Journal of the American College of CardiologyMar 31, 2025

How Chronic Kidney Disease May Affect Tirzepatide's Impact in Patients with Heart Failure, Preserved Heart Pumping, and Obesity

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 20, 2026

Abstract

Patients with chronic kidney disease (CKD) and obesity-related heart failure with preserved ejection fraction (HFpEF) experienced a 2-fold increase in the risk of worsening heart failure events.

CKD was associated with greater severity of heart failure, indicated by worse functional class, lower Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores, and reduced 6-minute walk distances.
Higher levels of NT-proBNP and cardiac troponin T were observed in patients with CKD.
Tirzepatide reduced the relative risk of major adverse heart failure events and improved quality of life, regardless of CKD status, with a numerically greater absolute risk reduction in patients with CKD.
Baseline eGFR measured by cystatin C was consistently lower than that measured by creatinine, with significant variability among individuals.
Tirzepatide increased eGFR at 52 weeks according to both creatinine and cystatin C assessments, although initial declines were noted at 12 weeks for eGFR-creatinine.

Simplified

BACKGROUND: Obesity leads to both heart failure with a preserved ejection fraction (HFpEF) and to chronic kidney disease (CKD); CKD may both influence the clinical course of obesity-related HFpEF; and incretin-based drugs may influence renal function.

OBJECTIVES: This analysis had dual objectives: 1) to evaluate the influence of CKD on the clinical responses to tirzepatide in patients with obesity-related HFpEF; and 2) to investigate the complexity of tirzepatide-related changes in renal function. For both objectives, we focused on discrepancies between creatinine-based and cystatin C-based estimates of the estimated glomerular filtration rate (eGFR).

METHODS: The SUMMIT trial randomly assigned 731 patients with HFpEF and a body mass index ≥30 kg/m, who were enriched for participants with CKD. Patients received either placebo or tirzepatide for a median of 104 weeks and were followed for cardiovascular death or worsening heart failure events and for changes in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) after 52 weeks. Because of the confounding produced by obesity and changes in muscle mass, eGFR was assessed at randomization and after 12, 24, and 52 weeks by both creatinine-based and cystatin C-based formulae. 2

RESULTS: Patients with CKD (based on creatinine or cystatin C) had greater severity of heart failure, as reflected by: 1) worse functional class, KCCQ-CSS scores, and 6-minute walk distance; 2) higher levels of NT-proBNP and cardiac troponin T; and 3) a 2-fold increase in the risk of worsening heart failure events. CKD did not influence the effect of tirzepatide to reduce the relative risk of major adverse heart failure events and to improve KCCQ-CSS, quality of life, and functional capacity, but the absolute risk reduction in the primary events was numerically greater in patients with CKD. Regarding renal function assessments, baseline eGFR-cystatin C was consistently ≈9 mL/min/1.73 mlower than that eGFR-creatinine, with significant individual variance. Furthermore, tirzepatide increased eGFR at 52 weeks, assessed by both creatinine-based and cystatin C-based formulae, but with considerable discordance in individual patients. Tirzepatide produced a decline in eGFR at 12 weeks with eGFR-creatinine (but not eGFR-cystatin C), and it led to an improvement in eGFR at 52 weeks in all patients (when assessed by cystatin C), but only in patients with CKD (when assessed by eGFR-creatinine). 2

CONCLUSIONS: The triad of obesity, HFpEF, and CKD identifies patients with considerable functional impairment and an unfavorable prognosis, who nevertheless respond favorably to tirzepatide. Long-term tirzepatide improves renal function (both by cystatin C and creatinine), but the measurement of eGFR in patients with obesity receiving incretin-based drugs is likely to be skewed by the effects of fat and muscle mass (and by changes in body composition) on the synthesis of both cystatin C and creatinine. (A Study of Tirzepatide [LY3298176] in Participants With Heart Failure With Preserved Ejection Fraction [HFpEF] and Obesity: The SUMMIT Trial; NCT04847557).

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Competing interests

Funding Support and Author Disclosures Dr Packer has served as a consultant for 89bio, AbbVie, Actavis, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, ARMGO, AstraZeneca, Attralus, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Lilly, Imara, Medtronic, Moderna, Novartis, Pharmacocosmos, Reata, Regeneron, Roche, and Salamandra. Dr Zile has received research support from the U.S. Department of Veterans Affairs (Project Nos. BX005943, BX005848); and has served as a consultant for Abbott, Adona Medical, Aria CV, Avery Therapeutics, Boehringer Ingelheim, Boston Scientific, Cardiovascular Research Foundation Clinical Trials Center, CVRx, DIASTOL Therapeutics, EBR, Edwards Lifesciences, Lilly, GenKardia, Innoventric, KestraMedical, Medtronic, Merck, Morphic Therapeutics, Novartis, Pulnova, Salubris Biotherapeutics, Sonata, SRNALYTICS, V-WAVE, and Vectorious. Dr Kramer has served as a consultant for Eli Lilly and Co; and has received research grant support from Eli Lilly and Co, Bristol Myers Squibb, and Cytokinetics. Drs Murakami and Ou are employees of Eli Lilly and Co. Dr Borlaug has received research grant support from the National Institutes of Health and the U.S. Department of Defense, AstraZeneca, Axon, Corvia, Novo Nordisk, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is a named inventor (U.S. Patent No. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure.

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How Chronic Kidney Disease May Affect Tirzepatide's Impact in Patients with Heart Failure, Preserved Heart Pumping, and Obesity

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