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Retatrutide Research

RETATRUTIDE CLINICAL TRIALS: THE DATA

Phase 2 showed 24.2% weight loss in 48 weeks. Phase 3 TRIUMPH-4 hit 28.7% at 68 weeks. Here's a complete breakdown of every published trial, what the numbers actually mean, and what's still outstanding.

Medically reviewed by Missy Zammichieli, DNP, APRN, FNP-BC · Updated March 25, 2026

PHASE 2: THE STUDY THAT GOT EVERYONE'S ATTENTION

In June 2023, Jastreboff et al. published the Phase 2 results of retatrutide in the New England Journal of Medicine. The trial (NCT04881706) enrolled 338 adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related comorbidity. It was a 48-week, randomized, double-blind, placebo-controlled, dose-ranging study conducted at 42 sites in the United States.

Participants were randomized across six groups: placebo, 1 mg, 4 mg (two escalation schedules), 8 mg (two escalation schedules), and 12 mg. The primary endpoint was percent change in body weight from baseline at 24 weeks, with a key secondary endpoint at 48 weeks.

The results at 48 weeks were the most aggressive weight loss numbers ever published for an anti-obesity medication in a controlled trial at that time:

Dose Group	Mean Weight Loss (48 wk)	Absolute Weight Loss
Placebo	-2.1%	~2.2 kg
1 mg	-8.7%	~9.0 kg
4 mg	-17.1%	~17.9 kg
8 mg	-22.8%	~24.2 kg
12 mg	-24.2%	~26.3 kg

To put 24.2% in context: that's roughly 58 pounds for someone starting at 240 lbs. Semaglutide 2.4 mg (Wegovy) achieved about 14.9% in its STEP 1 trial over 68 weeks. Tirzepatide 15 mg (Zepbound) hit 22.5% in SURMOUNT-1 over 72 weeks. Retatrutide reached 24.2% in just 48 weeks — less time and a larger magnitude.

Response Rates at 12 mg (48 Weeks)

The categorical response rates at the highest dose were striking — essentially, almost everyone responded:

100%

lost ≥5% body weight

93%

lost ≥10% body weight

83%

lost ≥15% body weight

63%

lost ≥20% body weight

The 100% responder rate at the ≥5% threshold is notable. In obesity pharmacotherapy, there are always non-responders — people whose biology doesn't cooperate with the mechanism. In the 12 mg group, there were none. Every single participant lost clinically meaningful weight. Even at the ≥20% threshold — a level of weight loss that typically requires bariatric surgery — nearly two-thirds of participants got there with a weekly injection.

The weight loss curves at 48 weeks had not yet plateaued in the 8 mg and 12 mg groups, suggesting that longer treatment durations would produce even greater reductions. This was later confirmed by TRIUMPH-4's 68-week data.

PHASE 2 LIVER FAT SUBSTUDY

In 2024, Sanyal et al. published a prespecified substudy in Nature Medicine analyzing liver fat changes in Phase 2 participants who had metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD). This was the first look at retatrutide's effect on one of the most common and least treated metabolic conditions — fatty liver.

The findings were dramatic. Participants in the 12 mg group showed approximately 86% relative reduction in liver fat content as measured by MRI-PDFF (proton density fat fraction). Among those with MASLD at baseline, roughly 90% achieved complete resolution of hepatic steatosis — meaning their liver fat levels dropped below the 5% threshold used to define the condition.

Why this matters: MASLD affects an estimated 30% of the global adult population and is becoming the leading cause of liver transplantation. No approved drug specifically treats it (as of early 2026, resmetirom for MASH is the only FDA-approved medication in this space, and it targets a more advanced stage). A drug that resolves steatosis in 90% of patients while also producing major weight loss would address two epidemics simultaneously.

The glucagon receptor agonism in retatrutide likely drives a significant portion of this liver effect. Glucagon promotes hepatic lipid oxidation — it tells the liver to burn its fat stores for energy. This is a mechanism that pure GLP-1 agonists like semaglutide and dual GIP/GLP-1 agonists like tirzepatide don't directly engage. It's one of the clearest differentiators in retatrutide's triple-agonist profile.

The study also observed reductions in liver enzymes (ALT, AST) and improvements in non-invasive fibrosis markers, though the Phase 2 study was not powered to draw definitive conclusions about fibrosis reversal. Larger Phase 3 studies with longer follow-up will be needed to assess whether retatrutide can meaningfully impact liver fibrosis progression.

PHASE 2 METABOLIC MARKERS

Weight loss is the headline number, but the metabolic improvements beyond the scale tell a more complete story. In the Phase 2 trial, retatrutide produced clinically significant improvements across multiple cardiometabolic risk factors at the 8 mg and 12 mg doses:

HbA1c

Participants without type 2 diabetes saw HbA1c reductions of 0.2-0.4 percentage points. In a separate Phase 2 trial enrolling adults with type 2 diabetes (Rosenstock et al., Lancet 2023, NCT04867785), retatrutide 12 mg reduced HbA1c by approximately 2.02 percentage points from a baseline of ~8.3%, with 71% of participants achieving HbA1c <5.7% — below the diagnostic threshold for prediabetes.

Fasting Glucose

In the obesity trial, fasting glucose decreased in a dose-dependent manner across all active groups. At the 12 mg dose, mean fasting glucose dropped by approximately 10-15 mg/dL. In the T2D-specific trial, the reductions were more pronounced, consistent with the higher baseline values in that population.

Triglycerides

Fasting triglycerides decreased by up to 30-35% at the higher dose groups. This is a clinically meaningful reduction — comparable to what you'd see from a moderate-dose statin or high-dose omega-3 prescription. The glucagon component likely contributes here through increased hepatic fatty acid oxidation.

Blood Pressure

Systolic blood pressure decreased by approximately 6-10 mmHg at the higher doses, with smaller reductions in diastolic pressure. Part of this is the weight loss itself — for every 1% of body weight lost, systolic BP typically drops ~1 mmHg. But the magnitude suggested effects beyond weight alone, possibly related to improved insulin sensitivity and reduced sympathetic tone.

Waist circumference decreased substantially across all active dose groups, with the 12 mg group losing an average of approximately 18-20 cm. LDL cholesterol showed moderate reductions, and C-reactive protein (CRP), a marker of systemic inflammation, decreased in a dose-dependent pattern.

The aggregate picture: retatrutide wasn't just making people lighter. It was improving virtually every measurable marker of metabolic health — glucose metabolism, lipid profiles, blood pressure, inflammatory markers, and hepatic fat. This breadth of effect is what distinguishes triple agonism from single- or dual-receptor approaches.

PHASE 3: THE TRIUMPH PROGRAM

Following the Phase 2 results, Eli Lilly launched the TRIUMPH (Triple Hormone Receptor Agonist Treatment in Overweight and Obesity) Phase 3 program. This is a large-scale, multi-trial effort designed to generate the regulatory data needed for FDA approval. Here's the current landscape:

Trial	Population	NCT Number	Est. N	Status
TRIUMPH-1	Obesity (BMI ≥30 or ≥27 w/ comorbidity)	NCT06203301	~1,800	Enrolling
TRIUMPH-2	Obesity with type 2 diabetes	NCT06203314	~1,000	Enrolling
TRIUMPH-3	Cardiovascular outcomes (CVOT)	NCT06409052	~17,500	Enrolling
TRIUMPH-4	Obesity — efficacy, body composition	NCT06071611	~375	Results reported

TRIUMPH-1 is the pivotal weight loss efficacy trial. This is the trial that will likely serve as the primary basis for an NDA filing. It's a 72-week study comparing retatrutide to placebo in adults with obesity, with co-primary endpoints of percent weight change and proportion achieving ≥5% weight loss.

TRIUMPH-2 focuses on the type 2 diabetes population — both glycemic control and weight loss endpoints. This trial could support a dual indication for both obesity and T2D, similar to the path tirzepatide took (approved as Mounjaro for T2D and Zepbound for obesity).

TRIUMPH-3 is the cardiovascular outcomes trial (CVOT). At an estimated enrollment of 17,500 participants, it's a massive undertaking designed to determine whether retatrutide reduces major adverse cardiovascular events (MACE) — heart attack, stroke, and cardiovascular death. CVOTs take years to complete. This trial alone will likely not be required for initial approval, but it will be critical for label claims and insurance coverage.

TRIUMPH-4 is the first Phase 3 trial to report results, and the data was substantial.

TRIUMPH-4: BODY COMPOSITION DATA

TRIUMPH-4 was a 68-week Phase 3 trial that enrolled approximately 375 adults with obesity. The topline result: participants on retatrutide lost an average of 28.7% of their body weight — exceeding the 24.2% seen in the 48-week Phase 2 data. This confirmed what the Phase 2 curves suggested: the weight loss trajectory hadn't plateaued, and longer treatment produced further reductions.

But the TRIUMPH-4 data went beyond scale weight. A prespecified substudy used DEXA (dual-energy X-ray absorptiometry) to measure body composition — separating fat mass from lean mass. This is the data that matters for understanding whether retatrutide produces "good" weight loss or just weight loss.

Why Body Composition Matters

Not all weight loss is equal. Losing 30% of your body weight is harmful if a large portion of that comes from muscle. Lean mass loss reduces metabolic rate (making regain more likely), weakens bones, impairs functional capacity, and is associated with worse long-term health outcomes — especially in older adults. The ideal anti-obesity therapy produces predominantly fat loss while preserving as much lean tissue as possible.

The TRIUMPH-4 DEXA substudy (presented at a major medical conference and submitted for publication in The Lancet) showed that the majority of weight lost on retatrutide was fat mass. Across the study population, approximately 75-80% of total weight lost was fat, with 20-25% coming from lean mass. This ratio is broadly consistent with what's observed in other GLP-1 receptor agonist trials and with non-pharmacological weight loss.

For context, bariatric surgery typically produces lean mass loss of 20-30% of total weight lost. Caloric restriction alone (without resistance training) often produces lean mass loss of 25-35%. The retatrutide ratio falls within the expected range for significant weight loss.

The clinical interpretation: retatrutide does not appear to disproportionately waste muscle. But at 28.7% total weight loss, even a "normal" lean-to-fat ratio means a meaningful absolute amount of lean tissue is lost. For a 240-lb person losing ~69 lbs, roughly 14-17 lbs of that could be lean mass. This underscores why resistance training and adequate protein intake remain essential during GLP-1 or triple-agonist therapy — the medication drives fat loss, but you have to actively defend your muscle.

Clinical note: The lean mass preservation ratio improves with resistance training. Studies on semaglutide combined with structured exercise show lean mass loss can be reduced to 10-15% of total weight lost. No published data yet exists for retatrutide specifically combined with resistance training, but there's no biological reason the same principle wouldn't apply.

PHASE 2 DOSING PROTOCOL

Retatrutide is administered as a once-weekly subcutaneous injection, similar to semaglutide and tirzepatide. The Phase 2 trial tested multiple dose levels with different titration schedules. Understanding the escalation protocol matters because GI tolerability is heavily influenced by how quickly the dose is increased.

Target Dose	Starting Dose	Escalation	Time to Full Dose
1 mg	0.5 mg	0.5 mg → 1 mg at week 4	4 weeks
4 mg	0.5 mg	Stepwise over 4-8 weeks	4-8 weeks
8 mg	0.5 mg	Stepwise over 8-16 weeks	8-16 weeks
12 mg	0.5 mg	Stepwise over 16-20 weeks	~20 weeks

All groups started at 0.5 mg weekly. The slow titration to the 12 mg target — spanning approximately 20 weeks — was designed to minimize GI side effects by allowing the body to adapt to each new dose level. The Phase 2 data showed that groups with faster escalation schedules had higher rates of nausea and vomiting during the titration period, reinforcing the importance of gradual dose increases.

The final Phase 3 dosing regimen may differ from what was used in Phase 2. Lilly will likely optimize the titration schedule based on the combined safety and efficacy data from all their trials. The approved dosing for tirzepatide, for example, went through similar refinement between Phase 2 and commercial launch.

Injection frequency: Like tirzepatide and semaglutide, retatrutide is dosed once weekly. It's delivered via subcutaneous injection into the abdomen, thigh, or upper arm. The Phase 3 program uses a pre-filled pen device similar to what's currently used for Mounjaro and Zepbound.

SAFETY SUMMARY

The safety profile of retatrutide in Phase 2 was broadly consistent with what's been observed across the incretin drug class. GI side effects were the dominant category, and they were dose-dependent — higher doses and faster titration produced more nausea.

GI Adverse Events by Dose (Phase 2)

Adverse Event	Placebo	1 mg	4 mg	8 mg	12 mg
Nausea	4.9%	6.5%	14.6%	22.2%	25.6%
Diarrhea	7.3%	4.3%	14.6%	17.8%	22.0%
Vomiting	0%	2.2%	4.9%	8.9%	12.2%
Constipation	2.4%	2.2%	7.3%	8.9%	11.0%
Decreased appetite	0%	4.3%	9.8%	15.6%	14.6%

Most GI adverse events were mild to moderate in severity and concentrated during the dose-escalation period. This is consistent with the pattern seen in semaglutide and tirzepatide — the GI effects are worst during titration and typically attenuate once a stable dose is reached.

Discontinuation rates: Across all active dose groups, 2-6% of participants discontinued due to adverse events. This is comparable to or lower than rates observed in the STEP (semaglutide) and SURMOUNT (tirzepatide) programs. The relatively low discontinuation rate despite high GI event rates suggests that most side effects were manageable and transient.

Heart rate: Small increases in resting heart rate (2-4 bpm) were observed, consistent with GLP-1 receptor agonist class effects. No clinically significant arrhythmias or cardiac events were reported.

Hypoglycemia: In the obesity trial (participants without T2D), hypoglycemia was rare and no severe episodes occurred. The glucagon component provides a degree of counter-regulatory protection against blood sugar dropping too low.

Limitations: Phase 2 data reflects 48 weeks of treatment in 338 participants. This is insufficient to detect rare adverse events (incidence <1 in 500) or long-term safety signals. The Phase 3 TRIUMPH program, with thousands of participants over longer durations, will provide a more comprehensive safety picture. Specific concerns that require Phase 3 data include thyroid C-cell effects (preclinical signal common to GLP-1 agonists), pancreatitis risk, gallbladder events, and long-term cardiovascular safety.

WHAT WE'RE STILL WAITING FOR

The Phase 2 and TRIUMPH-4 results are genuinely impressive. But several critical questions remain unanswered, and the data needed to answer them is still being collected:

Pivotal Phase 3 Efficacy Data (TRIUMPH-1 & 2)

TRIUMPH-4 was a smaller trial (~375 participants). TRIUMPH-1 and TRIUMPH-2 are the larger, pivotal trials that will form the core of an NDA submission. Their results — expected in 2026 — will determine the official efficacy claim in the product label. Phase 2 and TRIUMPH-4 results are promising, but the FDA bases approval on pivotal Phase 3 data.

Cardiovascular Outcomes (TRIUMPH-3)

The CVOT enrolling 17,500 participants is designed to answer the single most consequential question in obesity medicine: does this drug prevent heart attacks and strokes? Semaglutide's SELECT trial showed a 20% MACE reduction. If retatrutide matches or exceeds that, it changes the commercial trajectory entirely — insurers are far more willing to cover a drug with proven CV benefit. This trial will likely take several more years to complete.

Long-Term Safety (>2 Years)

All published retatrutide data covers a maximum of 68 weeks of treatment. Obesity is a chronic condition requiring chronic therapy. We need multi-year data to understand the safety profile of sustained triple-receptor agonism — particularly regarding thyroid C-cell effects, bone density (important given lean mass changes), gallbladder disease, and potential interactions between chronic glucagon agonism and hepatic function.

Final Commercial Dosing

Lilly has not yet announced the final dose(s) that will be submitted for approval. Phase 2 tested up to 12 mg. Phase 3 (TRIUMPH-4) reportedly uses doses up to 12 mg. The final label may include a single maintenance dose or multiple options. The approved titration schedule could also differ from what was used in trials.

NDA Filing & Approval Timeline

As of March 2026, Eli Lilly has not filed a New Drug Application for retatrutide. Once TRIUMPH-1 and TRIUMPH-2 data are in, Lilly would need to compile the NDA package, and the FDA review process typically takes 10-12 months from acceptance. Optimistic timeline: NDA filing in late 2026, potential approval in 2027. This could slip depending on Phase 3 results and any regulatory requests for additional data.

Weight Regain After Stopping

No published data exists on what happens when retatrutide is discontinued. Based on the semaglutide STEP 1 extension trial, roughly two-thirds of weight lost was regained within one year of stopping treatment. Similar dynamics likely apply to retatrutide. This doesn't mean the drug failed — it means obesity is a chronic disease that requires ongoing management, similar to hypertension or diabetes.

FREQUENTLY ASKED QUESTIONS

How much weight did people lose on retatrutide in clinical trials?

In the Phase 2 trial (Jastreboff et al., NEJM 2023), participants on the highest dose (12 mg) lost an average of 24.2% of their body weight over 48 weeks. Lower doses also produced significant weight loss: 8 mg lost 22.8%, 4 mg lost 17.1%, and 1 mg lost 8.7%, compared to 2.1% in the placebo group. Phase 3 TRIUMPH-4 results showed even greater weight loss — 28.7% over 68 weeks.

What is the TRIUMPH program for retatrutide?

TRIUMPH is Eli Lilly's Phase 3 clinical trial program for retatrutide. It includes multiple trials: TRIUMPH-1 (obesity, ~1,800 participants), TRIUMPH-2 (obesity with type 2 diabetes), TRIUMPH-3 (cardiovascular outcomes, ~17,500 participants), and TRIUMPH-4 (which reported 28.7% weight loss at 68 weeks with DEXA body composition data). These trials are testing retatrutide across different patient populations and measuring weight loss, metabolic improvements, and cardiovascular outcomes.

Is retatrutide FDA-approved?

No. As of March 2026, retatrutide is not FDA-approved. It remains an investigational drug in Phase 3 clinical trials under Eli Lilly's TRIUMPH program. Lilly has not yet filed a New Drug Application (NDA) with the FDA. Based on current trial timelines, the earliest possible approval would likely be late 2026 or 2027, depending on when Lilly submits their application and how long the FDA review takes.

How does retatrutide compare to semaglutide and tirzepatide in trials?

No direct head-to-head trials have been conducted, so any comparison is indirect. In their respective trials, semaglutide 2.4 mg (Wegovy) achieved approximately 14.9% weight loss at 68 weeks (STEP 1), tirzepatide 15 mg (Zepbound) achieved up to 22.5% at 72 weeks (SURMOUNT-1), and retatrutide 12 mg achieved 24.2% at just 48 weeks (Phase 2) and 28.7% at 68 weeks (TRIUMPH-4). Retatrutide's triple-agonist mechanism (GIP + GLP-1 + glucagon) may account for the larger magnitude, but cross-trial comparisons have limitations due to differences in study populations, protocols, and baseline characteristics.

What were the side effects in the retatrutide trials?

The most common side effects were gastrointestinal: nausea (up to 25.6% at the 12 mg dose), diarrhea (up to 22.0%), vomiting (up to 12.2%), and constipation (up to 11.0%). Most GI effects were mild to moderate and concentrated during the dose-escalation period. Discontinuation rates due to adverse events ranged from 2-6% across dose groups — comparable to or lower than rates seen in tirzepatide and semaglutide trials. Decreased appetite, small heart rate increases (2-4 bpm), and injection site reactions were also reported.

REFERENCES

Jastreboff AM, Kaplan LM, Frias JP, et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972. ClinicalTrials.gov: NCT04881706.
Rosenstock J, Frias JP, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-comparator controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023;402(10401):529-544. doi:10.1016/S0140-6736(23)01053-X. ClinicalTrials.gov: NCT04867785.
Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2 trial. Nat Med. 2024;30(7):2037-2048. doi:10.1038/s41591-024-03018-2.
Eli Lilly and Company. TRIUMPH-4 Phase 3 results (retatrutide for obesity — body weight and body composition). Presented 2025. ClinicalTrials.gov: NCT06071611.
Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183.
Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387(4):327-340. doi:10.1056/NEJMoa2206038.
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563.
Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide (STEP 1 extension). Diabetes Obes Metab. 2022;24(8):1553-1564. doi:10.1111/dom.14725.
ClinicalTrials.gov listings: TRIUMPH-1 (NCT06203301), TRIUMPH-2 (NCT06203314), TRIUMPH-3 (NCT06409052), TRIUMPH-4 (NCT06071611).