JACC-beschouwing: placebo in trials met incretine-therapie bij hartfalen — wetenschap versus ethiek

Recent trials have shown that glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dual gastric inhibitory polypeptide/GLP-1 RAs improve symptoms and functional capacity in patients with heart failure (HF) with preserved ejection fraction and obesity, with or without type 2 diabetes. These studies enrolled modest sample sizes and had few worsening HF events or cardiovascular (CV) deaths, limiting definitive conclusions regarding those endpoints. At the same time, the benefits of these drugs on major adverse CV and kidney outcomes in patients with obesity, diabetes, and chronic kidney disease raise questions about placebo-controlled designs in future HF trials. This article explores scientific, practical, and ethical considerations surrounding the design of future incretin-based therapy trials in HF. We highlight the current gaps in evidence and emphasize the need for event-driven outcome trials in HF. The use of placebo ensures methodologic rigor but may raise ethical concerns in the context of cardiometabolic benefit with GLP-1 RAs. Abandoning placebo, however, risks incomplete safety and efficacy data and premature therapeutic extrapolation. Such studies are essential to define the efficacy, durability, and safety of incretin-based therapy across the HF spectrum and to clarify whether improvements in patient-reported outcomes are bolstered by other benefits. To support balanced decision making, we introduce a structured framework outlining when placebo remains appropriate, when active comparison may be required, and how trial design features can address the ethical and operational challenges unique to incretin-based HF research. Ethically robust, clinically focused, and methodologically rigorous trials remain the only means to inform guideline recommendations and insurance coverage. The HF population is too large, too vulnerable, and too costly to remain without definitive evidence guiding the use of these therapies.