Ladies and gents, Eli Lilly has outdone itself again, with the Phase 3 results of its triple GLP-1/GIP/glucagon receptor agonist, retatrutide, showing astonishing weight loss results for patients with obesity.
- Most people are already familiar with Novo’s Ozempic, which targets just the GLP-1 receptor and Lilly’s Mounjaro, which targets both the GLP-1 and GIP receptors.
- Retatrutide takes it a step further and targets those receptors as well as the glucagon receptor, which means it increases calorie burning and fat breakdown.
- This has far reaching implications for cardiovascular risk, since visceral fat mass has been shown to directly increase CVD risk through cytokine release, high BP, and high LDL-C.
Doing the due diligence in testing this additional receptor design, Eli Lilly’s TRIUMPH-1 trial randomized 2.3k adults with obesity but without diabetes to one of three retatrutide doses or placebo and followed up after 80 weeks.
- The lowest dose, 4mg, led to a 17.6% weight reduction.
- Upping that to 9mg led to a 23.7% weight reduction.
- At the highest dose of 12mg, weight reduction was 25%.
- Meanwhile placebo patients saw a 3.9% weight reduction.
Those weight-loss numbers are among the highest reported for the GLP-1 drug class, with even placebo-adjustment of the data showing weight loss of roughly 20–21 percentage points at the two higher doses.
- The tapering off of weight loss effect between the 9mg and 12mg dose is likely due to the limited amount of receptors the drug can act on at once (receptor saturation).
- For reference, the maximum clinical doses of Mounjaro and Ozempic lead to 22% and 15% average bodyweight reduction, respectively.
Beyond weight, retatrutide improved two clinically important complications that enrolled patients faced: knee osteoarthritis and sleep apnea, the latter of which is also a direct CV risk factor caused by excessive body weight.
- Roughly 10% of patients enrolled with obstructive sleep apnea.
- Those on the two highest doses of retatrutide saw their nighttime hypoxic events decrease by over 30 less per night throughout the study
Retatrutide’s most common adverse events were gastrointestinal but the trial reported no unexpected safety issues beyond that familiar pattern.
- Taking retatrutide also led to mild heart rate elevation (~6 bpm), though it’s unlikely this would be a safety issue down the line.
The Takeaway
Eli Lilly’s Mounjaro isn’t exactly an old drug by any means, so it’s not like it needed a direct sequel with retatrutide, but it’s hard to deny how compelling of an improvement these results are. By adding glucagon receptor agonism to how we treat obesity, it looks like patients will have yet another more effective option for reducing one of their biggest CVD risk factors.
