Key Points
- The SUMMIT randomized control trial demonstrated that tirzepatide significantly reduced worsening heart failure events among patients with HFpEF and obesity compared to placebo.
- This secondary analysis focused on the 60% of SUMMIT patients with the triad of HFpEF, obesity, and CKD, as they represent a population of patients with cardiovascular-kidney-metabolic syndrome, an especially high-risk group.
- The relative benefits of tirzepatide were the same amongst those with and without CKD, indicating that baseline eGFR did not influence the magnitude of the relative risk reduction in major adverse heart failure outcomes from tirzepatide. The absolute risk reduction was numerically greater among those with CKD.
- At one year tirzepatide was associated with an improvement in eGFR in all patients when assessed using cystatin C, but only those with CKD when estimated by serum creatinine; though these measurements may be confounded by the effect of the treatment on fat and muscle mass. Albuminuria also improved similarly for patients with and without CKD.
The SUMMIT trial demonstrated that tirzepatide reduced worsening heart failure events in patients with heart failure with preserved ejection fraction (HFpEF) and obesity compared to placebo. Many patients with these conditions also have chronic kidney disease (CKD). However, whether incretin-based therapies such as tirzepatide have a differential effect in this subpopulation is uncertain.
On March 31st 2025, results from the “Interplay of Chronic Kidney Disease and the Effect of Tirzepatide in Heart Failure, Preserved Ejection Fraction and Obesity” were presented at ACC Scientific Sessions 2025 on behalf of the SUMMIT investigators, with simultaneous publication in the Journal of the American College of Cardiology. The purpose of this study was to evaluate the influence of CKD on the clinical response to tirzepatide in SUMMIT trial patients, and to assess changes in renal function with tirzepatide in the SUMMIT population.
The SUMMIT trial randomized 731 patients with HFpEF and obesity to placebo or tirzepatide for a median of 104 weeks. The primary outcome was a composite of (CV) death or worsening HF events. The current analysis stratified SUMMIT patients by the presence of CKD defined as a estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 by either cystatin c or creatinine measures, and compared baseline characteristics and outcomes in the two groups. This secondary analysis also looked at changes in estimated glomerular filtration rate (eGFR) and albuminuria both overall and by CKD status.
The 441 patients with CKD were older, had a worse functional class, a greater burden of HF symptoms, a lower 6-minute walk distance, higher levels of NT-proNBNP and troponin, and a two-fold higher risk of worsening HF events compared to those without CKD. The presence of CKD did not influence the relative risk reduction of tirzepatide on the primary outcome, however the absolute risk reduction was numerically greater in CKD patients: for every 100 patients treated for one year, tirzepatide prevented 3.6 primary endpoint events for those with CKD versus 1.6 primary endpoint events for those without CKD. Improvements in secondary outcomes, including functional capacity, HF symptoms burden, hsCRP, and body weight were similar for those with or without CKD.
Among all patients, tirzepatide was associated with a reduction in eGFR as measured by creatinine at 12 weeks (-3.0 mL/min/1.73 m2, [95% CI: 4.5 to 1.5 mL/min/1.73 m2], P < 0.001), followed by a significant improvement in eGFR by 1 year (between-group change, tirzepatide vs. placebo +1.9 mL/min/1.73 m2 [95% CI: 0.2-3.7 mL/min/1.73 m2], P = 0.03). When using cystatin-C, there was no decrease in eGFR at 12 weeks, and the improvement at 1 year was even more pronounced (+2.9 [95% CI: 0.9-4.9], P = 0.004). When stratified by CKD, the effect size in the improvement in eGFR was similar for both groups when measured by cystatin C, but the effect size was larger in the CKD group when eGFR was measured using creatinine. Tirzepatide also led to a decrease in albuminuria that was similar in both groups. There was no difference in gastrointestinal side effects by CKD status.
Milton Packer, MD, Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center in Dallas concluded: “Most patients with obesity who have HFpEF and chronic kidney disease are not getting any effective treatment. We were very pleased to see the improvement in kidney function, which paralleled the favorable effects on the heart and on obesity.”