Metabolic bariatric surgery in face of new anti-obesity medications-10 + 1 challenges - mtod3027.pdf

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• Multiple novel drugs are underway in the phase of development, clinical trials, or pending license for commercial use, including GLP-1 glucagon dual agonists, novel GIP/GLP-1 dual agonists, GIP/GLP-1/glucagon triple agonists, GIP RAs, novel GLP-1 RAs, glucagon analogs, leptin sensitizers, neuropeptide Y receptor type 2 (Y2R) agonists, amylin/calcitonin dual agonists, amylin analogs, drugs targeting the ghrelin pathway, mitochondrial uncouplers, appetite suppressants, etc.[125]. A few examples: survodutide, a dual GLP-1/glucagon RA, led to ≥ 20% weight loss in almost 40% of patients with obesity and without T2DM in a phase 2 trial[145]; retatrutide, a triple GIP/GLP-1/glucagon RA safely led to ≥ 5% weight loss in all participants and 24% weight loss on average at 48 weeks from its initiation[146,147]. Not only new drugs with novel mechanisms of action, but also drugs with different pharmacokinetics are under investigation. For example, orforglipron is an oral GLP-1 RA which, in contrast to oral semaglutide, is non-peptide, consequently not disintegrated in the gastrointestinal tract, a feature with direct implications to its bioavailability[148]. Daily orforglipron resulted in mean weight loss of 8.6%-12.6%, depending on dose, over a period of 36 weeks in a phase 2 trial[149