Combination Pharmacotherapies for Obesity—Current Evidence and Future Directions

INTRODUCTION: Conventional single-agent drugs yield modest, plateauing weight loss and often lead to weight regain. Combination pharmacotherapy is a logical next step to target complementary pathways of weight control while reducing toxicity and treatment burden. This review synthesises mechanisms and clinical evidence for fixed-dose combinations, multi-agonist peptides, add-on regimens and multimodal strategies integrating pharmacotherapy with procedures. METHODS: We conducted a narrative review of clinical trials and observational studies on approved and emerging obesity pharmacotherapy combinations, focusing on mechanistic complementarity, efficacy, safety and practical implementation. Agents were mapped to three domains of energy homeostasis-homeostatic appetite regulation, hedonic-reward circuitry and peripheral metabolic effector pathways-to inform interpretation of combination strategies. RESULTS: Fixed-dose combinations such as phentermine-topiramate and naltrexone-bupropion yield greater weight loss than their individual components but also carry gastrointestinal, cardiovascular and neuropsychiatric risks. Multi-agonist peptides integrating GLP-1, GIP, glucagon, or amylin deliver double-digit weight loss and improve glycemic and cardiometabolic profiles, but increase the risk of gastrointestinal adverse events, requiring close monitoring. Add-on regimens that combine GLP-1 agonists with approved obesity medications or SGLT-2 inhibitors, and multimodal strategies that pair drugs with bariatric or endoscopic procedures, generally show additive rather than truly synergistic effects on weight loss. CONCLUSIONS: Available data suggest that combination pharmacotherapy can extend current approaches to precision obesity care, generally providing additive benefits alongside increased regimen complexity, costs and adverse-event risks. Thoughtful, phenotype-guided selection and comparative studies versus potent monotherapies, enriched by multi-omics and behavioural insights, may clarify which patients benefit most and sustainably from these strategies.