Precision Obesity Medicine Maps Best Drugs to Patient Phenotype and Age

Obesity affects over 650 million adults globally and drives type 2 diabetes, atherosclerotic cardiovascular disease (ASCVD), heart failure, chronic kidney disease, fatty liver disease, and mechanical and behavioral complications. Yet treatment has historically been weight-centric and uniform. This 2025 narrative review by Tuccinardi, Masi, Watanabe, and colleagues — drawing on a PRISMA-guided search of 1,296 titles and full review of 212 papers — proposes a structured precision medicine framework that matches pharmacologic therapy to patient phenotype, complication burden, age, and behavioral profile rather than simply targeting BMI reduction.

For cardiovascular phenotypes, semaglutide is designated the preferred agent in established ASCVD, given its demonstrated reduction in major adverse cardiovascular events (MACE) in the SELECT trial. Tirzepatide is recommended for high-risk individuals without overt disease. Both agents improve symptoms, functional capacity, and Kansas City Cardiomyopathy Questionnaire (KCCQ-CSS) scores in Heart Failure with Preserved Ejection Fraction (HFpEF), independent of glycemic status or absolute weight loss magnitude — a finding with major implications for a condition that has few proven therapies. In chronic kidney disease, GLP-1 receptor agonists reduce albuminuria and slow eGFR decline, earning a "should be preferred" designation based on Phase III data.

For metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory form MASH, both GLP-1 RAs and the dual GIP/GLP-1 agonist tirzepatide demonstrate marked histological improvements — including reduction in hepatic steatosis, lobular inflammation, and fibrosis scores — placing them at the top of the hepatic phenotype treatment hierarchy. For mechanical complications such as obstructive sleep apnea, tirzepatide achieved clinically significant reductions in apnea-hypopnea index (AHI) in the SURMOUNT-OSA trial, while both classes reduce pain and improve function in obesity-related osteoarthritis through weight-dependent mechanisms.

Behavioral phenotypes receive dedicated attention. GLP-1 RAs are preferred for emotional eating due to their satiety-enhancing central and peripheral effects. Naltrexone/bupropion is specifically recommended for binge eating disorder and reward-driven eating, targeting dopaminergic and opioid pathways distinct from incretin biology. This mechanistic alignment of drug to eating subtype represents a genuinely novel clinical application. For pediatric obesity (from age 12 in the US, 12-18 in EU), liraglutide and semaglutide both carry regulatory approval and demonstrate efficacy in randomized trials. For older adults with sarcopenic obesity, the framework highlights the risk of lean mass loss with aggressive weight reduction and recommends agents like liraglutide and orlistat combined with resistance training and adequate protein intake to preserve muscle while reducing fat.

The review introduces explicit evidence tiers: "should be preferred" requires at least one Phase III RCT with phenotype-specific primary endpoints and regulatory approval; "may be considered" applies to Phase II data, secondary endpoints, or consistent real-world evidence; "not recommended" reflects absent efficacy or safety concerns. Figures 1 and 2 provide color-coded visual maps of drug-phenotype pairings across the lifespan. A key limitation is that this is a narrative rather than quantitative meta-analysis, and evidence quality varies substantially across phenotypes. The authors acknowledge that many real-world populations have overlapping phenotypes requiring individualized shared decision-making rather than rigid algorithmic application.