Why Three Receptors? The Glucagon Rationale

GLP-1 monoagonists hit one receptor; tirzepatide hits two (GIP + GLP-1). Retatrutide adds a third — glucagon (GCG). The biological rationale: glucagon agonism may reduce energy intake further and, uniquely, increase energy expenditure and alter substrate utilization beyond what the other two can do alone.

This is why researchers speculate retatrutide may surpass dual agonists — and why its phase 2 data showed participants still losing weight at week 48 with no plateau. This thread explores the glucagon pathway and the trade-offs (a novel safety profile under active study).