A major trial called SURMOUNT-5 compared the two biggest weight-loss drugs on the market, head to head. Tirzepatide (sold as Zepbound for obesity) produced about 22% weight loss over the trial. Semaglutide (the active drug in Ozempic and Wegovy) produced about 15%. Tirzepatide won the weight-loss race by a wide margin.
The primary numbers came from Aronne et al. in the New England Journal of Medicine ↗ last year. A new follow-up analysis this week, published in the Journal of Endocrinological Investigation ↗, added another tirzepatide advantage: in people who started with prediabetes, more of them returned to normal blood sugar on tirzepatide than on semaglutide.
So why is the weight-loss question not fully settled?
Because the bigger the total weight loss, the bigger the absolute amount of muscle that goes with it. Weight-loss drugs in this class do not selectively remove fat. They drive weight loss mostly by suppressing appetite, and people on them lose both fat and muscle. The typical ratio is about three kilos of fat lost for every kilo of muscle lost. That ratio has been stable across the class. The total amount of muscle lost depends on how much total weight comes off.
On a simple illustration: a 100-kilo adult who loses 15% on semaglutide drops about 3.9 kilos of muscle. The same person on tirzepatide drops 21.6% of their weight — about 5.4 kilos of muscle. Tirzepatide wins on fat, but its bigger total comes with a bigger muscle cost.
Separate real-world data flagged last week suggested the ratio itself may be less favorable on tirzepatide, not just the absolute number. That part is not yet confirmed in a peer-reviewed comparison. SURMOUNT-5 did not publish a body-composition analysis. If Lilly releases one, it will settle this directly. Until then, the muscle-mass question stays open.
What would fix the tradeoff. A third hormone receptor called the glucagon receptor can be added to the GLP-1 target in a single drug. Adding glucagon drives fat burning through a second pathway without increasing muscle loss in the same way. This is the mechanism behind drugs like retatrutide (Lilly's triple-receptor agonist) and DA-1726 (a smaller company's dual agonist). Retatrutide is currently in late-stage trials.
From our side. Our GLP-1 receptor page ↗ and glucagon receptor page ↗ between them catalog the candidate molecules in this design space, including retatrutide ↗ itself. The question that SURMOUNT-5 opens and a new trial will close is whether a triple-receptor drug beats tirzepatide on the muscle ratio, not just on the total.
The weight-loss race has a winner for the current drug pair. The body-composition race is the one the next generation of drugs will be measured on.