Positive Results for Tirzepatide in Those With the Cardiovascular-Kidney-Metabolic Triad | ACC 2025

Tirzepatide produced similar benefits in people with chronic kidney disease as it did in people without and showed signs of improving kidney functions, according to results presented today at the American College of Cardiology (ACC) Scientific Session in Chicago.

Results from the SUMMIT trial, which included people with heart failure with a preserved ejection fraction (HFpEF) and a body mass index of 30 or greater, showed that the 441 people in the trial with chronic kidney disease experienced approximately the same relative reduction in cardiovascular death or events indicative of worsening heart failure as those without chronic kidney disease. Moreover, the results suggest that the drug may benefit kidney function.

“We were very pleased to see the improvement in kidney function, which paralleled the favorable effects on the heart and on obesity,” said Milton Packer, M.D., of Baylor University Medical Center at Dallas, in a news release from the AAC. Packer is the lead and corresponding author of the study reporting the results that was simultaneously in the Journal of the American College of Cardiology (JACC) with Packer’s presentation of the data at the ACC meeting in Chicago.

Packer and his colleagues also reported that chronic kidney disease did not influence the gastrointestinal symptoms from tirzepatide. Gastrointestinal symptoms were reported by 54.2% of tirzepatide-treated patients with chronic kidney disease compared with 27.5% randomly assigned to receive a placebo. In people without chronic kidney disease, the difference was approximately the same (58.8% vs. 24.8%).

Tirzepatide is marketed by Eli Lilly as Mounjaro as a diabetes drug and Zepbound as a weight loss drug. It is a glucagon-like peptide 1 receptor agonist like semaglutide (sold as Ozempic and Wegovy) but has an additional mechanism of action as a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist that may make it more effective. The FDA approved tirzepatide as a diabetes drug in May 2022 and as a weight loss drug in November 2023.

Packer and his colleagues are investigating tirzepatide as the overlap among cardiovascular disease, obesity, diabetes and chronic kidney is getting more attention from cardiologists and other clinicians. In 2023, the American Heart Association put out a special presidential advisory about what it dubbed cardiovascular-kidney-metabolic syndrome, or CKM for short. In today’s JAAC paper, Packer and his colleagues discuss the interplay of the diseases. Both hypertension and diabetes increase the risk of HFpEF and chronic kidney, they note, and obesity increases the kidneys’ susceptibility to harm from high blood pressure. Systemic and endothelial inflammation leads to HFpEF and to declines in kidney function. Meanwhile, they suggest there is a feedback loop whereby compromised kidneys result in abnormalities of the heart’s left ventricular mass and diastolic filling that are identical to those seen in HFpEF. Packer and his colleagues also note some of the medications used to HFpEF — diuretics, for example — may stress the kidneys, in contrast to their findings suggesting that tirzepatide may have some kidney benefit in the CKM population.

The overall SUMMIT results that Packer and his colleagues reported in the New
England Journal of Medicine in November 2024 showed that a composite end point encompassing death from cardiovascular causes or events indicative of worsening heart failure occurred in 36 patients (9.9%) in the tirzepatide group and 56 patients (15.3%) in the placebo group. Today they reported that on that primary events endpoint, the effect of tirzepatide in patients with or without chronic kidney disease was similar: a 33% reduction in patients with chronic kidney disease and a 42% reduction in patients without it.

They also calculated the event rates per 100 patients. By that measure, tirzepatide was more protective against death from cardiovascular disease and events related to worsening of heart failure among those with chronic kidney disease than those without it (3.6 fewer deaths or worsening heart failure events among those with chronic kidney disease compared with 1.6 fewer among those without it).

The SUMMIT results for tirzepatide’s effects on the kidney are complicated by the fact that Packer and his colleagues used two different ways of calculating an estimated glomerular filtration rate (eGFR), based on serum creatinine levels and the other on cystatin C levels. Using eGFR based on creatinine levels, they observed an early dip in eGFR at 12 weeks, but renal function appeared to be improved at a year but only in patients in a certain eGFR 4 range. When they used eGFR based on cystatin C, they didn’t see any early dip, and the improvement was across the full range of eGFR values.

The overall results from the SUMMIT trial suggest some benefits for the kidneys from tirzepatide. Tirzepatide, relative to placebo, decreased the urine albumin-creatine ratio, a commonly used test of kidney function, at 24 and 52 weeks when study participants with and without chronic kidney disease were combined, according to results reported by Packer and his colleagues. Macroalbuminuria is another indicator of the health of the kidney, and at 52 weeks, 55 (15%) patients who had been randomly assigned to the placebo group met the criteria for macroalbuminuria compared with 32 (8.8%) in those randomly assigned to tirzepatide.

There was, though, a cautionary note sounded about the favorable results for kidney health in an editorial in JACC accompanying Packer's study. M. ter Maaten, M.D., Ph.D., and Javed Butler, M.D., M.P.H., MBA, noted that observed improvements eGFR have not been consistently correlated with clinical benefit.