Abstract:
Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have progressed from glucose-lowering agents to established cardioprotective therapies, with an unusually large and rapidly growing base of completed, adjudicated cardiovascular outcome trials (CVOTs).
Objective: To quantitatively synthesize all completed placebo-controlled GLP-1 RA CVOTs reporting three-point major adverse cardiovascular events, MACE: cardiovascular death, nonfatal myocardial infarction, non-fatal stroke, as the primary outcome, and to contextualize this synthesis with secondary outcome data, heart failure subgroup effects, and head-to-head comparison against SGLT2 inhibitors.
Methodology: Nine completed CVOTs (ELIXA, LEADER, SUSTAIN-6, EXSCEL, Harmony Outcomes, REWIND, PIONEER-6, AMPLITUDE-O, SELECT; total N=77,684) were identified through a structured literature search. Trial-level hazard ratios (HR) and 95% confidence intervals (CI) for 3-point MACE were extracted from primary publications and pooled using a random-effects (DerSimonian-Laird) model, with heterogeneity quantified by Cochran's Q and I².
Results: GLP-1 RAs significantly reduced 3-point MACE versus placebo (pooled HR 0.85, 95% CI 0.80–0.91, P<0.001), with moderate heterogeneity across trials (I²=45%, Pheterogeneity=0.066). Individual trial estimates ranged from HR 0.73 (AMPLITUDE-O) to HR 1.02 (ELIXA), with 7 of 9 trials favoring treatment. Secondary outcome pooling from the published literature showed consistent reductions in cardiovascular death (~13%), non-fatal stroke (~16%), heart failure hospitalization (~10%), all-cause mortality (~12%), and a composite kidney outcome (~17%). A clinically important effect-modification signal emerged for heart failure: pooled benefit for the composite of HF hospitalization or cardiovascular death was confined to patients without baseline HF history (HR 0.84, 95% CI 0.76–0.92) and was not statistically significant in those with baseline HF (HR 0.96, 95% CI 0.84–1.08). In headto-head network meta-analysis against SGLT2 inhibitors (14 trials, 117,633 patients), the two classes showed statistically indistinguishable MACE reduction (GLP-1 RA HR 0.86 vs. SGLT2i HR 0.89; between-class HR 1.03, 95% CI 0.94–1.13), though SGLT2 inhibitors were superior for heart failure hospitalization and renal outcomes.
Conclusions: This synthesis, anchored on nine large, high-quality CVOTs with a combined 77,684 randomized participants, provides robust, statistically well-powered evidence of a genuine GLP-1 RA class effect on MACE reduction, with important heterogeneity by baseline heart failure status and complementary (rather than superior) efficacy relative to SGLT2 inhibitors — findings substantially better supported by the volume and consistency of available RCT evidence than is currently possible for sex-stratified heart failure pharmacotherapy outcomes.
Keywords: GLP-1 agonists, SGLT2 inhibitors, Cardioprotective action, gender stratification, MACE, COVT
Biography:
Dr. Manjula M.J., MBBS, MD, is a medical academician, researcher, and educator with a strong interest in clinical research, medical education, and academic mentorship. She is actively involved in postgraduate teaching, thesis guidance, scientific writing, and research methodology. As a UNAI SDG Coordinator, she contributes to promoting the United Nations Sustainable Development Goals through academic and institutional initiatives, with particular interest in health and sustainability. Her professional interests include diabesity-related research, clinical data analysis, manuscript development, and capacity building among medical students and postgraduate trainees. She is committed to integrating evidence-based medicine, research, education, and social responsibility to create meaningful impact in healthcare and academia.
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