Paradigm shift in obesity treatment: an extensive review of current pipeline agents.

Obesity is a multifaceted disease that poses a significant public health challenge. Recent discoveries in understanding the biological pathways that regulate satiety and metabolism have led to a shift in the treatment paradigm for obesity. Thus, the gap between pharmacological and surgical interventions has diminished. The latest approved antiobesity medications help to achieve weight loss comparable to surgery. These GLP-1 analog-based therapies not only cause substantial weight loss but also improve obesity-associated comorbidities. However, there are still unmet needs in obesity care, and treatment options with alternative pathways are necessary. Whether achieved through lifestyle changes or medication, weight loss often leads to muscle mass loss and reduced energy expenditure, resulting in rebound weight gain. Moreover, addressing severe obesity and comorbidities, such as metabolic-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatohepatitis (MASH), heart failure with preserved ejection fraction, and obstructive sleep apnea, necessitates the development of additional therapeutic strategies. Various antiobesity medications with novel mechanisms of action are currently in the pipeline. Myostatin-activin pathway inhibitors are under development to preserve muscle mass, and combination therapies with glucagon agonists address MAFLD and MASH. Amylin agonists offer a promising alternative to those unable to tolerate GLP-1 analogs. Mitochondrial uncouplers are under investigation for enhancing energy expenditure, NLRP-3 inhibitors for reducing inflammation, and GWAS targets for additional weight loss benefits. Combination therapies, such as dual or triple hormonal receptor agonists, are being developed to maximize weight loss and optimize tolerability. These emerging medications in the clinical trial pipeline show promise for more tolerable and sustainable obesity management.