As blogged previously, the TRIUMPH-1 study of retatrutide demonstrated previously unsurpassed weight loss, now well into the range seen with metabolic and bariatric surgery. The full results of this study were just published, giving us a wealth of details not only on the health benefits and potential side effects of retatrutide, but also key messages on how we need to shift our approach to dosing of obesity medications as well as treatment targets.

As a reminder (more here), the TRIUMPH-1 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 (-19% in those taking treatment as intended)
  • -23.7% with retatrutide 9mg weekly (-25.9% in those taking treatment as intended)
  • -25% with retatrutide 12mg weekly (-28.3% in those taking treatment as intended)
  • -3.9% with placebo (-2.2% in those taking treatment as intended)

Impressively, weight reduction of at least 35% was seen in 27% of people taking retatrutide 12mg.

Beyond weight loss, the TRIUMPH-1 study looked at a subgroup of people with knee osteoarthritis, finding that retatrutide resulted in a reduction in knee pain of up to 62%. In a subgroup of people with obstructive sleep apnea, retatrutide improved the apnea hypopnea index by 57.3%. More than 90% of people with prediabetes reverted to normal blood sugars, and there were improvements in blood pressure, cholesterol, inflammation (hsCRP), and quality of life.

While the proportion of people stopping treatment due to adverse events were low, the percentage of people completing the trial in the placebo group was suboptimal (72%, vs 88-90% in the retatrutide groups). Learning (as seen in other recent trials): placebo comparisons are no longer ethical nor appropriate in obesity medicine trials. Our hands are tied as clinical trial investigators on this, as placebo remains a requirement from regulatory agencies (eg the American FDA, European EMA, Health Canada). This needs to change. It is especially difficult to keep placebo patients on treatment, because they are not seeing the results they had hoped for, and are understandably turning to other prescription treatments instead.

The percentage of patients who reached their assigned dose of retatrutide was 98%, 94%, and 90% with the 4mg, 9mg, and 12mg doses. Yet, at the end of the study (week 80), the percentage of people who continued to receive their assigned doses was quite a bit lower at 75%, 59%, and 54% respectively. The most common reasons for dose reductions were perceived excessive weight loss (2.7-9.8%), having a BMI of 22 or less (2.6-6%), and gastrointestinal events (1.4-6.2%). Knowing how highly effective retatrutide is for weight loss, it’s not suprising to see that a substantial number of people had to decrease the dose because their assigned dose was too much for them. Learning: the goal of obesity medicine trials should be to use the minimum effective dose needed to reach treatment targets for each patient, rather than the current approach of trying to get people to the maximum possible dose.

So what should the treatment target be? Authors looked at their data with BMI targets in mind:

  • a BMI of <30 was reported in about 60% and a BMI of <25 was reported in more than 25% of people who received the retatrutide 12mg dose
  • amongst those with less severe obesity (BMI 30-35) at the start, a BMI of <30 was seen in more than 90% of people receiving either the 9mg or 12mg dose
  • a BMI of <25 was seen in more than half of participants in the retatrutide groups (vs 6.3% in placebo group)

While we should focus primarily on health gains rather than weight loss, and while the best BMI target for each individual will vary, I very much applaud a shift away from percent weight loss towards a treat-to-target BMI category approach, and/or a waist-based approach (more blogged here).

BOTTOM LINE: Retatrutide is highly effective for improvement in weight and obesity-related health issues. Clinical studies and real-world use of highly effective obesity medicines should aim for the lowest dose needed for each individual to achieve treatment goals of improving health. If weight loss is to continue to be a treatment target, this should be defined NOT by percent weight loss, but rather by a more refined treat-to-target approach that evaluates how many people can get to healthier BMI or waist-based targets with medication.


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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