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Type 2 Diabetes Editorial Ten Years of Vildagliptin Stefano Del Prato Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy A fter many years of limited therapeutic opportunities, the treatment of type 2 diabetes has become more target and pathophysiologically driven. A typical example is represented by the development of the dipeptidyl peptidase-4 (DPP-4) inhibitors, allowing for more physiological regulation of the endocrine pancreas and leading to a previously unmet risk-to-benefit balance. Vildagliptin, one of the earliest DPP-4 inhibitors, has been tested across the entire spectrum of type 2 diabetes and has been in clinical use for 20 years. This publication critically reviews the main steps in the clinical development of this agent. Keywords Type 2 diabetes, DPP-4 inhibitors, vildagliptin Disclosure: Stefano Del Prato has received reseach support from AstraZeneca, MSD, Novartis and Boehringer Ingelheim, and consultancy fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GSK, MSD, Novartis, Novo Nordisk, Sanofi, Servier and Takeda. This article is a short opinion piece and has not been submitted to external peer reviewers but was reviewed by a member of the Editorial Board before publication. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 13 June 2017 Published Online: 22 August 2017 Citation: European Endocrinology, 2017;13(2):54–5 Corresponding Author: Stefano Del Prato, Department of Clinical and Experimental Medicine University of Pisa, Via Roma 67,. I-56100 Pisa, Italy. E: stefano.delprato@med.unipi.it Support: The publication of this article was supported by Novartis Pharma AG. 54 Until the turn of the century, treatment of hyperglycaemia in type 2 diabetes was limited to two main classes of drugs: sulphonylureas and biguanides. Though belonging to two distinct classes, these drugs shared two main characteristics: the first one is that they have been used to lower blood glucose much longer, before their mode of action could be understood; the second is that they both were the result of serendipitous discovery. In more recent years, through improved understanding of the pathophysiology of the disease, better drugs have been developed to target the specific mechanisms that are responsible for hyperglycaemia, thus providing a more physiological approach to the treatment of type 2 diabetes. A typical example has been the development of inhibitors of the dipeptidyl peptidase-4 (DPP- 4) enzyme. This enzyme is responsible for the degradation of many peptides, including incretins, hormones released by endocrine cells in the intestine in response to the ingestion of a meal. Specific DPP- 4 inhibitors have been developed because of the appreciation of the critical role played by the incretins, and in particular, glucagon-like peptide-1 (GLP-1), in the regulation of glucose-dependent stimulation of insulin and glucagon secretion, and the potential reduced production of GLP-1 from intestinal L-cells in hyperglycaemic individuals. Under these circumstances, DPP-4 inhibition ensures persistence of endogenously secreted GLP-1 in the systemic circulation. A vast body of literature and many clinical trials have set the basis for the current clinical use of these drugs. These studies have lent the evidence of their efficacy and good tolerability profile. Because of this evidence, DPP-4 inhibitors have become the standard of care and more often used as second-line treatment upon metformin failure or as initial therapy in people with metformin intolerance. Among the DPP-4 inhibitors, vildagliptin is an orally available, small-molecule, competitive reversible DPP-4 inhibitor for the treatment of type 2 diabetes. It is currently used in more than 132 countries around the world, and it celebrates its 20th year in the diabetes pharmacopeia. Over the last two decades, the flexibility and efficacy of vildagliptin, and other DPP-4 inhibitors, have been tested in many clinical conditions with particular references to patients at higher risk, including the elderly, those with impaired kidney function, and those on insulin treatment. With respect to this, the development programme of vildagliptin and its assessment in the clinical setting remains unique among DPP-4 inhibitors, particularly with respect to the two extremes of the curve of the natural history of diabetes, that is, the time of the diagnosis of diabetes and the most advanced stages TOU C H ME D ICA L ME D IA