Tirzepatide improves kidney, cardiovascular function in patients with obesity and HFpEF

The drug tirzepatide improved kidney function and cardiovascular outcomes among patients with obesity and heart failure with preserved ejection fraction (HFpEF) compared with placebo at one year, according to featured clinical research presented at the American College of Cardiology's Annual Scientific Session (ACC.25) and simultaneously published in JACC. The overall rate of cardiovascular death or worsening heart failure, the trial's primary endpoint, was higher in the 60% of study participants who also had chronic kidney disease. However, tirzepatide reduced the risk of the primary endpoint to a similar degree in patients with and without kidney disease.

In the new analysis of data from the SUMMIT trial, researchers focused on patients with obesity, chronic kidney disease and HFpEF because they commonly have interacting root causes and are associated with poor outcomes, indicating a significant unmet need.

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. This drug improves kidney function, obesity and HFpEF outcomes, thus improving all three elements that interact to create this syndrome."

Milton Packer, MD, Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center in Dallas and study's first author

HFpEF occurs when the heart muscle cannot enlarge sufficiently to accommodate the blood it receives, causing pressure in the heart to become elevated. Chronic kidney disease occurs when the kidneys do not filter waste from the blood as they should, leading to a buildup of toxins. Both are chronic conditions that progressively worsen over time.

Tirzepatide targets two receptors in order to shrink fat cells and reduce the impacts that enlarged fat cells have on heart and kidney health. The drug is approved by the U.S. Food and Drug Administration for treating obesity through its impacts on weight loss, as well as for treating Type 2 diabetes through its impact on blood sugar levels. Previous studies have shown improved kidney function with other drugs in the same class but this trial is the first to assess tirzepatide's impact on kidney and cardiovascular outcomes in people with obesity, chronic kidney disease and HFpEF, a triad of conditions estimated to affect about 2 million to 3 million U.S. adults.

The SUMMIT trial enrolled 731 patients with HFpEF and a body mass index of 30 m²/kg or higher. About 60% of the study participants also had chronic kidney disease. Half were randomly assigned to receive tirzepatide and half received a placebo. Neither patients nor their clinicians were aware of which regimen they had been assigned.

At one year, patients taking tirzepatide had a 38% lower rate of cardiovascular death or worsening heart failure (defined as worsening heart failure symptoms in addition to hospitalization or the intensification of diuretic medications) compared with the placebo group. Participants taking tirzepatide also had a better average Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) than the placebo group, showing a significant improvement in terms of the study's second primary endpoint, a measure of heart failure severity.

For both of these primary endpoints, researchers observed similar improvement with tirzepatide in patients with and without chronic kidney disease. Overall, participants with chronic kidney disease faced poorer outcomes across multiple metrics compared to participants without chronic kidney disease, experiencing more severe heart failure symptoms on average and seeing twice the risk of worsening heart failure during the study.

The researchers used two strategies for assessing kidney function, measuring creatinine and cystatin C at 12, 24 and 52 weeks. Ultimately, participants taking tirzepatide showed significant improvements over those taking placebo in terms of both markers of kidney function, although the results showed different patterns over time and among different patient groups.

"Most patients with obesity who have HFpEF and chronic kidney disease are not getting any effective treatment," Packer said. "We were very pleased to see the improvement in kidney function, which paralleled the favorable effects on the heart and on obesity."

Researchers said that both creatinine and cystatin C levels can be affected by factors such as obesity and skeletal muscle mass. Despite this potential confounder, the agreement among the two measurements in terms of the direction of change among study groups offers confirmation of the positive impact of tirzepatide on kidney functioning, Packer said.

The researchers plan to continue to analyze data from the SUMMIT trial for further insights on the molecular mechanisms that contribute to the interplay between obesity, kidney disease and heart failure.

The study was funded by Eli Lilly and Company.

This study was simultaneously published online in JACC at the time of presentation.