Retatrutide is an investigational drug that has completed a phase 2 trial, while tirzepatide is an approved medicine sold under the brand names Mounjaro and Zepbound. At Longevity Benchmark, we review the published clinical evidence on retatrutide vs tirzepatide to examine what trials have evaluated and what remains unstudied. The two molecules have never been evaluated head to head in a published clinical trial.

Tirzepatide is approved for chronic weight management and for type 2 diabetes, and the phase 3 SURMOUNT-1 trial enrolled 2,539 adults. Retatrutide has published data from a single 338-person phase 2 dose-finding study and has no approved commercial product, which makes the stage of clinical development the central distinction between them.

The Verdict

Published clinical data establishes that tirzepatide is an approved dual GIP and GLP-1 receptor agonist evaluated in large phase 3 trials, whereas retatrutide is an investigational triple agonist whose published clinical evidence is limited to a 338-person phase 2 trial. Retatrutide has no approved commercial product, no confirmed prescription dosing protocol, and no published head-to-head comparison against tirzepatide. While participants on the highest evaluated dose of 12 mg in the 48-week retatrutide phase 2 trial achieved a mean weight change of -24.2%, confirmatory phase 3 efficacy and long-term cardiovascular safety data have not been published. Tirzepatide has documented outcomes in the 2,539-person SURMOUNT-1 trial, but no published cardiovascular outcomes trial for it is available to cite here. Clinical decisions regarding incretin therapy belong to the reader and their licensed prescriber.

Retatrutide vs Tirzepatide, Side by Side

CriterionRetatrutideTirzepatide
Receptor targets Agonist of GIP, GLP-1, and glucagon receptors Dual agonist of GIP and GLP-1 receptors
Development stage Investigational compound with published phase 2 data Approved prescription medicine
Approved US products None Mounjaro (type 2 diabetes) and Zepbound (chronic weight management)
Largest published trial and phase Phase 2 trial (NEJM 2023) SURMOUNT-1 phase 3 trial (NEJM 2022)
Trial cohort size 338 adults in phase 2 trial 2,539 adults in SURMOUNT-1 trial
Longest published follow-up 48 weeks in phase 2 trial 72 weeks in SURMOUNT-1 trial
Headline weight result -24.2% mean weight change at 48 weeks with 12 mg versus -2.1% placebo in phase 2 -20.9% mean weight change at 72 weeks with 15 mg versus -3.1% placebo in SURMOUNT-1
Published head-to-head against the other No published head-to-head trial against tirzepatide No published head-to-head trial against retatrutide
Cardiovascular outcomes evidence No published cardiovascular outcomes trial No equivalent published cardiovascular outcomes trial has been published

One Is Approved and One Is Not

Retatrutide is an investigational drug that has completed a phase 2 trial and is not an approved medicine, while tirzepatide is approved and sold in the United States as Mounjaro for type 2 diabetes and Zepbound for chronic weight management. Both injectable formulations of tirzepatide are administered once weekly by subcutaneous injection.

Retatrutide has no approved product. Anything supplied outside an authorized clinical trial is not an approved medicine, and its contents are not something anyone can verify.

The approved United States prescribing information for Mounjaro and Zepbound carries a boxed warning about thyroid C-cell tumours observed in rodents. Cost, insurance coverage, and reimbursement rules are outside what this page can verify. Specific prescribing terms and contraindications can be checked directly in the official prescribing information for each approved product.

Three Receptors Versus Two

Retatrutide acts as an agonist across three separate endocrine receptors, whereas tirzepatide acts across two. Retatrutide (development code LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors, with Eli Lilly serving as the sponsor.

Tirzepatide is a dual GIP and GLP-1 receptor agonist manufactured by Eli Lilly.

For broader context within incretin research, semaglutide is a single GLP-1 receptor agonist manufactured by Novo Nordisk. Semaglutide is sold in the United States as Ozempic for type 2 diabetes, Wegovy for chronic weight management, and Rybelsus as an oral tablet for type 2 diabetes. We examine related metabolic pathways in our articles on GLP-1 and the brain and fasting insulin.

What the Retatrutide Phase 2 Trial Found

Efficacy data for retatrutide comes from a 48-week phase 2 trial. In the double-blind, randomised, placebo-controlled retatrutide phase 2 trial (clinical trial registry NCT04881760), researchers enrolled 338 adults with a body mass index (BMI) of 30 or greater, or a BMI of 27 to under 30 plus at least one weight-related condition. In that trial, 51.8% of the participants were men. Participants received once-weekly subcutaneous injections of retatrutide or placebo, with percent body-weight change at 24 weeks designated as the primary end point. Eli Lilly funded the trial.

In the retatrutide phase 2 trial, mean weight change at 24 weeks was -7.2% in the 1 mg group, -12.9% in the combined 4 mg group, -17.3% in the combined 8 mg group, and -17.5% in the 12 mg group, compared to -1.6% in the placebo group.

At 48 weeks in the retatrutide phase 2 trial, mean weight change reached -8.7% with 1 mg, -17.1% with the combined 4 mg dose, -22.8% with the combined 8 mg dose, and -24.2% with 12 mg, compared to -2.1% with placebo. A phase 2 trial serves to evaluate preliminary efficacy and select doses for future study, which differs from a confirmatory trial.

  • 4 mg dose arm. In the combined 4 mg cohort of the retatrutide phase 2 trial, 92% of participants reached 5% or more weight loss, 75% reached 10% or more, and 60% reached 15% or more at 48 weeks.
  • 8 mg dose arm. In the combined 8 mg cohort of the retatrutide phase 2 trial, 100% of participants reached 5% or more weight loss, 91% reached 10% or more, and 75% reached 15% or more at 48 weeks.
  • 12 mg dose arm. In the 12 mg cohort of the retatrutide phase 2 trial, 100% of participants reached 5% or more weight loss, 93% reached 10% or more, and 83% reached 15% or more at 48 weeks.
  • Placebo cohort. In the placebo group of the retatrutide phase 2 trial, 27% reached 5% or more weight loss, 9% reached 10% or more, and 2% reached 15% or more at 48 weeks.

What the Tirzepatide Phase 3 Trial Found

Confirmatory clinical data for tirzepatide in weight management comes from the phase 3 SURMOUNT-1 study. In the 72-week, double-blind SURMOUNT-1 trial, 2,539 adults with a BMI of 30 or greater, or 27 or greater with a weight-related complication, were randomised to receive once-weekly subcutaneous tirzepatide or placebo. Diabetes was an exclusion criterion in the SURMOUNT-1 trial. Mean baseline weight was 104.8 kg and mean baseline BMI was 38.0. Eli Lilly funded the trial.

In the SURMOUNT-1 trial, mean weight change at 72 weeks was -15.0% with tirzepatide 5 mg, -19.5% with 10 mg, and -20.9% with 15 mg, compared to -3.1% in the placebo group. The proportion of participants achieving at least 5% weight loss in the SURMOUNT-1 trial was 85% on 5 mg, 89% on 10 mg, and 91% on 15 mg, versus 35% on placebo. Reductions of 20% or more were achieved by 50% in the 10 mg group and 57% in the 15 mg group, compared to 3% on placebo.

In the SURMOUNT-1 trial, adverse events led to treatment discontinuation in 4.3% of the 5 mg group, 7.1% of the 10 mg group, and 6.2% of the 15 mg group, versus 2.6% in the placebo group. A 2,539-person phase 3 study conducted over 72 weeks provides a larger clinical dataset than a 338-person phase 2 trial conducted over 48 weeks. Related clinical metrics are explored in our review of visceral fat.

The Comparison Between Retatrutide vs Tirzepatide Has Never Been Run

No clinical trial has directly compared retatrutide against tirzepatide in the same study population. Any assessment comparing the two compounds relies on observations drawn from separate trials that enrolled different populations, used different study durations, and evaluated different clinical endpoints.

Tirzepatide has been evaluated against semaglutide in dedicated head-to-head trials. In the 72-week, open-label, phase 3b SURMOUNT-5 trial, 751 adults with obesity without type 2 diabetes were randomised to receive the maximum tolerated dose of tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg). In the SURMOUNT-5 trial, least-squares mean weight change was -20.2% (95% CI -21.4 to -19.1) with tirzepatide versus -13.7% (95% CI -14.9 to -12.6) with semaglutide (P<0.001). Waist circumference reduction in SURMOUNT-5 was -18.4 cm with tirzepatide compared to -13.0 cm with semaglutide (P<0.001). Eli Lilly funded the SURMOUNT-5 trial.

In the 40-week, open-label SURPASS-2 trial of 1,879 patients with type 2 diabetes, mean baseline HbA1c was 8.28%, mean age was 56.6 years, and mean weight was 93.7 kg. Tirzepatide doses of 5, 10, and 15 mg produced HbA1c reductions of -2.01, -2.24, and -2.30 percentage points, compared to -1.86 with semaglutide 1 mg. In SURPASS-2, differences versus semaglutide were -0.15 percentage points (95% CI -0.28 to -0.03, P=0.02) for 5 mg, -0.39 (95% CI -0.51 to -0.26, P<0.001) for 10 mg, and -0.45 (95% CI -0.57 to -0.32, P<0.001) for 15 mg. Body weight differences in SURPASS-2 favoured tirzepatide by -1.9 kg, -3.6 kg, and -5.5 kg (P<0.001 for all). Eli Lilly funded SURPASS-2. No equivalent comparative trial exists for retatrutide. For more on glycaemic testing, see our guide comparing A1c vs fasting glucose.

Reported Adverse Events and Safety Observations

Gastrointestinal adverse events were the most common side effects reported across trials for both drugs. Across these studies, gastrointestinal complaints were mostly mild to moderate in severity and occurred primarily during dose escalation.

In the 338-person retatrutide phase 2 trial, gastrointestinal events were dose-related, mostly mild to moderate, and partially mitigated by initiating therapy at a 2 mg rather than a 4 mg starting dose. The retatrutide phase 2 trial also documented dose-dependent heart rate increases that peaked at 24 weeks and declined thereafter.

In the SURPASS-2 trial comparing tirzepatide with semaglutide, nausea was reported in 17 to 22% of tirzepatide patients across doses and 18% of semaglutide patients. Diarrhea occurred in 13 to 16% on tirzepatide and 12% on semaglutide. Vomiting was reported in 6 to 10% on tirzepatide and 8% on semaglutide. Hypoglycemia with blood glucose below 54 mg/dL occurred in 0.6% on 5 mg, 0.2% on 10 mg, and 1.7% on 15 mg of tirzepatide, compared to 0.4% on semaglutide. Serious adverse events were recorded in 5 to 7% of tirzepatide patients and 3% of semaglutide patients in SURPASS-2.

For additional comparison, in the 68-week STEP 1 trial of semaglutide 2.4 mg in 1,961 adults without diabetes, 4.5% of semaglutide participants discontinued treatment due to gastrointestinal events versus 0.8% on placebo. Novo Nordisk funded STEP 1. In SURMOUNT-1, adverse events led to discontinuation in 4.3%, 7.1%, and 6.2% of participants across the 5 mg, 10 mg, and 15 mg tirzepatide arms, compared to 2.6% in the placebo group. Dietary considerations during treatment are outlined in our guide on nutrient dense foods on GLP-1.

Cardiovascular Evidence and Long-Term Unknowns

Retatrutide has no published cardiovascular outcomes trial. The 338-person phase 2 trial evaluated safety over 48 weeks and was not sized or designed to evaluate cardiovascular outcomes or low-incidence adverse events.

No equivalent published cardiovascular outcomes trial for tirzepatide is available to cite here. Consequently, long-term cardiovascular safety comparisons cannot be made between the two compounds on equal terms.

By comparison, cardiovascular outcomes for semaglutide 2.4 mg were evaluated in the SELECT trial. In the SELECT trial, 17,604 patients aged 45 years or older with preexisting cardiovascular disease and a BMI of 27 or greater without diabetes were followed for a mean of 39.8 months. The primary cardiovascular end point occurred in 6.5% of semaglutide participants versus 8.0% of placebo participants, reflecting a hazard ratio of 0.80 (95% CI 0.72 to 0.90, P<0.001). Adverse events leading to permanent discontinuation in the SELECT trial occurred in 16.6% of semaglutide patients compared to 8.2% of placebo patients (P<0.001). Novo Nordisk funded the SELECT trial.

Until large-scale confirmatory trials are published, the long-term safety profile and clinical outcomes of retatrutide remain unestablished. Exercise interactions with metabolic health can be explored in our breakdown of Zone 2 vs HIIT.

What Would Change the Retatrutide vs Tirzepatide Evidence

The comparison between retatrutide and tirzepatide would change if a completed confirmatory trial evaluates retatrutide in a larger population, if a head-to-head trial against tirzepatide is published, or if an approved commercial product becomes available through regulatory review.

Currently, tirzepatide is approved and sold as Mounjaro and Zepbound, and the phase 3 SURMOUNT-1 trial enrolled 2,539 adults. Retatrutide remains an investigational molecule whose published clinical data is limited to a single 338-person phase 2 dose-finding trial.

Neither drug represents an automatic choice over the other across all clinical contexts. Clinical decisions regarding prescription incretin therapy belong to the reader and their licensed prescriber. Related background is in our review of insulin resistance and weight loss.

Frequently Asked Questions

Is retatrutide approved?

Retatrutide is not an approved medicine. It is an investigational compound that has completed a 48-week phase 2 clinical trial sponsored by Eli Lilly. Retatrutide has no approved product. Anything distributed or sold as retatrutide outside an authorized clinical trial is not an approved medicine and its composition cannot be verified. By contrast, tirzepatide is an approved drug sold in the United States under the brand names Mounjaro for type 2 diabetes and Zepbound for chronic weight management.

Is retatrutide stronger than tirzepatide?

The available evidence cannot confirm whether retatrutide is more effective than tirzepatide because the two molecules have never been tested against each other. In the 338-person retatrutide phase 2 trial, participants on the 12 mg weekly dose achieved a mean weight reduction of -24.2% at 48 weeks, compared to -2.1% on placebo. In the 2,539-person SURMOUNT-1 phase 3 trial, tirzepatide 15 mg weekly achieved a mean weight change of -20.9% at 72 weeks, versus -3.1% on placebo. Cross-trial comparisons between a 48-week phase 2 study and a 72-week phase 3 trial do not establish clinical superiority.

Has retatrutide been compared to tirzepatide in a trial?

No head-to-head trial comparing retatrutide directly to tirzepatide has been published. Tirzepatide has been evaluated in head-to-head trials against semaglutide. In the 72-week SURMOUNT-5 trial of 751 adults with obesity, tirzepatide demonstrated a -20.2% weight reduction compared to -13.7% with semaglutide (P<0.001). In the 40-week SURPASS-2 trial of 1,879 patients with type 2 diabetes, tirzepatide reduced HbA1c and body weight significantly more than semaglutide 1 mg. However, no trial has directly tested retatrutide alongside tirzepatide in the same participant cohort.

What is the difference between a triple agonist and a dual agonist?

The difference lies in the number of receptor pathways targeted by the molecule. Retatrutide is a triple agonist targeting the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. Tirzepatide is a dual agonist targeting only the GIP and GLP-1 receptors. Both compounds were developed by Eli Lilly. In contrast, semaglutide is a single agonist targeting only the GLP-1 receptor. These receptor definitions represent the specific pharmacological targets documented in published trial protocols.

What side effects did the retatrutide trial report?

In the 338-person retatrutide phase 2 trial, the most common adverse events with retatrutide were gastrointestinal. Symptoms were dose-related, mostly mild to moderate in severity, and partially mitigated when participants initiated therapy at a 2 mg starting dose rather than a 4 mg dose. The trial also reported dose-dependent increases in heart rate that peaked at 24 weeks and declined thereafter. These observations come from a 48-week dose-finding trial; broader safety data in larger populations have not been published.

Why does a phase 2 result not settle the comparison?

A phase 2 clinical trial is an exploratory, dose-finding study conducted in a relatively small group of participants. The retatrutide phase 2 trial enrolled 338 adults and evaluated outcomes over 48 weeks. Phase 3 trials, such as the 2,539-person SURMOUNT-1 study for tirzepatide, are larger confirmatory trials designed to demonstrate efficacy and safety over longer periods. Phase 2 trials do not establish long-term safety, low-frequency adverse events, or cardiovascular outcomes. Without published phase 3 confirmatory results, clinical comparability remains unproven.

When will retatrutide be available?

There is no confirmed date for when retatrutide might become available as an approved medicine. Retatrutide has no approved product, and no approval or availability date is something this page can state. Retatrutide has no approved commercial product, and anything offered outside an authorized clinical trial is not an approved medicine. Anything supplied outside an authorised clinical trial is not an approved medicine.

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