Effects of tirzepatide (GIP/GLP-1 dual receptor agonist) on cardiorenal biomarkers and functional capacity in heart failure: a systematic review and meta-analysis

BACKGROUND: Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated clinical benefits in heart failure with preserved ejection fraction (HFpEF) and obesity. However, its effects on cardiorenal biomarkers and functional capacity have not been comprehensively synthesized. We hypothesized that tirzepatide produces significant reductions in cardiorenal biomarkers and improvements in functional capacity compared to placebo or standard of care. METHODS: This systematic review and meta-analysis (PROSPERO: CRD42026137255) searched PubMed, Embase, CENTRAL, Web of Science, and Scopus from inception to April 17, 2026, without restrictions. Randomized controlled trials and prospective observational studies reporting NT-proBNP, high-sensitivity C-reactive protein (hsCRP), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), 6-minute walk test (6 MWT), or renal outcomes with tirzepatide vs placebo or standard of care were included. Data were pooled using random-effects models with Hartung-Knapp-Sidik-Jonkman adjustment. RESULTS: Seven studies (5 RCTs, 2 observational; 5406 participants) were included. Tirzepatide significantly reduced hsCRP by 34.3% (95% CI: -38.4% to -30.1%; P < .0001; I2 = 0.0%; 6 studies) and NT-proBNP by 17.6% (95% CI: -26.7% to -8.5%; P = .0001; I2 = 58.1%; 3 studies). In the SUMMIT trial, KCCQ-CSS improved by 5.1 points (P < .001) and 6 MWT by 15.8 m (P = .004). Single-trial data demonstrated estimated glomerular filtration rate (eGFR) preservation (+2.90 mL/min/1.73 m2/year; 95% CI: 0.94 to 4.86) and urine albumin-to-creatinine ratio reduction (-25.0%; 95% CI: -36.0% to -13.0%). CONCLUSION: Tirzepatide produces consistent anti-inflammatory effects and significant natriuretic peptide reductions, supported by moderate Grading of Recommendations Assessment, Development and Evaluation certainty. Evidence for functional and renal outcomes remains limited to single-trial analyses and should be considered hypothesis-generating pending larger dedicated heart failure trials. PROSPERO REGISTRATION: CRD42026137255.