Enter retatrutide (LY3437943), a novel triple hormone receptor agonist developed by Eli Lilly, targeting glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon (GCG) receptors. This unique mechanism has shown remarkable potential in early human trials for tackling obesity, T2D, and related conditions like non-alcoholic fatty liver disease (NAFLD). In this blog post, we’ll dive into the latest findings from published phase 2 trials, explore retatrutide’s efficacy and safety, and look ahead to its future in phase 3 studies.
What is Retatrutide?
Retatrutide is a single peptide designed to activate three key receptors involved in metabolic regulation. By engaging GIP, GLP-1, and GCG receptors, it aims to suppress appetite, enhance glycemic control, and promote energy expenditure. Its pharmacokinetics allow for convenient once-weekly injections, with a half-life of approximately 6 days. Preclinical studies demonstrated its ability to delay gastric emptying, reduce food intake, and promote weight loss, setting the stage for human trials.
Phase 2 Trials: Obesity
A landmark phase 2 trial, published in The New England Journal of Medicine on June 26, 2023, evaluated retatrutide’s efficacy and safety in 338 adults with obesity (BMI ≥30 kg/m² or 27–30 kg/m² with weight-related conditions, excluding T2D). Participants were randomized to receive weekly subcutaneous doses of retatrutide (1 mg, 4 mg, 8 mg, or 12 mg) or placebo for 48 weeks. The results were striking:
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Weight Loss: At 24 weeks, retatrutide achieved mean weight reductions of 7.2% (1 mg), 12.9% (4 mg), 17.3% (8 mg), and 17.5% (12 mg), compared to 1.6% for placebo. By 48 weeks, these figures increased to 8.7%, 17.1%, 22.8%, and 24.2%, respectively, versus 2.1% for placebo.
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Weight Loss Thresholds: At the highest doses (8 mg and 12 mg), 100% of participants achieved at least 5% weight loss, with 91–93% reaching 10% or more and 75–83% achieving 15% or more.
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Subgroup Differences: Participants with a BMI ≥35 experienced greater weight loss (26.5% at 8 mg, 26.4% at 12 mg) compared to those with BMI <35 (21.3% and 21.5%). Women also lost more weight than men (28.5% vs. 19.8% at 8 mg; 26.6% vs. 21.9% at 12 mg).
The trial also noted improvements in cardiometabolic markers like blood pressure, triglycerides, and cholesterol levels, suggesting broader health benefits. However, participants had not yet reached a weight plateau by 48 weeks, hinting at even greater potential with longer treatment.
Phase 2 Trials: Type 2 Diabetes
Another phase 2 trial, published in The Lancet on August 12, 2023, focused on retatrutide’s effects in 281 adults with T2D (HbA1c 7.0–10.5%, BMI 25–50 kg/m²). Participants received retatrutide (0.5 mg, 4 mg, 8 mg, or 12 mg), dulaglutide (1.5 mg), or placebo for 36 weeks. Key findings included:
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Glycemic Control: Retatrutide reduced HbA1c by 1.3–2.0% at 24 weeks for doses ≥4 mg, compared to 0% for placebo and 1.4% for dulaglutide. Up to 82% of participants achieved HbA1c <6.5%, and 31% reached normoglycemia (HbA1c <5.7%).
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Weight Loss: At 36 weeks, weight reductions were dose-dependent: 3.19% (0.5 mg), 7.92–10.37% (4 mg), 16.34–16.81% (8 mg), and 16.94% (12 mg), compared to 3.0% for placebo and 2.02% for dulaglutide.
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Safety: No severe hypoglycemia was reported, and the safety profile was comparable to other incretin-based therapies.
These results highlight retatrutide’s dual benefits in glycemic control and weight loss, surpassing dulaglutide in efficacy.
NAFLD Substudy
A substudy within the obesity trial, published in Nature on June 10, 2024, examined retatrutide’s impact on 98 participants with NAFLD and ≥10% liver fat. At 24 weeks, liver fat reductions were significant: 42.9% (1 mg), 57.0% (4 mg), 81.4% (8 mg), and 82.4% (12 mg), compared to a 0.3% increase in the placebo group. Over 90% of participants at the highest dose achieved normal liver fat levels, suggesting retatrutide’s potential in treating metabolic dysfunction-associated steatotic liver disease (MASLD).
Safety and Tolerability
Across trials, retatrutide’s most common side effects were mild to moderate gastrointestinal issues (nausea, vomiting, diarrhea, constipation), particularly during dose escalation. These were dose-dependent and mitigated with lower starting doses (e.g., 2 mg vs. 4 mg). Dose-related increases in heart rate were observed, peaking at 24 weeks and declining thereafter. No severe hypoglycemia or deaths were reported, aligning retatrutide’s safety profile with other incretin-based therapies.
Ongoing and Future Research
While phase 2 results are promising, retatrutide’s long-term efficacy and safety require further exploration. The TRIUMPH phase 3 trials, initiated in August 2023, are evaluating retatrutide for obesity, T2D, NAFLD, knee osteoarthritis, and obstructive sleep apnea in larger, more diverse populations. These trials, expected to conclude by February 2026, will provide critical data on sustained weight loss, cardiovascular outcomes, and kidney function.
Challenges and Considerations
Despite its promise, retatrutide faces challenges. Current trials have been conducted primarily in the United States, limiting ethnic diversity. Long-term effects on body composition (e.g., muscle vs. fat loss) and safety in pediatric populations remain unstudied. Additionally, the cost and accessibility of retatrutide will be critical for widespread adoption.
Conclusion
Retatrutide represents a groundbreaking advancement in obesity and T2D management, with phase 2 trials demonstrating unprecedented weight loss (up to 24.2% at 48 weeks) and glycemic control (HbA1c reductions up to 2.0%). Its triple agonist mechanism offers superior efficacy compared to existing therapies, with potential benefits for NAFLD and cardiovascular health. While gastrointestinal side effects and heart rate increases are notable, they align with the safety profiles of similar drugs. As phase 3 trials progress, retatrutide could redefine metabolic pharmacotherapy, offering hope for millions battling obesity and T2D.
For more details, check out the published studies:
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The New England Journal of Medicine (Obesity Trial):
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The Lancet (T2D Trial):
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Nature (NAFLD Substudy):
