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Medscape
12 hours ago
- Health
- Medscape
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.
Medscape
14-05-2025
- Health
- Medscape
Semaglutide May Cut Cardiovascular Risk Before Weight Loss
MÁLAGA, Spain — Semaglutide (Wegovy) is associated with a 41% reduction in the risk for major adverse cardiovascular events (MACEs) within 6 months of initiation — well before patients achieve substantial weight loss or reach the full 2.4 mg weekly dose — according to new data from the SELECT trial. 'The cumulative incidence of MACEs during the first 6 months showed a hazard ratio of 0.59,' said Donna Ryan, MD, professor emerita at Pennington Biomedical Research Center in Baton Rouge, Louisiana. Ryan, a member of the SELECT steering committee, presented the data alongside Jorge Plutzky, MD, director of Preventive Cardiology at Brigham and Women's Hospital and professor of medicine at Harvard Medical School, Boston. The findings were presented at the European Congress on Obesity (ECO) 2025. Early Benefits The early cardiovascular (CV) benefit emerged before participants reached the target dose of semaglutide or experienced meaningful weight reduction. The hazard ratio (HR) of MACEs for patients receiving semaglutide was 0.63 (95% CI, 0.41-0.95) during the first 3 months. 'The HRs for MACEs were below 1 before the weight loss started and before participants reached the top dose,' Ryan said. 'Almost immediately, the risk is less on semaglutide than on placebo.' The first statistically significant reduction in MACEs occurred by day 20 after randomization, with sustained significance evident by day 86. In the first 6 months, 67 MACEs occurred in the semaglutide arm vs 113 in the placebo arm (HR, 0.59; 95% CI, 0.44-0.80). The researchers observed a 53% reduction in CV deaths (14 deaths with semaglutide vs 30 deaths with placebo) and a 43% reduction in nonfatal myocardial infarction. The reduction in nonfatal stroke was not statistically significant (HR, 0.87; 95% CI, 0.47-1.58). Design and Execution These new findings add to results from the main SELECT trial, which previously was reported by Medscape Medical News . That trial found a 20% reduction in MACEs over nearly 40 months in patients with overweight or obesity and established CV disease (CVD; HR, 0.80; 95% CI, 0.72-0.90; P < .001). 'The design and precision of execution give us confidence in the results,' Ryan said. SELECT enrolled 17,604 participants aged 45 years or older with overweight or obesity (body mass index ≥ 27) and established CVD, which was defined as prior myocardial infarction, stroke, or symptomatic peripheral artery disease. Eligible participants did not have type 2 diabetes, although two-thirds of participants had prediabetes. Participants were randomly assigned to once-weekly subcutaneous semaglutide or placebo (titrated to 2.4 mg by week 16) alongside standard-of-care treatments including statins, antihypertensives, and antiplatelet therapy. 'This was not a weight loss study,' Ryan emphasized. 'We thought that the drug itself might have properties beneficial to cardiovascular outcomes apart from weight loss.' CV Benefits First In the first 12 months, semaglutide was associated with a 9% reduction in body weight. However, this degree of weight loss was not yet apparent when the early CV benefit emerged. At week 4, change in body weight was −1.1% for patients on semaglutide compared with placebos (95% CI, −1.2 to −1.1). By week 12, the difference was −3.6% (95% CI, −3.7 to −3.5). To explore whether weight loss explained the early benefit, investigators compared daily hazard ratios for MACEs with average weight change over time. The dissociation between the curves suggested that the early CV benefit may occur independently of weight loss. Potential Mechanisms Asked to comment by Medscape Medical News , Jason Halford, PhD, head of the School of Psychology at the University of Leeds, Leeds, England, and past president of the European Association for the Study of Obesity, London, England, said that the results were surprising. 'This [study] suggests that [the benefits are] not mediated by weight loss and that there must be some other mechanism underpinning it,' Halford said. 'Possibly a reduction in inflammation, because obesity is an inflammatory disease, and it's a component of many other diseases.' These findings may inform early treatment decisions in patients with obesity and CVD, even before significant weight loss has been achieved. Halford suggested that the findings could have implications for CV medicine. 'Of course, they are managing CVD with other therapies, and it would be interesting to compare not one antiobesity drug with another but to see how this impacts existing treatments for CVD. It might be preferable to use one drug to treat two things, for example.' Halford also noted that as new antiobesity drugs and combinations of mechanisms emerge, comparisons should extend beyond weight loss to include CV outcomes. 'These early data shift the narrative. We knew the long-term benefits, but the short-term effect is unexpected.'
