Retatrutide is a ‘triple G’ agonist of the GLP1, glucagon, and GIP receptors. As blogged previously, topline results of the TRIUMPH-4 study of retatrutide for knee osteoarthritis in people with obesity revealed clinically important improvement in knee osteoarthritis pain, and weight loss of 28.7% (71lb) with the highest dose of 12mg dose weekly, for people who took the 12mg dose as intended through the trial.

Topline results of the larger TRIUMPH-1 study has reinforced the existing knowledge base of retatrutide to provide very impressive weight loss results. This was a phase 3 study including 2,339 people with obesity, randomized to receive retatrutide at a dose of 4mg, 9mg, 12mg weekly, or placebo.

At 80 weeks, weight loss was:

  • -17.6% with retatrutide 4mg weekly
  • -23.7% with retatrutide 9mg weekly
  • -25% with retatrutide 12mg weekly
  • -3.9% with placebo.

For people who took the treatment as intended, people on the highest 12mg dose lost an average of 28.3% weight (70.3lbs) over 80 weeks.

The study also looked at longer term weight loss in 532 people who completed the main 80 week study and tolerated their assigned dose of medication. In these people, the study found that weight decreased further by the 2 year mark, for a total of:

  • -25.7% with retatrutide 4mg weekly
  • -28.7% with retatrutide 9mg weekly
  • -29.9% with retatrutide 12mg weekly.

People with a body mass index (BMI) of 35+ at the start of the study lost an average of 30.3% (85lb) at the 2 year mark. This degree of weight loss is aligned with what we typically see with bariatric surgery (eg gastric bypass surgery). Metabolic health improvements were seen with retatrutide, including blood pressure, cholesterol, and improvement in inflammation (hsCRP).

From a tolerability perspective, retatrutide is showing overall a similar range of gastrointestinal (GI) side effects as with other GLP1 based treatments. According to the press release, with retatrutide 4mg, 9mg and 12mg respectively:

  • nausea: 28.6%, 38.4%, 42.4%, vs 14.8% with placebo
  • diarrhea: 25.2%, 34.1%, 32%, vs 13.5% with placebo
  • constipation: 23.8%, 25.9%, 26.1%, vs 10.9% with placebo
  • vomiting: 10.6%, 22.8%, 25.3%, vs 4.8% with placebo
  • dysesthesia (altered skin sensation, more on this blogged previously here): 5.1%, 12.3%, 12.5%, vs 0.9% with placebo

They also noted a higher likelihood of urinary tract infections with retatrutide (7.5% with 4mg, 8.8% with 9mg, 8.4% with 12mg, vs 5.3% with placebo), for reasons unclear. One could speculate that if a person were to become dehydrated due to GI side effects, that could increase the risk of urinary tract infections; however, urinary tract infections have not been noted to be seen more commonly in other studies of GLP1s despite similar GI side effect profiles. There was numerically slightly higher upper respiratory tract infections as well (14.2% with 4mg, 12.2% with 9mg, 13.1% with 12mg, vs 11.6% with placebo). I look forward to the full publication to learn more about these findings. The percentage of people stopping treatment due to adverse events were quite low at 4.1% (4mg), 6.9% (9mg), 11.3% (12mg), vs 4.9% (placebo).

Why is retatrutide so effective for weight loss? As a triple-G, it stimulates the receptors of three naturally occuring hormones involved in appetite and metabolism. While each of these is a long topic unto itself and beyond the scope of today’s post, in brief:

  • GLP-1: decreases appetite and cravings, slows gastric (stomach) emptying
  • GIP: decreases appetite, may have benefits in fat tissue
  • Glucagon: decreases appetite, slows gastric (stomach) emptying, may increase energy expenditure, benefits to liver health

With such robust weight loss findings, I want to point out again that for ALL weight management medications, 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) if needed to avoid excessive weight loss. For some people, the weight loss seen in this retatrutide study would be welcome and beneficial to improve health and wellbeing; but for some people, this amount of weight loss would be way too much. Personalizing treatment is essential.

BOTTOM LINE: Based on these topline results, retatrutide has again demonstrated previously unsurpassed weight loss (now well into the range achieved with bariatric surgery). 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.

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


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