Retatrutide Results: Weight Loss Data from Clinical Trials

Overview

Retatrutide produced the highest weight loss ever reported in a randomized phase 2 anti-obesity clinical trial. At the 12 mg maintenance dose over 48 weeks, participants lost a mean of 24.2% of their body weight, with over 90% achieving at least 10% weight loss. These phase 2 results from Jastreboff et al. (NEJM 2023) have generated significant interest, though phase 3 confirmation from the TRIUMPH trial program is still underway. This article presents the clinical trial data in detail, including dose-specific outcomes, metabolic benefits beyond weight, and how retatrutide results compare to other anti-obesity medications.

Phase 2 Trial Overview

The pivotal phase 2 trial of retatrutide for obesity, published by Jastreboff et al. in the New England Journal of Medicine in 2023, enrolled 338 adults with obesity (BMI of 30 or greater) or overweight (BMI of 27 or greater) with at least one weight-related comorbidity. Participants were randomized to receive either placebo or retatrutide at escalating doses titrated to maintenance levels of 1 mg, 4 mg, 8 mg, or 12 mg per week. The treatment period was 48 weeks, with retatrutide administered as a once-weekly subcutaneous injection. Dosing followed a gradual titration schedule to minimize gastrointestinal side effects, with participants reaching their target maintenance dose over approximately 16 to 24 weeks depending on the dose group. The primary endpoint was percentage change in body weight from baseline to week 48.

Weight Loss by Dose Group

Retatrutide demonstrated a clear dose-response relationship for weight loss across all groups. The 1 mg maintenance dose produced approximately 8.7% mean body weight loss at 48 weeks. The 4 mg dose group achieved approximately 17.5% mean weight loss. At 8 mg, participants lost approximately 22.8% of their body weight, and the 12 mg group — the highest dose tested — achieved approximately 24.2% mean body weight loss. For comparison, the placebo group lost approximately 2.1% of body weight over the same period. All active dose groups showed statistically significant weight loss compared to placebo. The 12 mg result of 24.2% represented the highest mean weight loss ever reported for any anti-obesity medication in a randomized clinical trial at the time of publication.

• Placebo: ~2.1% mean body weight loss
• 1 mg maintenance dose: ~8.7% mean body weight loss
• 4 mg maintenance dose: ~17.5% mean body weight loss
• 8 mg maintenance dose: ~22.8% mean body weight loss
• 12 mg maintenance dose: ~24.2% mean body weight loss
• All active dose groups achieved statistically significant weight loss vs placebo

Milestone Achievement Rates

Beyond mean weight loss, the proportion of participants reaching clinically meaningful weight loss thresholds provides additional perspective on the consistency of retatrutide results. In the 12 mg group, more than 90% of participants achieved at least 10% body weight loss — a threshold widely considered clinically significant for improving obesity-related health outcomes. Approximately 75% of participants in the 12 mg group achieved at least 15% weight loss, and roughly 63% achieved at least 20% weight loss. The 20% threshold is considered transformative for the treatment of obesity, as it approaches the level of weight reduction typically seen only with bariatric surgery. Even the 4 mg dose group showed strong responder rates, with approximately 70% of participants achieving at least 10% weight loss.

• 12 mg dose: >90% achieved at least 10% weight loss
• 12 mg dose: ~75% achieved at least 15% weight loss
• 12 mg dose: ~63% achieved at least 20% weight loss
• 4 mg dose: ~70% achieved at least 10% weight loss
• The 20% threshold is considered transformative, approaching bariatric surgery-level outcomes

Weight Loss Trajectory Over Time

An important finding from the phase 2 trial was the trajectory of weight loss over the 48-week treatment period. Weight loss was progressive throughout the study, and notably, the weight loss curves had not plateaued in most dose groups by week 48. This suggests that continued weight loss may have occurred with longer treatment duration — a question that the phase 3 TRIUMPH trials, with their longer treatment periods of 52 to 72 weeks, are designed to address. The steepest rate of weight loss was observed between approximately weeks 12 and 36, after dose titration was complete and participants had reached their full maintenance dose. During the initial titration phase, weight loss occurred more gradually, which is expected given the lower doses used during escalation. The absence of a clear plateau at 48 weeks distinguishes retatrutide from some other anti-obesity medications where weight loss tends to level off earlier in treatment.

Metabolic Improvements Beyond Weight

Retatrutide demonstrated benefits beyond weight loss across several metabolic parameters. In a separate phase 2 trial focused on type 2 diabetes (Rosenstock et al., Lancet 2023), participants receiving retatrutide at the 12 mg dose achieved a mean HbA1c reduction of approximately 1.3%, compared to 0.4% in the placebo group. In a subanalysis of participants with metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), retatrutide produced liver fat reductions of up to 81% — a result attributed in part to the glucagon receptor agonism component of the drug. Across dose groups in the obesity trial, improvements were also observed in blood pressure, triglyceride levels, and waist circumference, consistent with the metabolic benefits typically seen with substantial weight loss.

• HbA1c reduction: -1.3% at 12 mg vs -0.4% placebo in the type 2 diabetes trial
• Liver fat reduction: Up to 81% in the MASLD subanalysis
• Blood pressure improvements observed across dose groups
• Triglyceride level reductions across dose groups
• Waist circumference reduction across dose groups

How Retatrutide Results Compare

While direct comparison across different clinical trials has inherent limitations due to differences in study populations, trial design, and treatment duration, placing retatrutide results alongside other anti-obesity medications provides useful context. Semaglutide 2.4 mg (Wegovy), evaluated in the STEP 1 trial (Wilding et al., NEJM 2021), produced approximately 14.9% mean body weight loss at 68 weeks. Tirzepatide at its highest dose of 15 mg, evaluated in the SURMOUNT-1 trial (Jastreboff et al., NEJM 2022), achieved approximately 22.5% mean body weight loss at 72 weeks. Retatrutide at 12 mg produced approximately 24.2% mean body weight loss at 48 weeks — a shorter treatment period than either comparator trial.

• Semaglutide 2.4 mg (STEP 1): ~14.9% weight loss at 68 weeks
• Tirzepatide 15 mg (SURMOUNT-1): ~22.5% weight loss at 72 weeks
• Retatrutide 12 mg (Phase 2): ~24.2% weight loss at 48 weeks
• Important caveat: Different trial populations, durations, and designs make direct comparison unreliable
• Head-to-head trials would be needed for definitive efficacy comparisons

What Phase 3 May Show

The TRIUMPH phase 3 trial program is enrolling larger, more diverse patient populations than the phase 2 study, which will provide a more robust assessment of retatrutide's efficacy and safety profile. Phase 3 results may differ from phase 2 for several reasons. Broader enrollment criteria typically include participants who may be harder to treat or less likely to adhere strictly to the protocol, which can modestly reduce average outcomes compared to earlier-stage trials. The longer treatment periods in TRIUMPH (52 to 72 weeks) will help answer the critical question of whether weight loss continues beyond 48 weeks or reaches a plateau. Real-world outcomes, once a drug is approved and prescribed outside of clinical trial settings, often differ from controlled trial results due to variations in patient adherence, comorbidities, and concomitant medications. Phase 3 data will also provide a clearer picture of rare side effects that may not emerge in smaller phase 2 studies.

• TRIUMPH trials are enrolling larger, more diverse populations
• Broader enrollment criteria may modestly affect average outcomes
• Longer treatment periods (52-72 weeks) will clarify plateau behavior
• Real-world results often differ from controlled trial settings
• Larger sample sizes will better characterize rare side effects

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References

1. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial (2023) — PubMed
2. 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 (2023) — PubMed
3. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1) (2022) — PubMed
4. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1) (2021) — PubMed
5. Retatrutide Phase 2 Trial Results: Efficacy on Liver Fat Reduction in Participants with MASLD (2024) — PubMed