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Int J Cardiol. 2016 May 15;211:88-95. doi: 10.1016/j.ijcard.2016.02.146. Epub 2016 Mar 2.

Effect of dipeptidyl peptidase-4 inhibitors on heart failure: A meta-analysis of randomized clinical trials.

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Clinical Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
Center for Pharmaceutical Outcomes Research, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA; Center of Pharmaceutical Outcomes Research, Faculty of Pharmaceutical Sciences, Naresuan University, Muang, Phitsanulok, Thailand.
Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Center of Pharmaceutical Outcomes Research, Faculty of Pharmaceutical Sciences, Naresuan University, Muang, Phitsanulok, Thailand; School of Pharmacy, Monash University Malaysia, Malaysia; School of Population Health, University of Queensland, Brisbane, Australia; School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA. Electronic address:



Recent studies have suggested that dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) may be associated with increased risk of heart failure (HF), but evidence was inconclusive. We aimed to determine the effects of DPP-4 inhibitors on risk of HF.


An extensive search in PubMed, EMBASE, CINAHL, IPA, Cochrane, and the manufacturers' websites for randomized controlled trials (RCT) of all DPP-4 inhibitors was performed up to June 2015. All RCTs comparing DPP-4 inhibitors to any comparators with minimum follow-up of 12 weeks were included. The primary outcome was the occurrence of HF.


A total of 54 studies with 74,737 participants were included for analysis. Overall, DPP-4 inhibitors were not associated with an increased risk of HF compared to comparators (relative risk (RR) 1.106; 95% CI 0.995-1.228; p=0.062). When analyzed individually, saxagliptin was significantly associated with the increased risk of HF (RR 1.215; 95% CI, 1.028-1.437; p=0.022), while others were not. Age ≥ 6 5 years, diabetes duration of ≥ 10 years and BMI ≥ 30 kg/m(2) were associated with an increased risk of HF among patients using saxagliptin.


Our meta-analysis suggested a differential effect of each DPP-4 inhibitor on the risk of HF. Use of saxagliptin significantly increases the risk of HF by 21% especially among patients with high CV risk while no signals were detected with other agents. This information should be taken into consideration when prescribing DDP-4 inhibitors.


Cardiovascular; Dipeptidyl-peptidase-4 inhibitors; Heart failure; Type 2 diabetes mellitus

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