Among patients with obesity-related heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD), the baseline estimated glomerular filtration rate (eGFR) did not impact the effect of tirzepatide on reducing major adverse HF events or to enhance health status, according to a post-hoc analysis of the SUMMIT trial presented during a Featured Clinical Research session at ACC.25 in Chicago and simultaneously published in JACC. However, the absolute risk reduction in the primary events was numerically greater in patients with CKD.

Of the 731 patients with HFpEF and a BMI ≥30kg/m² in SUMMIT, 60% had CKD. Results from the main trial showed a 38% reduction with tirzepatide compared with placebo in the primary endpoint of cardiovascular death or worsening heart failure, the study's primary endpoint, as well as improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores.

In the present analysis, the researchers examined outcomes in relation to eGFR as measured by creatine-based and cystatin-C based estimates, assessed at randomization and after 12, 24 and 52 weeks.

Results showed that the severity of HF was greater in those with CKD, including a twofold increase in the risk of worsening HF events. Furthermore, the effect of tirzepatide was similar in patients with and without CKD for the relative reduction in HF events and improving quality of life.

Overall, patients with CKD faced worst outcomes, including a 50% increase in risk of worsening HF, as well as lower quality of life and higher levels of NT-proBNP and cardiac troponin T.

Looking at the assessments of renal function, eGFR measured by cystatin C was about 9 mL/min/1.73 m² lower than when measured by creatinine and the authors note there was significant individual variance. At 52 weeks, there was an increase in eGFR with tirzepatide as measured with cystatin C or creatinine methods, also 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).

"This drug improves kidney function, obesity and HFpEF outcomes," said the study's first author, Milton Packer, MD, FACC. "The interplay of these three conditions identifies a patient population as exceptionally high risk, which means it's a patient population that is exceptionally in need of treatments that work."

Regarding the individual variance in eGFR measurements, "These discrepancies highlight significant limitations in estimating kidney function, supporting the consideration of directly measuring GFR, both in clinical trials and practice," write Jozine M. ter Maaten, MD, PhD, and Javed Butler, MD, MPH, MBA, FACC, in an accompanying editorial comment. "Such an approach would be especially valuable in the setting of [cardio-kidney-metabolic] syndrome and when evaluating therapies such as GLP1RAs that influence muscle mass and adiposity, factors known to affect eGFR estimates."