Retatrutide drew the attention of the medical world through a series of phase 2 trials whose results were so strong that some commentators called them a record for drugs of this kind. Three publications in leading medical journals — the New England Journal of Medicine, The Lancet and Nature Medicine — showed a consistent, powerful effect in three related areas: obesity, type 2 diabetes and fatty liver. Below we go through each trial in turn.
What phase 2 is and why it matters
Trials of a new drug are divided into stages called phases. Phase 1 assesses safety and the drug's behaviour in the body in a small group. Phase 2 is the first stage at which a larger group of patients is used to assess whether the drug works and to select the best doses. Only phase 3 confirms the result on a large scale. Phase 2 results are therefore not definitive proof but a strong signal — and in retatrutide's case an exceptionally strong one, which justified launching a broad phase 3 programme.
Obesity — the phase 2 trial (NEJM, 2023)
How the trial was designed: a carefully designed placebo-controlled trial (with a group receiving an inert injection) testing several doses (Jastreboff et al., NEJM, 2023; registry number NCT04881760). It enrolled 338 adults with obesity or overweight, without type 2 diabetes. Four doses of retatrutide were tested — 1, 4, 8 and 12 mg once weekly by subcutaneous injection — over 48 weeks, against placebo.
The main result: at the highest dose of 12 mg the average weight loss was 17.5% at 24 weeks and 24.2% at 48 weeks (after subtracting the placebo effect — about 16% and 22% respectively). In absolute terms that is an average of about 26 kg. It is one of the highest weight-loss figures recorded for a drug at this stage of research.
How many people responded: every participant on 8 mg or 12 mg lost at least 5% of their body weight. As many as 64% of those on 12 mg lost at least 20% — a level rarely seen outside weight-loss surgery. Importantly, at week 48 weight loss had still not levelled off, suggesting it might have continued with longer treatment.
Additional benefits: alongside body weight, waist circumference, blood pressure, blood lipids and measures of sugar handling also improved — that is, cardiovascular risk factors, not just weight.
Type 2 diabetes — the phase 2 trial (Lancet, 2023)
How the trial was designed: the phase 2 trial in people with type 2 diabetes (Rosenstock et al., The Lancet, 2023) enrolled 281 participants, who received retatrutide at 0.5, 4, 8 or 12 mg, the comparator drug dulaglutide 1.5 mg (an approved GLP-1 drug) or placebo, over 36 weeks. The presence of a real comparator matters — it allows retatrutide to be compared not only with placebo but with a diabetes drug in actual use.
Blood-sugar control: retatrutide at 4–12 mg lowered HbA1c by about 1.3–2.0 percentage points (HbA1c reflects average blood sugar over roughly the previous 3 months), while placebo produced no change and dulaglutide about 1.4 points — so retatrutide outperformed the comparator drug. HbA1c below 6.5% was reached by up to 82% of participants, and below 5.7% (the normal, “non-diabetic” range) by up to 31%.
Body weight: alongside this, weight loss of up to about 16.9% was recorded — an unusually high figure for people with diabetes, in whom losing weight tends to be harder than in people without it.
The liver — the phase 2a trial in fatty liver (Nature Medicine, 2024)
The liver data proved the most striking. In a phase 2a trial in metabolic-dysfunction-associated fatty liver disease (MASLD, formerly called NAFLD; Sanyal et al., Nature Medicine 2024), liver fat content was measured by magnetic resonance imaging.
After 24 weeks the amount of fat in the liver fell by 81.4% at the 8 mg dose and 82.4% at 12 mg (in the placebo group the change was +0.3%). 86% of participants on 12 mg reached a normal liver fat content (below 5%), and steatosis resolved in over 85% of those studied. It is a landmark result for a disease that has no approved effective treatment yet. The most likely explanation is retatrutide's glucagon pathway, which intensifies fat burning and improves the working of liver cells' “power stations” (mitochondria).
Safety and tolerability
Across all three trials safety was similar to the drug class as a whole. The commonest adverse effects involved the stomach and intestines (nausea, vomiting, diarrhoea), were dose-dependent, mostly mild to moderate and eased over time. They were partly mitigated by slower dose escalation (starting at 2 mg instead of 4 mg). Serious adverse effects occurred in about 4% of those taking retatrutide — the same as in the placebo group (4%) — and the investigators saw no significant new warning signals.
Heart rate: a transient, dose-dependent rise in heart rate was observed — typical of drugs with a glucagon component. Importantly and reassuringly, that rise peaked at around week 24 and then declined at weeks 36 and 48 rather than building. Small increases in some measures (uric acid, for instance) were also recorded in some people. All of these points are being closely monitored in the phase 3 trials, including the large cardiovascular trial.
How to read these results
Two things help in understanding these numbers. First, results are often reported both as a “placebo-subtracted” value (the difference from the placebo group) and as an absolute value — which is why, for instance, 24.2% and 22% describe the same effect counted two ways. Second, the use of a real comparator (dulaglutide) in the diabetes trial means retatrutide's advantage is not merely “better than nothing” but “better than a drug in actual use” — which greatly strengthens the result's credibility.
The liver — why this is more than fat
Reducing liver fat by over 80% is not just an impressive imaging number. Fatty liver (MASLD) can be the beginning of more dangerous states: liver inflammation, scarring (fibrosis) and, in extreme cases, cirrhosis and cancer. Clearing fat from the liver and normalising measures of its function (the enzyme ALT, for instance) is a signal that the disease can be halted or reversed at an early stage. Since fatty liver still lacks widely approved effective drugs, an effect this strong makes retatrutide one of the most interesting candidates in liver disease too — which separate phase 3 trials address.
What these numbers mean in practice
To picture the scale: for a person weighing 110 kg, losing 24% is about 26 kg — a difference that genuinely changes blood pressure, blood sugar, joint loading and cardiovascular risk. By comparison, lifestyle change alone usually gives a few per cent, and earlier drugs in the low teens. It has to be remembered, though, that these are results achieved during treatment: as across this drug class, part of the effect is usually not maintained after stopping, which makes such therapies long-term rather than one-off. That is a real limitation, discussed further in our piece on the phase 3 programme.
What follows from this
Three independent phase 2 trials, three different areas, one consistent conclusion: acting on three pathways at once produces a stronger effect than earlier drugs, with acceptable tolerability. It was precisely these results that justified launching the phase 3 programme. The mechanism behind the data is described in our article on how retatrutide works, and its large-scale confirmation in the piece on the phase 3 TRIUMPH programme.
Sources
- Jastreboff AM et al. (2023), Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial, New England Journal of Medicine — nejm.org
- Rosenstock J et al. (2023), Retatrutide for people with type 2 diabetes: a phase 2 trial, The Lancet — thelancet.com
- Sanyal AJ et al. (2024), Triple hormone receptor agonist retatrutide for MASLD: a randomized phase 2a trial, Nature Medicine 30(7):2037–2048 — pmc.ncbi.nlm.nih.gov
- The obesity trial registration — ClinicalTrials.gov NCT04881760
For in-vitro laboratory research only. It is not a human medicine and is not for treatment.
