Does CKD reduce tirzepatide benefits on HFpEF patients with obesity?

Long-term treatment with tirzepatide results in improved renal function in patients with heart failure with preserved ejection fraction (HFpEF) and obesity, regardless of the absence or presence of chronic kidney disease (CKD), according to a post hoc analysis of the SUMMIT trial presented at ACC.25.

However, the measurement of estimated glomerular filtration rate (eGFR) in patients receiving incretin-based drug may be “skewed by the effects of fat and muscle mass on the synthesis of both cystatin C and creatinine,” according to the researchers.

"This drug improves kidney function, obesity, and HFpEF outcomes," said first author Dr Milton Packer, Baylor University Medical Center, Dallas, Texas, US. [https://www.acc.org/Latest-in-Cardiology/Journal-Scans/2025/03/24/16/30/mon-9am-summit-acc-2025]

"The interplay of these three conditions [ie, obesity, HFpEF, and CKD] identifies a patient population as exceptionally high risk, which means it's a patient population that is exceptionally in need of treatments that work," he added.

The SUMMIT trial included 731 patients with HFpEF and a BMI ≥30 kg/m², of whom 441 (60 percent) had CKD. Participants were randomized to receive tirzepatide or placebo for a median of 104 weeks and were followed for cardiovascular death or worsening heart failure events, as well as for changes in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) after 52 weeks.

Packer and his team assessed eGFR at randomization and after 12, 24, and 52 weeks by creatinine- and cystatin C-based formulae due to the confounding produced by obesity and changes in muscle mass.

Heart failure was more severe among patients with CKD, as shown by the following: worse functional class, KCCQ-CSS scores, and 6-minute walk distance; higher levels of NT-proBNP and cardiac troponin T; and a twofold increase in the risk of worsening heart failure events. [J Am Coll Cardiol 2025;doi:10.1016/j.jacc.2025.03.009]

CKD, however, showed no impact on the effect of tirzepatide in reducing the relative risk of major adverse heart failure events and in improving the quality of life, functional capacity, and KCCQ-CSS scores of patients. Those with CKD also exhibited greater absolute risk reduction in the primary events.

Creatinine, cystatin C

Looking at renal function assessments, baseline eGFR measured by cystatin C was about 9-mL/min/1.73 m² lower than that assessed by creatinine, with significant individual variance. At 52 weeks, eGFR measured by both creatinine and cystatin C increased with tirzepatide, “but with considerable discordance in individual patients.”

In addition, tirzepatide use resulted in eGFR decrease at 12 weeks with creatinine, but not cystatin C, and in improvement at 52 weeks in all patients when assessed by cystatin C, but only in those with CKD when assessed by creatinine.

“In the SUMMIT trial, the presence or absence of CKD did not influence the favourable effects of tirzepatide on worsening heart failure events, on health status assessed by KCCQ-CSS, on exercise tolerance assessed by 6-minute walk distance, and on functional capacity or quality of life,” the researchers said. 

A previous trial also found no influence of CKD on the effect of dapagliflozin in patients with HFpEF. [JAMA Cardiol 2023;8:56-65]

“However, it was not clear that this pattern of response would apply to incretin-based treatments, since the influence of baseline kidney function on the responses to semaglutide in patients with HFpEF enrolled in the STEP-HFpEF and STEP-HFpEF-DM trials was not reported,” the researchers said. [N Engl J Med 2023;389:1069-1084; N Engl J Med 2024;390:1394-1407]

"Therefore, the findings of the SUMMIT trial are novel and important,” they added.