Overview of Novel Mechanisms in Obesity Pharmacotherapy and Implications for Cardiovascular Disease: A Narrative Review.

PURPOSE OF REVIEW: While nutrient-stimulated hormone (NuSH) therapies (e.g., glucagon-like pepide-1 receptor agonists and dual/triple agonists) have transformed the landscape of obesity pharmacotherapy, the next generation of medications may target body composition optimization or other cardiovascular benefits. This review examines novel obesity mechanisms outside of the NuSH class.

RECENT FINDINGS: Unique mechanisms for obesity treatment include peripherally restricted cannabinoid-1 receptor antagonism, myostatin/activin inhibitors, selective androgen receptor modulators, melanocortin-4 receptor agonism, mitochondrial modulation, thyroid receptor agonists, and fibroblast growth factor analogues. By targeting fat distribution, muscle preservation, inflammatory/oxidative stress pathways, lipid metabolism, and energy expenditure, these agents may improve both the magnitude and quality of weight loss. Early evidence suggests complementary roles alongside NuSH-based therapies for induction, augmentation, and maintenance strategies. Several non-NuSH agents have demonstrated potential in preclinical and early clinical studies to optimize body composition, but additional studies are required to prove large-scale, long-term safety and efficacy.