Hormonal
Glucagon receptor agonism (GCGRA), particularly in triagonists like retatrutide, increases energy expenditure and enhances weight loss efficacy compared to GLP-1/GIP agonists alone, though it carries risks of adverse events like tachycardia.
Triagonist medications (combining GLP-1, GIP, and Glucagon effects) can achieve higher weight loss (up to 24%) than current GLP-1 drugs by actively increasing how many calories you burn, not just by reducing appetite. While these drugs can cause side effects like rapid heart rate, doctors can manage this by starting with very low doses and increasing them slowly. This approach offers a more sustainable path to weight loss by counteracting the body's tendency to slow down metabolism.
Glucagon receptor agonism (GCGRA) has been one of the few approaches demonstrated to increase EE in both rodent and human studies... The most advanced drug, retatrutide, demonstrated average weight loss of 24% in a Phase 2 clinical trial without a plateau in effects after 48 weeks of treatment
Why this rating
Supported by Phase 2 clinical data for retatrutide and multiple pre-clinical/human mechanistic studies.
Source
Improving incretin-mediated body weight loss via energy expenditure
Andrew J. Elmendorf et al. · Trends in Endocrinology and Metabolism · 2026
DOI 10.1016/j.tem.2025.12.004
More from this paper
- Energy expenditure can be increased through specific physiological mechanisms independent of physical activity, including UCP1-dependent thermogenesis in brown/beige fat, futile cycling of substrates (creatine, glucose, lipids), and ion pumping (Na+/K+-ATPase, SERCA).Strong
- Current incretin-based therapies (GLP-1 and GLP-1/GIP agonists) primarily reduce body weight through decreased food intake, but they fail to increase energy expenditure (EE) and often cause a compensatory drop in basal metabolic rate, which hinders sustainable weight loss.Good
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