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Published on 6 June 2008

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Vildagliptin: a new option for the treatment of type 2 diabetes

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This DPPIV inhibitor promotes glucose homoeostasis, and in phase III studies consistently cut HbA1c levels with no apparent risk of hypoglycaemia or weight gain, and a beneficial adverse-effect profile

Martin Füchtenbusch
MD PhD

Adjunct Professor of Internal Medicine

Diabetes Research Institute
Technical University of Munich
Germany

While the number of people with type 2 diabetes mellitus (T2DM) continues to rise dramatically, the quality of diabetes treatment has made progress in recent years. As shown by the recent NHANES survey, mean HbA1c levels fell from 7.82% in the cohort assessed in 1999 to 7.18% in 2004.[1] Viewed from a more global perspective, mortality from ischaemic heart disease has also halved – from 524 per 100,000 individuals in 1980 to 266 per 100,000 in 2000 – due to better treatment and a reduction in classical risk factors such as high cholesterol, arterial hypertension and smoking (the latter accounting for approximately 60%).[2] However, in parallel with this, the observed increase in obesity and diabetes reduced this beneficial change in classical risk factors for ischaemic heart disease by 18%, demonstrating the paramount importance of diabetes as a leading cause of vascular disease and premature death.[2]

However, while current antidiabetic agents are effective in lowering glucose levels in many patients, they cannot provide optimal control over the long term. Moreover, side-effects such as weight gain, hypoglycaemia and oedema limit their use in the individual patient. In addition, other aspects of the pathophysiology of T2DM, such as inappropriate glucagon secretion in the face of hyperglycaemia, compromised islet function of beta and alpha cells and defective incretin effects, are not overcome by standard therapy.[3] GLP-1 and GIP are released from the gut soon after a meal, in response to carbohydrate intake particularly, and to a lesser extent to fat intake.[4] They are responsible for the incretin effect – the difference between the higher insulin response evoked by orally administered glucose and the lesser response evoked by an intravenously administered equal glucose dose. DPPIV inhibitors prevent rapid degradation of these hormones, allowing the latter to increase the ratio of insulin/glucagon, increase insulin secretion and action, reduce fasting and postprandial glucose values, and reduce HbA1c values.

Thus, therapeutic agents such as DPPIV inhibitors and incretin analogues offer a promising new way to improve glucose homoeostasis over the long term. The first DPPIV inhibitor, sitagliptin, was marketed in Europe in 2007, and vildagliptin will be available for clinical use in 2008.

Clinical data and discussion
Pharmacology
Vildagliptin belongs to the class of N-substituted glycyl-2-cyanopyrrolidines and contains a nitrile, an amine and an adamantine group adjacent to the amine allowing chemical stability and oral administration.[5] Following the administration of 100 mg vildagliptin > 90% of DPPIV inhibition persists > 12 hours, thus allowing for once- or twice-daily dosing. It has a half-life of about 90 min.6 Maximum plasma levels of vildagliptin are reached after 1.7 h. Around 70% of vildagliptin is metabolised in the kidney by hydrolysation, leaving nonactive metabolites. There is no metabolisation by CYP450 enzymes, suggesting that concomitant use of medications metabolised by these enzymes does not alter the elimination of vildagliptin. Vildagliptin should be used in dual combination therapy with either metformin or a glitazone in a dose of two 50 mg daily, in combination with a sulphonyurea in a dose of 50 mg daily. In patients with renal impairment and a glomerular filtration rate < 50 ml/min, vildagliptin should not be used. Also, in patients with hepatic impairment, vildagliptin must not be prescribed. Hepatitis was seen in a very few patients treated with vildagliptin throughout phase III studies; therefore, levels of the liver enzymes ALT and AST should be measured initially before treatment and then every three months during the first year. When levels of AST or ALT are found to exceed three times the upper limit of normal values (ULT), vildagliptin should not be given in the first place or be discontinued, respectively. An actual meta-analysis showed the relative risk of cough was increased (RR 1.86) with treatment with vildagliptin, as was the relative risk of urinary tract infection (RR 2.72, data from one study only) and headache (RR 1.47, eight studies included).[7]

Clinical data
Vildagliptin in drug-naive patients with T2DM was compared with placebo in three studies over 24 weeks, showing HbA1c reductions for vildagliptin of 0.6%,[8] 0.9%[9] and 1.2%[10] respectively, with the extent of effectiveness in lowering HbA1c levels depending on baseline HbA1c levels. However, noninferiority of vildagliptin was not proven when compared with metformin.[11] Data from a systematic meta-analysis of incretin therapy in T2DM showed that vildagliptin lowered HbA1c levels by some 0.73% and lowered fasting blood glucose by 12 mg/dl (with eight studies including monotherapy and combination therapy included). A slight weight gain of 0.4 kg was observed over 24 weeks (eight studies included in the meta-analysis).[7]

Vildagliptin monotherapy also consistently improved both fasting and meal test-derived measures of beta-cell function in drug-naive patients with T2DM in a study that pooled all placebo- or active-controlled trials conducted in drug-naive patients with T2DM receiving monotherapy (n = 1,855) or placebo (n = 347). In the overall population, vildagliptin significantly increased HOMA-B both relative to baseline and compared with placebo, and significantly decreased the proinsulin-to-insulin ratio relative to baseline and compared with placebo.[12]

How vildagliptin acts on islet function and glucose utilisation has been addressed in more detail by a recent study that applied glucose clamps and examined GLP-1 levels after vildagliptin over six weeks in 16 patients with T2DM.[13] In these cases, vildagliptin lowered postprandial glucagon levels by 16%, increased postprandial levels of GLP-1 and GIP threefold and twofold respectively, reduced fasting plasma glucose and postprandial plasma glucose levels by 1.3 and 1.6 mmol/l (both p < 0.01), and improved glucose responsiveness of insulin secretion by 50% (p < 0.01).

Examined by glucose clamp, insulin sensitivity and glucose clearance improved after vildagliptin (p < 0.01), also showing improved glucose metabolism in peripheral tissues. It has been an issue for debate whether DPPIV inhibitors can promote satiety in people with T2DM.

In a small recent study of 14 patients, 50 mg vildagliptin twice a day over 10 days did not alter satiation or gastric volume as assessed by visual analogue scales (VAS).[14] These findings are not in line with reports showing that treatment with GLP-1 analogues – which lead to supraphysiological GLP-1 levels – do promote satiety and reduce appetite.

Similarly to the results obtained in monotherapy, vildagliptin was also effective in combination with metformin over 24 weeks (-1.1% HbA1c vs metformin alone),[15] or pioglitazone (-0.7% HbA1c vs pioglitazone alone).[16] Vildagliptin was also tested as an add-on therapy in combination with glimepirid (4 mg) compared with glimepirid alone over 24 weeks in 515 patients with T2DM. One 50 mg and two 50 mg doses of vildagliptin added to glimepirid reduced mean HbA1c levels by 0.6% and 0.7% respectively compared with the active comparator group (p < 0.001).[17] The incidence of hypoglycaemic events was low but slightly higher in the group receiving vildagliptin 100 mg (3.6%) than in the group receiving vildagliptin 50 mg (1.2%) or placebo (0.6%). In this context, a pivotal safety issue is whether vildagliptin when given in combination with a sulphonylurea would accentuate or worsen sulphonylurea-induced hypoglycaemia. To address this, 16 healthy nondiabetic subjects were given vildagliptin without glibenclamide after an overnight fast to study hypoglycaemic events. Glibenclamide led to hypoglycaemia defined as < 1.9 mmol/l, but this was not accentuated by the simultaneous administration of vildagliptin (p = 0.25). The integrated incremental responses of total GLP-1 were reduced by vildagliptin by 72% (with glibenclamide) and 48% (without glibenclamide). The authors explain this in terms of a possible negative feedback regulation of GLP-1 and GIP secretion limiting enhancement of active incretin levels.[18] Nevertheless, it still appears that, with regard to hypoglycaemia, caution must prevail when using sulphonylureas together with vildagliptin.

An interesting question is whether adding vildagliptin to insulin therapy in patients with longstanding T2DM would further improve glucose control. If so, insulin therapy alone would not compensate for all aspects of pathophysiology active even in longstanding T2DM. To address this, 300 patients with T2DM were treated either with vildagliptin (two 50 mg doses daily) and insulin or placebo while continuing insulin therapy over 24 weeks. The combination therapy reduced HbA1c levels by 0.5% compared with 0.2% in the placebo group (p = 0.01).[19]

Hypoglycaemic events were less common (p < 0.001) and less severe (p < 0.05) in patients receiving vildagliptin than in those receiving placebo. This appears to be a clinically relevant finding as it shows that risk of hypoglycaemia can be reduced in patients treated with high doses of insulin.

Conclusion
DPP-4 inhibitors are a new class of antidiabetic drugs with efficacy comparable to that of current oral antidiabetic treatments. Vildagliptin is effective as monotherapy in patients inadequately controlled with diet and exercise and as add-on therapy in combination with metformin, sulphonylureas, thiazolidinediones, and insulin. Vildagliptin is well tolerated, has a low risk of hypoglycaemia and is weight-neutral. However, the long-term durability of its beneficial effects on glycaemic control, as well as beta-cell mass and function resulting in a modification of the course of T2DM, remains to be established. â–

References
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4. Drucker D. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26:2929-40.
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12. Pratley RE, Schweizer A, Rosenstock J, Foley JE, Banerji MA, Pi-Sunyer FX, Mills D, Dejager S. Robust improvements in fasting and prandial measures of beta-cell function with vildagliptin in drug-naive patients: analysis of pooled vildagliptin monotherapy database. Diabetes Obes Metab Epub ahead of print, 17 Dec 2007.
13. Azuma K, Rádiková Z, Mancino J, Toledo FG, Thomas E, Kangani C, et al. Measurements of islet function and glucose metabolism with the dipeptidyl peptidase 4 inhibitor vildagliptin in patients with type 2 diabetes. J Clin Endocrinol Metab 2008;93(2):459-64.
14. Vella A, Bock G, Giesler PD, Burton DB, Serra DB, Saylan ML, et al. The effect of dipeptidyl peptidase 4 inhibition on gastric volume, satiation and enteroendocrine secretion in Type 2 diabetes: a double blind, placebo-controlled crossover study. Clin Endocrinol (Oxf) 2008 Mar 10 [Epub ahead of print].
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