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Well this is exciting indeed! The topline results of the TRIUMPH-4 study of retatrutide for knee osteoarthritis in people with obesity was just released (this is the first phase 3 study of retatrutide to report!). While the main purpose of this study was to see if retatrutide could reduce knee pain (which it did), one can’t help but be a bit gobsmacked by the impressive weight loss results – weight loss which may be appropriate for some people, but certainly not all.

Retatrutide is a ‘triple G’: GLP1, glucagon, and GIP agonist all rolled up into one molecule. In the TRIUMPH 4 study (disclosure: I am an investigator), 445 people with obesity (BMI 27+) and knee osteoarthritis were randomized to receive retatrutide 9mg weekly, 12mg weekly, or placebo. We don’t yet know much about baseline characteristics, except that 84% of participants had a BMI of at least 35.

At 68 weeks, knee pain was reduced by 67% with the 9mg dose, 63% with the 12mg dose, vs 35% with placebo. Fourteen percent of people on retatrutide 9mg, and 12% of people on 12mg were completely free of knee pain at 68 weeks, compared to 4% of people on placebo.

Weight loss was 20% (51lb/23kg) with the 9mg dose, 23.7% (60lb/27kg) with the 12mg dose, and 4.6% (12lb/5.3kg) with placebo (treatment regimen estimand). For people who took the 12mg dose as intended through the whole trial (efficacy estimand), average weight loss was a whopping 28.7% (71lb) with the 12mg dose.

Benefits were seen to inflammation (hsCRP) and cholesterol with retatrutide, as well as an impressive systolic BP redution of 14mmHg with the 12mg dose. (see my prior blog on the importance of watching blood pressure particularly in people on blood pressure medication, as blood pressure medication needs often decrease when taking weight loss medication).

From a tolerability perspective, retatrutide is showing overall a similar range of GI side effects as with other GLP1 based treatments. While we should not compare across trials, if we look at the SURMOUNT-5 trial (previously blogged here) which evaluated semaglutide 2.4mg (Wegovy) and tirzepatide (Mounjaro/Zepbound), retatrutide looks to have similar nausea and constipation, and more diarrhea. Vomiting was similar to semaglutide (tirzepatide had less vomiting).

According to the press release, with retatrutide 9mg and 12mg respectively:

  • nausea: 38% and 43%, vs 11% with placebo
  • diarrhea: 35% and 33% vs 13% with placebo
  • constipation: 22% and 25% vs 9% with placebo
  • vomiting: 20% and 21% vs 0 with placebo

Discontinuation rates due to adverse events were 12% and 18% with retatrutide 9mg and 12mg vs 4% with placebo, and this included discontinuations for excessive weight loss – I am looking forward to the full publication to deep dive on these details. As blogged previously, new and emerging weight loss medications are very powerful, which isn’t a bad thing – provided that people taking these treatments and their health care team understands that many people do not need the full dose, and we need to find the right dose for each person. As discussed in our Obesity Canada 2025 Pharmacotherapy Clinical Practice Guidelines (disclosure: I am the lead author), we should titrate weight management medications as needed, as tolerated, and as appropriate, to help each person achieve their treatment goals. This includes watching for weight loss that may be too much or too fast, and decreasing medication (or sometimes pausing treatment) to avoid excessive weight loss. For many people, the weight loss seen in this retatrutide study would be way too much. In line with this need for dose flexibility, retatrutide is actually being studied at 5 different doses (2mg, 4mg, 6mg, 9mg, and 12mg). For people with BMI 35+ at the start of the study, discontinuation rates were lower, which may be because there was less excessive weight loss, or could be related to better GI tolerance as the total body dose exposure is lower with a larger body (again, looking forward to the full publication!).

Dysesthesia, a collection of altered skin sensations (see my prior blog on this), was noted in 9% of people in the 9mg group and 21% of people in the 12mg group, vs 0.7% with placebo. These events were generally mild and rarely led to stopping treament.

BOTTOM LINE: Based on these topline results, retatrutide is emerging as a highly effective strategy to improve pain in people with knee osteoarthritis, accompanied by a previously unsurpassed weight loss (now well into the range achieved with bariatric surgery), and improvements in cardiometabolic health. Retatrutide has not been able to crack the nut on improving gastrointestinal tolerability of GLP1 based medications. As for other highly effective weight loss medications, if/when retatrutide becomes approved, it will need to be titrated carefully as needed, as tolerated, and as appropriate to each individual to help them achieve their treatment goals, being cautious to avoid excessive weight loss. Retatrutide is also under study as a treatment for type 2 diabetes, sleep apnea, back pain, MASH (‘fatty liver’), and for protection of cardiovascular and kidney health. Very exciting times!!!

Disclaimer:   I am an investigator in clinical trials of retatrutide, semaglutide, and tirzepatide. I receive honoraria as a continuing medical education speaker and consultant from the maker of retatrutide and tirzepatide (Eli Lilly), and semaglutide (Novo Nordisk).


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