A Systematic Review and Meta‐Analysis of Malnutrition and Metabolic Failure in High‐Potency Incretin Therapy

Abstract

Objective: High-potency incretin therapy achieved substantial weight loss, but the extreme energy deficits it induced may obscure the underlying nutritional deterioration. This meta-analysis synthesized data from 19 randomized trials across the SURMOUNT, STEP, SCALE, and OASIS programs to quantify the nutritional and body composition consequences of these agents in adults with obesity. Methods: This systematic review and meta-analysis followed PRISMA 2020 guidelines. Risk of bias was assessed using the Cochrane RoB2 tool, and certainty of evidence was rated using the GRADE approach. Continuous outcomes were pooled using mean differences within a random-effects model. Results: Daily energy intake declined by 24.00%-39.20% across drug classes, with model-estimated daily deficits reaching 1200 kcal. Tirzepatide 15 mg was associated with a mean fat-free mass (FFM) reduction of 1.60 kg, representing 2.80% of body weight. Investigator-reported malnutrition occurred in only 0.12% of participants. Objective laboratory screening identified low total lymphocyte counts below 910 per microliter in 2.90% of active-therapy participants, nearly double the 1.77% in placebo arms, indicating that standard adverse event reporting underestimates true nutritional risk. Pancreatic lipase increased by a mean of 31% in the SCALE program, representing a secondary metabolic signal. Conclusions: Given these findings, a Tiered Stepped-Care Algorithm is proposed, mandating baseline screening of albumin and total lymphocyte count, periodic monitoring at weeks 12, 24, and 52, and defined intervention thresholds to prevent sarcopenia and frailty, particularly in adults aged 65 years and older.