Glucagon-Like Peptide-1 Receptor Agonists and Dual GIP/GLP-1 Receptor Co-Agonism in Heart Failure with Preserved Ejection Fraction: A Systematic Review of Randomized and Real-World Evidence

Abstract

Background: This is a reconciliation (umbrella-style) systematic review of existing randomized and observational evidence. Heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF) are frequently associated with obesity and cardiometabolic dysfunction. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and tirzepatide have emerged as candidate disease-modifying therapies for obesity-related HFpEF, but consistency of benefit across trial designs, phenotypes, and diabetes status requires critical synthesis.

Objective: To systematically review randomized and real-world evidence on GLP-1 receptor agonist and dual GIP/GLP-1 receptor co-agonist therapy in HFpEF or HFmrEF, and to critically compare these findings against independently conducted meta-analyses.

Methods: We searched PubMed, Embase, Cochrane CENTRAL, Scopus, and Web of Science from inception to June 2026, supplemented by ClinicalTrials.gov and major cardiology/endocrinology congress proceedings. Risk of bias was assessed using the Cochrane RoB 2 tool. Given substantial cross-trial heterogeneity, we conducted a structured narrative synthesis and critically compared findings against six independently conducted meta-analyses.

Results: Six pivotal trial-level data sources met eligibility criteria: STEP-HFpEF, STEP-HFpEF DM, SUMMIT, SELECT, FLOW, and a four-trial pooled analysis. Semaglutide and tirzepatide produced consistent placebo-corrected improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, 6-minute walk distance, and body weight, with reductions in C-reactive protein and loop diuretic requirement. In SUMMIT, tirzepatide reduced cardiovascular death or worsening heart failure events by 38% (HR 0.62, 95% CI 0.41–0.95), driven by fewer heart failure hospitalizations/urgent visits. An independent meta-regression synthesis corroborated reductions in heart failure hospitalization/events and found no significant effect modification by diabetes status. A large real-world target trial emulation of 97,690 patients found reduced heart failure hospitalization or all-cause mortality with semaglutide and tirzepatide. Gastrointestinal adverse events were more frequent, without a HFpEF-specific safety signal. Exploratory two-study pooling yielded HR 0.67 (95% CI 0.54–0.84; P=0.0004).

Conclusion: GLP-1RAs and tirzepatide produce robust improvements in symptoms, function, and inflammatory/congestive biomarkers in obesity-related HFpEF and HFmrEF, with an emerging signal for reduced heart failure hospitalization independent of diabetes status. A mortality benefit remains statistically unconfirmed.