Phase 2 trial (NEJM 2023): retatrutide's first big result

The Phase 2 trial, published in the New England Journal of Medicine in June 2023, is the study that put retatrutide on the map. It is still the only obesity trial of the drug to have been through full peer review, and it is where most of what is known about heart rate, liver enzymes and the pancreas comes from.

What the trial did

Participants were adults aged 18 to 75 with a BMI of 30 to 50, or 27 to 30 with high blood pressure, abnormal blood fats or cardiovascular disease. People with diabetes were excluded, as were people with a history of pancreatitis, significant kidney impairment, uncontrolled blood pressure, recent heart attack or stroke, or a personal or family history of medullary thyroid cancer.^[3]

They were assigned at random to placebo or to one of four target doses of retatrutide, injected once a week, alongside diet and activity advice. As a design detail, some of the 8 mg and 12 mg groups began on a lower starting dose than others so the investigators could test whether a gentler start reduced stomach side effects; it partly did.^[1] That is a fact about how the trial was built, not guidance for anything outside it.

The primary outcome was percentage change in body weight at 24 weeks; 48-week results were the main secondary outcome. Registered as NCT04881760.^[3]

Weight loss

Placebo-adjusted, the 12 mg arm was about 16 percentage points ahead of placebo at 24 weeks and about 22 points ahead at 48.^[1] Weight loss rose with dose across the 1 mg, 4 mg, 8 mg and 12 mg groups, and at 48 weeks the curves had not clearly flattened, which is why the Phase 3 trials were designed to run for 80 weeks. The 2023 figures were the first sign that a triple agonist might exceed what the two-target drug tirzepatide had shown, and they were the basis for the whole TRIUMPH programme.

At 48 weeks, 83% of people on 12 mg had lost at least 15% of their body weight, compared with 2% on placebo.^[1] As the how to read a trial page explains, that also means about one in six on the top dose lost less than 15%.

Side effects

Stomach and gut. Nausea, diarrhoea, vomiting and constipation were the most common events. They rose with dose, were mostly mild to moderate, and were concentrated in the weeks when the dose was being stepped up. The groups that began on a lower starting dose had fewer of them.^[1] See nausea, vomiting and gut effects.

Heart rate and rhythm. Resting heart rate rose in a dose-dependent way, peaked at around week 24, and had declined by weeks 36 to 48. The paper's summary does not give a beats-per-minute figure; a fair description is a few to about ten beats per minute at the higher doses. Abnormal heart rhythms (arrhythmias) were recorded in 2% to 11% of participants across the retatrutide groups against 2% on placebo, mostly mild to moderate. One was severe: a prolonged QT interval in a participant who was also taking ondansetron, an anti-sickness medicine known to prolong QT on its own.^[1] The Phase 3 announcements have not yet reported heart-rate or rhythm data, so this trial is still the best evidence on the point.^[4] See heart rate and rhythm.

Liver. About 1% of participants had a temporary rise in the liver enzyme ALT to more than three times the upper limit of normal.^[1] These rises settled. They are a different thing from the acute liver injuries seen in Australia in people using unlicensed products, which are covered in the safety section.

Pancreas. Blood levels of the pancreatic enzymes amylase and lipase rose in some participants without symptoms, which is seen across this drug class. One participant developed acute pancreatitis, a serious event.^[1] See pancreatitis and gallbladder.

The liver-fat sub-study

Ninety-eight participants who also had fatty liver disease (MASLD) with liver fat of 10% or more had it measured by MRI. After 24 weeks, liver fat had fallen by 82.4% on 12 mg and by 42.9% on 1 mg, against a 0.3% rise on placebo, and 86% of the 12 mg group reached a normal liver-fat level.^[5] That result, published in Nature Medicine in 2024, is covered on the other indications page.

What Phase 2 could not tell us

• Anything beyond 48 weeks. The TRIUMPH-1 trial ran to 80 weeks and added a 104-week extension.
• Rare events. A trial of 338 people cannot detect something that happens to one person in a thousand.
• Effects in people with diabetes, heart disease, kidney disease or over 75, who were all excluded.
• The new skin-sensation side effect, dysesthesia, which only emerged in the larger Phase 3 trials.