Retatrutide

What it is

Retatrutide (LY3437943) is an investigational triple agonist at GLP-1, GIP, and glucagon receptors developed by Eli Lilly. It represents the next generation of incretin-based metabolic therapies, building on the dual GIP/GLP-1 mechanism of tirzepatide by adding glucagon receptor activation.

Retatrutide is currently in late-stage clinical trials for type 2 diabetes and obesity. It has not received FDA approval and is not available outside of clinical trials.

Mechanism of action

The triple agonist mechanism combines:

• GLP-1 receptor activation: the established GLP-1 effects on insulin secretion, glucagon suppression, gastric emptying, and central appetite control
• GIP receptor activation: additional metabolic effects similar to those contributed by tirzepatide
• Glucagon receptor activation: increases energy expenditure through effects on hepatic glucose production and metabolic rate. The glucagon component is the conceptual addition to existing therapies.

The metabolic rate effect from glucagon agonism is hypothesized to provide an “energy expenditure” component complementing the appetite reduction of GLP-1 mechanisms — addressing weight loss from both intake and expenditure sides.

Clinical trial findings

Phase II trial data has been encouraging:

• Mean weight loss of approximately 24% at 48 weeks at the highest doses studied
• HbA1c reductions exceeding those seen with tirzepatide
• Generally manageable side effect profile during titration

Phase III trials are ongoing. If results confirm Phase II findings, retatrutide may produce the largest weight loss effects yet seen with a non-surgical intervention.

Why we don’t prescribe it at The Tide

Retatrutide is not yet FDA-approved and is not available through legal compounding pathways. We do not prescribe medications outside of approved channels. We are following the development program closely and will reassess prescribing status when and if retatrutide receives FDA approval.

Patients seeking maximum metabolic and weight loss benefit are currently best served by FDA-approved tirzepatide, which produces among the largest effects of any approved therapy.

Side effects and contraindications

Side effect profile in trials is similar to other incretin therapies — GI effects during titration, possible glucose effects from the glucagon component requiring monitoring. Same general contraindications as other incretin therapies expected if/when approved.