ACC Revises Obesity Control Strategies in Heart Failure

A new Scientific Statement from the American College of Cardiology (ACC) has named two anti-obesity drugs as options for symptom control in patients with heart failure.

The benefit for these incretin mimics, semaglutide and tirzepatide, is attributed to symptom control, according to the statement. The document, published on June 13 in the Journal of the American College of Cardiology, states that each medication has the potential to reduce cardiovascular (CV) events related to heart failure, but neither has yet done so on the basis of level 1 evidence.

The new recommendation appl ies only to heart failure with preserved ejection fraction (HFpEF). The safety and efficacy of these drugs has yet to be established for heart failure with reduced ejection fraction (HFrEF), according to the ACC statement.

The new anti-obesity drugs were approved initially for type 2 diabetes. On the basis of substantial weight loss and their relative safety, the FDA subsequently granted indications for obesity alone in patients with at least one additional obesity-related comorbidity, such as hypertension, dyslipidemia, or obstructive sleep apnea.

Current Indications for Incretin Mimetics

Semaglutide has an indication for patients with CV disease, but not heart failure specifically, and obesity on the basis of the 2023 SELECT trial. Tirzepatide has an indication for patients with sleep apnea and obesity in the absence of diabetes on the basis of the 2024 SURMOUNT-OSA trial.

In the 2023 STEP-HFpEF trial with semaglutide and the 2025 SUMMIT trial with tirzepatide, each agent was associated with a reduction in symptoms of heart failure in patients with HFpEF. However, the study designs and outcomes differed.

For one, the HFpEF entry criterion was a left ventricular ejection fraction ≥ 45% in STEP-HFpEF but ≥ 50% in the SUMMIT trial. In dual primary endpoints, both included changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ), but the first of the two trials evaluated weight change, while the second evaluated a composite endpoint of CV death and heart failure-related events.

By listing semaglutide and tirzepatide as options within a comprehensive review of the treatment of obesity in heart failure, the new document steps in front of current regulatory guidance. In a table that juxtaposed FDA-approved indications for these drugs to evidence-based benefits as defined by the statement, only the latter identifies a role in heart failure.

“The intent of the Writing Committee in including this table was to highlight that there are no FDA-approved heart failure indications for the use of incretin-based anti-obesity medications to date,” said Michelle M. Kittleson, MD, PhD, director of Heart Failure Research at Cedars-Sinai Medical Center in Los Angeles, who chaired the committee.

“While clinicians might identify individuals with heart failure who meet the standard FDA-approved indications, it is important to also identify which of those patients also meet inclusion criteria for th e heart failure trials were benefit was shown,” Kittleson said.

Semaglutide acts on the GLP-1 receptor alone. Tirzepatide is an agonist of both the GLP-1 receptor and glucose-dependent insulinotropic polypeptide. Both drugs are associated with strong signals of CV benefit overall and in heart failure specifically, even if the evidence in HFpEF is “stronger,” according to the statement.

Incretin drugs mimic hormones that downregulate appetite. They are considered third-generation anti-obesity agents on the basis of their targeted mechanism and a low relative risk for adverse events. More than a dozen such agents are now in various stages of development, according to the ACC statement.

Semaglutide and Tirzepatide Trials Differ

In the STEP-HFpEF trial, which like SUMMIT trial, was placebo controlled, the 7.8-point gain (P <.0001) in the KCCQ on active therapy vs placebo was statistically significant, as was the percent body weight loss (-13.3% vs -2.6%; P < .001).

The SUMMIT trial found a 6.9-point gain in the KCCQ score (P < .001) relative to placebo, while the rate the composite event endpoint of CV death from events associated with heart failure was lower (9.9% vs 15.3%; P = .026), but CV deaths occurred in only 13 patients. Heart failure events were observed in 81 patients over 2 years of follow-up.

In both studies, significant gains in the secondary endpoints of physical and exercise function were associated with the assigned weight-loss drug.

On the evidence so far, the authors of the ACC statement concluded that despite the marginal benefit observed in the SUMMIT trial, no firm conclusions can be made about the ability of incretin therapies to protect patients with HFpEF against hard endpoints, Kittleson said.

Until more data are available, she cautioned against the risk for “indication creep,” the willingness to offer these drugs for potential benefits that have yet to be confirmed. Still, she added, “the goal of the writing group was to strike a tone of cautious optimism guided by the available data.”

Part of this optimism has been fueled by the 2023 SELECT trial, which enrolled more than 17,000 patients with overweight with CV disease but no diabetes. Relative to placebo, semaglutide was associated with a 20% reduction (P < .001) in the composite primary endpoint of CV death, nonfatal myocardial infarction, and nonfatal stroke. Only 24% of patients in this study had heart failure, but the risk reduction in this group was consistent with that of the study population as a whole.

Obesity is listed in most guidelines, including a 2024 ACC Expert Consensus Decision Pathway for Treatment of HFrEF, as a common comorbidity of heart failure and potentially treatable risk factor for symptoms and progression of the condition. However, the new statement differs from prior guidelines. Typically, lifestyle modifications are identified as a first step toward weight loss.

“Patients should not be required to try and fail lifestyle changes prior to initiating pharmacotherapy,” according to Olivia Gilbert, MD, a cardiologist specializing in advanced heart failure and transplantation at Atrium Wake Forest Baptist Medical Center, in Wake Forest, North Carolina. Although Gilbert was not part of the writing committee for the new document, she has been involved in developing clinical guidance statements for the ACC.

The incretin therapies are more effective than lifestyle medications and safer than procedure-based weight-loss interventions, Gilbert said, providing a basis for suggesting they can be considered first line therapy for patients with symptomatic HFpEF.

“Lifestyle interventions should always be offered in conjunction with obesity medications,” she said.

Kittleson and Gilbert reported no potential financial conflicts of interest.