Effects of Glucagon-like Peptide-1 Receptor Agonists on Cardiovascular and Renal Outcomes: A Systematic Review, Meta-analysis, and Meta-regression Analysis

Abstract

Background: Cardiovascular and renal effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been inconsistent in cardiovascular outcome trials, and factors associated with the efficacy of GLP-1RAs remain to be clarified. Objective: To evaluate cardiovascular and renal outcomes with GLP-1RAs and associations between these outcomes and the magnitude of HbA1c or weight reduction. Data Sources and Study selection: We searched PubMed/MEDLINE for randomized, placebo-controlled trials of GLP-1RAs published until 11 August 2021 and selected trials reporting major adverse cardiovascular events (MACE) as the primary outcome. Data Extraction and Synthesis: We extracted data of 60,080 individuals from eight studies (ELIXA, LEADER, SUSTAIN-6, EXSCEL, HARMONY, PIONEER 6, REWIND, and AMPLITUDE-O) and conducted a meta-analysis with a random-effects model to calculate pooled hazard ratios (HRs) of primary and secondary outcomes. Furthermore, we performed a univariable meta-regression analysis of these outcomes with HbA1c or weight reduction. Main outcomes and Measures: The primary outcome was MACE (a composite of cardiovascular mortality, nonfatal stroke, and nonfatal myocardial infarction). Secondary outcomes included components of MACE, all-cause mortality, hospitalization due to heart failure, and renal outcomes. Safety outcomes were severe hypoglycemia, pancreatitis, pancreatic cancer, and retinopathy. Results: GLP-1RAs reduced MACE (HR 0.86; 95% CI 0.80, 0.93; P < 0.001) and secondary outcomes including cardiovascular mortality (0.87; 0.80 0.94; P = 0.001), nonfatal myocardial infarction (0.90; 0.83, 0.98; P = 0.020) nonfatal stroke (0.83; 0.76, 0.92; P < 0.001), and the composite renal outcome (0.80; 0.73, 0.87; P < 0.001). No increase in the incidence of safety outcomes was observed with GLP-1RAs. Meta-regression analysis showed that HbA1c reduction was associated with logarithm of HR (log-HR) of MACE (P = 0.045; R2 = 0.64) and the composite renal outcome (P = 0.045; R2 = 0.80), whereas weight reduction was not associated with any outcome. Every 1.0% HbA1c reduction was associated with a decrease in log-HR of MACE and the composite renal outcome by 0.27 and 0.35, respectively. Conclusions: GLP-1RAs showed favorable effects on cardiovascular and renal outcomes. Furthermore, reduction in HbA1c, but not body weight, was associated with cardiovascular and renal risk reduction during the treatment with GLP-1RAs.