Molecularly guided pharmacotherapy for obesity: emerging targets, clinical efficacy, and personalized therapeutic approaches

Abstract

Obesity is a complex, chronic disease whose aetiology is complex and highly variable, and is linked to a network of neural, endocrine, adipose, genetic, epigenetic and metabolic pathways. This molecular complexity also drives significant differences in the clinical course of disease, drug sensitivity and weight regain, thus making standardized treatment, which is largely based on BMI and clinical empiricism, challenging. This narrative review explores the molecular mechanisms involved in obesity and the potential to apply the knowledge of molecular mechanisms to develop more personalized treatment strategies using advances in pharmacology. It focuses on hypothalamic appetite-satiety pathways, gut–brain hormonal communication, inflammation and metabolic dysfunction in adipose tissue, and known and novel drug targets. The review focuses on the evidence available on GLP-1 receptor agonism, GIP–GLP-1 co-agonism, multi-agonism with glucagon, signaling of amylin, melanocortin pathways, and novel central and peripheral targets. Studies have shown that some dual- and triple-receptor drugs are more effective at causing weight loss, and practitioners should consider tolerability, sustainability, cardiometabolic effects, and response when choosing drugs or drug combinations for patients. Inter-individual variability may be further explained by genetic, epigenetic, metabolic, and tissue-specific factors, which may help identify mechanisms of resistance. In conclusion, Inter-individual variability may be attributed to genetic, epigenetic, metabolic, and tissue-specific factors, and most suggested molecular or biomarker predictors have not yet proven sufficiently valid or useful for routine drug selection. Receptor-targeted drugs, including GLP-1 receptor agonists and GIP–GLP-1 co-agonists, are currently clinically actionable for patients with common obesity and available to specific patients with obesity, genotype-directed molecular therapeutic drugs are clinically actionable only for selected genetically defined types of obesity. However, the use of pharmacogenomic, biomarker, and multi-omics methods to guide the choice of anti-obesity drugs are still in their early stages of clinical investigation.