Diet & Weight

CATEGORY: DIET & WEIGHT

A weekly injection pairing two appetite-regulating medicines—cagrilintide–semaglutide—reduced body weight by an average of 20.4% over 68 weeks in a randomized trial of 3,417 adults with obesity or overweight, versus 3.0% with placebo, and more than half of the people taking it lost at least a fifth of their body weight.¹

Two Fullness Signals Instead of One

The combination joins two copies of natural hormones. Semaglutide mimics GLP-1, a hormone the gut releases after eating that tells the brain you are full and slows the stomach’s emptying. Cagrilintide mimics amylin, a second fullness hormone, released by the pancreas alongside insulin. The researchers’ stated reasoning was that the two molecules act on different appetite-control regions of the brain, so their effects should add up rather than overlap—the dietary equivalent of turning down both the thermostat and the space heater instead of just one. The trial, called REDEFINE 1, put that expectation to a direct test by including each medicine alone as its own comparison group.¹

Sixty-Eight Weeks, Four Groups, One Coin Toss

Researchers in 22 countries enrolled 3,417 adults who did not have diabetes and who had obesity, or overweight plus at least one weight-related health problem; on average they were 47 years old and weighed 106.9 kilograms (about 236 pounds) at the start. Each was assigned by chance, double-blind, to the weekly combination injection (2,108 people), to semaglutide alone (302), to cagrilintide alone (302), or to placebo (705), with every group also receiving diet and physical-activity counseling. Doses were stepped up over 16 weeks and then held for a year while the trial tracked body weight, waist size and blood pressure.¹

A Fifth of Body Weight, and More Than Its Parts

After 68 weeks, weight had fallen by an average of 20.4% with the combination versus 3.0% with placebo. The pairing also beat its own ingredients—by 5.5 percentage points over semaglutide alone and 8.9 over cagrilintide alone—just as the researchers had posited. More than half of the people on the combination (53.6%) lost at least 20% of their body weight, roughly one in three (34.7%) lost a quarter or more, and about one in five (19.3%) lost 30% or more; on placebo, fewer than 2% reached even the 20% mark. Among those who stayed on treatment, the average loss came to 21.6 kilograms—close to 48 pounds, about what an airline allows in a checked suitcase. Waistlines shrank by 13.4 centimeters more than with placebo, and systolic blood pressure fell 6.7 millimeters of mercury more.¹

Mostly Stomach Trouble, Mostly Passing

The main cost was digestive. Gastrointestinal complaints—nausea, vomiting, diarrhea, constipation—affected 79.6% of people on the combination versus 39.9% on placebo, though the trial describes them as mainly mild to moderate and transient, clustering around dose increases. Serious adverse events occurred in 9.8% of the combination group versus 6.1% on placebo, and 5.9% stopped the medicine because of side effects.¹

Where It Lands Among the Newest Options

The result places the combination at the top of the range set by existing randomized trials of weight-loss medicines. In a head-to-head randomized trial of 751 adults with obesity, tirzepatide produced an average 20.2% weight loss over 72 weeks, against 13.7% for semaglutide alone.² The cagrilintide–semaglutide combination is still investigational: it is under regulatory review and not yet available, so its trial results describe what the medicine did under study conditions rather than a treatment currently on pharmacy shelves.

Key Takeaways

• In a 68-week randomized trial of 3,417 adults with obesity or overweight, a weekly cagrilintide–semaglutide injection cut body weight by an average of 20.4%, versus 3.0% with placebo; 53.6% of those taking it lost at least a fifth of their body weight.
• The combination outperformed each of its two component medicines given alone, matching the researchers’ expectation that the two hormone signals would add up.
• Digestive side effects were common—79.6% versus 39.9% on placebo—but mostly mild to moderate and temporary, and 5.9% stopped treatment because of side effects.
• The medicine is not yet approved; its average result sits alongside the 20.2% seen with tirzepatide, the most effective approved medicine in a comparable randomized trial.

References

1. Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine. 2025;393(7):635–647. link
2. Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. New England Journal of Medicine. 2025;393(1):26–36. link

More from Diet & Weight!

CATEGORY: DIET & WEIGHT Adults with obesity who had lost about a fifth of their body weight on tirzepatide and were then switched to a placebo regained 14% of their body weight over the following year, while those who kept… Read More →

CATEGORY: DIET & WEIGHT In the first randomized trial to directly compare the two most widely used weight-loss injections, adults with obesity taking tirzepatide lost an average of 20.2% of their body weight over 72 weeks, compared with 13.7% for… Read More →