The history of antiobesity pharmacotherapies is marked by disappointments, often entangled with societal pressure promoting weight loss and the prevailing conviction that excess body weight signifies a lack of willpower. However, categories of emerging pharmacotherapies generate hope to reduce obesity rates. This systematic review of phase 2 and phase 3 trials in adults with overweight/obesity investigates the effect of novel weight loss pharmacotherapies, compared to placebo/control or US Food and Drug Administration-approved weight loss medication, through searching Medline, Embase, and ClinicalTrials.gov (2012-2024). We identified 53 phase 3 and phase 2 trials, with 36 emerging antiobesity drugs or combinations thereof and 4 withdrawn or terminated trials. Oral semaglutide 50 mg is the only medication that has completed a phase 3 trial. There are 14 ongoing phase 3 trials on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, and TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide and survodutide), GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA (retatrutide), dapagliflozin, and the combination sibutramine/topiramate. Completed phase 2 trials on incretin-based therapies showed a mean percent weight loss of 7.4% to 24.2%. Almost half of the drugs undergoing phase 2 trials are incretin analogs. The obesity drug pipeline is expanding rapidly, with the most promising results reported with incretin analogs. Data on mortality and obesity-related complications, such as cardio-renal-metabolic events, are needed. Moreover, long-term follow-up data on the safety and efficacy of weight maintenance with novel obesity pharmacotherapies, along with studies focused on underrepresented populations, cost-effectiveness assessments, and drug availability, are needed to bridge the care gap for patients with obesity. SIGNIFICANCE STATEMENT: Obesity is the epidemic of the 21st century. Except for the newer injectable medications, drugs with suboptimal efficacy have been available in the clinician's armamentarium for weight management. However, emerging alternatives of novel agents and combinations populate the current obesity therapeutic pipeline. This systematic review identifies the state and mechanism of action of emerging pharmacotherapies undergoing or having completed phase 2 and phase 3 clinical trials. The information provided herein furthers the understanding of obesity management, implying direct clinical implications and stimulating research initiatives.
