Tirzepatide demonstrates statistically significant improvements in adult patients who have heart failure with preserved ejection fraction and obesity.
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Trial Name: A Study of Tirzepatide (LY3298176) in Participants With Heart Failure With Preserved Ejection Fraction (HFpEF) and Obesity: The SUMMIT Trial
ClinicalTrials.gov ID: NCT04847557
Sponsor: Eli Lilly and Company
Completion Date: July 2, 2024
Positive topline results from the phase 3 SUMMIT clinical trial (NCT04847557) were recently announced. The trial, which evaluated the safety and efficacy of tirzepatide (Mounjaro, Zepbound; Eli Lilly and Company) injections compared with placebo in adults with heart failure with preserved ejection fraction (HFpEF) and obesity, demonstrated statistically significant improvements in both primary end points.1
Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist. The agent is a single molecule that activates the body’s receptors for both GIP and GLP-1, which are natural incretin hormones and found in areas of the brain that are significant in regulating appetite.1
Additionally, tirzepatide is approved by the FDA for adults with type 2 diabetes (T2D) to improve glycemic control (Mounjaro) and for adults with obesity (body mass index [BMI]: ≥30 kg/m2) or who are overweight (BMI: ≥27 kg/m2) with weight-related comorbidities (Zepbound). Both approvals are recommended to be used as an add-on to diet and exercise. Currently, there are ongoing studies to assess the use of tirzepatide in chronic kidney disease and in morbidity/mortality in obesity.1
SUMMIT (NCT04847557) is a multicenter, randomized, double-blind, parallel, placebo-controlled phase 3 trial that compared the efficacy and safety of tirzepatide with placebo in 731 adult patients with HFpEF and obesity, with or without T2D. Patients were randomly assigned to receive either subcutaneous tirzepatide maximum tolerated dose (MTD) of 5, 10, or 15 mg, or placebo. Treatments were administered once weekly. The starting dose of tirzepatide (2.5 mg) was increased by 2.5 mg every 4 weeks until a patient’s MTD was achieved. Patients who were able to tolerate 15 mg of tirzepatide continued to receive 15 mg as their MTD, those who tolerated 10 mg but not 15 mg remained on 10mg as their MTD, and those who tolerated 5 mg but not 10 mg remained on 5 mg as their MTD.1,2
The 2 primary end points were to reduce the risk of the composite end point of time-to-first occurrence of urgent heart failure visit, hospitalization because of heart failure, oral diuretic intensification, and cardiovascular death to study completion, which was a median follow-up of 104 weeks; and change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) from baseline to week 52. Secondary end points included percent change from baseline in body weight, change from baseline in high-sensitivity c-reactive protein (hsCRP), time to all-cause death, a hierarchical composite of all-cause mortality, change from baseline in exercise capacity (measured by 6-minute walk distance), among others, all of which were assessed at the 52-week period or up to 120 weeks.1,2
According to the findings, both primary end points and all key secondary end points were met, including improvement in exercise capacity, reduction in the inflammation marker hsCRP, and mean body weight reduction from baseline to 52 weeks. The findings demonstrated that tirzepatide led to an approximate 15.7% body weight reduction compared with placebo, which was about 2.2%.1
The overall safety profile for tirzepatide was also consistent with previous studies, with the most common adverse events in SUMMIT being gastrointestinal (mild to moderate in severity), and consisted of diarrhea, nausea, constipation, and vomiting. The investigators note that SUMMIT results will continue to be evaluated.1
"HFpEF accounts for nearly half of all heart failure cases, and in the U.S. almost 60% of those impacted also live with obesity. Despite a continuing increase in the number of people with both HFpEF and obesity, treatment options remain limited," said Jeff Emmick, MD, PhD, senior vice president of product development at Lilly, in a news release. "Previous incretin studies in this population focused on symptoms and physical limitations. In a first-of-its-kind trial, tirzepatide reduced severity of symptoms and improved heart failure outcomes in people with HFpEF and obesity."1
