Meta-Analysis
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Cardiol. Oct 26, 2021; 13(10): 585-592
Published online Oct 26, 2021. doi: 10.4330/wjc.v13.i10.585
Cardiovascular efficacy and safety of dipeptidyl peptidase-4 inhibitors: A meta-analysis of cardiovascular outcome trials
Dimitrios Ioannis Patoulias, Aristi Boulmpou, Eleftherios Teperikidis, Alexandra Katsimardou, Fotios Siskos, Michael Doumas, Christodoulos E Papadopoulos, Vassilios Vassilikos
Dimitrios Ioannis Patoulias, Alexandra Katsimardou, Fotios Siskos, Michael Doumas, Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
Aristi Boulmpou, Eleftherios Teperikidis, Christodoulos E Papadopoulos, Vassilios Vassilikos, Third Department of Cardiology, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
Author contributions: Patoulias DI and Doumas M conceived and designed the study; Patoulias DI, Boulmpou A and Teperikidis E collected and analyzed data; Patoulias DI, Boulmpou A and Siskos F performed study quality and risk of bias assessment; Patoulias DI, Boulnpou A, Katsimardou A and Papadopoulos CE wrote the first draft of the study; Doumas M and Vassilikos V critically revised the final draft.
Conflict-of-interest statement: The authors declare no conflict of interest.
PRISMA 2009 Checklist statement: The present meta-analysis was conducted according to 2009 PRISMA Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dimitrios Ioannis Patoulias, MD, MSc, Doctor, Research Fellow, Research Scientist, Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Konstantinoupoleos 49 Str., Thessaloniki 54642, Greece. dipatoulias@gmail.com
Received: March 29, 2021
Peer-review started: March 29, 2021
First decision: June 25, 2021
Revised: July 8, 2021
Accepted: September 10, 2021
Article in press: September 10, 2021
Published online: October 26, 2021
Processing time: 205 Days and 14.3 Hours
Abstract
BACKGROUND

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a generally safe and well tolerated antidiabetic drug class with proven efficacy in type 2 diabetes mellitus (T2DM). Recently, a series of large, randomized controlled trials (RCTs) addressing cardiovascular outcomes with DPP-4 inhibitors have been published.

AIM

To pool data from the aforementioned trials concerning the impact of DPP-4 inhibitors on surrogate cardiovascular efficacy outcomes and on major cardiac arrhythmias.

METHODS

We searched PubMed and grey literature sources for all published RCTs assessing cardiovascular outcomes with DPP-4 inhibitors compared to placebo until October 2020. We extracted data concerning the following “hard” efficacy outcomes: fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospitalization for heart failure, hospitalization for unstable angina, hospitalization for coronary revascularization and cardiovascular death. We also extracted data regarding the risk for major cardiac arrhythmias, such as atrial fibrillation, atrial flutter, ventricular fibrillation and ventricular tachycardia.

RESULTS

We pooled data from 6 trials in a total of 52520 patients with T2DM assigned either to DPP-4 inhibitor or placebo. DPP-4 inhibitors compared to placebo led to a non-significant increase in the risk for fatal and non-fatal myocardial infarction [risk ratio (RR) = 1.02, 95%CI: 0.94-1.11, I2 = 0%], hospitalization for heart failure (RR = 1.09, 95%CI: 0.92-1.29, I2 = 65%) and cardiovascular death (RR = 1.02, 95%CI: 0.93-1.11, I2 = 0%). DPP-4 inhibitors resulted in a non-significant decrease in the risk for fatal and non-fatal stroke (RR = 0.96, 95%CI: 0.85-1.08, I2 = 0%) and coronary revascularization (RR = 0.99, 95%CI: 0.90-1.09, I2 = 0%), Finally, DPP-4 inhibitors demonstrated a neutral effect on the risk for hospitalization due to unstable angina (RR = 1.00, 95%CI: 0.85-1.18, I2 = 0%). As far as cardiac arrhythmias are concerned, DPP-4 inhibitors did not significantly affect the risk for atrial fibrillation (RR = 0.95, 95%CI: 0.78-1.17, I2 = 0%), while they were associated with a significant increase in the risk for atrial flutter, equal to 52% (RR = 1.52, 95%CI: 1.03-2.24, I2 = 0%). DPP-4 inhibitors did not have a significant impact on the risk for any of the rest assessed cardiac arrhythmias.

CONCLUSION

DPP-4 inhibitors do not seem to confer any significant cardiovascular benefit for patients with T2DM, while they do not seem to be associated with a significant risk for any major cardiac arrhythmias, except for atrial flutter. Therefore, this drug class should not be the treatment of choice for patients with established cardiovascular disease or multiple risk factors, except for those cases when newer antidiabetics (glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors) are not tolerated, contraindicated or not affordable for the patient.

Keywords: Dipeptidyl peptidase-4 inhibitors; Cardiovascular outcomes; Atrial fibrillation; Atrial flutter; Type 2 diabetes mellitus

Core Tip: The antidiabetic efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors has already been proven in recently published large randomized controlled trials. The purpose of the present meta-analysis was to clarify the impact of antidiabetic therapy with DPP-4 inhibitors on surrogate cardiovascular outcomes, and to elucidate the effect of these drugs on major cardiac arrhythmias. According to our analysis, this drug class does not significantly affect the risk for any of the addressed cardiovascular outcomes; however, it increases the risk for atrial flutter compared to placebo.