Combination Pharmacotherapies for Obesity-Current Evidence and Future Directions

Area of Science:

• Pharmacology and Endocrinology
• Metabolic Disease Research
• Obesity Medicine

Background:

• Single-agent obesity drugs show limited efficacy and often result in weight regain.
• Combination pharmacotherapy targets complementary pathways for improved weight management and reduced burden.
• This review explores fixed-dose combinations, multi-agonist peptides, and multimodal strategies.

Purpose of the Study:

• To synthesize mechanisms and clinical evidence for obesity pharmacotherapy combinations.
• To evaluate efficacy, safety, and implementation of combined obesity treatments.
• To map agents to energy homeostasis domains for understanding combination strategies.

Main Methods:

• Conducted a narrative review of clinical trials and observational studies.
• Focused on approved and emerging obesity pharmacotherapy combinations.
• Analyzed mechanistic complementarity, efficacy, safety, and practical implementation.

Main Results:

• Fixed-dose combinations (e.g., phentermine-topiramate) improve weight loss but carry risks.
• Multi-agonist peptides achieve significant weight loss and improve cardiometabolic profiles, with GI risks.
• Add-on and multimodal strategies show additive, rather than synergistic, weight loss effects.

Conclusions:

• Combination pharmacotherapy enhances precision obesity care with additive benefits but increased complexity and risks.
• Phenotype-guided selection and comparative studies are crucial for identifying optimal patient candidates.
• Multi-omics and behavioral insights may further personalize sustainable obesity treatment strategies.