AHA 2024: Tirzepatide Lowers Risk of Worsening Heart Failure, CVD Death in Adults With Obesity

New research findings from the SUMMIT trial presented at the American Heart Association (AHA) 2024 Scientific Sessions demonstrate that participants with heart failure with preserved ejection fraction (HFpEF) and obesity who took tirzepatide (Mounjaro, Zepbound; Lilly) for an average of 2 years had reduced combined risk of worsening heart failure events and cardiovascular events, as well as improved health status and functional capacity compared with the placebo group.¹

Mounjaro medication box | Image credit: © Cynthia | stock.adobe.com

Tirzepatide is a long-acting agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. It has been FDA-approved for the treatment of type 2 diabetes for weight management in individuals with overweight or obesity. Notably, earlier research of tirzepatide has confirmed 12% to 21% weight loss in patients with obesity taking tirzepatide.¹

“Obesity contributes to worsening heart failure, and while tirzepatide causes considerable weight loss, research is lacking on its effects on cardiovascular outcomes,” said lead study author Milton Packer, MD, a distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas and a visiting professor at Imperial College in London, in a news release. “This is the first trial that tested the effect of any medication on major heart failure outcomes in patients with HFpEF and obesity.”¹

In findings from the phase 3 SURMOUNT-1 trial (NCT04184622), the percentage of patients who lost more than 20% of their body weight was over 50% in the tirzepatide 10-mg and 15-mg groups, compared with just 3% in the placebo group. Because obesity is a major risk factor for the development of type 2 diabetes and cardiovascular diseases, reduced body weight is significant.²

Additionally, tirzepatide has shown significant promise in reducing liver fat content compared with insulin degludec in a subpopulation of patients with type 2 diabetes in the SURPASS-3 study.³ The impact of tirzepatide in individuals with nonalcoholic steatohepatitis will be assessed in the ongoing SYNERGY-NASH trial (NCT0416673).⁴

The new findings, from the international SUMMIT trial, include a total of 731 adults aged 40 years and older who had been diagnosed with HFpEF and obesity at health centers in 9 countries, including the US. All participants had ejection fraction of 50% or more and all had body mass index (BMI) measurements of 30 kg/m2 or higher.¹

Participants were randomly assigned in nearly equal numbers to either the tirzepatide or placebo arms and received a weekly injection. The weekly dose was gradually titrated from 2.5 mg to a potential maximum dose of 15 mg per week, and all participants continued taking their regular medications, including those for heart failure, while enrolled in the study.¹

With a median follow-up of 2 years and a maximum of 3 years, investigators found that cardiovascular death or worsening heart failure events occurred in 36 patients (9.9%) of the tirzepatide group, compared with 56 patients (15.3%) in the placebo group. Worsening heart failure events occurred in 29 patients (8%) of the tirzepatide group versus 52 patients (14.2%) in the placebo group, representing a 46% reduction in risk for individuals taking tirzepatide.¹

There were 15 total cardiovascular deaths among both groups, 11 of which were not preceded by worsening heart failure. Two deaths in the tirzepatide group occurred after patients had not taken the medication for more than 15 months.¹

At 1 year of follow-up, Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (KCCQ-CSS) were improved by an average of 6.9 points more in the tirzepatide group compared with the placebo group, suggesting participants perceived greater improvements in health and function with tirzepatide. Additionally, participants had 11.9% greater weight loss in the tirzepatide group compared with the placebo group, measured at 1 year.¹

Participants in the tirzepatide group also improved their 6-minute walking distance test at 1 year by an average of 18.3 meters further, compared with the placebo group. Finally, individuals in the tirzepatide group had less systemic inflammation, based on a high-sensitivity C-reactive protein measure. When compared with placebo, on average, the difference in the percent changes in the tirzepatide group was 32.9%, indicating lower levels of inflammation.¹

“These results indicate tirzepatide produced meaningful benefits for people living with heart failure with preserved ejection fraction and obesity,” Packer said. “The patients experienced a lower combined risk of worsening heart failure events and cardiovascular disease death, along with improved health status and exercise tolerance. This is the first trial to demonstrate that a medication can change the clinical trajectory of the disease in patients with HFpEF and obesity.”¹

Importantly, researchers noted that the use of BMI to measure body size is a limitation. Individuals with HFpEF often have a higher-than-normal waist-to-height ratio, suggesting visceral adiposity or high belly fat, with a BMI lower than 30 kg/m2, which does not meet the criteria for an obesity diagnosis. Further research should clarify the most accurate parameters for individuals who can benefit from treatment.¹

REFERENCES

1. Tirzepatide lowered risk of worsening heart failure and CVD death for obese adults. News release. American Heart Association. November 16, 2024. Accessed November 16, 2024. https://newsroom.heart.org/news/tirzepatide-lowered-risk-of-worsening-heart-failure-and-cvd-death-for-obese-adults

2. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. New Eng J Med. 2022;387:205-216. doi:10.1056/NEJMoa2206038

3. Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomized, open-label, parallel-group, phase 3 trial. Lancet. 2021;398(10300):583-598. doi:10.1016/S0140-6736(21)01443-4

4. Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for metabolic dysfunction–associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391:299-310. doi:10.1056/NEJMoa2401943