Retatrutide phase 2 NEJM data has positioned this investigational triple agonist as one of the most closely watched developments in obesity pharmacotherapy. Published in the New England Journal of Medicine in June 2023, the 48-week phase 2 trial by Jastreboff et al. evaluated retatrutide — a once-weekly injectable agent targeting GLP-1, GIP, and glucagon receptors simultaneously — across multiple doses in adults with obesity or overweight without type 2 diabetes. The results, particularly at higher doses, attracted widespread scientific attention. This article explains how retatrutide works, summarises the key trial findings, reviews its safety profile, and contextualises what these early data mean for future obesity treatment in the UK.

What Is Retatrutide and How Does It Work?

Retatrutide is an investigational once-weekly triple agonist that simultaneously activates GLP-1, GIP, and glucagon receptors, distinguishing it from approved agents such as semaglutide and tirzepatide. It has not received MHRA authorisation and remains unavailable in the UK.

Retatrutide is an investigational once-weekly injectable medicine being developed by Eli Lilly for the treatment of obesity and overweight. It belongs to a novel class of agents known as triple agonists, meaning it simultaneously activates three distinct hormone receptors: the glucagon-like peptide-1 (GLP-1) receptor, the glucose-dependent insulinotropic polypeptide (GIP) receptor, and the glucagon receptor. This triple mechanism of action distinguishes retatrutide from currently approved medicines such as semaglutide (a GLP-1 receptor agonist) and tirzepatide (a dual GIP/GLP-1 receptor agonist).

The GLP-1 component promotes insulin secretion, reduces appetite, and slows gastric emptying, helping patients feel fuller for longer. The GIP component is thought to enhance the metabolic effects of GLP-1 and may also contribute to improved fat metabolism. The glucagon receptor component is hypothesised — based largely on preclinical and early clinical observations — to increase energy expenditure and promote fat breakdown (lipolysis), which may offer additional metabolic benefits. However, glucagon receptor agonism also increases hepatic glucose output and resting heart rate, effects that will require careful monitoring in ongoing and future trials. Whether the triple agonist mechanism translates into meaningfully greater clinical benefit over dual agonists in humans has not yet been established in head-to-head trials.

As of the time of writing, retatrutide has not received marketing authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) and it remains under clinical investigation. It is not currently available on the NHS or through private prescription in the UK. Its development represents a significant area of interest in obesity pharmacotherapy, particularly given the limitations of existing treatments in achieving sustained, substantial weight reduction in all patient groups.

Key reference: Jastreboff AM et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514–526.

Overview of the Phase 2 NEJM Trial Design and Participants

The phase 2 trial was a randomised, double-blind, placebo-controlled, dose-ranging study enrolling 338 adults with obesity or overweight without type 2 diabetes, assessing retatrutide doses of 1 mg, 4 mg, 8 mg, and 12 mg over 48 weeks.

A phase 2, randomised, double-blind, placebo-controlled, dose-ranging study evaluating retatrutide was published in the New England Journal of Medicine (NEJM) in June 2023 (Jastreboff et al.; NCT04881760 on ClinicalTrials.gov). This study was designed to assess the efficacy and safety of retatrutide across a range of doses over a 48-week treatment period, with a subsequent follow-up phase.

The study enrolled 338 adult participants who met specific eligibility criteria. Participants were required to have a body mass index (BMI) of 27 kg/m² or greater with at least one weight-related comorbidity, or a BMI of 30 kg/m² or greater without comorbidities. Individuals with type 2 diabetes were excluded from this particular trial, meaning the results reflect outcomes in adults with obesity or overweight but without diabetes. Participants were randomly assigned to receive one of several doses of subcutaneous retatrutide — 1 mg, 4 mg, 8 mg, or 12 mg — or placebo, administered once weekly.

The trial incorporated a dose-escalation schedule, meaning participants were gradually titrated up to their target dose over a number of weeks to improve tolerability. For the higher doses (8 mg and 12 mg), additional slower titration cohorts were included to further characterise tolerability. All participants also received lifestyle counselling as part of the study protocol, which is consistent with standard clinical practice in obesity management. The primary endpoint was the percentage change in body weight from baseline to week 48, with secondary endpoints including the proportion of participants achieving clinically meaningful weight loss thresholds and changes in cardiometabolic risk markers.

As a phase 2 dose-ranging study, this trial was not designed to provide the definitive efficacy evidence required for regulatory submission; that is the purpose of the ongoing phase 3 programme.

Weight Loss Results at 48 Weeks: Key Percentage Findings

At 48 weeks, the 12 mg retatrutide dose produced a mean body weight reduction of approximately 24.2%, compared with approximately 2.1% in the placebo group, with weight loss still ongoing at trial end.

The weight loss results reported at 48 weeks attracted considerable attention from the medical and scientific community. Participants receiving the highest doses of retatrutide achieved substantial reductions in body weight compared with those receiving placebo.

Key findings from the trial (Jastreboff et al., NEJM 2023) included:

• Placebo group: Mean body weight reduction of approximately 2.1% from baseline at 48 weeks.

• 1 mg dose group: Mean weight reduction of approximately 8.7%.

• 4 mg dose group: Mean weight reduction of approximately 17.3%.

• 8 mg dose group: Mean weight reduction of approximately 22.8%.

• 12 mg dose group: Mean weight reduction of approximately 24.2% — the highest recorded in the trial.

These figures represent least-squares mean percentage changes from baseline body weight, and the results in the higher-dose groups were statistically significant compared with placebo. In the 12 mg group, a substantial proportion of participants achieved weight loss of 15% or more, and many exceeded 20% — thresholds considered clinically meaningful in obesity medicine. Notably, weight loss appeared to be ongoing and had not plateaued at week 48 in the higher-dose groups, suggesting that longer treatment durations might yield further reductions.

It is important to contextualise these findings appropriately. Phase 2 trials are primarily designed to assess dose-response relationships and safety signals rather than to definitively establish efficacy at a population level. Sample sizes are smaller than those used in phase 3 trials, and results may not fully reflect outcomes in more diverse, real-world populations. Nonetheless, the magnitude of weight loss observed — particularly at the 8 mg and 12 mg doses — was described by the investigators as among the most substantial reported in a pharmacological obesity trial to date.

Reference: Jastreboff AM et al. N Engl J Med. 2023;389(6):514–526.

Safety Profile and Side Effects Reported in the Trial

The most common adverse effects were gastrointestinal — particularly nausea, vomiting, and diarrhoea — occurring most frequently during dose escalation and generally mild to moderate in severity.

As with other incretin-based therapies, the most commonly reported adverse effects in the retatrutide phase 2 trial were gastrointestinal in nature. These were generally consistent with the known side-effect profile of GLP-1 receptor agonists and were most frequently observed during the dose-escalation phase.

Commonly reported side effects included:

• Nausea — the most frequently reported adverse event across all active dose groups; reported in approximately 40–60% of participants in higher-dose groups

• Vomiting — reported in approximately 20–30% of participants at higher doses

• Diarrhoea

• Constipation

• Decreased appetite (which, whilst contributing to weight loss, can also be uncomfortable)

The majority of gastrointestinal events were mild to moderate in severity and tended to diminish over time as participants adjusted to the medication. Discontinuation rates due to adverse events were higher in the active treatment groups compared with placebo, particularly at higher doses, though the overall discontinuation rate remained relatively modest.

Gallbladder-related events, including cholelithiasis (gallstones) and cholecystitis, were reported in a small number of participants receiving active treatment — a finding consistent with the known class effect of GLP-1 receptor agonists. A modest increase in resting heart rate was also observed in some participants receiving higher doses, which is an anticipated effect of glucagon receptor agonism and warrants ongoing monitoring in future trials. No cases of pancreatitis or thyroid malignancy were reported during the trial period, though these remain areas of ongoing surveillance given their association with this drug class.

Patients should seek urgent medical attention if they experience severe or persistent abdominal pain, which may be a symptom of pancreatitis or gallbladder disease. Maintaining adequate hydration is important during episodes of significant nausea, vomiting, or diarrhoea.

As this is a phase 2 trial, the full long-term safety profile of retatrutide has not yet been established. Phase 3 trials with larger populations and longer follow-up periods will be essential to characterise the safety profile more comprehensively. Once retatrutide is licensed, suspected side effects should be reported via the MHRA Yellow Card scheme at yellowcard.mhra.gov.uk.

References: Jastreboff AM et al. N Engl J Med. 2023;389(6):514–526; MHRA/EMC SmPC: Wegovy (semaglutide 2.4 mg); MHRA/EMC SmPC: Mounjaro (tirzepatide).

How These Results Compare to Other Weight Loss Medicines

Retatrutide's 24.2% mean weight loss at 48 weeks exceeds phase 3 data for semaglutide 2.4 mg (~14.9% at 68 weeks) and is comparable to tirzepatide 15 mg (~22.5% at 72 weeks), though no direct head-to-head trials have been conducted.

To appreciate the significance of the retatrutide phase 2 findings, it is helpful to compare them with the efficacy data for currently approved weight management medicines in the UK.

Orlistat (Xenical®/Alli®), a lipase inhibitor available on the NHS, typically produces mean weight loss of around 3–5% compared with placebo over 12 months, making it a modest option for many patients.

Liraglutide 3 mg (Saxenda®), a once-daily GLP-1 receptor agonist licensed by the MHRA for weight management, produces mean weight loss of approximately 5–8% compared with placebo over 56 weeks in clinical trials and remains available in the UK.

Semaglutide 2.4 mg (Wegovy®), a once-weekly GLP-1 receptor agonist licensed by the MHRA and recommended by NICE (Technology Appraisal TA875) for use in specific circumstances, demonstrated mean weight loss of approximately 14.9% from baseline at 68 weeks in the STEP 1 phase 3 trial (Wilding JPH et al., N Engl J Med. 2021;384:989–1002) — a landmark result at the time of its publication.

Tirzepatide (Mounjaro®), the dual GIP/GLP-1 receptor agonist, is licensed by the MHRA for the treatment of type 2 diabetes. A separate weight-management indication is subject to ongoing MHRA and NICE appraisal processes as of the time of writing. In the SURMOUNT-1 phase 3 trial (Jastreboff AM et al., N Engl J Med. 2022;387:205–216), tirzepatide achieved mean weight loss of up to approximately 22.5% at the highest dose (15 mg) at 72 weeks in adults with obesity without diabetes — results considered exceptional.

The retatrutide phase 2 data, showing up to approximately 24.2% mean weight loss at 48 weeks with the 12 mg dose, suggests that the triple agonist mechanism may offer incremental benefit over dual agonism. However, no direct head-to-head comparisons have been conducted, and the 48-week timeframe in the retatrutide trial is shorter than the 68–72 week endpoints used in the semaglutide and tirzepatide phase 3 trials, making direct numerical comparison imprecise. Phase 3 data will be required before any firm conclusions can be drawn.

References: NICE TA875; Wilding JPH et al. N Engl J Med. 2021;384:989–1002; Jastreboff AM et al. N Engl J Med. 2022;387:205–216; MHRA/EMC SmPCs for Wegovy, Saxenda, Orlistat, and Mounjaro.

What the Findings Mean for Future Treatment in the UK

Retatrutide requires phase 3 trial completion, MHRA marketing authorisation, and a NICE health technology appraisal before it could be used in the UK; current patients should follow NICE-recommended obesity management pathways.

The retatrutide phase 2 results have generated considerable scientific interest and optimism within the obesity medicine community, including in the UK. However, it is important to maintain a measured perspective on what these findings mean in practical terms for patients and clinicians at this stage.

Retatrutide is currently undergoing phase 3 clinical trials, which will involve larger, more diverse populations and longer follow-up periods. These trials will be essential to confirm the efficacy signals observed in phase 2, establish the long-term safety profile, and generate the robust evidence base required for regulatory review. Before retatrutide can be considered for use in the UK, it would need to receive a marketing authorisation from the MHRA, followed by a health technology appraisal by NICE to determine its clinical and cost-effectiveness relative to existing treatments.

For UK patients currently living with obesity, the most appropriate course of action remains engagement with existing evidence-based services. NICE guidance — including Technology Appraisal TA875 (semaglutide 2.4 mg for managing overweight and obesity), Clinical Guideline CG189 (Obesity: identification, assessment and management), and Public Health Guidance PH53 (Weight management: lifestyle services for overweight or obese adults) — recommends a structured, tiered approach to weight management. This typically begins with lifestyle interventions and, where appropriate, pharmacological treatment with licensed medicines such as orlistat or semaglutide 2.4 mg. Patients with a BMI of 40 kg/m² or greater, or 35 kg/m² or greater with significant comorbidities, may be referred to specialist tier 3 or tier 4 weight management services, depending on local pathways. Further information on NHS treatment options is available at nhs.uk.

Patients who are concerned about their weight or who have not achieved adequate results with current treatments should speak with their GP or a specialist weight management service. Self-administering unlicensed or unregulated medicines obtained outside of legitimate healthcare channels carries significant safety risks and should be strongly discouraged.

The development of retatrutide reflects a broader and encouraging shift in how obesity is understood — as a complex, chronic, and treatable medical condition rather than a lifestyle failing. If phase 3 data confirm the phase 2 findings, retatrutide could represent a meaningful addition to the UK's future obesity treatment toolkit.

References: NICE TA875; NICE CG189; NICE PH53; NHS.UK: Obesity — Treatment; MHRA/EMC SmPC: Mounjaro (tirzepatide).

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