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Retatrutide explained: mechanism, potential and clinical status

Published · RetaRadar

Retatrutide is an experimental medicine developed by Eli Lilly. It is being studied for obesity, type 2 diabetes and several related conditions. It has attracted attention because trial participants lost a lot of weight.

It is still investigational. No regulator has approved it. This article explains how it is designed to work, what the trials have shown so far, and where it stands in September 2026.

What retatrutide is

Retatrutide is a single molecule that acts on three hormone receptors. Lilly calls it a "triple hormone receptor agonist". Its development code is LY3437943. It is designed to be given once a week.

The three receptors are:

Older medicines in this class act on fewer targets. Semaglutide acts on GLP-1 only. Tirzepatide acts on GLP-1 and GIP. Retatrutide adds the glucagon receptor. Lilly describes it as "first-in-class" for this reason (Lilly, July 2026).

How it is thought to work

GLP-1 and GIP are gut hormones released after eating. Drugs that mimic them can raise insulin release when blood sugar is high. GLP-1 drugs also reduce appetite and slow stomach emptying. Together, these effects can lower blood sugar and food intake.

Glucagon is usually known for raising blood sugar. But glucagon receptor activity may also increase the energy the body uses and affect how the liver handles fat. Researchers included it to see whether it adds to the weight effects of the other two.

In a phase 2 sub-study, people with fatty liver disease saw large falls in liver fat. Liver fat returned to normal levels in more than 85% of participants in the two highest dose groups (Sanyal et al., Nature Medicine 2024).

How much each receptor contributes in people is not fully known. The combined effect is what the trials measure.

What the phase 2 trials showed

Two phase 2 studies were published in June 2023.

Obesity. The main obesity trial was published in the New England Journal of Medicine (Jastreboff et al., NEJM 2023). It enrolled 338 adults with obesity, or overweight with a related health problem, but without diabetes. It ran for 48 weeks in the United States. People in the highest dose group lost an average of 24.2% of their body weight. The placebo group lost 2.1%. The authors noted that weight had not yet levelled off when treatment stopped. The most common side effects were gastrointestinal.

Type 2 diabetes. A second trial, published in The Lancet, enrolled 281 adults with type 2 diabetes for 36 weeks. It compared retatrutide with placebo and with dulaglutide, an approved GLP-1 medicine. Retatrutide lowered HbA1c (a measure of long-term blood sugar) and body weight. At the higher doses, weight fell by close to 17% (Rosenstock et al., Lancet 2023; ADA Meeting News). The authors said these results guided dose choice for phase 3.

The phase 3 programme

Lilly started its TRIUMPH phase 3 programme in 2023. The first four registration trials enrolled more than 5,800 people. They test retatrutide for obesity, knee osteoarthritis pain and obstructive sleep apnoea (TRIUMPH design paper, PubMed). A separate TRANSCEND-T2D programme covers type 2 diabetes.

Results reported by Lilly so far are topline results. Most have not yet been published in full in peer-reviewed journals.

TRIUMPH-4 (December 2025). This trial included 445 adults with obesity or overweight and knee osteoarthritis. Over 68 weeks, average weight loss reached 28.7% in the highest dose group, against 2.1% with placebo. Knee pain scores also improved. Discontinuation due to side effects was higher with retatrutide than with placebo (Lilly, December 2025; Clinical Trials Arena).

TRANSCEND-T2D-1 (March 2026). This 40-week trial enrolled 537 adults with type 2 diabetes. HbA1c fell by an average of 1.7 to 2.0 percentage points across doses. The highest dose group lost an average of 16.8% of body weight (Lilly, March 2026). Full results were published in The Lancet in June 2026 (Lilly, June 2026, via Drugs.com).

TRIUMPH-1 (May 2026). This is the main obesity trial, with 2,339 adults without diabetes. At 80 weeks, the highest dose group lost an average of 28.3% of body weight. Nearly half of that group lost 30% or more. In an extension for people with a higher starting BMI, average loss reached 30.3% at 104 weeks (Lilly, May 2026). Lilly later reported improvements in sleep apnoea and knee pain in sub-studies.

TRIUMPH-2 and TRIUMPH-3 (July 2026). TRIUMPH-2 enrolled 1,152 adults with obesity and type 2 diabetes. The highest dose group lost an average of 20.8% of body weight over 80 weeks. TRIUMPH-3 enrolled 1,949 adults with severe obesity and established heart disease. Average weight loss reached 22.6% (Lilly, July 2026).

TRIUMPH-3 also counted major heart events. There were fewer events than expected in both groups. The results did not show a clear difference between retatrutide and placebo. A dedicated heart and kidney outcomes trial, TRIUMPH-Outcomes, is listed as ongoing (ClinicalTrials.gov NCT06383390). Other trials compare retatrutide with tirzepatide and test weight maintenance.

Side effects reported so far

The most common side effects were digestive. They included diarrhoea, nausea, constipation, reduced appetite and vomiting. Lilly says these were mostly mild to moderate.

Some participants reported dysesthesia, an unusual skin sensation such as tingling or altered touch. It was more common with retatrutide than placebo. Rates of stopping treatment because of side effects varied by trial and dose. In some groups they were clearly higher than with placebo.

Long-term safety is not yet known. Trials so far have lasted up to about two years.

Regulatory status

As of 25 September 2026, retatrutide is not approved anywhere that we could find.

In July 2026, Lilly said it plans to submit a Biologics License Application to the US Food and Drug Administration in the first quarter of 2027 (Lilly, July 2026). Lilly says it has the data to support "global submissions". We found no public record of a submission to the European Medicines Agency.

Lilly states that retatrutide "cannot be legally sold or marketed for human use". The FDA says retatrutide cannot be used in compounding under US federal law. It has warned companies selling it labelled "for research purposes" (FDA).

Where it stands in South Africa

Retatrutide is not registered with the South African Health Products Regulatory Authority (SAHPRA). In July 2026, a SAHPRA compliance manager told the Mail & Guardian that it "is still under clinical investigation" and not approved for sale in any market. SAHPRA urged anyone who had bought products marketed as retatrutide from unofficial sources to stop using them (Mail & Guardian, July 2026).

SAHPRA has also warned about unregistered GLP-1 products sold on social media (SAHPRA, November 2025). In 2026 it acted against the unlawful manufacture of unregistered GLP-1 and GIP medicines (SAHPRA GLP-1 updates).

Some South African research suppliers list retatrutide, for example https://leolab.co.za/peptides/retatrutide/ .

The bottom line

Retatrutide acts on three hormone receptors at once. Five phase 3 trials have reported positive topline results. Weight loss in the highest dose groups was larger than seen with many current medicines. But most phase 3 data are not yet fully published. Long-term safety is unknown. Regulators have not reviewed it. Lilly's first planned US filing is in early 2027.

Retatrutide is an investigational compound. It is not approved for general medical or consumer use in South Africa. This article is for information only and is not medical advice.

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