Triple Hormone Receptor Agonist for Treatment of Obesity and Knee Osteoarthritis

Jack Cush, MD

Oct 05, 2026 10:00 am

The NEJJM reports that Retatrutide, an investigational incretin agent, was shown to yield up to 25% weight reduction, with subanalyses also showing reduced pain with knee osteoarthritis, and less apnea–hypopnea events in participants with obstructive sleep apnea.

Retatrutide (RET) is a novel triple-receptor agonist of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors (GR).

In was a phase 3, randomized, double-blind trial, that randomized 2339 obese adults without diabetes to receive a once-weekly subcutaneous injection of retatrutide (4 mg, 9 mg, or 12 mg) or placebo for 80 weeks. This group included 574 adults with moderate or severe knee osteoarthritis (pain plus radiographic evidence) and 243 obstructive sleep apnea patients. Primary endpoint was the percent change in body weight and the change in the WOMAC pain score (ranging from 1 to 10), and the change in the apnea–hypopnea index.

Overall the mean percent change in body weight

RET 4-mg dose −17.6%
RET 9-mg dose −23.7%
RET 12-mg dose −25.0%
PBO −3.9% (P<0.001 for comparisons with 9 mg and 12 mg doses).

Among the 574 knee osteoarthritis patients, WOMAC pain score reductions in the RET were −3.2, −3.5, and −3.6 versus −1.9 with placebo (P<0.001). Similarly with obstructive sleep apnea improvements were significantly greater in the RET groups (−22.9, −34.3, and 31.7 versus −9.9; P<0.001).

The most common adverse events were gastrointestinal.

In adults with obesity, the investigational agent retatrutide offers a substantial benefit in weight reduction. Moreover, knee OA patients had a significant decrease in knee pain (>60%).

Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity

Article

Osteoarthritis, Obesity and GLP-1s

Tom Appleton, MD, PhD Sep 8, 2026

We all know that osteoarthritis is the most common form of arthritis in the world, and that obesity is its most modifiable risk factor. What I really want to focus on is the role that GLP-! receptor agonists might be playing in our management of osteoarthritis. So why does this matter?