Retatrutide
Triple Incretin Agonist
Overview
Retatrutide is the first drug to activate all three major metabolic receptors — GLP-1, GIP, and glucagon — in a single molecule. In its Phase 2 obesity trial, participants taking the highest dose lost a mean of 24.2% of their body weight over 48 weeks.[1] That's a bigger number than any approved weight-loss drug has produced in a comparable timeframe.
It's developed by Eli Lilly under the compound designation LY3437943, and it's currently in Phase 3 trials. You can't get it yet — not from a clinic, not from a compounding pharmacy, not legally from any source. But if the Phase 3 data holds up, it could become the most effective pharmacological obesity treatment ever approved.
Mechanism of Action
GLP-1 + GIP + Glucagon receptor agonism
Start with what you already know about GLP-1 drugs: they slow gastric emptying, reduce appetite, and improve insulin secretion in a glucose-dependent way. That's the foundation. Retatrutide does all of that — and then adds two more layers.
The GIP receptor component amplifies the insulin response and appears to improve how fat tissue handles energy storage and release.[3] This is the same receptor tirzepatide targets alongside GLP-1, and it's part of why dual agonists outperformed pure GLP-1 drugs in head-to-head comparisons.
The glucagon receptor layer is what's new. Glucagon receptor agonism increases basal metabolic rate — your resting calorie burn goes up. It also drives fatty acid oxidation in the liver, which is why retatrutide showed signals for liver fat reduction in the Phase 2 diabetes trial.[2] The net effect is a drug that suppresses intake (GLP-1 + GIP), improves insulin dynamics (GLP-1 + GIP), and increases output (glucagon) — all three levers pulled at once.
The glucose-dependent nature of the GLP-1 and GIP components matters for safety: insulin secretion is amplified only when blood glucose is elevated, which limits hypoglycemia risk compared to older diabetes drugs like sulfonylureas.
What the Evidence Shows
The Phase 2 obesity trial published in the New England Journal of Medicine in 2023 is the primary efficacy data we have.[1] Participants were adults with obesity or overweight plus at least one weight-related comorbidity, without diabetes. The trial ran 48 weeks at maintenance dose, following a ~24-week escalation period.
At the 12 mg dose, mean weight loss was 24.2% — roughly 58 lbs from a starting weight around 240 lbs. To put that in BMI (body mass index) terms: a participant starting at a BMI of 38 would end near 29, crossing from obese to overweight. The 8 mg dose produced approximately 17.3% weight loss, and 4 mg produced approximately 8.7%.[1]
The Lancet published the Phase 2 diabetes trial alongside the obesity data in 2023.[2] In people with type 2 diabetes, retatrutide produced dose-dependent reductions in HbA1c (a 90-day average of blood glucose levels) of up to 2.2 percentage points at the highest dose — a clinically meaningful reduction that would move many patients from poorly controlled to well-controlled diabetes. Weight loss in this population reached approximately 16.9% at the highest dose over 36 weeks, somewhat lower than the non-diabetic obesity trial, which is consistent with what's seen across the GLP-1 class.[2]
A 2024 review in Diabetes Care and a 2025 systematic review in Annals of Internal Medicine both position retatrutide as the leading edge of a new generation of incretin-based therapies, with the triple agonist mechanism producing the highest weight loss percentages seen in any pharmacological trial to date.[3][4] Neither review changes the fundamental status: Phase 2 data, no Phase 3 results yet, no approved indication.
Side Effects
The side effect profile looks like the rest of the GLP-1 class, amplified somewhat by the higher weight loss and the glucagon component. The Phase 2 trials provide the most reliable data we have.[1][2]
If you're enrolled in a retatrutide trial and experience severe abdominal pain (possible pancreatitis), significant changes in heart rate, or GI symptoms that prevent normal eating or hydration, contact your trial coordinator immediately — don't wait for your next scheduled visit.