Dipeptydil peptidase-4 inhibitors in type 2 diabetes: A meta-analysis of randomized clinical trials

https://doi.org/10.1016/j.numecd.2009.03.015Get rights and content

Abstract

Background and Aim

The role of Dipeptidyl Peptidase-4 (DPP-4) inhibitors in the treatment of type 2 diabetes is debated; many recent trials, which were not included in previous meta-analyses, could add relevant information.

Methods and Results

All available randomized controlled trials (RCTs), either published or unpublished, performed in type 2 diabetic patients with DPP-4 inhibitors, with a duration >12 weeks were meta-analyzed for HbA1c, BMI, hypoglycemia, and other adverse events. A total of 41 RCTs (9 of which are unpublished) was retrieved and included in the analysis. Gliptins determine a significant improvement of HbA1c in comparison with a placebo (−0.7 [−0.8:−0.6]), with a low risk of hypoglycemia. DPP-4 inhibitors show a similar efficacy in monotherapy and in combination with other agents. The risk of cardiovascular events and all-cause death with DPP-4 inhibitors is 0.76 [0.46–1.28] and 0.78 [0.40–1.51], respectively.

Conclusions

DPP-4 inhibitors reduce HbA1c, although to a lesser extent than sulphonylureas, with no weight gain and no hypoglycemic risk; further data are needed to assess their long-term safety.

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

References (52)

  • S.E. Inzucchi

    Incretin enhancers and the evolution of antihyperglycemic therapy in type 2 diabetes

    Endocrinol Metab Clin North Am

    (2007)
  • R.E. Amori et al.

    Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis

    JAMA

    (2007)
  • D.Q. Pham et al.

    Sitagliptin: a novel agent for the management of type 2 diabetes mellitus

    Am J Health Syst Pharm

    (2008)
  • Richter B, Bandeira-Echtler E, Bergerhoff K, et al. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes...
  • M. Egger et al.

    Meta-analysis: principles and procedures

    BMJ

    (1997)
  • C.B. Begg et al.

    Operating characteristics of a rank correlation test for publication bias

    Biometrics

    (1994)
  • M. Egger et al.

    Bias in meta-analysis detected by a simple, graphical test

    BMJ

    (1997)
  • M. Hanefeld et al.

    Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes

    Curr Med Res Opin

    (2007)
  • M.A. Nauck et al.

    Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial

    Diabetes Obes Metab

    (2007)
  • R. Scott et al.

    Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes

    Int J Clin Pract

    (2007)
  • A.J. Garber et al.

    Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea

    Diabetes Obes Metab

    (2008)
  • V. Fonseca et al.

    Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes

    Diabetologia

    (2007)
  • G. Bolli et al.

    Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study

    Diabetes Obes Metab

    (2008)
  • E. Bosi et al.

    Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin

    Diabetes Care

    (2007)
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