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Findings from the Phase III SUMMIT trial (NCT04847557) show that over a median of two years, tirzepatide (Zepbound and Mounjaro; Eli Lilly) lowered the risk of worsening heart failure events or death from cardiovascular causes and improved the physical capabilities of patients with heart failure with preserved ejection fraction (HFpEF) and obesity.1,2 These results, also published by The New England Journal of Medicine, indicate that the benefits of tirzepatide in this patient population include weight loss, reduced systemic inflammation, and improved exercise tolerance, according to the study authors.3
“Cardiometabolic diseases, such as heart failure and obesity, are closely linked and often coexist. New approaches are needed to address the interrelated nature of these diseases,” Jeff Emmick, MD, PhD, senior vice president, product development, Lilly, said in a press release.
“Currently, no treatments are available specifically for obesity-related HFpEF in the US. The SUMMIT data suggest that, if approved, tirzepatide could provide a significant advancement for these patients, potentially setting a new standard of care,” Emmick added.1
Tirzepatide was approved in November 2023 as the first and only medication indicated for obesity that activates both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) hormone receptors.4 It is indicated for adults with obesity and a BMI of 30 kg/m2 or greater, or overweight individuals with a BMI of 27 kg/m2 or greater who also have weight-related medical problems, including hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea, or cardiovascular disease.4 Tirzepatide’s mechanisms of action include stimulation of first- and second-phase insulin secretion and decreased glucagon levels in a glucose-dependent manner.
Trials have shown that dual GIP/GLP-1 agonist therapy produces superior glucose control and weight loss compared to selective GLP-1 receptor agonists.5 GLP-1 and GIP are classified as incretins, which are expressed throughout the body, in areas such as pancreatic beta cells and the gastrointestinal tract.
The international, double-blind, randomized, placebo-controlled SUMMIT trial enrolled 731 patients with heart failure, an ejection fraction of at least 50%, and a body-mass index of at least 30. Investigators randomly assigned 364 patients to receive tirzepatide and 367 to receive placebo for at least 52 weeks with a median duration of follow-up of 104 weeks. The trial’s two primary endpoints were composite of adjudicated death from cardiovascular causes or a worsening heart-failure event and change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS).3
“In contrast to earlier trials, the SUMMIT trial did not require patients to have increased levels of natriuretic peptides, because these peptides may not be meaningfully elevated in many patients with obesity-related heart failure with preserved ejection fraction, despite increased cardiac filling pressures and substantial functional impairment,” the study authors wrote. “Among patients who are likely to have heart failure with preserved ejection fraction, the measurement of natriuretic peptides does not add meaningfully to the identification of the disease.”3
Tirzepatide achieved both of the trial’s primary endpoints, lowering the risk of heart failure outcomes by 38% compared to placebo and reducing the risk of hospitalization for heart failure by 56%. Further, patients in the tirzepatide cohort experienced an approximately 25-point improvement in KCCQ-CSS vs. a 15-point improvement in the placebo cohort.
Adjudicated death from cardiovascular causes or a worsening heart-failure event was observed in 9.9% of patients in the tirzepatide cohort compared with 15.3% of patients in the placebo cohort (hazard ratio, 0.62; 95% confidence interval [CI], 0.41 to 0.95; P=0.026). Worsening heart-failure events were observed in 8.0% of patients in the tirzepatide cohort compared with 14.2% of patients in the placebo cohort (hazard ratio, 0.54; 95% CI, 0.34 to 0.85); whereas adjudicated death from cardiovascular causes occurred in 2.2% of patients in the tirzepatide cohort compared 1.4% of patients in the placebo cohort (hazard ratio, 1.58; 95% CI, 0.52 to 4.83).
At 52 weeks, the mean (±SD) change in KCCQ-CSS was 19.5±1.2 in the tirzepatide cohort vs. 12.7±1.3 in the placebo cohort (between-group difference, 6.9; 95% CI, 3.3 to 10.6; P<0.001).
Tirzepatide also achieved all of the trial’s key secondary endpoints. Patients in the tirzepatide cohort demonstrated improved exercise capacity by walking approximately 30 meters farther in six minutes than patients in the placebo cohort, at 38.2 meters vs. 7.9 meters. Patients in the tirzepatide cohort also experienced an average drop in body weight of 15.7% compared to 2.2% in the placebo cohort. Patients in the tirzepatide cohort achieved a 43.4% reduction in high-sensitivity C-reactive protein compared with a 3.5% reduction in the placebo cohort.
In terms of safety, adverse events causing discontinuation were observed in 6.3% of patients in the tirzepatide cohort compared with 1.4% of patients in the placebo cohort.
“The effects of tirzepatide are probably related to its ability to reduce fat mass, thus diminishing the resulting expansion of plasma volume and inflammatory response that appear to underlie the pathogenesis of heart failure with preserved ejection fraction. Patients treated with tirzepatide had a decline in high-sensitivity CRP level, as was observed in trials with semaglutide,” the study authors wrote. “Independent of weight loss, agonism of GLP-1 receptors may reverse the proinflammatory biologic features of adipocytes, thus muting their ability to cause microvascular rarefaction and fibrosis in the myocardium. GIP receptors are abundant in epicardial adipocytes, and it is possible that the addition of GIP receptor agonism to GLP-1 receptor agonism not only results in additional weight loss but also suppresses inflammation in adjacent heart tissue. The effects of tirzepatide on lowering systolic blood pressure and increasing heart rate may contribute to its beneficial effects in patients with heart failure with preserved ejection fraction.”3
References
1. Lilly’s tirzepatide reduced the risk of worsening heart failure events by 38% in adults with heart failure with preserved ejection fraction (HFpEF) and obesity. News release. Eli Lilly. November 16, 2024. Accessed November 18, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-reduced-risk-worsening-heart-failure-events
2. A Study of Tirzepatide (LY3298176) in Participants With Heart Failure With Preserved Ejection Fraction (HFpEF) and Obesity: The SUMMIT Trial. ClinicalTrials.gov. Updated July 22, 2024. Accessed November 18, 2024. https://clinicaltrials.gov/study/NCT04847557
3. Packer M., et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. Published November 16, 2024. DOI: 10.1056/NEJMoa2410027
4. FDA Approves Lilly’s Zepbound™ (tirzepatide) for Chronic Weight Management, a Powerful New Option for the Treatment of Obesity or Overweight with Weight-Related Medical Problems. Eli Lilly and Company. News release. November 8, 2023. Accessed November 18, 2024, https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-zepboundtm-tirzepatide-chronic-weight
5. Rosenstock, J, et. al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-155. doi: 10.1016/S0140-6736(21)01324-6. Accessed November 18, 2024.