Retatrutide Phase 2 Trial Analysis
A detailed breakdown of the phase 2 clinical trial data for retatrutide — the first triple-receptor agonist to produce up to 24.2% weight loss in 48 weeks.
A detailed breakdown of the phase 2 clinical trial data for retatrutide — the first triple-receptor agonist to produce up to 24.2% weight loss in 48 weeks.
Table of Contents
- Why Retatrutide Matters
- The Triple-Agonist Mechanism
- Phase 2 Obesity Trial Design
- Weight Loss Results
- Phase 2 Type 2 Diabetes Trial
- Cardiometabolic Improvements
- Liver Fat Substudy
- Body Composition Analysis
- How Retatrutide Compares to Semaglutide and Tirzepatide
- Safety and Tolerability
- What the Phase 3 Program Looks Like
- FAQ
- The Bottom Line
- References
Why Retatrutide Matters
When Eli Lilly presented retatrutide data at the American Diabetes Association's 83rd Scientific Sessions in June 2023, endocrinologists used a phrase that rarely appears in clinical research: "This raises the bar."
The reason was simple. In a field where semaglutide had already produced weight loss results that seemed improbable a decade earlier, and where tirzepatide had pushed those numbers even higher, retatrutide entered the picture and exceeded both.
The phase 2 trial results — published simultaneously in the New England Journal of Medicine and The Lancet — showed up to 24.2% mean body weight reduction at 48 weeks. That figure has since been surpassed by the first phase 3 readout, which showed 28.7% at 68 weeks. But the phase 2 data remains the foundation: the trial that proved the triple-agonist concept works in humans and set the stage for everything that followed.
This analysis walks through the trial designs, dose-response data, metabolic effects, body composition findings, safety profile, and what it all means in the context of existing GLP-1 and GIP/GLP-1 therapies.
The Triple-Agonist Mechanism
Three Receptors, Three Effects
Retatrutide (LY3437943) is the first molecule to agonize three incretin and metabolic hormone receptors simultaneously:
| Receptor | Location | Primary Effect | EC50 |
|---|---|---|---|
| GIP (glucose-dependent insulinotropic polypeptide) | Gut, pancreas, adipose tissue, brain | Insulin secretion, fat metabolism | 0.064 nM (most potent) |
| GLP-1 (glucagon-like peptide 1) | Gut, pancreas, brain, heart | Appetite suppression, gastric emptying delay, insulin secretion | 0.775 nM |
| Glucagon | Liver, adipose tissue, brown fat | Energy expenditure, hepatic fat oxidation, lipolysis | 5.79 nM |
The molecule is most potent at the GIP receptor and least potent at the glucagon receptor. This ratio appears to be intentional — glucagon receptor activation at high levels could raise blood glucose, so the lower potency at this receptor may help balance the metabolic effects.
Why Glucagon Changes the Equation
To understand why retatrutide produces greater weight loss than GLP-1 or GIP/GLP-1 agents alone, the glucagon receptor component is the key differentiator.
Semaglutide works through one pathway — GLP-1 receptor activation reduces appetite and slows gastric emptying. Tirzepatide adds GIP receptor agonism, which improves insulin sensitivity in fat tissue and may contribute to greater satiety signals. Retatrutide adds glucagon on top of both.
Glucagon receptor activation drives several distinct metabolic processes:
- Increased hepatic fatty acid oxidation — Glucagon signals directly to the liver, increasing the breakdown of stored fat for energy
- Decreased lipogenesis — New fat production in the liver drops
- Lipolysis in adipose tissue — Stored fat is released as free fatty acids
- Thermogenesis — In preclinical models, glucagon activation increases energy expenditure through effects on brown adipose tissue
In preclinical studies, retatrutide promoted weight loss by reducing food intake and increasing energy expenditure compared to calorie-matched controls. This dual action — eating less plus burning more — may explain the gap between retatrutide's results and those of existing therapies. However, the energy expenditure increase in humans has been modest and not yet shown to be clinically significant on its own.
Phase 2 Obesity Trial Design
The obesity trial (Jastreboff et al., 2023) was a multicenter, double-blind, placebo-controlled, randomized phase 2 study conducted across the United States. Published in the New England Journal of Medicine, it enrolled 338 adults meeting these criteria:
- BMI of 30-50 kg/m^2, or BMI of 27-29 kg/m^2 with at least one weight-related condition
- No type 2 diabetes
- Age 18-75 years
Participants were randomized in a 2:1:1:1:1:2:2 ratio to seven groups:
| Group | Dose | Starting Dose | n |
|---|---|---|---|
| Placebo | -- | -- | 70 |
| Retatrutide 1 mg | 1 mg | 1 mg | 69 |
| Retatrutide 4 mg (slow) | 4 mg | 2 mg | ~34 |
| Retatrutide 4 mg (fast) | 4 mg | 4 mg | ~33 |
| Retatrutide 8 mg (slow) | 8 mg | 2 mg | ~35 |
| Retatrutide 8 mg (fast) | 8 mg | 4 mg | ~35 |
| Retatrutide 12 mg | 12 mg | 2 mg | 62 |
The use of different starting doses (2 mg vs. 4 mg escalation) for the 4 mg and 8 mg groups was a deliberate design choice to assess whether slower dose titration could reduce gastrointestinal side effects — a recurring challenge with GLP-1 class agents.
The primary endpoint was percentage change in body weight at 24 weeks. The secondary endpoint was percentage change at 48 weeks.
Weight Loss Results
Primary Endpoint: 24 Weeks
The least-squares mean percentage change in body weight at 24 weeks:
| Group | Weight Change (%) | Placebo-Adjusted |
|---|---|---|
| Placebo | -1.6% | -- |
| Retatrutide 1 mg | -7.2% | -5.6% |
| Retatrutide 4 mg (combined) | -12.9% | -11.3% |
| Retatrutide 8 mg (combined) | -17.3% | -15.7% |
| Retatrutide 12 mg | -17.5% | -15.9% |
At just 24 weeks — roughly six months — the 12 mg group had already lost more than 17% of body weight. For context, the STEP 1 trial of semaglutide 2.4 mg showed 14.9% weight loss at 68 weeks (over 16 months). Retatrutide reached comparable territory in less than half the time.
Secondary Endpoint: 48 Weeks
The weight loss curves had not plateaued at 24 weeks. By 48 weeks, the results were:
| Group | Weight Change (%) | Placebo-Adjusted |
|---|---|---|
| Placebo | -2.1% | -- |
| Retatrutide 1 mg | -8.7% | -6.6% |
| Retatrutide 4 mg (combined) | -17.1% | -15.0% |
| Retatrutide 8 mg (combined) | -22.8% | -20.7% |
| Retatrutide 12 mg | -24.2% | -22.1% |
The 12 mg group achieved a placebo-adjusted mean weight loss of 22.1%. The weight loss trajectory between weeks 24 and 48 showed the curves were still trending downward, suggesting a longer trial might have produced even greater reductions.
Weight Loss Thresholds
The proportion of participants reaching clinically meaningful weight loss targets at 48 weeks tells a practical story:
| Threshold | 4 mg | 8 mg | 12 mg | Placebo |
|---|---|---|---|---|
| >= 5% weight loss | 92% | 100% | 100% | 27% |
| >= 10% weight loss | 75% | 91% | 93% | 9% |
| >= 15% weight loss | 60% | 75% | 83% | 4% |
At the 8 mg and 12 mg doses, every single participant lost at least 5% of body weight. More than 9 in 10 lost at least 10%. These response rates — especially the near-universal 5% threshold — are notable because individual variability has been a persistent challenge with GLP-1 therapies. Some patients respond dramatically while others see modest effects. Retatrutide's consistency across participants at higher doses stands out.
Waist Circumference
Waist circumference — a proxy for visceral fat and cardiovascular risk — decreased across all retatrutide groups:
- Retatrutide groups: -6.5 to -19.6 cm reduction at 48 weeks
- Placebo: -2.6 cm reduction
The 19.6 cm reduction (roughly 7.7 inches) in the highest-responding group represents a meaningful shift in body fat distribution, not just total weight.
Phase 2 Type 2 Diabetes Trial
A parallel phase 2 trial (Rosenstock et al., 2023) evaluated retatrutide specifically in people with type 2 diabetes (T2D). Published in The Lancet, the study enrolled 281 participants from 42 U.S. centers.
Eligibility criteria:
- Adults aged 18-75 with type 2 diabetes
- HbA1c of 7.0-10.5%
- BMI of 25-50 kg/m^2
- Treated with diet and exercise alone, or a stable dose of metformin (at least 1,000 mg daily)
Participants were randomized to retatrutide (0.5 mg, 4 mg, 8 mg, or 12 mg), dulaglutide 1.5 mg (an active comparator), or placebo for 36 weeks. Mean baseline characteristics: age 56 years, 56% women, BMI 35.0, HbA1c 8.3%.
HbA1c Reductions
The primary endpoint — HbA1c change from baseline at 24 weeks — showed clear dose-response effects:
| Group | HbA1c Change at 36 Weeks | HbA1c <= 6.5% at 36 Weeks |
|---|---|---|
| Placebo | -0.3% | 5% |
| Dulaglutide 1.5 mg | -1.4% | 43% |
| Retatrutide 0.5 mg | -0.4% | Not reported |
| Retatrutide 4 mg | -1.4% | Not reported |
| Retatrutide 8 mg | -1.9% | 77-82% |
| Retatrutide 12 mg | -2.2% | 82% |
The 12 mg dose reduced HbA1c by 2.16 percentage points at 36 weeks — an estimated 0.80% greater reduction than dulaglutide 1.5 mg (95% CI: -1.16 to -0.44). At the 8 mg and 12 mg doses, roughly 4 in 5 participants reached an HbA1c of 6.5% or below, a threshold often considered diabetes remission.
Weight Loss in T2D
Weight loss in the diabetes trial was substantial but somewhat lower than the obesity trial, consistent with the pattern seen across GLP-1 class agents (patients with T2D typically lose less weight than those without):
| Group | Weight Change at 36 Weeks |
|---|---|
| Placebo | -3.0% |
| Dulaglutide 1.5 mg | -2.0% |
| Retatrutide 0.5 mg | -3.2% |
| Retatrutide 4 mg | -7.9% to -10.4% |
| Retatrutide 8 mg | -16.3% to -16.8% |
| Retatrutide 12 mg | -16.9% |
Dulaglutide Comparison
Retatrutide showed superior efficacy to dulaglutide 1.5 mg — a widely prescribed GLP-1 receptor agonist with proven cardiovascular benefits — on both HbA1c and body weight. At retatrutide doses of 4 mg and above, weight reductions were significantly greater than dulaglutide (all p<0.0001).
This comparison is important because dulaglutide 1.5 mg represents a well-established treatment in the GLP-1 class, not a weak comparator. Beating it on both glycemic control and weight loss simultaneously supports the value of triple-receptor agonism.
Cardiometabolic Improvements
Both phase 2 trials collected exploratory data on cardiovascular and metabolic biomarkers. Treatment with retatrutide was associated with improvements in:
- Systolic and diastolic blood pressure
- Triglycerides
- LDL cholesterol (approximately 20% reduction)
- Total cholesterol
- Fasting glucose and insulin
The LDL cholesterol reduction is particularly interesting. The researchers noted that this may reflect glucagon agonism's effects on PCSK9 degradation — a mechanism entirely separate from the weight-loss-driven lipid improvements seen with GLP-1 agents alone.
Another notable finding: 72% of participants who had prediabetes at baseline in the obesity trial reverted to normoglycemia during retatrutide treatment.
Liver Fat Substudy
A prespecified substudy evaluated liver fat content in participants with obesity and nonalcoholic fatty liver disease (NAFLD), using MRI-based proton density fat fraction measurements (Sanyal et al., 2024). Published in Nature Medicine, the results were extraordinary:
| Dose | Liver Fat Change at 24 Weeks | Liver Fat Change at 48 Weeks |
|---|---|---|
| Placebo | +0.3% | Not reported |
| Retatrutide 1 mg | -42.9% | Further reduction |
| Retatrutide 4 mg | -57.0% | Further reduction |
| Retatrutide 8 mg | -81.4% | Further reduction |
| Retatrutide 12 mg | -82.4% | Further reduction |
All doses achieved statistical significance versus placebo (p<0.001). At the 12 mg dose, more than 90% of participants with obesity and NAFLD achieved normalization of liver fat.
Supporting the mechanistic connection, levels of beta-hydroxybutyrate — a biomarker of fatty acid oxidation — increased 2- to 3-fold in a dose-dependent pattern at doses of 4 mg and above. The largest increases appeared by week 24, coinciding with the period of greatest liver fat reduction, and the correlation between beta-hydroxybutyrate and liver fat changes was statistically significant.
This liver fat effect likely reflects glucagon receptor activation driving hepatic fatty acid oxidation — a direct mechanism beyond what GLP-1 or GIP/GLP-1 agents can achieve. The degree of reduction (exceeding 80%) outperforms the liver fat data from tirzepatide and semaglutide trials, making retatrutide a potential treatment for metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH).
For more context on how incretin-based therapies are reshaping obesity treatment, see our guides on peptides for obesity and best peptides for fat loss.
Body Composition Analysis
A critical question with any weight-loss therapy is what kind of tissue is actually being lost. A body composition substudy using dual-energy X-ray absorptiometry (DXA) was published in The Lancet Diabetes & Endocrinology in 2025, drawing from the type 2 diabetes trial (Garvey et al., 2025).
Of the 189 participants enrolled in the substudy, 103 completed both baseline and week 36 DXA scans. The results:
| Dose | Total Fat Mass Change | Android Visceral Fat Change |
|---|---|---|
| Placebo | -4.5% | Not reported |
| Dulaglutide 1.5 mg | -2.6% | Not reported |
| Retatrutide 0.5 mg | -4.9% | Minimal |
| Retatrutide 4 mg | -15.2% | Substantial |
| Retatrutide 8 mg | -26.1% | Significant |
| Retatrutide 12 mg | -23.2% | -31.4% |
The 8 mg group showed the greatest total fat mass reduction (-26.1%), while the 12 mg group showed the largest decrease in android visceral fat (-31.4%). The slightly lower total fat mass loss in the 12 mg group versus the 8 mg group may reflect sample size variability in a substudy.
The finding that matters most: the proportion of lean mass loss to total weight loss was similar to other obesity treatments. This means retatrutide, despite producing much greater total weight loss, did not cause a disproportionate loss of muscle mass. The "fat loss index" — the ratio of fat mass lost to total mass lost — was consistent with GLP-1 and GIP/GLP-1 agents.
How Retatrutide Compares to Semaglutide and Tirzepatide
While no head-to-head trials exist, cross-trial comparisons tell a consistent story. A systematic review of 26 randomized controlled trials with 15,491 participants calculated the following placebo-adjusted weight loss figures:
| Agent | Receptor Targets | Max Weight Loss (vs. Placebo) | Trial Duration |
|---|---|---|---|
| Semaglutide 2.4 mg | GLP-1 | ~14% | 68 weeks |
| Tirzepatide 15 mg | GLP-1 + GIP | ~18% | 72 weeks |
| Retatrutide 12 mg (Phase 2) | GLP-1 + GIP + Glucagon | ~22% | 48 weeks |
| Retatrutide 12 mg (Phase 3) | GLP-1 + GIP + Glucagon | ~26-29% | 68 weeks |
Three observations stand out:
-
Each added receptor corresponds to greater weight loss. GLP-1 alone produces approximately 14% reduction. Adding GIP pushes it to approximately 18%. Adding glucagon reaches 22-29%.
-
Retatrutide achieved superior phase 2 results in less time. The 48-week phase 2 results (24.2%) exceeded tirzepatide's 72-week results and semaglutide's 68-week results.
-
Response rates improve, not just means. The near-universal response at higher doses (100% achieving at least 5% weight loss at 8 mg and 12 mg) suggests retatrutide may partially solve the individual variability problem seen with earlier agents.
An important caveat: cross-trial comparisons have inherent limitations. Patient populations, baseline characteristics, trial sites, and statistical methodologies differ between studies. Only head-to-head trials can definitively establish superiority.
Safety and Tolerability
The safety profile of retatrutide was broadly consistent with the GLP-1 receptor agonist class.
Most common adverse events (obesity trial):
The most frequently reported side effects were gastrointestinal — nausea, diarrhea, vomiting, and constipation. These were dose-related, mostly mild to moderate in severity, and occurred more frequently with retatrutide than with placebo.
Discontinuation rates:
Adverse events leading to treatment discontinuation ranged from 6% to 16% in the retatrutide groups versus 0% in the placebo group. The incidence of serious adverse events was 4% with placebo and 0-6% across retatrutide doses.
Starting dose matters:
The trial's dose-escalation comparison showed that starting at 2 mg (rather than 4 mg) before escalating to target doses partially mitigated gastrointestinal side effects. This finding directly informed the dose-titration schedules used in the phase 3 program.
Type 2 diabetes trial safety:
In the diabetes trial, mild-to-moderate gastrointestinal adverse events occurred in 35% of retatrutide participants, 13% of placebo participants, and 35% of dulaglutide participants. There were no reports of severe hypoglycemia and no deaths during the study.
What about glucagon-driven glucose increases?
A theoretical concern with glucagon receptor agonism is hyperglycemia, since glucagon stimulates hepatic glucose output. In practice, the concurrent GLP-1 and GIP receptor activation appeared to counterbalance this effect. Fasting glucose and HbA1c improved rather than worsened, even in participants without diabetes.
What the Phase 3 Program Looks Like
Based on the phase 2 data, Eli Lilly launched the TRIUMPH phase 3 development program — a suite of clinical trials evaluating retatrutide across multiple conditions:
- TRIUMPH-1 through TRIUMPH-3: Chronic weight management in adults with obesity or overweight
- TRIUMPH-4: Obesity with knee osteoarthritis (first Phase 3 results announced — 28.7% weight loss at the highest dose, with substantial reductions in knee pain and improvements in physical function)
- TRIUMPH-5: Obesity with obstructive sleep apnea
- Additional trials in type 2 diabetes and metabolic liver disease
Seven additional phase 3 readouts are expected in 2026. If approved, retatrutide would likely be marketed as a next-generation weight management therapy, building on the commercial success of tirzepatide (Zepbound/Mounjaro) and semaglutide (Wegovy/Ozempic).
For a broader look at the incretin-based therapy pipeline and how these medications fit into the obesity treatment picture, see our guide on peptides for obesity.
FAQ
When will retatrutide be available? Retatrutide is not yet FDA-approved. With phase 3 results expected throughout 2026, the earliest possible approval would likely be late 2026 or 2027, assuming positive trial outcomes and a standard regulatory review timeline.
Is retatrutide stronger than semaglutide or tirzepatide? Based on cross-trial comparisons, retatrutide appears to produce greater weight loss than both semaglutide (GLP-1 alone) and tirzepatide (GLP-1/GIP). Phase 2 data showed 24.2% weight loss at 48 weeks with retatrutide versus approximately 15% with semaglutide at 68 weeks and approximately 22% with tirzepatide at 72 weeks. No head-to-head trial has been conducted.
What makes retatrutide different from tirzepatide? The main difference is the glucagon receptor. Tirzepatide activates GLP-1 and GIP receptors. Retatrutide activates those same two receptors plus the glucagon receptor. This third pathway increases liver fat oxidation, promotes thermogenesis, and may contribute to the greater weight loss observed in trials.
Does retatrutide cause muscle loss? The DXA body composition substudy showed that the ratio of fat mass loss to total weight loss was similar to other obesity medications. Despite producing greater overall weight loss, retatrutide did not cause a disproportionate loss of lean (muscle) mass.
What were the main side effects? Gastrointestinal events — nausea, diarrhea, vomiting, and constipation — were the most common side effects, consistent with other GLP-1 class therapies. These were mostly mild to moderate and could be partially reduced by starting with a lower dose (2 mg) before escalating.
Can retatrutide treat fatty liver disease? Phase 2 data showed an 82.4% reduction in liver fat at the highest dose, with over 90% of NAFLD participants achieving liver fat normalization. A dedicated phase 2a trial in metabolic dysfunction-associated steatotic liver disease (MASLD) has been published in Nature Medicine, and further studies are ongoing.
The Bottom Line
The retatrutide phase 2 program produced some of the most impressive weight loss and metabolic improvement data ever published for a pharmacotherapy. The 24.2% mean weight loss at 48 weeks, combined with the liver fat reductions exceeding 80%, the favorable body composition profile, and the robust glycemic control in type 2 diabetes, validated the hypothesis that adding glucagon receptor activation to the GLP-1/GIP dual-agonist framework meaningfully increases therapeutic benefit.
The safety profile showed no unexpected signals beyond the established GI tolerability challenges of the incretin class, and the dose-escalation data provided a practical path to reducing those side effects.
What moves this from interesting to potentially practice-changing is the phase 3 trajectory. Early TRIUMPH results — 28.7% weight loss at 68 weeks in the osteoarthritis trial — suggest the phase 2 findings were not a ceiling but a floor. If the remaining seven phase 3 readouts in 2026 are consistent, retatrutide will likely become the most effective pharmacological weight loss treatment available, and the first to routinely produce weight reductions approaching those of bariatric surgery.
References
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Jastreboff AM, et al. "Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial." New England Journal of Medicine. 2023;389(6):514-526. NEJM
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Rosenstock J, et al. "Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA." The Lancet. 2023;402(10401):529-544. Lancet
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Sanyal AJ, et al. "Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial." Nature Medicine. 2024;30:2037-2048. Nature Medicine
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Garvey WT, et al. "Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial." Lancet Diabetes & Endocrinology. 2025. Lancet D&E
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Eli Lilly and Company. "Lilly's phase 2 retatrutide results published in The New England Journal of Medicine." Press release, June 26, 2023. Lilly Investor Relations
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American Diabetes Association. "ADA Highlights Novel Agent Retatrutide Which Results in Substantial Weight Reduction." June 2023. ADA
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Giblin MJ, et al. "Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials." Diabetes, Obesity and Metabolism. 2026. Wiley
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Habegger KM. "Metabolic effects of glucagon receptor activation in emerging obesity treatments." UAB Heersink School of Medicine. UAB