Gastric bypass surgery mimetic approaches

•Three gastric bypass mimetic approaches are reviewed.•Key concept #1 is that the combination of GLP-1 and FGF21 is essential for success.•Key concept #2 is that a fixed-dose combination approach will be required.•Approaches are expected to have high probability of success in translation to clinic.

Gastric bypass surgery is effectively a polypharmacological approach for treatment of obesity, type 2 diabetes and nonalcoholic steatohepatitis (NASH). The gastric bypass mimetic approaches reviewed are fixed-dose combinatorial pharmacological approaches. There are two key concepts incorporated into these gastric bypass surgery mimetic approaches. The first key concept is that the combination of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21) is essential for success of any gastric bypass surgery mimetic approach. This combination affords the potential for durable weight loss, glycemic control and reduction in liver lipids. The second key concept is that a fixed-dose combination approach is preferred over post-approval combination of the individual components because the individual components alone often lack sufficient efficacy for development.