Keeping muscle on tirzepatide: what the T-REx trial shows, and where protein and creatine fit

Losing muscle along with fat is one of the main worries about GLP-1 and dual GIP/GLP-1 medicines such as tirzepatide (Mounjaro, Zepbound) and semaglutide (Wegovy, Ozempic). It is also the main pitch for a new wave of "GLP-1 companion" protein powders, creatine and muscle supplements. On 9 November 2026, Nature Medicine published T-REx, which its authors describe as the first randomised trial of resistance training combined with tirzepatide. It tracked body composition every eight weeks and measured strength.

Short answer: weight training three times a week cut lean tissue loss by about 1.1 kg over 40 weeks and turned a 6.5% to 9% drop in strength into a gain of 10.7% to 17.5%, with the same fat loss. No supplement has published results showing it preserves muscle or strength in people taking a GLP-1 medicine. Creatine has good evidence alongside training in older adults generally, and trials of creatine, HMB and higher protein in GLP-1 users are under way.

What the T-REx trial did

Researchers at the University of Western Australia enrolled 120 sedentary adults aged 50 to 70, 60 men and 60 postmenopausal women, with obesity, or with overweight plus a weight-related condition. People with diabetes or cardiovascular disease were excluded. Everyone received weekly tirzepatide injections for 40 weeks, increased towards 15 mg. Half were randomised to three supervised one-hour resistance sessions a week in a research gym; the other half kept to their usual activities. All participants were told to maintain hydration, protein and fibre intake, but there was no specific diet programme. Attendance at the gym sessions averaged 91%, and 111 of the 120 participants (93%) completed the trial.

The results

• Weight and fat: both groups lost about 22 kg (22.61 kg on tirzepatide alone, 22.28 kg with training) and about 17 to 18 kg of fat. Training made no difference to fat loss.
• Lean tissue: lean soft tissue fell by 4.67 kg on tirzepatide alone and 3.57 kg with training, a difference of 1.09 kg (97.5% CI 0.43 to 1.75). Appendicular lean mass, the arms and legs, followed the same pattern. Most of the lean loss happened in the first 24 weeks and then plateaued.
• Strength: on tirzepatide alone, bench press, lat pulldown and knee extension strength fell by 8.4%, 6.5% and 9.0%. With training they rose by 10.7%, 15.7% and 17.5%.
• Heart and metabolic markers: blood pressure, glucose, insulin, HbA1c, total cholesterol and triglycerides improved similarly in both groups. Training did not add to those changes.
• Side effects: nausea affected about half of participants, and vomiting, constipation, diarrhoea and indigestion about a third each, at similar rates in both groups. Of six serious adverse events, five were in the tirzepatide-only group; all were judged unrelated to tirzepatide or training.

What the trial cannot tell you

DXA scans measure lean soft tissue, which includes water and other non-fat tissue as well as muscle, and the authors note that fat tissue itself contains about 15% lean mass, so some lean loss is expected with any large fat loss. A 2026 review in Nutrients adds that lean mass loss on these medicines is broadly proportional to weight lost, and that lean mass is not a direct measure of skeletal muscle or of muscle injury from the drug. The trial was open-label, so participants and the staff running strength tests knew who was training. It ran at one centre, in people without diabetes or heart disease, with supervised gym sessions that most people will not get in routine care. Eli Lilly, which makes tirzepatide, supplied the drug and reviewed the protocol. It also reviewed the manuscript before submission, and the authors report that no changes were made to the manuscript. Three authors have received speaker fees from Lilly, one has also advised Lilly, and one has received speaker fees from Novo Nordisk.

Where protein fits

T-REx did not give extra protein. In a subset with food diaries, protein intake was similar in both groups, which suggests the strength gap came from training rather than diet. A 2025 joint Advisory from four US obesity and nutrition organisations notes that targets of 1.2 to 1.6 g of protein per kilogram a day have been proposed during active weight loss, and that using actual body weight can overestimate needs in people with obesity. It also describes an absolute target of 80 to 120 g a day, with protein-rich foods first and a shake if appetite makes the target hard to reach, and says more protein alone is unlikely to be enough without strength training. LEAN-PREP, a 232-person trial in Kuwait with the University of Glasgow, is randomising people on semaglutide or tirzepatide to resistance exercise, a 1.6 g/kg protein target, or both, with MRI-measured thigh muscle as the main outcome. Its estimated primary completion is August 2029.

Where creatine and HMB fit

Creatine has consistent evidence for muscle in older adults, but almost all of it comes alongside training. A 2017 meta-analysis of 22 randomised trials in 721 adults with an average age of 57 to 70 found 1.37 kg more lean tissue with creatine than placebo during resistance training, with small extra strength gains. A 2026 Texas A&M trial in 64 sedentary adults aged 45 to 65 found that 10 g a day for 12 weeks added about 1.1 kg of lean tissue even without exercise. That trial was small, participants chose whether to join the exercise programme, and creatine draws water into muscle, which DXA counts as lean tissue. AlzChem, a creatine manufacturer, supplied the supplements, and the senior author chairs its scientific advisory board.

None of those trials involved GLP-1 medicines. A 40-person placebo-controlled pilot at the University of Saskatchewan is now giving creatine or placebo during 12 weeks of resistance training to people on GLP-1 therapy, with sit-to-stand performance as the main outcome; it is recruiting and its estimated primary completion is May 2027. HMB (beta-hydroxy-beta-methylbutyrate), another muscle supplement, will be compared with placebo in a 90-person Vanderbilt trial of adults aged 65 to 85 starting semaglutide, using 3 g of calcium HMB plus 800 IU of vitamin D3 a day. That trial has not started recruiting.

Our view

• If you are on tirzepatide or semaglutide, resistance training is the intervention with randomised evidence for keeping muscle and strength. T-REx showed it with three supervised sessions a week; how far less frequent or unsupervised training gets you is not yet known.
• Strength may matter more than the scan. The lean-mass difference was about 1 kg, but the net strength difference between the groups was about 19% to 23%, and the trial authors treat that strength gap as the change most relevant to function.
• Eat enough protein, from food first, and use a shake if appetite makes that hard. It is the basis that training builds on, not a substitute for it.
• Creatine is a reasonable optional extra if you are training, with no GLP-1 trial results yet. Ask a pharmacist or doctor first if you have kidney disease.
• Treat any supplement sold as "GLP-1 muscle support" with suspicion. No supplement has published results showing it preserves muscle or strength in people on these medicines.

UK advice and rules

NICE recommends tirzepatide for managing overweight and obesity alongside a reduced-calorie diet and increased physical activity, for adults who meet its BMI and weight-related condition criteria. The MHRA's July 2026 advice to people prescribed a GLP-1 medicine is to take it only as prescribed, alongside good nutrition and exercise, which it says can help support muscle, bone and overall health. Protein powders and creatine are regulated as foods or food supplements. Food Standards Agency guidance treats a food supplement as a food, not a medicine, and not as a product intended to treat or prevent disease. Ask your prescriber or a physiotherapist about a strength programme, and report a suspected side effect through the MHRA Yellow Card scheme.

FAQ

How much muscle do people lose on tirzepatide?

In T-REx, people who did not train lost 4.67 kg of lean soft tissue out of about 22.6 kg of total weight lost over 40 weeks. Lean soft tissue includes water and other non-fat tissue as well as muscle, so this overstates pure muscle loss.

Does resistance training reduce weight loss on a GLP-1 medicine?

Not in T-REx. Weight and fat loss were almost identical with and without training. The difference was in lean tissue and strength.

Should I take creatine on Mounjaro or Wegovy?

There are no published results in people taking these medicines. Creatine helps lean tissue and strength alongside resistance training in older adults in general, and a placebo-controlled pilot in GLP-1 users is recruiting. Tell your prescriber about any supplement you take.

How much protein do I need?

A US joint Advisory notes that targets of 1.2 to 1.6 g per kilogram a day have been proposed during active weight loss, and that using actual body weight can overestimate needs in people with obesity. It also describes about 80 to 120 g a day, mainly from food. Your clinician or a dietitian can adjust that for kidney disease or other conditions.