Abstract

Vildagliptin for the treatment of diabetes

Author(s): George P Samraj

The prevalence of Type 2 diabetes (DM2) has reached epidemic proportions in essentially all industrialized nations. The burgeoning population of DM2 has been attributed to parallel increases in obesity, sedentary lifestyle and less healthy dietary component choices (e.g., high glycemic index foods). By the time DM2 is diagnosed, at least 50% of b‑cell function has been lost; this loss appears to progress inexorably, despite treatment. Because control of glucose has been shown to reduce diabetic microvascular complications, and improve quality of life, tools that enhance this process are valuable to clinicians and patients alike. We have evolved in our understanding of DM2 to recognize that multiple metabolic defects contribute to this disorder. Accordingly, it is uncommon that any monotherapy can consistently provide durable control of DM2. Pharmacotherapies that address the multiple metabolic derangements now identified in DM2, especially amongst the incretin class, may also be helpful as they have often been found to be more ‘user friendly’ because they result in less weight gain, less hypoglycemia, and have the utility to be particularly useful for addressing postprandial glucose excursions. Our discussion will focus upon vildagliptin, an oral dipeptidyl peptidase type 4 inhibitor, one of the earliest oral incretin enhancers to be trialed in clinical use, and will be restricted to DM2, rather than Type 1 diabetes in which no role for noninsulin therapies has been clearly defined. Salutary metabolic effects of glucagon like peptide (GLP)-1 and glucosedependent insulinotropic peptide or gastric inhibitory peptide have been difficult to capture, since their half-life is very brief (12 min). For GLP‑1 and gastric inhibitory peptide, the enzyme responsible for degradation is DPP-4; hence, DPP-4 inhibitors delay GLP‑1 degradation, prolonging the therapeutic effect. The two currently available novel therapeutic approaches to capture incretin effects are DPP-4 inhibition, and parenteral GLP‑1 agonism (i.e., exenatide, liraglutide). As DM2 can uncommonly be controlled with monotherapy, it is important to evaluate add-on treatments. In a meta-analysis of 27 randomized controlled trials (mean duration 32 weeks) addressing DM2 inadequately controlled with metformin, comparable degrees of improved glucose control were achieved with various pharmacotherapeutic classes including a‑glucosidase inhibitors, DPP-4 inhibitors, glinides, GLP‑1 agonists, sulfonylurea and thiazolidinediones (TZD). Incretins and a‑glucosidase inhibitors were associated with weight neutrality; as has been consistently noted in multiple trials, sulfonylurea and thiazolidinedione had a significant incidence of weight gain; hypoglycemia was more frequent with sulfonylurea.