Retatrutide

Retatrutide is an investigational triple agonist targeting GLP-1, GIP, and glucagon receptors simultaneously. The glucagon receptor component adds a thermogenic effect — increased resting energy expenditure — on top of the appetite suppression and insulin secretion from GLP-1/GIP signaling. This triplicate approach hypothetically addresses obesity through three independent physiological mechanisms: appetite reduction, insulin sensitization, and direct fat mobilization via glucagon-stimulated lipolysis.

Phase 2 (NEJM 2023): 48-week trial showed 24.2% mean weight reduction at 12 mg — highest pharmacological weight loss data published at time of reporting.

Glucagon thermogenesis: Distinct from dual agonists; direct increase in energy expenditure observed alongside caloric restriction.

Liver fat: ~40% reduction in hepatic fat assessed by MRI-PDFF; significant implications for NASH research.

Triglycerides: Marked reduction alongside visceral adipose tissue decrease.

Tolerability: Dose-dependent GI side effects consistent with incretin class; Phase 3 now underway.