Semaglutide Shows Promise for Heart Failure Patients with Obesity
LISBON — A new analysis from the STEP-HFpEF program reveals that the diabetes and weight-loss drug semaglutide significantly improves symptoms and physical limitations related to heart failure in patients with obesity, regardless of diuretic use. This research was presented at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2024 Congress and simultaneously published in the European Heart Journal.
Consistent Benefits Across Diuretic Subgroups
Dr. Subodh Verma, a cardiovascular surgeon at the University of Toronto, highlighted that semaglutide “produced consistent beneficial effects on body weight, exercise function, and biomarkers of inflammation and congestion across the subgroups of diuretic use and dose.” The benefits were particularly pronounced in patients who were receiving loop diuretics at baseline. The study demonstrated that semaglutide reduced the daily loop diuretic dose by approximately 20% compared to placebo, decreased the initiation of new loop diuretics by 77%, and increased loop diuretic discontinuations by more than 2.5 times.
Disease-Modifying Potential
Dr. Verma stated, “These results suggest disease-modifying effects of semaglutide in obesity-related heart failure with preserved ejection fraction.” Dr. Dimitrios T. Farmakis, from the National and Kapodistrian University of Athens, who was not involved in the study, noted the STEP-HFpEF program as a significant advancement in heart failure treatment, adding that semaglutide offers more than just weight loss; it provides some improvement in the syndrome itself. However, Farmakis pointed out that there are still “missing pieces of the puzzle.”
Key Areas for Future Research
For patients with obesity, there is a need to establish semaglutide’s efficacy and safety beyond one year, including any potential renal or other side effects. For heart failure patients in general, it is crucial to determine if semaglutide is effective regardless of left ventricular ejection fraction and whether the effects are specific to semaglutide or common to all GLP-1 receptor agonist analogs. Additionally, the effects on different ethnic groups need further study due to the underrepresentation of non-White individuals in the trials.
Mechanism of Action and Diuretic Effects
Dr. Verma acknowledged that the changes in loop diuretic dose were analyzed in isolation, without considering other medications. The precise mechanism by which semaglutide affects plasma volume, natriuresis, and cardiac structure and function remains unclear. He noted that patients with heart failure with preserved ejection fraction are often given loop diuretics as a first-line treatment, but these can cause electrolyte imbalances, worsening kidney function, and hypotension, particularly in patients with obesity-related heart failure.
Improving Heart Failure Management
Loop diuretics have been found to be less effective in decongesting patients with obesity-related heart failure with preserved ejection fraction and can negatively impact kidney function. The STEP-HFpEF program has already shown that semaglutide, compared to placebo, improves heart failure-related symptoms, physical limitations, exercise function, reduces inflammation, and leads to significant weight loss.
Pooled Data Analysis
The current analysis combined data from the STEP-HFpEF and STEP HFpEF DM trials to evaluate the efficacy and safety of once-weekly semaglutide 2.4 mg across different diuretic doses and changes in diuretic use over 52 weeks. The trials included 1,145 patients aged 18 years or older with a body mass index over 30, who were randomized to receive standard-of-care treatment plus semaglutide or placebo, with dose escalation over the first 16 weeks.
Diuretic Use and Efficacy
Patients were assessed for diuretic use, type, and dose at weeks 20, 36, and 52, considering loop diuretics, thiazide diuretics, and mineralocorticoid receptor agonists as diuretics, but not sodium-glucose cotransporter 2 inhibitors. All diuretic doses were converted to furosemide equivalents.
Results and Improvements
Dr. Verma reported that adding semaglutide to standard-of-care therapy led to greater improvements in the Kansas City Cardiomyopathy Questionnaire–Clinical Summary Scores compared to placebo. Patients not on diuretics improved their score by 3.2 points, while those treated with more than 40 mg/day of loop diuretics improved by 11.6 points. Semaglutide was consistently effective in reducing body weight across diuretic doses, with patients losing 6.9%-9.4% of body weight over the study period. It also improved 6-minute walking distance, C-reactive protein levels, and N-terminal pro b-type natriuretic peptide levels.
Reduction in Diuretic Dose
Over the study period, patients on semaglutide were significantly more likely to reduce their loop diuretic dose and less likely to increase it compared to those on placebo. On average, semaglutide users reduced their loop diuretic dose by 17%, while the placebo group increased theirs by 2.4%, resulting in an estimated treatment difference of 11.8 mg/day. Semaglutide users were also significantly less likely to initiate new loop diuretics (6.1% vs. 20.1%) and more likely to discontinue them (5.9% vs. 2.3%).
These findings underscore the potential of semaglutide as a transformative treatment for patients with obesity-related heart failure with preserved ejection fraction, offering not only weight loss benefits but also improvements in heart failure symptoms and reductions in diuretic use.