SUMMIT analysis finds tirzepatide benefit holds in kidney disease and flags eGFR test mismatch

An analysis of the SUMMIT trial reports that tirzepatide (marketed as Mounjaro and Zepbound) reduced the relative risk of major heart failure events in people with obesity-related heart failure with preserved ejection fraction whether or not they also had chronic kidney disease. The same analysis found that two standard ways of estimating kidney function often gave different answers for the same patient ^[1].

The SUMMIT trial randomly assigned 731 patients with heart failure with preserved ejection fraction (HFpEF) and a body mass index of at least 30 kg/m2, and specifically enrolled a large share of patients who also had chronic kidney disease (CKD). Participants received either placebo or tirzepatide for a median of 104 weeks. They were followed for cardiovascular death or worsening heart failure events, and their quality of life was measured with the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 52 weeks ^[1].

Patients with CKD started out sicker. They had worse functional class, lower KCCQ-CSS scores and shorter six-minute walk distances, higher levels of NT-proBNP and cardiac troponin T, and about twice the risk of worsening heart failure events. Even so, CKD did not change the relative benefit of tirzepatide on major heart failure events, or on KCCQ-CSS, quality of life and functional capacity. The absolute risk reduction in the primary events was numerically greater in patients with CKD ^[1].

The second part of the analysis looked at how kidney function was measured. At randomization, estimated glomerular filtration rate (eGFR) calculated from cystatin C averaged about 9 mL/min/1.73 m2 lower than eGFR calculated from creatinine, with what the authors described as significant individual variance. In other words, the two formulas often disagreed for individual patients ^[1].

During treatment, tirzepatide increased eGFR at 52 weeks by both the creatinine-based and cystatin C-based formulas, but with "considerable discordance" between them in individual patients. Creatinine-based eGFR showed a decline at 12 weeks that cystatin C did not. By 52 weeks, cystatin C showed improvement in all patients, while creatinine showed improvement only in patients with CKD ^[1].

The authors concluded that measuring eGFR in patients with obesity who are taking incretin-based drugs is likely to be skewed by the effects of fat and muscle mass, and by changes in body composition, on the body's production of both cystatin C and creatinine ^[1].

Why it matters for patients

An eGFR result is an estimate, not a direct measurement of kidney function, and the trial data show the choice of formula can matter: the average gap between the two estimates was about 9 mL/min/1.73 m2 at the start of the study ^[1].

Weight loss changes muscle mass, and creatinine comes from muscle. That means a creatinine-based eGFR can shift during rapid weight loss even if the kidneys themselves have not changed. The analysis describes this as a measurement problem rather than evidence of kidney harm ^[1].

For patients who have both heart failure with preserved ejection fraction and chronic kidney disease, the results offer some reassurance on one point: having CKD did not blunt tirzepatide's relative benefit on heart failure events, and the absolute risk reduction was numerically larger in that group ^[1].

The analysis does not report the exact number of heart failure events in each group, the size of the eGFR changes in mL/min/1.73 m2 at 12 and 52 weeks, or how often the two formulas disagreed by a clinically meaningful amount. Those figures have not been disclosed in the abstract. It also covers only tirzepatide, in a population defined by HFpEF and a BMI of at least 30 kg/m2, so the findings have not been shown to apply to other GLP-1 or incretin medications or to other patient groups.

What happens next

The findings were published on March 28, 2025 ^[1]. The SUMMIT trial is registered as NCT04847557 ^[1]. Whether the measurement issues described here will change how kidney function is monitored in people taking tirzepatide, or how future trials report kidney outcomes, has not been reported.