How does tirzepatide influence renal function in patients with heart failure, preserved ejection fraction, and obesity, and what challenges exist in its assessment?

Tirzepatide, an incretin-based drug, was investigated in The SUMMIT Trial to evaluate its effects on renal function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). The study focused on how tirzepatide impacts renal function and the complexities of assessing these changes. This assessment relied on both creatinine-based and cystatin C-based estimated glomerular filtration rate (eGFR) formulae, which can be influenced by changes in body composition due to the drug.

Long-term treatment with tirzepatide improves renal function, as indicated by both cystatin C and creatinine measurements. However, the assessment of eGFR in patients receiving incretin-based drugs like tirzepatide is likely to be skewed due to the drug's effects on fat and muscle mass, which impact the synthesis of both cystatin C and creatinine.

Specifically:

Tirzepatide initially caused a decline in eGFR at 12 weeks when measured by eGFR-creatinine, but not when measured by eGFR-cystatin C.

At 52 weeks, tirzepatide led to an improvement in eGFR in all patients when assessed by cystatin C, but only in patients with Chronic Kidney Disease (CKD) when assessed by eGFR-creatinine.

Overall, tirzepatide increased eGFR at 52 weeks, as evaluated by both creatinine-based and cystatin C-based formulae, though there was considerable discordance among individual patients.