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

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Abstract

Background

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.

Methods

An extensive search in PubMed, EMBASE, CINAHL, IPA, Cochrane, ClinicalTrial.gov 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.

Results

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  65 years, diabetes duration of ≥ 10 years and BMI  30 kg/m2 were associated with an increased risk of HF among patients using saxagliptin.

Conclusions

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.

Introduction

In recent years, numerous advancements have been made in the discovery and introduction of new anti-diabetes medications which have helped to expand options for the management of diabetes mellitus. While the ability of anti-diabetic drugs to provide glycemic control is essential, their effects on cardiovascular disease (CVD) may be of equal importance since CVD is the major cause of morbidity and mortality among patients with diabetes [1], [2]. Based on this principle along with recent concern raised by previous drugs [3], the US Food and Drug Administration (FDA) requires the assessment of cardiovascular (CV) safety for new anti-diabetes agents [4]. Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are new anti-diabetic drugs that reduce blood glucose mainly by suppressing glucagon release through the enhancement of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP) [5]. Presently, members in this drug class include sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin. These agents have recently been introduced into clinical practice with wide acceptance and are currently recommended by international and national guidelines worldwide.

In response to FDA guidance, two large international multicenter randomized controlled phase III-IV studies; Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53) [6] and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) [7] were recently conducted to assess the CV safety of saxagliptin and alogliptin, respectively. The SAVOR-TIMI 53 study reported a small, but significant 27% increase in rate of HF related hospitalization in patients treated with saxagliptin compared to placebo [6], while the EXAMINE study showed a numerical excess that did not achieve statistical significance in the risk of HF related hospitalization [7]. These reports were followed by two meta-analyses of randomized, controlled trials evaluating the effects of DPP-4 inhibitors and HF [8], [9]. Both meta-analyses showed that DPP-4 inhibitors significantly increased the risk of HF [8], [9]. However, those two meta-analyses were conducted with key limitations including restrictive inclusion criteria, failure to assess the effect of important patient characteristics on risk and small sample size in some members of the DPP-4 inhibitors. A recent meta-analysis published in February 2015 by Savarese G. et al. [10] aimed at evaluating the effects of DPP-4 inhibitors on various cardiovascular outcomes with heart failure as a part of such analysis. The heart failure results of the study were in line with two previous meta-analyses [8], [9]. However, a new large multicenter randomized controlled trial study; Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) [11] reported the rate of hospitalization of HF did not differ between the two groups (3.1% in both groups). We therefore aimed to conduct an updated and more comprehensive meta-analysis with the focus on 3 key issues; 1) broadening inclusion criteria to include studies with ≥ 12 weeks of exposure, 2) assessing the effect of important patient characteristics on risk, and 3) including newer studies published after previous meta-analyses, especially from the newer agents which may be under-represented in previous meta-analyses [8], [9] and the results from the TECOS study [11]. This may help improve the understanding on the effect of DPP-4 inhibitors on risk of HF.

Section snippets

Search strategy

An electronic literature search of PubMed, EMBASE, the Cochrane Library, CINAHL, IPA, and www.ClinicalTrial.gov were conducted using keywords including alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin, dipeptidyl peptidase 4 inhibitors, DPP-4 inhibitors, DPPIs and gliptin. The results of unpublished studies were identified through searching of www.clinicaltrials.gov, www.clinicaltrialresults.org and the manufacturers' websites. The FDA (www.fda.gov) and European Medicines Agency

Study selection

Through our extensive search 4152 studies were identified. However, only 54 studies were included into the data analysis while 4098 studies were excluded. Reasons for exclusion were irrelevance or failure to meet inclusion/exclusion criteria (4080), post-hoc analysis in nature (8) and data duplication (10). As a result, a total of 54 studies with 74,737 patients were included in the final analysis (9 with alogliptin [7], [21], [22], [23], [24], [25], [26], 7 with linagliptin [24], [27], [28],

Discussion

In the past decade, a number of novel anti-diabetic drugs have been discovered and introduced into clinical practice mostly based on the evidence of their effectiveness in glucose control. Typically, years will have passed before the risk–benefit of a certain drug class will be fully realized especially its off-target side effects. During these early years of drug introduction, vigilant observation and evaluation remains the only option to increase awareness on drug safety [3], [57]. In this

Conclusion

Our meta-analysis suggested a differential effect of each DPP-4 inhibitor on the risk of heart failure. Use of saxagliptin significantly increases the risk of heart failure by 21% especially among patients with high CV risk. There was no signal detected with sitagliptin. For other agents, their information was too limited to draw any conclusion. Attempts should be made to conduct outcome studies with adequate statistical power to clearly evaluate the safety of these agents. Until such

Statement of authorship

The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

Authors' disclosures

None.

Funding

None.

Conflict of interest

None.

Acknowledgment

Author Contributions: Miss. Junporn Kongwatcharapong had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition of data: Kongwatcharapong J., Dilokthornsakul P.

Analysis and interpretation of data: Kongwatcharapong J., Dilokthornsakul P., Chaiyakunapruk N.

Drafting of the manuscript: Kongwatcharapong J., Dilokthornsakul P., Chaiyakunapruk N., Nathisuwan S.

Critical

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