination survey, HbA1C was less than 7% in only ~40% of patients with diabetes.5 In part, the failure to achieve glycaemic goals in a larger fraction of the population reflects limitations in current treatment options for patients with type 2 diabetes mellitus, who represent the overwhelming majority (~95%) of patients with diabetes in most regions. All available oral antidiabetic agents are associated with side effects that limit their use.6 Sulphonylureas, meglitinides, and insulin are associated with weight gain and hypoglycaemia; TZDs also cause weight gain and may cause peripheral oedema and metformin and -glucosidase inhibitors are associated with gastrointestinal side effects. Moreover, with the possible exception of the TZDs, glycaemic control gradually worsens over time with most treatments.3,7 The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that < 40% of patients with type 2 diabetes could be controlled (HbA1C < 7%) on a single agent after three years. The high rate of monotherapy failure necessitates the use of combinations of multiple agents and eventually insulin in many patients. To understand why this is the case, a working knowledge of the pathophysiology of type 2 diabetes is helpful.

Key words: GLP-1, GIP, incretin hormone, incretin enhancer, DPP-4, diabetes.

Diabetes and Metabolism Translational Medicine Unit, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Vermont College of Medicine, USA. 2 Novo Nordisk Inc. 100 College Road West, Princeton, New Jersey 08540, USA; and Division of Endocrinology and Diabetes, Department of Medicine, New York University School of Medicine, New York, New York, USA.
1

Correspondence to: Professor Richard E Pratley Diabetes and Metabolism Translational Medicine Unit, FAHC/UHC - Arnold 3412, One South Prospect Street, Burlington, VT 05401, USA. Tel: +1 802 847 8901; Fax: +1 802 847 3401 E-mail: rpratley@uvm.edu

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ype 2 diabetes mellitus is a growing problem in most parts of the world. There is now good evidence that controlling hyperglycaemia can help prevent many of the serious complications associated with the disease. Despite this evidence and the availability of several classes of oral antidiabetic agents and insulin, many people with diabetes do not achieve adequate glycaemic control (i.e. HbA1C < 6.5 or 7.0%). Thus, there is an urgent unmet medical need to develop new and better treatments for type 2 diabetes. Among the most promising new classes of drugs for type 2 diabetes are those that leverage the incretin hormone glucagon-like peptide-1 (GLP-1). Vildagliptin, an orally available, potent and specific inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme that rapidly inactivates GLP-1, augments endogenous active GLP-1 and gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP) and reduces hyperglycaemia in patients with type 2 diabetes. Studies to date in patients exposed for up to one year indicate that vildagliptin produces clinically significant reductions in HbA1C when used as monotherapy and in combination with metformin, glimepiride, or insulin. In general, the drug has proved to be well tolerated with low rates of hypoglycaemia and gastrointestinal side effects (including nausea) and no weight gain or oedema. Br J Diabetes Vasc Dis 2006;6:1506

Multiple metabolic defects contribute to hyperglycaemia in type 2 diabetes

While there is general agreement that both genetic and environmental factors play critical roles in the development of type 2 diabetes, there is growing awareness that it is a heterogeneous disorder, with differences in the phenotype, presentation and course between populations, pedigrees and individuals.8 Nevertheless, most patients with type 2 diabetes manifest a common set of abnormalities, including obesity (especially an abdominal distribution), insulin resistance in the liver, skeletal muscle and adipose tissue, and quantitative and qualitative

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Abbreviations DPP-4 FDA GIP GLP-1 HbA1C IC50 OAD Tmax TZD dipeptidyl peptidase-4 (4 also written as Latin numeral IV) Food and Drug Administration glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide) glucagon-like peptide-1 haemoglobin A1C inhibitory concentration (50%) oral antidiabetic Time to maximal plasma concentration thiazolidinedione

Figure 1. Biological actions of GLP-1 and GIP on organs and peripheral tissues Following meal ingestion GLP-1 and GIP are released from intestinal L-cells and K-cells, respectively. GLP-1 and GIP lower glucose by stimulating insulin release from the endocrine pancreas and improve glucose uptake and utilisation in peripheral tissues (liver, muscle and adipose). In contrast to GIP, GLP-1 brings about feelings of satiety and fullness by interaction with its receptors in the brain. GLP-1 also exerts inhibitory effects on gastric emptying

Meal ingestion Stomach

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GLP-1
Satiety

defects in insulin secretion.9 These abnormalities precede and predict type 2 diabetes and worsen during its development, and can accordingly be considered the primary metabolic defects in the pathogenesis of the disease.9-11 In addition, hypersecretion of glucagon in the fasting state and failure to normally suppress glucagon following a meal contributes to dysregulation of endogenous glucose production, which is elevated in proportion to the degree of hyperglycaemia in patients with type 2 diabetes.12 Similar abnormalities in glucagon secretion can be seen in subjects with impaired glucose tolerance, however, it is not clear whether they predict type 2 diabetes akin to insulin resistance and impaired insulin secretion. Finally, autopsy studies performed in recent years indicate that beta-cell mass is decreased in people with diabetes and, to a lesser degree, also in those with impaired fasting glucose.13 Thus, the pathogenesis of type 2 diabetes is characterised by multiple metabolic abnormalities including insulin resistance in key tissues and islet dysfunction, with impaired insulin secretion, glucagon dysregulation, and structural lesions. While the relative contributions of these abnormalities may vary from patient to patient and among individual patients over time, all are undoubtedly significant in the development of hyperglycaemia and thus represent important therapeutic targets.

Gastric emptying

Gut

L-cells

K-cells

GIP

Pancreas

Brain

Insulin

Glycogensynthesis

Liver

Glucoseuptake

Muscle

Lipogenesis

Adipose

Reproduced with permission from Green et al. Br J Diabetes Vasc Dis 2005;5:13440

GLP-1 and the therapeutic potential of incretin hormones

The demonstration that the incretin hormone GLP-1 can improve glycaemic control in patients with type 2 diabetes has led to the rapid development during the last decade of a promising new class of therapeutic agents for type 2 diabetes.14-16 GLP-1 (7-36) is a 30 amino acid polypeptide that is encoded by the proglucagon gene and secreted from the L-cells in the ileum in response to nutrients in the gut15 (figure 1). GLP-1 is an incretin hormone, meaning that it potentiates the insulin response to an oral glucose challenge relative to an isoglycaemic intravenous glucose challenge.15 In vivo, the incretin effect is substantial, accounting for as much as two thirds of the insulin response to an oral glucose challenge in normal individuals. GIP, a 40 amino acid peptide secreted by the K cells of the duodenum, also manifests incretin activity in normal humans.16 GLP-1 and GIP account for approximately 90% of incretin activity. The incretin response is largely absent in patients with type 2

diabetes due to abnormalities in both GLP-1 and GIP. GLP-1 secretion is decreased by 2025% and the beta-cell response to GLP-1 is impaired in patients with diabetes.17-20 Despite this, infusions of GLP-1 are capable of normalising glucose levels in patients with type 2 diabetes.14 In contrast, GIP levels are either normal or slightly increased in patients with type 2 diabetes and insulin responses to infused GIP (but not pulse administration) are markedly blunted, additionally GIP does not appear to correct hyperglycaemia to the same extent as infused GLP-1.19,21 Thus, GLP-1 and to a lesser extent GIP, analogues are actively being explored as possible treatments for diabetes.22 GLP-1 has multiple physiological effects that could lead to improved glycaemic control in diabetes.15,16 Acting through a specific G-protein coupled receptor on beta-cells it increases insulin secretion in a glucose dependent manner and increases transcription of the proinsulin gene, thus increasing availability of insulin for secretion from beta-cells. Importantly, GLP-1 also has independent effects on alpha-cells to inhibit glucagon secretion ('glucagonostatic'). This effect may explain much of the acute glucose-lowering effect of GLP-1. Both the alpha- and beta-cell effects are glucose-dependent, therefore, the risk for hypoglycaemia is low with GLP-1 based therapies. Some studies also

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suggest that GLP-1 has independent effects to increase insulin action in skeletal muscle.23 At high concentrations, GLP-1 slows gastric emptying, resulting in delayed absorption of glucose and nutrients from the gut.24 GLP-1 receptors in the hypothalamus may modulate satiety and food intake, leading to weight loss with prolonged exposure. Finally, both GLP-1 and GIP have been shown to induce beta-cell proliferation, differentiation and neogenesis and decrease apoptosis in multiple preclinical models.25,26 The net effect of these changes is to increase beta-cell mass. Thus, GLP-1 has both acute metabolic effects to improve glycaemia and long-term effects that may reverse progressive loss of beta-cells over time. Although promising as a novel therapeutic approach for type 2 diabetes, the practical utility of native GLP-1 is limited. GLP-1 (7-36) is rapidly inactivated by an enzyme called DPP-4 that cleaves the two N-terminal amino acids to form inactive GLP-1 (9-36).27,28 Consequently, the half-life of active GLP-1 (736) in the circulation is only 12 minutes and the majority (80%) of circulating GLP-1 is the inactive form. To address this, a number of GLP-1 analogues that are resistant to inactivation by DPP-4 and have prolonged activity relative to native GLP-1 have been synthesised (termed 'incretin mimetics').15,16 A GLP-1 mimetic, exenatide (Byetta), has recently been approved in the US for treatment of type 2 diabetes in patients failing to achieve adequate glycaemic control on oral antidiabetic therapy.29,30 Exenatide, like GLP-1, is a peptide, and must be given twice a day by injection. An alternative approach, which obviates the need for injections, is to inhibit the enzymatic activity of DPP-4, to augment levels of endogenous active GLP-1 and GIP, such agents are termed 'incretin enhancers'. DPP-4 (also known as CD26) is a membrane associated protein ubiquitously expressed on the surface of endothelial cells and T-cell lymphocytes, and is also present in the circulation in a soluble form which retains its enzymatic function.28 Cell surface CD26, in addition to the DPP-4 enzymatic activity related to its extracellular segment, has other signal transferring functions independent of DPP-4. The latter does not appear to be affected by DPP-4 inhibitors, and may be the reason why the immune activating component of CD26 is not affected by DPP-4 inhibitors. DPP-4 is an amino terminal serine peptidase with in vitro activity against many hormones and chemokines.28 DPP-4 appears to be the major pathway for the in vivo inactivation of GLP-1 and GIP. In contrast, most other regulatory peptides that are substrates for DPP-4 in vitro appear to be metabolised by alternative pathways.28 Mice and rats in which the DPP-4 gene has been knocked-out or is mutated have increased GLP-1 levels and improved glucose tolerance relative to wild-type animals, demonstrating the importance of the incretin system in normal glucose homeostasis and providing proof-ofconcept that inhibition of DPP-4 can improve glycaemic control.31,32 Several pharmaceutical companies have synthesised orally available, small molecule inhibitors of DPP-4 (termed 'gliptins') and a number of these compounds are in various stages of development. Two of these 'gliptins', vildagliptin (LAF237, Novartis, NJ, USA, with the proposed trade name

Table 1.

Some key characteristics of GLP-1 agonists compared with DPP-4 inhibitors15,16,29,35 Characteristics GLP-1 agonists DPP-4 inhibitors i.e. incretin i.e. incretin mimetics enhancers ? X ? X

Category

Islet function

glucose-dependent insulin secretion glucagon secretion Improve beta-cell function Increase beta-cell mass in rodents Increase beta-cell mass in humans

Safety and tolerability

Injection Oral Lower risk of hypoglycaemia than insulin secretagogues and insulin Specificity Induce satiety and weight-loss

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X X X X

Slows gastric emptying Increased nausea and vomiting

Key: X = No; = Yes; ? = Unknown

'Galvus') and sitagliptin (MK-O431, Merck, NJ, USA, with the proposed trade name 'Januvia'), were both submitted for FDA approval in early 2006. Vildagliptin will be the main focus for this brief review. A comparison of some of the key characteristics of incretin mimetics versus incretin enhancers are noted in table 1.

Vildagliptin: a potent and specific inhibitor of DPP-4

Vildagliptin is an N-substituted glycyl-2-cyanopyrrolidine (figure 2). It is a potent competitive and reversible inhibitor of human and rodent DPP-4 in vitro, with a median inhibitory concentration (IC50) ~23 nmol/L.33 Importantly, vildagliptin inhibits DPP-4 with high specificity relative to other similar peptidases where its IC50 exceeds 200 mol/L.33 This specificity is of potential clinical importance as inhibition of DPP-8 and DPP-9 has been associated with immune, histopathological and gastrointestinal toxicity in various animal models.34 In healthy humans, vildagliptin is rapidly and almost completely absorbed (~85% of administered dose) after oral administration with a tmax of 12-hours.33,35,36 Plasma levels were linearly related to dose and the plasma half-life ranged from 1.54.5 hours with doses from 25 to 200 mg. The drug does not appear to accumulate with multiple dosing and the pharmacokinetics are not affected by food. Most of the drug is metabolised with hydrolysis of the cyano moiety dominating (55%), but a fraction (22%) is also excreted unchanged by the kidneys.33,35,36 The drug is minimally metabolised by the major cytochrome P450 enzymes that metabolise many other drugs and is neither an inhibitor nor

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Figure 2. Vildagliptin (chemical structure is based on the common design for DPP-4 inhibitors: a L-amino acid with a protonable N-terminal primary amine in the P-2 site) exhibits high-affinity, reversible, DPP-4 inhibition resulting in increased levels of active GLP-1

Vildagliptin (Galvus) H O N

HO

N N

Mixed meal

Intestinal release of GLP-1

Inhibition DPP-4 DPP-4

Active GLP-1

Inactive GLP-1

Adapted from J Shannon, Development Pipeline 2006, www.novartis.com, accessed 25th May 2006

an inducer of these enzymes. In the circulation, vildagliptin is not extensively protein bound (417%). No adjustment of dose is necessary in either hepatic or renal insufficiency.37 Single doses of vildagliptin (25200 mg) rapidly inhibit plasma DPP-4, achieving > 90% inhibition within 3060 minutes.33,35 The duration of inhibition is dose dependent; with the anticipated therapeutic doses of 50 mg and 100 mg, DPP-4 activity is inhibited by ~70 and 90% at 12 hours and remains inhibited by ~40% at 24 hours with the higher dose. In drug nave patients with type 2 diabetes, four weeks of treatment with vildagliptin at a dose of 100 mg per day reduced both fasting and postprandial plasma glucose levels, resulting in significant decreases in HbA1C.38 Vildagliptin treatment also improved insulin secretion, as assessed by the insulin responses relative to the glucose responses to a standard mixed meal, increased both basal and postprandial GLP-1 levels, and decreased glucagon levels. The drug appeared well tolerated. The results of additional phase 2 and phase 3 studies of vildagliptin in patients with type 2 diabetes have recently been made available and are summarised below.

Vildagliptin as monotherapy
Several phase 2 and phase 3 studies have examined the use of vildagliptin as monotherapy for patients with type 2 diabetes

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inadequately controlled with diet and exercise alone. A 12-week dose-ranging study in 279 patients compared dosing regimens of 25, 50 and 100 mg once daily and 25 mg twice daily.39 From a mean baseline HbA1C of ~7.7%, vildagliptin at doses of 50 and 100 mg a day produced significant reductions in HbA1C of ~0.5%. Another 12-week study in 98 patients demonstrated that vildagliptin at a dose of 25 mg twice daily decreased HbA1C by 0.6% (p=0.0012) relative to placebo from a baseline of 8.0%.40 In a subset of subjects with a higher initial baseline ranging between 8.09.5%, a 1.2% reduction in HbA1C was observed. In this study, fasting and prandial glucose levels were reduced by 1.1+0.4 (p=0.0043) and 1.9+0.5 mmol/L (p<0.0001), respectively. In a 24-week phase 3 study in 380 patients managed with diet and exercise (baseline HbA1C 7.511%), vildagliptin at doses of 50 and 100 mg per day and 50 mg twice daily (these are the predominant doses used in the published phase 2/3 studies) reduced HbA1C by 0.80.9% from baseline. The reduction in HbA1C was highly significant for all doses of vildagliptin relative to placebo (which reduced HbA1C by 0.3% in this study), but none of the dosing regimens was significantly different from one another. Two additional phase 3 studies of vildagliptin monotherapy have recently been reported. In the first, a 52-week head-to-head study versus metformin, vildagliptin 50 mg twice daily (n=526) reduced HbA1C by 1.0% from a starting HbA1C of 8.7%, whereas metformin at a dose of 2,000 mg per day (n=254) reduced HbA1C by 1.4% (p<0.05 compared to vildagliptin in the intention-to-treat analyses).41 The reductions in HbA1C were sustained for the entire 52 weeks with both vildagliptin and metformin. In the second study, vildagliptin 50 mg twice daily for 24 weeks was similar to rosiglitazone 8 mg per day.42 In a subset of subjects with higher HbA1C levels at baseline (mean 10%), vildagliptin (n=166) reduced HbA1C by 1.82% while rosiglitazone (n=88) reduced HbA1C by 1.86%.42

Vildagliptin in combination

Two studies have examined the glucose lowering effects of vildagliptin when added-on to metformin monotherapy. The first, a 12-week phase 2 study in 107 patients on metformin demonstrated that vildagliptin at a dose of 50 mg per day reduced HbA1C by 0.6% from a mean baseline of 7.7%, whereas HbA1C was unchanged in the group randomised to placebo.43 Patients in this study were followed during a 40-week extension for a total of 52 weeks. The reductions in HbA1C were sustained in the group receiving metformin plus vildagliptin, whereas HbA1C increased over the course of the year in subjects treated with metformin plus placebo. At the end of the extension, HbA1C was 1.1% lower in those who received vildagliptin in addition to metformin compared to those who received metformin alone. Notably, fasting and prandial glucose concentrations were significantly lower, whereas insulin responses to a standard meal challenge were significantly higher after 52 weeks of treatment with vildagliptin. A 3-arm 24-week phase 3 study in 416 patients on metformin monotherapy (baseline HbA1C 7.511%) compared the effects of vildagliptin at doses of 50 mg

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Table 2.

Potential safety and tolerability issues with DPP-4 inhibitors Current status No nausea and vomiting. GLP-1 levels with incretin enhancers are more physiological compared to the pharmacological levels with incretin-mimetics No apparent immune activation/suppression seen/expected in preclinical and clinical studies to date. Further surveillance indicated Current DPP-4 inhibitors in advanced development are highly DPP-4 specific and do not exhibit toxicity of the type seen with DPP 8/9 inhibition in animals Although a wide variety of peptides are substrates for DPP-4 in vitro, most appear to have alternative metabolic pathways in vivo. Further studies are required including post-marketing surveillance

Potential issue Supraphysiological GLP-1 levels (e.g. nausea and vomiting seen with incretin mimetics may be related in part to higher GLP-1 levels than normal) Potential effects on immune function due to CD26 (marker of T-cell activation and proliferation) inhibition Effects of DPP-4 inhibitors on other DPP isoforms (i.e. DPP 8/9 inhibition is associated with significant toxicity in animals) Effects of DPP-4 inhibition on other putative DPP-4 substrates (e.g. substance P, NPY, PYY, GLP-2, GHRH and various chemokines)

Key: NPY = neuropeptide Y; PYY = peptide YY, GLP-2 = glucagon-like peptide -2; GHRH = Growth Hormone Releasing Hormone

per day (n=143) and 50 mg twice a day (n=143) to placebo (n=130).44 Starting from a mean HbA1C of ~8.5%, both the 50 mg per day and 50 mg twice daily doses of vildagliptin significantly decreased HbA1C relative to placebo by 0.7% and 1.1%, respectively, although the difference between doses was not statistically significant. A similar phase 3 study examined the effects of vildagliptin added to sulphonylurea monotherapy. This study compared vildagliptin 50 mg per day (n=132) and 50 mg twice a day (n=132) to placebo (n=144) added-on to glimepiride 4 mg per day. Starting from a mean HbA1C ~8.7%, the 50 mg per day and 50 mg twice daily doses of vildagliptin significantly decreased HbA1C relative to placebo by 0.8 and 0.9%, respectively. Finally, a phase 3 study of vildagliptin 50 mg twice a day (n=144) or placebo (n=152) in insulin-treated type 2 diabetic patients demonstrated significant reductions in HbA1C in the group treated with vildagliptin (-0.5%) compared to those receiving placebo.45 Of note, the improvements in HbA1C with vildagliptin occurred in association with a lower total daily insulin dose and no episodes of significant (defined as blood glucose levels < 3.1 mmol/L with symptoms of hypoglycaemia and patient unable to initiate self-treatment) hypoglycaemia (compared with six episodes in those treated with insulin plus placebo). Collectively, the results to date indicate that vildagliptin monotherapy at daily doses of 50100 mg produces clinically significant reductions in HbA1C, comparable to those observed with rosiglitazone, although possibly less than those observed with metformin at one year. Vildagliptin also produces clinically significant reductions in HbA1C in patients already treated with metformin, glimepiride or insulin who are not at goal. The reductions in HbA1C with vildagliptin are attributable to improvements in both fasting and postprandial glucose levels and are associated with higher active GLP-1 levels, lower glucagon levels and improvements in insulin secretion. Improvements in insulin sensitivity have also been demonstrated in some studies, however, whether these changes are direct or indirect remains to be determined. Vildagliptin appears to work well in patients with higher

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baseline HbA1C levels and effects are durable for up to one year. Interestingly, small, but statistically significant reductions in blood pressure have been noted with vildagliptin therapy.46 Finally, a study in 31 drug nave patients with type 2 diabetes suggests that vildagliptin reduces post-prandial lipemia.47

Safety and tolerability of vildagliptin

In general, vildagliptin as monotherapy and in combination with other antidiabetic treatments has proved to be well tolerated for periods up to 52 weeks.35,41,43 The incidence of hypoglycaemia is low and similar to that with metformin or rosiglitazone.39,41,42 Even with treatment of up to 52 weeks, there is no apparent weight gain or oedema.41,43 The incidence of GI side effects is comparable to placebo and is much less than in metformin-treated patients.39,41 In addition, the incidence of cardiac adverse events (including arrhythmias and conduction abnormalities) and hypertension with vildagliptin is comparable to placebo and is also less than with metformin.41 Table 2 highlights some of the uncertainties regarding the safety of DPP-4 inhibitors.

Orally available DPP-4 inhibitors, which augment endogenous active GLP-1 to lower glucose, are promising additions to the therapeutic armamentarium for diabetes treatment. Vildagliptin, a potent and specific DPP-4 inhibitor, exemplifies the promise of the class. It produces clinically significant reductions in HbA1C as monotherapy and in combination with metformin, sulphonylureas, TZDs and insulin, bringing many patients to glycaemic goal. Since it is well tolerated, not associated with weight gain and has a low potential to provoke hypoglycaemia, it may be an appropriate first choice for many patients when diet and exercise have failed and is also suitable as add-on therapy when patients do not achieve glycaemic goals. Further studies in patients with pre-diabetes will elucidate the potential utility of this class of drugs in the prevention of diabetes, whereas longer-term studies will clarify whether DPP-4 inhibition, through augmented GLP-1, can modify the progressive nature of type 2 diabetes and result in durable control.

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Key messages

Incretin hormones like GLP-1 and GIP physiologically augment glucose-dependent insulin secretion after meals GLP-1 and GIP display multiple biological actions that result in improvements in islet function (e.g. both alphaand beta-cell) and other important metabolic effects GLP-1 (incretin) mimetics (e.g. exenatide) are already on the market in the US, with proven efficacy in glucose control in type 2 diabetes patients DPP-4 inhibitors ('incretin enhancers') are an attractive, new class of OAD agents that are in advanced clinical development for type 2 diabetes

Vidagliptin is a good example of the DPP-4 inhibitor class ('gliptins'), and to date, has been shown to be an effective and well-tolerated OAD in type 2 diabetes during clinical development

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HUMALOG MIX25* CARTRIDGE AND PEN (100U/ML) HUMALOG IS INSULIN LISPRO (HUMAN INSULIN ANALOGUE) ABBREVIATED PRESCRIBING INFORMATION Humalog Mix25 is a white, sterile suspension of 25% insulin lispro solution and 75% insulin lispro protamine suspension. Uses: Treatment of patients with diabetes mellitus who require insulin. Dosage and Administration: The dosage should be determined by the physician, according to the requirement of the patient. Humalog Mix25 may be given shortly before meals and, when necessary, can be given soon after meals. Humalog Mix25 should only be given by subcutaneous injection. Humalog Mix25 cartridges are to be used with a CE marked pen. Follow the pen manufacturers directions for loading the pen and priming it. Patients should be advised to always keep a spare pen and/or cartridge. Humalog takes effect rapidly (approximately 15 minutes). See Summaries of Product Characteristics for additional information, including time-action profiles. Contra-indications: Hypoglycaemia. Hypersensitivity to insulin lispro or to any of the excipients. Special Warnings and Special Precautions for Use: Usage in pregnancy: Data on a large number of exposed pregnancies do not indicate any adverse effect of insulin lispro on pregnancy or on the health of the foetus/newborn. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Patients should be advised to inform their doctors if they are pregnant or contemplating pregnancy. Insulin lispro should be used in children only when an advantage is expected compared to soluble insulin, for example, in the timing of the injection in relation to meals. Insulin requirements may be reduced in the presence of renal impairment, hepatic impairment, illness or emotional disturbances. In patients with chronic hepatic impairment, an increase in insulin resistance may lead to increased insulin requirements. Transferring to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, species, and/or method of manufacture may result in the need for a change in dosage. Changes in early warning symptoms of hypoglycaemia may occur on transfer between different types of insulin products. The patients ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia. This may constitute a risk in situations where these abilities are of special importance (eg, driving a car or operating machinery). Side-effects: Hypoglycaemia is the most frequent undesirable effect of insulin therapy. Lipodystrophy and hypersensitivity have been reported rarely. Legal Category: POM. Prices: 29.46 - 5 x Mix25 cartridges. 30.98 - 5 x Mix25 prefilled pens. Marketing Authorisation Numbers: Humalog Mix25 cartridge: EU/1/96/007/008, Humalog Mix25 Pen 3ml: EU/1/96/007/016. Date of Preparation or Last Review: March 2005. Full Prescribing Information is Available From: Eli Lilly and Company Limited, Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL. Telephone: 01256 315 999. * HUMALOG MIX25 (insulin lispro) is a trademark of Eli Lilly and Company.

Information about adverse event reporting can be found at www.yellowcard.gov.uk Adverse events should also be reported to Eli Lilly and Company Limited (Tel. no. 0870 2401125)