Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan

Abstract

Obesity is a biologically complex and heterogeneous disease that requires individualized, phenotype- and complication-oriented therapeutic strategies. The introduction of advanced pharmacotherapies, including GLP-1 receptor agonists (GLP-1 RA), dual Glucose-dependent Insulinotropic Polypeptide/Glucagon-like Peptide-1 (GIP/GLP-1) agonists, and emerging triple agonists, has facilitated a shift from weight-centric goals to precision-based obesity care. This review provides a clinical framework for pharmacologic treatment, organized by phenotype, obesity-related complications, age, and behavioral traits. DESIGN: Narrative review of randomized trials, meta-analyses, real-world evidence, and international guidelines through May 2025. Evidence was synthesized across key obesity phenotypes, cardiometabolic, hepatic, renal, mechanical, behavioral, and stratified by life stage, including pediatric, reproductive-age, and older adults, with attention to safety, cost-effectiveness, and special populations. RESULTS: In established Atherosclerotic Cardiovascular Disease, semaglutide significantly reduces major adverse cardiovascular events. Tirzepatide offers cardiometabolic benefits for high-risk people without overt disease. Both agents improve symptoms and function in Heart Failure with Preserved Ejection Fraction, irrespective of glycemia or weight loss. In Chronic Kidney Disease, they decrease albuminuria and eGFR decline. In Metabolic Dysfunction-Associated Steatotic Liver Disease, GLP-1 RAs and GIP/GLP-1 RAs demonstrate marked histological improvements. Mechanical complications such as osteoarthritis and sleep apnea are improved by anti-obesity medications-induced weight loss. GLP-1 RAs and naltrexone/bupropion prove effective against binge and emotional eating. In youths, liraglutide and semaglutide are both approved and effective. Liraglutide and orlistat preserve lean mass alongside resistance training and adequate protein intake in older and sarcopenic people. CONCLUSIONS: An anti-obesity treatment framework focused on both phenotype and complication burden improves the personalization of obesity care and supports clinical decision-making throughout a person’s lifespan.

Part of CIRS Nexus · Curated by Lauren Lowenstein, The Biotoxin Lady

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