SUMMIT analysis flags a measurement problem with kidney function during rapid weight loss

A new analysis of the SUMMIT trial has found that a standard kidney function test can give misleading numbers in people with obesity, and that tirzepatide's benefit for heart failure held up even in patients with chronic kidney disease (CKD) ^[1].

SUMMIT enrolled 731 patients with heart failure with preserved ejection fraction (HFpEF) and a body mass index of 30 or higher, and it deliberately included many people with CKD ^[1]. Patients got either tirzepatide or a placebo for a median of 104 weeks, and researchers tracked cardiovascular death, worsening heart failure events, and quality-of-life scores using the Kansas City Cardiomyopathy Questionnaire ^[1].

The analysis focused on how doctors measure kidney function, called estimated glomerular filtration rate, or eGFR. There are two common ways to estimate it: one based on creatinine, a waste product from muscle, and one based on cystatin C, a protein made by most cells in the body ^[1]. In this study, the cystatin C-based eGFR was consistently about 9 mL/min/1.73 m2 lower than the creatinine-based eGFR at the start of the trial, and the two measures often disagreed substantially for individual patients ^[1].

The discrepancy carried into how the drug's effects on kidney function looked over time. At 12 weeks, tirzepatide was linked to a drop in eGFR when measured by creatinine, but not when measured by cystatin C ^[1]. By 52 weeks, tirzepatide was linked to an increase in eGFR under both formulas, but the improvement showed up in all patients when using cystatin C, while the creatinine-based measure showed improvement only in patients who already had CKD ^[1]. The researchers say this pattern likely reflects how obesity, and the fat and muscle mass changes from rapid weight loss, affect the body's production of both creatinine and cystatin C, which can skew either estimate ^[1].

On the heart failure side, patients with CKD in the trial had more severe disease at baseline, including worse functional class, lower six-minute walk distances, higher NT-proBNP and cardiac troponin T levels, and about twice the risk of worsening heart failure events compared with patients without CKD ^[1]. Despite that greater baseline severity, CKD did not reduce the relative benefit of tirzepatide on the combined risk of cardiovascular death or worsening heart failure, nor on improvements in quality of life and functional capacity measured by the KCCQ score ^[1]. In fact, the absolute risk reduction in heart failure events was numerically larger in patients who had CKD, since they started at higher risk ^[1].

Why it matters for patients

For people with obesity taking incretin-based drugs like tirzepatide, a single kidney function number from a routine lab test may not tell the full story. Because rapid weight loss changes both fat and muscle mass, the two most common ways of estimating kidney function can move in different directions or by different amounts, and for some patients they disagreed substantially ^[1]. That means a temporary dip in one eGFR measurement at an early clinic visit is not necessarily a sign that kidney function is getting worse, and a rise in another measurement is not automatically proof it is improving.

The finding also offers reassurance for a specific group: people who have both heart failure with preserved ejection fraction and reduced kidney function. This analysis found that having CKD did not stop tirzepatide from helping with heart failure events and quality of life, even though these patients started out sicker and at higher risk ^[1]. Patients and clinicians who are trying to interpret kidney lab results during treatment may need to consider both creatinine-based and cystatin C-based estimates, along with the broader clinical picture, rather than relying on a single number.

This analysis does not address other GLP-1 or dual GLP-1/GIP drugs, such as semaglutide (Ozempic, Wegovy, Rybelsus) or orforglipron (Foundayo), and it is not yet known whether the same measurement discrepancy applies to those medicines specifically ^[1].