Dipeptydil peptidase-4 inhibitors in type 2 diabetes: A meta-analysis of randomized clinical trials
Introduction
Oral Dipeptidyl Peptidase-4 (DPP-4) inhibitors sitagliptin [1] and vildagliptin [2], which increase circulating levels of Glucagon-Like Peptide-1 (GLP-1), have recently been approved for use in type 2 diabetes; other molecules of the same class (such as saxagliptin and alogliptin) are under development.
The role of those new drugs in the treatment of type 2 diabetes is debated. The consensus algorithm of the American Diabetes Association and the European Association for the Study of Diabetes [3], [4], in its revised version [4], suggests limiting the use of GLP-1 receptor agonists and DPP-4 inhibitors only in some specific cases, without considering those agents in the mainstream (“Tier 1”) of the algorithm. Conversely, DPP-4 inhibitors are not even included as a second choice, although their use is contemplated in selected patients. The reasons for this exclusion are their perceived limited efficacy on HbA1c in comparison with other agents, their poorly defined safety profile, and their cost [3], [4].
Efficacy and safety need to be assessed through a comprehensive review of currently available clinical trials. Some detailed reviews of published studies have been recently published [1], [2], [5]; furthermore, some meta-analyses have been performed [1], [6], [7], [8]. However, currently available meta-analyses included only published studies, without any attempt at retrieving data from completed and publicly disclosed, although not formally published, clinical trials. Furthermore, several trials have been published in the last few months, increasing in a relevant manner the available data base for the assessment of the clinical profile of DPP-4 inhibitors.
The aim of the present study is to offer a comprehensive and updated synthesis of all available clinical data on the safety and efficacy of DPP-4 inhibitors.
Section snippets
Methods
A meta-analysis was performed including all randomized clinical trials, either with a cross-over or a parallel series design, enrolling patients with type 2 diabetes, with a duration of at least 12 weeks, comparing Dipeptidyl Peptidase-4 (DPP) inhibitors with a placebo or other active drugs (oral hypoglycemic agents and/or insulin). Trials with a shorter duration were excluded, due to the fact that they could not yield relevant information on glycated hemoglobin, which had been chosen as the
Results
The trial flow is summarized in Fig. 1, and the characteristics of the trials included in the meta-analysis are summarized in Table 1. Among the trials included, 32 were described in publications in peer-reviewed journals; results of 9 unpublished trials were disclosed on different websites. Furthermore, 10 unpublished trials, the results of which were undisclosed, could be identified (Table 2). Notably, results could be retrieved for the large majority of trials on currently available DPP-4
Discussion
DPP-4 inhibitors have been proposed as an alternative to currently available therapies (sulphonylureas, thiazolidinediones or insulin), mainly as an add-on treatment in patients failing with metformin monotherapy. However, even the most recent version of the ADA–EASD consensus algorithm does not consider these drugs a viable option, except for selected cases [4]. The reasons for exclusion from the main treatment algorithm are scarce efficacy, limited amount of available evidence and high cost.
Conflict of interest
Authors did not receive any compensation for their contribution. All authors have seen and approved the final version.
Dr. Edoardo Mannucci1 (MD) has the following conflicts of interest:
1) Speaking fees from Abiogen Pharma, Glaxo-Smith–Kline, Guidotti, Eli Lilly, Menarini, Merck Sharp & Dome (manufacturer of sitagliptin), Merck KgA, Novo Nordisk, Novartis (manufacturer of vildagliptin), Sanofi Aventis, and Takeda.
2) Consultancy fees from Novartis (manufacturer of vildagliptin), Novo Nordisk, and
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