Results from the SUMMIT trial presented at the American College of Cardiology's Annual Scientific Session (ACC.25) and simultaneously published in JACC reveal that tirzepatide significantly improves kidney function and cardiovascular outcomes in patients with obesity and heart failure with preserved ejection fraction (HFpEF).
Significant Cardiovascular and Renal Benefits
The SUMMIT trial enrolled 731 patients with HFpEF and a body mass index of 30 kg/m² or higher, with approximately 60% also having chronic kidney disease (CKD). After one year of treatment, patients receiving tirzepatide showed a 38% reduction in the rate of cardiovascular death or worsening heart failure compared to the placebo group (P=0.026).
"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," said Milton Packer, MD, Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center in Dallas and the study's first author. "This drug improves kidney function, obesity and HFpEF outcomes, thus improving all three elements that interact to create this syndrome."
Kidney function improvements were documented using both creatinine and cystatin C measurements at 12, 24, and 52 weeks. Despite different patterns over time, both markers ultimately showed significant improvements in kidney function among participants taking tirzepatide compared to those on placebo.
Addressing a Complex Patient Population
The trial specifically targeted the intersection of obesity, HFpEF, and CKD—a triad of conditions estimated to affect 2-3 million U.S. adults. Patients with CKD demonstrated greater severity of heart failure at baseline, including worse functional class, lower Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (KCCQ-CSS), reduced 6-minute walk distances, higher NT-proBNP and cardiac troponin T levels, and a two-fold increase in the risk of worsening heart failure events.
While tirzepatide reduced the relative risk of major adverse heart failure events and improved quality of life metrics similarly across all patients, those with CKD appeared to gain greater absolute risk reduction from treatment.
Study Design and Methodology
The SUMMIT trial utilized a rigorous double-blind, placebo-controlled design. Patients were randomized to receive either tirzepatide or placebo for a median of 104 weeks. The tirzepatide group started at 2.5mg weekly, with doses gradually increased by 2.5mg every four weeks as tolerated, reaching a target of 15mg weekly by week 20.
Participants were required to have HFpEF with a left ventricular ejection fraction of 50% or higher and a BMI of at least 30kg/m². Additional inclusion criteria ensured patients were at elevated risk, requiring either left atrial enlargement, elevated left ventricular pressures, or elevated NT-proBNP levels.
Mechanism of Action
Tirzepatide targets two receptors—GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide)—to shrink fat cells and reduce the impacts that enlarged fat cells have on heart and kidney health. The drug is currently FDA-approved for treating obesity and Type 2 diabetes.
"Most patients with obesity who have HFpEF and chronic kidney disease are not getting any effective treatment," Packer noted. "We were very pleased to see the improvement in kidney function, which paralleled the favorable effects on the heart and on obesity."
Measurement Challenges and Considerations
Researchers acknowledged that both creatinine and cystatin C levels can be affected by factors such as obesity and skeletal muscle mass. The study revealed interesting patterns in these measurements:
- Baseline eGFR-cystatin C was consistently approximately 9mL/min/1.73m² lower than eGFR-creatinine
- Tirzepatide produced an initial decline in eGFR at 12 weeks when measured by creatinine, but not when measured by cystatin C
- By 52 weeks, tirzepatide improved eGFR in all patients when assessed by cystatin C, but only in patients with CKD when assessed by creatinine
Despite these complexities, the agreement between the two measurements in terms of the overall direction of change provides confidence in tirzepatide's positive impact on kidney function.
Future Implications
The SUMMIT trial results suggest tirzepatide could become an important treatment option for patients with this complex syndrome of obesity, HFpEF, and CKD. Researchers plan to continue analyzing data from the trial to gain further insights into the molecular mechanisms underlying the interplay between these conditions.
The study was funded by Eli Lilly and Company, which markets tirzepatide under the brand name Mounjaro. Industry experts predict tirzepatide will likely be increasingly prescribed for broader cardiometabolic disease management beyond its traditional use for Type 2 diabetes.
