Preventive cardiology
Meta-Analysis of Effect of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Risk in Type 2 Diabetes Mellitus

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Patients with type 2 diabetes mellitus (DM) have a very high risk for major adverse cardiovascular (CV) events. Previous studies have shown that traditional oral diabetic medications, despite lowering blood glucose levels, generally do not improve CV outcomes. The safety of some oral hypoglycemic medications has been questioned. We aimed to evaluate the CV safety of dipeptidyl peptidase-4 (DPP4) inhibitors, a novel class of oral diabetic medications, by performing a meta-analysis of DPP4 inhibitors for type 2 DM. A search of electronic databases of published and unpublished literature (until September 30, 2011) was performed to identify randomized controlled trials of ≥24 weeks that compared DPP4 inhibitors to other oral diabetic medications. A meta-analysis was performed using fixed and random effects to determine risk ratio (RR) for adverse CV events with DPP4 inhibitor monotherapy compared to other oral diabetic medications or to placebo. Eighteen randomized met our inclusion criteria, comprising 4,998 patients who were randomized to DPP4 inhibitors and 3,546 to a comparator, with a median duration of therapy of 46.4 weeks. In pooled analysis, the RR of any adverse CV event with a DPP4 inhibitor was 0.48 (0.31 to 0.75, p = 0.001), and the RR for nonfatal myocardial infarction or acute coronary syndrome was 0.40 (0.18 to 0.88, p = 0.02). In conclusion, this meta-analysis provides evidence that DPP4 inhibitors are safe from a CV standpoint and may possibly decrease risk of adverse CV events.

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Methods

This meta-analysis was designed to evaluate the CV safety of DPP4 inhibitors in patients with type 2 DM. We adhered to the recommendations set forth by the Quality of Reporting of Meta-analyses statement for improving the quality of meta-analyses.2

A computerized literature search was performed to identify RCTs comparing DPP4 inhibitors to other oral hypoglycemic agents for treatment of type 2 DM. MEDLINE (from 1980 to September 2011), Cochrane Collaborative database, Scopus (//www.scopus.com

Results

Of the 1,304 citations identified initially, 28 full-text articles were reviewed for relevance. Ten RCTs that examined the efficacy of DPP4 inhibitors but did not report data on adverse CV events, including 5,631 patients, were excluded. Eighteen nonoverlapping RCTs met our inclusion criteria (Figure 1). Pooled analysis included 8,544 patients (4,998 randomized to a DPP4 inhibitor and 3,546 to placebo or other oral hypoglycemic agents). Of patients randomized to receive DPP4 inhibitor therapy,

Discussion

The present meta-analysis is the first adequately powered study to demonstrate that DPP4 inhibitors as a class appear to decrease the risk of CV events during long-term treatment. In contrast, multiple drugs for type 2 DM including sulfonylureas, insulin, and rosiglitazone have been associated with increased risk of CV events.21, 22 Because of concerns regarding this potential for type 2 DM drugs to worsen CV prognosis, since 2008 the Federal Drug Administration has required that all new

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