Effect of Vildagliptin on Glucagon Concentration During Meals in Patients with Type 1 Diabetes

Introduction

Vildagliptin is a potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for the rapid degradation of circulating glucagon-like peptide-1 (GLP-1). Mechanistic studies have shown that vildagliptin improves islet function in patients with type 2 diabetes (T2DM) [1], [2]. In Phase 2 and 3 studies, vildagliptin was shown to be well tolerated and to decrease HbA_1c when given as monotherapy [3] or when added to metformin [4], thiazolidinediones [5], sulfonylureas [6], or insulin [7].

In addition to the well documented effect of GLP-1 to augment glucose-induced insulin release, this incretin hormone is known to suppress glucagon secretion. Vildagliptin, not unexpectedly, also decreases glucagon levels in patients with T2DM [1]. Because vildagliptin increases insulin secretion relative to a glycemic stimulus in patients with T2DM [2] and insulin suppresses glucagon release, it is unclear whether the suppression of glucagon secretion seen during treatment with vildagliptin reflects a direct inhibitory effect of GLP-1 on the α-cell or whether the glucagon effect is mediated indirectly through changes in insulin. Therefore, the present study was performed to determine the effects of vildagliptin on glucagon secretion in patients with type 1 diabetes (T1DM) who have no endogenous insulin. Although a 100 mg daily dose of vildagliptin (in single or divided doses) was found to be the maximally effective in Phase 3 trials [3] when the present study was planned, the maximum effective dose was unknown and a 100 mg b.i.d. dose regimen was selected.

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