Retatrutide Clinical Trials: Up to 24% Weight Loss
Retatrutide
24.2%
Mean weight loss at 48 weeks with retatrutide 12 mg in the phase 2 obesity trial, with weight still declining at study end.
Jastreboff et al., New England Journal of Medicine, 2023
Jastreboff et al., New England Journal of Medicine, 2023
View as imageNo approved weight loss drug had produced 24% mean body weight reduction in a controlled trial until retatrutide. Published in the New England Journal of Medicine, the phase 2 retatrutide clinical trial results showed the 12 mg dose produced 24.2% mean weight loss at 48 weeks in adults with obesity, and the weight curves had not yet plateaued.[1] Phase 3 data pushed that number higher still: up to 28.7% at 68 weeks. For context on how retatrutide's triple receptor mechanism enables these numbers, the mechanism article explains why three targets produce more weight loss than two.
Retatrutide (LY3437943) is the first triple agonist targeting GLP-1, GIP, and glucagon receptors simultaneously. Developed by Eli Lilly, it builds on the dual agonist approach of tirzepatide by adding glucagon receptor activation, which increases energy expenditure and promotes hepatic fat oxidation. The liver fat reduction data has been one of the most surprising findings in the program.
Key Takeaways
- Retatrutide 12 mg produced 24.2% mean weight loss at 48 weeks in the phase 2 obesity trial, with no plateau reached (Jastreboff et al., 2023)
- At 48 weeks, 100% of participants on 8 mg or 12 mg lost at least 5% body weight, and 83% on 12 mg lost at least 15% (Jastreboff et al., 2023)
- Phase 3 TRIUMPH-4 results showed 28.7% mean weight loss at 68 weeks with the 12 mg dose (Eli Lilly, 2025)
- In type 2 diabetes patients, retatrutide 12 mg produced 16.9% weight loss at 36 weeks alongside HbA1c reductions of 2.02% (Rosenstock et al., 2023)
- A body composition substudy found retatrutide reduced fat mass preferentially, with the fat-to-lean mass loss ratio more favorable than semaglutide (Coskun et al., 2025)
- Gastrointestinal adverse events were dose-related and partially mitigated by starting at 2 mg rather than 4 mg (Jastreboff et al., 2023)
The Phase 2 Obesity Trial: The NEJM Study
The landmark phase 2 trial, published in the New England Journal of Medicine in 2023, enrolled 338 adults with a BMI of 30 or higher (or 27+ with a weight-related condition) and randomized them to one of six retatrutide dose groups (1 mg, 4 mg with 2 mg start, 4 mg with 4 mg start, 8 mg with 2 mg start, 8 mg with 4 mg start, or 12 mg with 2 mg start) or placebo for 48 weeks. About 51.8% of participants were men, an unusually balanced sex distribution for an obesity trial.[1]
The primary endpoint was percentage change in body weight at 24 weeks. The results by dose:
- 1 mg: -7.2% at 24 weeks, -8.7% at 48 weeks
- 4 mg combined: -12.9% at 24 weeks, -17.1% at 48 weeks
- 8 mg combined: -17.3% at 24 weeks, -22.8% at 48 weeks
- 12 mg: -17.5% at 24 weeks, -24.2% at 48 weeks
- Placebo: -1.6% at 24 weeks, -2.1% at 48 weeks
The dose-response relationship was clear and steep. At 48 weeks on the 12 mg dose, 100% of participants had lost at least 5% of body weight, 93% had lost at least 10%, and 83% had lost at least 15%.[1]
The most striking aspect of these data was the trajectory. Weight loss was still accelerating at 48 weeks. The curves had not flattened, meaning the true maximum effect of retatrutide at the highest dose was unknown at the time of publication. Doggrell (2023) noted this in a commentary: the drug was "showing promise" precisely because it appeared to have room to run beyond what any other agent had achieved.[2]
Phase 2 in Type 2 Diabetes
Rosenstock et al. (2023) published a parallel phase 2 trial in The Lancet, evaluating retatrutide in 281 adults with type 2 diabetes. The design was double-blind, placebo-controlled, with an active comparator arm (dulaglutide 1.5 mg). At 36 weeks, the retatrutide 12 mg group achieved a mean HbA1c reduction of 2.02 percentage points from a baseline of approximately 8.3%, bringing most participants near or below the 7% threshold.[3]
Weight loss in the diabetes population was substantial but lower than in the obesity-only trial: 16.9% at 36 weeks for the 12 mg dose. This is consistent with a general pattern in incretin pharmacology where patients with type 2 diabetes lose less weight than those without diabetes on the same drug. The reasons are not fully understood but likely involve differences in insulin resistance, beta cell function, and metabolic set points.
The diabetes trial also provided early safety signals. Gastrointestinal events were again the most common adverse events, with nausea, diarrhea, and vomiting occurring at higher rates in the retatrutide groups than in placebo or dulaglutide. Dose-dependent increases in heart rate peaked at 24 weeks and then declined, a pattern also observed in the obesity trial.[3]
Phase 3: The TRIUMPH Program
The phase 3 clinical program, called TRIUMPH, includes multiple trials across obesity, type 2 diabetes, and metabolic liver disease. The first readout came from TRIUMPH-4, which evaluated retatrutide in adults with obesity or overweight and knee osteoarthritis.
In December 2025, Eli Lilly announced topline results: the 12 mg dose produced an average weight loss of 28.7% (approximately 71.2 pounds) after 68 weeks. This exceeded the phase 2 result, confirming the dose-response curve that had suggested a higher ceiling. Participants also reported substantial relief from osteoarthritis pain, connecting weight loss to functional outcomes.
Seven additional TRIUMPH trials are expected to complete in 2026, with results anticipated across multiple indications. The program also tests a 4 mg maintenance dose in addition to the 9 mg and 12 mg treatment doses, which will help define how much drug is needed once the target weight is reached.
Body Composition: Where the Weight Comes From
One limitation of headline weight loss numbers is they do not distinguish fat from lean tissue. Coskun et al. (2025) published a body composition substudy from the phase 2 diabetes trial in The Lancet Diabetes & Endocrinology, using DXA scanning to measure fat mass and lean mass changes. Retatrutide reduced fat mass preferentially, with a more favorable ratio of fat-to-lean mass loss compared to what has been observed with semaglutide alone.[4]
This may be a direct consequence of the glucagon receptor component. Glucagon promotes hepatic fat oxidation and increases energy expenditure, which could shift the metabolic balance toward fat mobilization and away from muscle catabolism. Knerr et al. (2022) had demonstrated this principle in preclinical work: triple GLP-1/GIP/glucagon agonists normalized body weight in obese mice with a body composition profile that favored fat loss.[5]
Whether this body composition advantage holds in larger phase 3 datasets and in patients without diabetes remains to be confirmed.
Liver Fat and MASH: An Unexpected Bonus
Sanyal et al. (2024) published a randomized phase 2a trial in Nature Medicine evaluating retatrutide specifically for metabolic dysfunction-associated steatotic liver disease (MASLD/MASH). The results were remarkable: retatrutide produced substantial reductions in liver fat content, with some patients achieving complete normalization of liver fat.[6]
The glucagon receptor agonism is the likely driver. Glucagon directly promotes hepatic fatty acid oxidation. Combined with the weight loss from GLP-1 and GIP agonism, the triple mechanism creates a powerful anti-steatotic effect. This has opened a potential new indication for retatrutide beyond obesity and diabetes, and dedicated phase 3 trials for MASH are in the TRIUMPH program. The MASH connection article covers this data in depth.
Safety Profile Across Trials
The safety data from the combined clinical development program show a consistent pattern. Abdrabou et al. (2025) conducted a systematic review and meta-analysis of randomized controlled trials, confirming that gastrointestinal events are the primary safety concern.[7]
Nausea, diarrhea, vomiting, and decreased appetite were the most frequent adverse events, occurring at higher rates with higher doses. In the phase 2 obesity trial, the starting dose affected tolerability: groups that started at 2 mg before escalating to the target dose had fewer gastrointestinal events than those starting at 4 mg.[1] This dose-titration finding directly informed the phase 3 protocol design.
Heart rate increases were dose-dependent, peaking around 24 weeks and declining thereafter. This pattern differs from the sustained heart rate elevation seen with some single GLP-1 agonists and may reflect a compensatory response. No cardiovascular events were attributed to retatrutide in the phase 2 program, but the dedicated cardiovascular outcomes trial has not yet reported.
Misra et al. (2025) conducted an independent systematic review of efficacy and safety across all published retatrutide trials and found no unexpected safety signals beyond the known gastrointestinal effects and heart rate changes.[8]
Katsi et al. (2025) described retatrutide as "a game changer in obesity pharmacotherapy" while noting that the long-term safety profile remains undefined given the relatively short duration of completed trials.[9]
How Retatrutide Compares to Existing Drugs
Sinha et al. (2025) published a comparison of GLP-1 receptor agonists, dual agonists, and retatrutide for weight loss. The hierarchy is clear in terms of weight reduction magnitude: retatrutide (24-29%) > tirzepatide (20-23%) > semaglutide 2.4 mg (15-17%) > liraglutide 3.0 mg (5-8%).[10]
This comparison comes with caveats. The retatrutide and tirzepatide data come from different trial populations, different timepoints, and different background treatments. Head-to-head comparisons do not yet exist for retatrutide versus tirzepatide or semaglutide, and the comparison article covers the nuances of these indirect comparisons.
The gastrointestinal adverse event rates appear broadly similar across the class, though the glucagon component of retatrutide may contribute additional nausea on top of the GLP-1 effect. Whether the extra weight loss justifies any extra tolerability burden is a question the TRIUMPH program will help answer.
Panou et al. (2026) provided an updated overview of retatrutide in type 2 diabetes and obesity, noting that the drug's position in the treatment landscape will depend not only on efficacy but on pricing, access, and long-term safety data that are still years away from maturation.[11]
What Remains Unknown
The phase 3 TRIUMPH results due in 2026 will answer several open questions, but some will persist:
- Weight regain after discontinuation: The phase 2 trial did not include a post-treatment follow-up period. Whether retatrutide's effects are durable after stopping, or whether weight rebounds as it does with semaglutide, is unknown.
- Cardiovascular outcomes: No dedicated outcomes trial has reported. The heart rate increases observed in phase 2 are concerning until long-term cardiovascular data are available.
- Optimal maintenance dosing: Whether patients can step down to 4 mg after achieving target weight, and whether that dose maintains the loss, is being tested in TRIUMPH but not yet reported.
- Muscle preservation: The Coskun et al. (2025) body composition data are encouraging but come from a substudy of a diabetes population. Whether the favorable fat-to-lean ratio holds in the broader obesity population and at higher doses needs confirmation.
Urva et al. (2022) provided the earliest human pharmacology data for LY3437943, showing the foundational dose-response and pharmacokinetic parameters that shaped the later clinical program.[12] From those early phase 1 results to the TRIUMPH phase 3 readouts, the trajectory has been consistent: retatrutide produces more weight loss than any previously tested molecule. The question now is whether the rest of the profile, safety, durability, access, matches the efficacy.
The Bottom Line
Retatrutide produced 24.2% mean weight loss at 48 weeks in phase 2 and up to 28.7% in phase 3, surpassing all existing GLP-1 and dual agonist drugs. The triple agonist mechanism (GLP-1 + GIP + glucagon) also drives substantial liver fat reduction and may preserve body composition better than single-target agents. Gastrointestinal adverse events are the primary safety concern, dose-dependent and mitigable with slower titration. Phase 3 TRIUMPH results throughout 2026 will define whether this translates into a first-line obesity treatment.