• Ling Li, Sheyu Li, Ke Deng, Jiali Liu, Per Olav Vandvik, Pujing Zhao, Longhao Zhang, Jiantong Shen, Malgorzata M Bala, Zahra N Sohani, Evelyn Wong, Jason W Busse, Shanil Ebrahim, German Malaga, Lorena P Rios, Yingqiang Wang, Qunfei Chen, Gordon H Guyatt, and Xin Sun.
• Chinese Evidence-based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
• BMJ. 2016 Jan 1; 352: i610.

ObjectivesTo examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of heart failure or hospital admission for heart failure in patients with type 2 diabetes.DesignSystematic review and meta-analysis of randomised and observational studies.Data SourcesMedline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov searched up to 25 June 2015, and communication with experts.Eligibility CriteriaRandomised controlled trials, non-randomised controlled trials, cohort studies, and case-control studies that compared DPP-4 inhibitors against placebo, lifestyle modification, or active antidiabetic drugs in adults with type 2 diabetes, and explicitly reported the outcome of heart failure or hospital admission for heart failure.Data Collection And AnalysisTeams of paired reviewers independently screened for eligible studies, assessed risk of bias, and extracted data using standardised, pilot tested forms. Data from trials and observational studies were pooled separately; quality of evidence was assessed by the GRADE approach.ResultsEligible studies included 43 trials (n=68,775) and 12 observational studies (nine cohort studies, three nested case-control studies; n=1,777,358). Pooling of 38 trials reporting heart failure provided low quality evidence for a possible similar risk of heart failure between DPP-4 inhibitor use versus control (42/15,701 v 33/12,591; odds ratio 0.97 (95% confidence interval 0.61 to 1.56); risk difference 2 fewer (19 fewer to 28 more) events per 1000 patients with type 2 diabetes over five years). The observational studies provided effect estimates generally consistent with trial findings, but with very low quality evidence. Pooling of the five trials reporting admission for heart failure provided moderate quality evidence for an increased risk in patients treated with DPP-4 inhibitors versus control (622/18,554 v 552/18,474; 1.13 (1.00 to 1.26); 8 more (0 more to 16 more)). The pooling of adjusted estimates from observational studies similarly suggested (with very low quality evidence) a possible increased risk of admission for heart failure (adjusted odds ratio 1.41, 95% confidence interval 0.95 to 2.09) in patients treated with DPP-4 inhibitors (exclusively sitagliptin) versus no use.ConclusionsThe relative effect of DPP-4 inhibitors on the risk of heart failure in patients with type 2 diabetes is uncertain, given the relatively short follow-up and low quality of evidence. Both randomised controlled trials and observational studies, however, suggest that these drugs may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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