What is Retatrutide?
Retatrutide is an investigational triple-hormone receptor agonist that simultaneously activates the glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors, currently in Phase 3 clinical trials for the treatment of obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). 1, 2
Mechanism of Action
Retatrutide is a synthetic peptide that acts as a triple agonist targeting three distinct metabolic hormone receptors: GLP-1R, GIPR, and glucagon receptor (GCGR). 1, 2
The drug potentiates prandial insulin secretion, inhibits appetite, increases satiety through both central mechanisms and reduced gastric motility, and increases lipolysis, lipid oxidation, and energy expenditure. 1
By activating adenylyl cyclases through these receptors, retatrutide increases intracellular cyclic AMP (cAMP) levels, which mediates its metabolic effects. 3
The addition of glucagon receptor agonism to the dual GLP-1/GIP activity provides additional peripheral effects that can induce weight loss comparable to bariatric surgery. 1
Clinical Efficacy Data
Weight Loss in Obesity
In the Phase 2 trial of 338 adults with obesity (BMI ≥30 or BMI 27-<30 with weight-related conditions), retatrutide demonstrated dose-dependent weight reduction over 48 weeks. 4
At 24 weeks, mean weight loss was 7.2% with 1 mg, 12.9% with 4 mg, 17.3% with 8 mg, and 17.5% with 12 mg, compared to 1.6% with placebo. 4
At 48 weeks, mean weight loss reached 8.7% with 1 mg, 17.1% with 4 mg, 22.8% with 8 mg, and 24.2% with 12 mg, compared to 2.1% with placebo. 4
A meta-analysis of randomized controlled trials (878 patients) confirmed significant reductions in body weight (mean difference -14.33%), BMI (mean difference -5.38), and waist circumference (mean difference -10.51 cm), all with P < 0.00001. 5
At 48 weeks with the 12 mg dose, 100% of participants achieved ≥5% weight loss, 93% achieved ≥10% weight loss, and 83% achieved ≥15% weight loss, compared to 27%, 9%, and 2% respectively with placebo. 4
Glycemic Control in Type 2 Diabetes
In patients with type 2 diabetes, retatrutide achieved 16.9% mean weight loss after 36 weeks. 2
HbA1c improved by 2.2%, with 82% of participants reaching HbA1c ≤6.5%. 2
Fasting plasma glucose decreased by a mean difference of 23.51 mg/dL (P < 0.00001). 5
Cardiometabolic Benefits
Retatrutide significantly reduced systolic blood pressure by 9.88 mm Hg and diastolic blood pressure by 3.88 mm Hg (both P < 0.00001). 5
The drug improved lipid profiles and reduced hepatic steatosis by 82%. 2
Waist circumference decreased significantly, indicating reduction in visceral adiposity. 2, 5
Safety Profile
The most common adverse events were gastrointestinal symptoms, which were dose-related and mostly mild to moderate in severity. 4, 2
Gastrointestinal side effects were partially mitigated by using a lower starting dose of 2 mg versus 4 mg. 4
A meta-analysis found no significant difference in overall adverse events between retatrutide and placebo groups (relative risk 1.11, P = 0.24). 5
Dose-dependent increases in heart rate were observed, peaking at 24 weeks and declining thereafter. 4
In isolated human atrial preparations, retatrutide increased force of contraction through the cAMP system, suggesting potential cardiac effects that require monitoring. 3
No major safety concerns were identified in Phase 2 trials. 2
Current Development Status
Retatrutide is currently in Phase 3 clinical trials for obesity, type 2 diabetes, and MASLD, with trials initiated on August 28,2023. 6, 2
The comprehensive Phase 3 program is evaluating efficacy, safety, and cardiovascular/renal outcomes in people with obesity and/or type 2 diabetes. 2
Retatrutide is not yet FDA-approved for any indication and remains investigational. 7
The drug represents the most advanced triple agonist candidate, with published Phase 2 data in both obesity and type 2 diabetes populations. 2
Clinical Context
Retatrutide is part of a new generation of multi-receptor agonist drugs being developed to address the growing obesity epidemic and its associated metabolic complications. 1, 6
Other triple agonists and combination regimens involving dual agonists (like tirzepatide) with additional mono-agonists are also in development, but retatrutide is the furthest along in clinical development. 2
If approved, retatrutide has the potential to become the most effective pharmacological treatment for obesity while offering substantial benefits in type 2 diabetes management and other cardiometabolic risk factors. 2