TRIUMPH-4 Explained: What Retatrutide Showed for Weight Loss and Knee Osteoarthritis

TRIUMPH-4 is a phase 3 clinical trial testing retatrutide, an experimental weight-loss medicine from Eli Lilly, in adults with obesity and knee osteoarthritis. Osteoarthritis (OA) is the wear-and-tear form of arthritis, and the knee is one of the most common sites. Many people with OA also carry extra weight, which loads the joint with every step.

The trial was the first phase 3 readout in the larger TRIUMPH program for retatrutide. Lilly announced topline results in December 2025, and further details were presented and discussed in early 2026. Topline means a company press-release summary; the full peer-reviewed paper gives more depth on safety, methods and subgroups.

The study measured two main things: how much weight people lost and how much their knee pain improved. Pain was assessed with a standard questionnaire called WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index), which scores pain, stiffness and function. Participants took weekly injections for 68 weeks, with placebo as a comparison.

Why does this matter? Most weight-loss trials focus on weight, blood sugar and heart risk. TRIUMPH-4 asks a more everyday question: does the treatment make life with a painful joint better? For many midlife women, knee and hip pain limit walking, strength work and daily activities, so the answer has real-world weight. Our guide to [joint pain in menopause](/blog/joint-pain-in-menopause-why-estrogen-loss-makes-you-ache) explains why those aches rise at this stage.

TRIUMPH-4 found that retatrutide 12 mg led to an average weight loss of 28.7% at 68 weeks, about 71.2 pounds, in adults with obesity and knee osteoarthritis. Participants also reported substantially less knee pain, with large reductions on the WOMAC pain scale compared with placebo. These figures come from Lilly's announcement and trade press coverage of it; the final published paper may refine them.

To put 28.7% in context, the STEP 1 trial (NEJM, 2021) found semaglutide 2.4 mg produced an average 14.9% weight loss over 68 weeks. SURMOUNT-1 (NEJM, 2022) found tirzepatide reached up to 20.9%. Retatrutide's number is higher, but the trials differ in population, design and dose, so direct comparisons are only rough. For an early look at the comparison, see our piece on [retatrutide versus semaglutide](/blog/retatrutide-vs-semaglutide-how-they-compare).

Average results also hide a range. Some people lose more, others less. The trial population had knee OA, which is not the same as the general population with obesity, and trials usually enroll people who are motivated and closely followed.

Finally, remember what a topline readout is not: it is not approval, and it is not a prescription. Retatrutide is still investigational, and the next steps are completing the other TRIUMPH trials and regulatory review.

Retatrutide differs from semaglutide and tirzepatide because it activates three receptors instead of one or two. Semaglutide (Ozempic, Wegovy) activates the GLP-1 receptor. Tirzepatide (Mounjaro, Zepbound) activates GLP-1 and GIP receptors. Retatrutide adds the glucagon receptor, giving a "triple agonist."

Here is what each does. GLP-1 reduces appetite, slows stomach emptying and helps insulin release after meals. GIP appears to support insulin release and may affect fat tissue and appetite signals. Glucagon raises energy expenditure and fat burning in the liver. Early studies suggest the combination boosts weight loss beyond GLP-1 alone.

A phase 2 trial published in NEJM in 2023 (Jastreboff and colleagues) found retatrutide produced up to 24.2% average weight loss at 48 weeks, which signaled what the phase 3 programs might show. Retatrutide also showed signs of reducing liver fat in related studies.

The extra receptor can bring extra considerations. Glucagon affects heart rate, so heart rate changes were noted in earlier work. Skin sensation changes (dysesthesia) have been discussed in connection with higher doses, so watch for how safety data are reported in the final papers. Our article on [Zepbound versus Wegovy](/blog/zepbound-vs-wegovy-which-works-better-for-weight-loss) shows how a head-to-head comparison is usually framed.

Knee pain improves with large weight loss because the joint carries less load and body-wide inflammation falls. In a classic analysis by Messier and colleagues (Arthritis & Rheumatism, 2005), each pound of weight lost removed about four pounds of load from the knee per step. Over thousands of steps a day, that adds up.

Fat tissue also releases inflammatory chemicals. Losing fat can lower that signaling, which may ease joint pain beyond the mechanical effect. Some researchers also think GLP-1-class drugs may act on pain pathways, but this is still being studied.

The STEP 9 trial (NEJM, 2024) tested semaglutide 2.4 mg in adults with obesity and knee OA. Average weight loss was 13.7% versus 3.2% with placebo, and WOMAC pain scores improved more with semaglutide. That makes TRIUMPH-4 part of a pattern: more weight loss, more pain relief. It also suggests that very large losses may deliver bigger pain benefits, although there is a limit to what any drug can do for a joint with advanced structural damage.

If you already struggle with joint pain on a GLP-1, our guide on [joint pain on a GLP-1 during menopause](/blog/joint-pain-on-glp1-during-menopause-why-it-overlaps) explains how pain can shift as you lose weight and what helps.

The main caveats are safety details, how long the benefit lasts and who the results apply to. Topline press releases highlight efficacy; the safety profile needs the full data. Earlier GLP-1-class medicines commonly cause nausea, diarrhea, constipation and vomiting, and a stronger drug may raise the chances of side effects or of stopping the medicine. Reports about dose-related skin sensation and heart rate changes make the final tables important.

Second, large weight loss means large changes in body composition. Studies of other GLP-1 and GIP medicines show that a portion of weight lost is lean mass. For midlife women, who are already losing muscle and bone as estrogen declines, that matters. Our articles on [muscle loss on a GLP-1 in menopause](/blog/muscle-loss-on-glp1-in-menopause-sarcopenia-risk) and the [bone density double risk](/blog/glp1-bone-density-in-menopause-the-double-risk) explain how to protect both. Researchers are testing muscle-sparing add-ons, as in the [BELIEVE trial of bimagrumab with semaglutide](/blog/bimagrumab-semaglutide-believe-trial-muscle-sparing-results).

Third, how long people maintain results is unknown. Stopping GLP-1 medicines usually leads to regain, as covered in [stopping a GLP-1](/blog/stopping-a-glp1-tapering-and-weight-regain-what-to-expect).

Finally, TRIUMPH-4 enrolled people with knee OA and obesity, so the results may not match what the drug does in people with different conditions. Other TRIUMPH trials will report on different groups.

For you today, TRIUMPH-4 means the next generation of weight-loss medicines is promising, but you cannot get retatrutide through a legitimate prescription yet. Be cautious with online sellers offering "retatrutide" as a research peptide. These products are not approved, and their purity, dose and safety are unknown. See our guide to [compounded versus brand GLP-1s](/blog/compounded-vs-brand-glp1-what-changed-2026) for how to judge sources.

If you have knee pain and a high BMI, the approved options already show benefit. Semaglutide improved knee pain in STEP 9, and weight loss, strength training and low-impact movement help. Ask your clinician whether an approved medicine fits you.

If you are in perimenopause or menopause, the best preparation is the same no matter which drug comes next. Protect muscle with protein and strength training, get your bone health checked, and keep hormone therapy in the conversation. A good plan makes every medicine safer and more effective.

Lea will keep tracking the research as full papers appear, so you can see what changes and what does not.

This article is educational and not medical advice. Discuss treatment decisions with your clinician.

New trial headlines move fast, and it is hard to know what applies to you. Lea can break down the evidence and help you prepare questions for your clinician.