Retatrutide, a new anti‑obesity peptide, cut body weight by about 22% compared with placebo and slashed liver fat by roughly 80% in adult trials lasting 48‑72 weeks. It performed even better than other popular drugs like semaglutide and tirzepatide, showing strong promise for tackling obesity and fatty‑liver disease.

Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are estimated to affect 13% and one-third of adults worldwide, respectively. The novel antiobesity medications achieve marked bodyweight loss and improve associated metabolic conditions, including MASLD. This review summarizes the development and mode of action and available published data on the effectiveness of approved and potential (off-label) antiobesity products in the management of adult and pediatric obesity and MASLD. Additionally, their safety is highlighted. The most effective antiobesity drugs evaluated in double-blind, randomized controlled trials include semaglutide, tirzepatide, and retatrutide with up to 10.8%, 17.8%, and 22.1% placebo-subtracted bodyweight loss, respectively, in adults after 48-72 weeks. Semaglutide also reduces placebo-subtracted body mass index mean by up to 16.7% in adolescents with obesity after 68 weeks. Moreover, these novel drugs are highly effective in treating adults with MASLD. Semaglutide and tirzepatide resolve metabolic dysfunction-associated steatohepatitis (MASH) without worsening of fibrosis placebo-subtracted in 41% and 53% of patients, respectively, after 52-72 weeks. Semaglutide, tirzepatide, and retatrutide reduce hepatic fat on magnetic resonance imaging-proton density fat fraction placebo-subtracted by 41%, 47%, and 81%, respectively, after 48-72 weeks. Tirzepatide also decreases fibrosis without worsening of MASH placebo-subtracted in up to 25% of patients. However, no pediatric trials have been conducted to study these novel drugs in biopsy-proven MASLD. In conclusion, the novel antiobesity drugs are highly effective in obesity and MASLD. However, more biopsy-based clinical trials are required to determine the effectiveness of these medications in adult metabolic dysfunction-associated steatohepatitis-associated fibrosis and pediatric MASLD. SIGNIFICANCE STATEMENT: This work reviews the current antiobesity medications, their structure, mode of action, and effectiveness. These medications are revolutionizing the management of metabolic dysfunction-associated steatotic liver disease by significantly reducing hepatic steatosis, disease activity, and even liver fibrosis.