Hormonal
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.
If you are using GLP-1 medications like semaglutide or tirzepatide, expect significant weight loss primarily from eating less, not from burning more calories. Be aware that your body will likely slow down its resting metabolism as you lose weight, which can make maintaining loss difficult. This is a known biological adaptation, not a personal failure. Future treatments may combine appetite suppression with energy expenditure boosting to overcome this.
Despite their unprecedented efficacy to lower body weight by 15–20% within one year of treatment, current therapeutics drive weight loss in humans predominantly through decreased food intake... a majority of clinical studies demonstrate a neutral or negative effect on EE, which has been proposed as a contributing factor in weight regain following the cessation of treatment
Why this rating
Supported by multiple clinical meta-analyses and human studies cited in the review (Refs 7, 17, 19).
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
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- 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
- 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.Good
Related findings · Hormonal
- Initial treatment for type 2 diabetes should be a combination of metformin and either an SGLT-2 inhibitor or a GLP-1 receptor agonist to achieve cardiorenal protection, rather than monotherapy or older agents like sulfonylureas.Strong
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- Continued weekly administration of 2.4 mg subcutaneous semaglutide prevents weight regain and promotes further weight loss in adults with overweight or obesity, whereas switching to placebo results in significant weight regain.Strong
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