Retatrutide vs tirzepatide: three receptors versus two, and no head-to-head result yet.

Tirzepatide is a dual agonist: it activates the GIP and GLP-1 receptors. Retatrutide is a triple agonist: it activates GIP, GLP-1 and glucagon receptors.

Medicines that act on these receptors are registered in Australia for type 2 diabetes and weight management; the how Mounjaro works explainer covers tirzepatide's dual action in more detail. Retatrutide keeps both of those actions and adds the glucagon receptor.

The balance is different, too. The 2023 Phase 2 paper reports that, compared with the body's own hormones, retatrutide is less potent at the human glucagon receptor (about 0.3 times) and GLP-1 receptor (about 0.4 times), and more potent at the GIP receptor (about 8.9 times). It is a single peptide given once weekly in trials, with a half-life of about six days. Tirzepatide is also a once-weekly injection; in Australia it comes as the KwikPen, which holds four weekly doses.

A third receptor does not automatically mean a better or safer medicine. Whether the added glucagon action changes the balance of benefit and harm is exactly what the trials, and later regulators, need to establish.

Not proven. Retatrutide's trial averages are higher, but no completed trial has compared the two directly.

The "treatment-regimen estimand" counts everyone, whether or not they stopped treatment. The "efficacy estimand" estimates the result if everyone had stayed on treatment, and gives the larger number. Comparing like with like matters: quoting retatrutide's efficacy figure against tirzepatide's treatment-regimen figure exaggerates the gap.

Even like-for-like, this is a cross-trial comparison, and it has three weaknesses. The trials ran for different lengths (72 versus 80 weeks). The populations differed: TRIUMPH-1 enrolled adults with obesity or overweight plus at least one related condition, with an average starting BMI of 40.0. And the trials were run at different times with different designs. Any of these can shift an average.

The SURMOUNT-1 result is from a peer-reviewed NEJM paper; the TRIUMPH-1 result is a Lilly topline release. A widely shared 30.3% retatrutide figure is from a 104-week extension subgroup of people with a BMI of 35 or more who tolerated their dose, not from the main trial.

Both mainly cause gastrointestinal effects. Retatrutide trials have also reported abnormal skin sensations and, in Phase 2, a rise in heart rate.

In TRIUMPH-1, on 12 mg retatrutide, nausea affected 42.4% of people (placebo 14.8%), diarrhoea 32.0% (13.5%), constipation 26.1% (10.9%) and vomiting 25.3% (4.8%). Dysaesthesia, meaning abnormal skin sensations such as tingling, burning or sensitivity to touch, affected 12.5% (0.9%), and 11.3% stopped because of adverse events (4.9%). The retatrutide side effects guide has the figures for every trial.

For tirzepatide, the Australian CMI is the reference. It warns that Mounjaro "may cause inflammation of the pancreas", that use with a sulfonylurea or insulin "may cause your blood sugar to be too low", and advises drinking plenty of fluids to avoid dehydration from vomiting or diarrhoea. Frequencies are covered in the Mounjaro side effects guide.

Putting the two sets of percentages side by side would repeat the cross-trial problem. Side-effect rates depend on the population, the dose schedule and how events were recorded. A head-to-head trial such as TRIUMPH-5 is the way to compare them under the same conditions.

TRIUMPH-5 is designed to compare retatrutide and tirzepatide directly, and it has not reported.

The trial is registered as NCT06662383 on ClinicalTrials.gov and as 2024-511450-49-00 in the EU Clinical Trials Information System. It compares retatrutide with tirzepatide in adults with obesity, and its primary outcome is the percentage change in body weight at week 80. The two registries give different enrolment figures and completion dates, so we do not quote either.

Until it reports, statements that retatrutide "beats" Mounjaro rest on cross-trial comparison. When results appear, the questions worth checking are which estimand is being quoted, the doses compared, the side-effect and discontinuation rates in each arm, and whether the results have been peer reviewed.

For anyone weighing up medicine for weight today, the relevant comparison is between options that are registered in Australia. The weight-loss medication in Australia guide and Mounjaro vs Wegovy explain those, and a GP can advise on whether any medicine is appropriate.