Resistance exercise to attenuate lean mass loss during tirzepatide therapy for obesity: a randomized controlled trial
- Design
- Randomized trial · 120 participants · Intermediate outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationINDIRECT: all participants had overweight or obesity (entry BMI ≥30, or ≥27 with a weight-related comorbidity; 86.7% obese), although they were aged 50−70 (mean 57.7) without diabetes or cardiovascular disease.
- Could weight loss explain it?
- Not applicableThe co-primary outcomes are body composition (fat and lean soft tissue mass), so weight-loss mediation is not applicable. Weight loss was similar in both arms, so the smaller lean mass loss with exercise is not explained by a difference in weight loss; tirzepatide's own changes were not separated from weight loss.
- Study tier
- Study tier 2MODERATE: single-centre, open-label randomized trial of 120 people, 111 completing, with intermediate outcomes (DXA body composition, strength); the randomization tests resistance exercise added to tirzepatide, and there is no arm without tirzepatide, so the drug's own effects are uncontrolled.
- Assessment
- Version 4 · Two reviewers differed; settled by a recorded ruling · Nov 11, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
In this 40-week randomized trial, 120 adults aged 50−70 with overweight or obesity and no diabetes all took tirzepatide and were assigned either to supervised resistance exercise three times a week or to their usual activities. Weight loss was similar in both groups (-22.61 kg and -22.28 kg) and fat mass loss did not differ, but the exercise group lost less lean soft tissue mass (-3.57 kg against -4.67 kg). Bench press, lat pulldown and knee extension strength fell in people on tirzepatide alone and rose with added exercise. Every participant took tirzepatide, so the trial tests the added exercise; the drug's own effects are changes over time with no untreated group for comparison.
01Findings
What the study reported
- Drugs
- Tirzepatide
- Treatment duration
- 40 weeks
- Dose
- initiated at 2.5 mg and increased by 2.5 mg every 4 weeks, aiming for a 15 mg weekly maintenance dose at week 20; 78 participants finished on 15 mg
- Route
- subcutaneous
- Comparator
- tirzepatide with usual activities (no resistance exercise); every participant received tirzepatide, with no arm without it
- Primary outcome
- co-primary: changes in DXA total fat mass and total lean soft tissue mass
- Effect
- Tirzepatide plus resistance exercise vs tirzepatide with usual activities: total lean soft tissue mass loss smaller (T = -4.67 kg, T+REx = -3.57 kg; between-group difference 1.09 kg, P < 0.001); total fat mass loss similar (T = -17.19 kg, T+REx = -17.98 kg; between-group difference -0.77 kg, P = 0.700); weight loss similar (T = -22.61 kg, T+REx = -22.28 kg, P = 0.694); bench press, lat pulldown and knee extension strength fell with tirzepatide alone and rose with T+REx (all P < 0.001 versus tirzepatide); no between-group difference in blood pressure, glycaemia or lipids (all P > 0.05)
- 97.5% confidence interval
- 0.43 to 1.75 kg for the lean soft tissue mass difference; −2.14 to 0.60 kg for the fat mass difference; Bonferroni-adjusted co-primary outcomes, labelled 95% CI in the abstract
- P value
- P < 0.001 (lean soft tissue mass); P = 0.700 (fat mass)
- Follow-up
- 40 weeks
- Adverse events
- Gastrointestinal events common and at similar frequencies in both arms (nausea in about half; vomiting, constipation, diarrhea and indigestion each about one-third); six serious adverse events (five in T, one in T+REx), all judged unrelated to treatment; six withdrawals for adverse events
- Limitations
- Single-centre, open-label 40-week trial of 120 people with no arm without tirzepatide, so tirzepatide's own effects are uncontrolled changes over time; DXA lean soft tissue mass is not the same as muscle mass, strength testers were not blinded, participants were sedentary adults without diabetes or cardiovascular disease, and the long-term effect of the lean mass difference is unknown.
Who was studied
- Mean age
- 57.7
- Age range
- 50.1−70.3
- Age min
- 50
- Sex distribution
- 50% female
- Bmi mean
- 33.08 (T) and 34.62 (T+REx), baseline marginal means; no whole-cohort mean stated
- Bmi min
- 27
- Obesity status
- required (BMI ≥30 kg m−2, or ≥27 kg m−2 with at least one weight-related comorbidity); 86.7% obese, 13.3% overweight
- Diabetes status
- excluded (history of diabetes mellitus)
- Cvd status
- excluded (history of cardiovascular disease)
- Ckd status
- eGFR <45 ml min−1 excluded; otherwise not reported
- Baseline condition
- overweight or obesity (sedentary, community-dwelling men and postmenopausal women aged 50−70)
- Sample size
- 120
- Inclusion exclusion
- men and postmenopausal women aged 50−70, BMI ≥30 or ≥27 with a weight-related comorbidity, under 60 minutes of moderate or higher intensity exercise a week; excluded diabetes, cardiovascular disease, pancreatitis, prior incretin therapy, bariatric surgery, statins or antihypertensives within 3 months, eGFR <45 and HbA1c >7.0%
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 120
- Randomization
- yes
- Blinding
- open-label
- Comparator
- tirzepatide with usual activities (no resistance exercise); every participant received tirzepatide, with no arm without it
- Follow up duration
- 40 weeks
- Outcome type
- intermediate
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- INDIRECT
- Statistical precision
- 97.5% CIs reported for the co-primary outcomes; 120 randomised, 111 (93%) completed
- Risk of bias
- not assessed
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- Western Australian State Government Research Excellence Award (REA2022) and Australian Postgraduate Awards; Eli Lilly supplied tirzepatide only
- Industry funded
- Partial
- Manufacturer
- Eli Lilly (supplied tirzepatide)
- Sponsor role
- Eli Lilly reviewed the protocol, supplied tirzepatide through an investigator-initiated trial program and reviewed a manuscript draft for intellectual property or new safety issues, with no changes made; no other funding and no role in trial conduct
- Author conflicts
- Three authors report speaker honoraria from Eli Lilly (with Novo Nordisk and Boehringer Ingelheim for some), one of them also an advisory role for Eli Lilly and shares in and an advisory role with ProGenis Pharmaceuticals, a fourth reports honoraria and grants from Abbott, Fresenius Kabi and Nutricia Australia, and the others declare no competing interests.
- Independent replication
- unknown
- Notes
- Authors declare relationships with the drug's manufacturer: Eli Lilly
Funding is shown on every study and never used to score it.
03Claims
Claims this study bears on
- GLP-1-induced weight loss causes clinically meaningful loss of muscle mass or function.Consistent, but doesn't test the claim
T-REx randomized 120 adults aged 50-70 with overweight or obesity, all taking tirzepatide, to resistance exercise or usual activities for 40 weeks: on tirzepatide alone, total lean soft tissue mass fell (-4.67 kg) and bench press, lat pulldown and knee extension strength fell; with exercise, lean-mass loss was smaller (difference 1.09 kg, 97.5% CI 0.43 to 1.75) and strength rose, with similar weight and fat-mass loss. No arm went without tirzepatide.
04Source
The source, as retrieved
Abstract
Incretin mimetics as obesity therapy induce substantial weight and fat loss but also decrease lean soft tissue mass, possibly impairing skeletal muscle function. Here, in this two-arm randomized controlled trial of adding resistance exercise (REx) to tirzepatide (T), 120 adults with overweight or obesity were treated with tirzepatide and randomized to thrice-weekly resistance exercise training or usual activities for 40 weeks. Tirzepatide was safe, and most participants tolerated up-titration to 15 mg weekly. Adherence to resistance exercise was 91%. Weight loss achieved was similar (T = -22.61 kg, T+REx = -22.28 kg, P = 0.694). For primary outcomes, loss of total fat mass was similar (T = -17.19 kg, T+REx = -17.98 kg, P = 0.700; between-group difference = -0.77 kg, 95% confidence interval (CI): -2.14 kg to 0.60 kg), but resistance exercise reduced loss of total lean soft tissue mass (T = -4.67 kg, T+REx = -3.57 kg, P < 0.001; between-group difference = 1.09 kg, 95% CI: 0.43-1.75 kg). For related endpoints, resistance exercise reduced loss of appendicular lean soft tissue mass (T = -3.55 kg, T+REx = -2.92 kg, P < 0.001). Upper and lower body muscle strength decreased with tirzepatide (bench press -4.09 kg, lat pulldown -4.42 kg, knee extension -4.42 kg) but increased with T+REx (+4.68 kg, +8.58 kg, +5.88 kg, respectively, all P < 0.001 versus tirzepatide). In conclusion, resistance exercise training attenuated loss of total lean soft tissue mass, representing an effective adjunct to tirzepatide anti-obesity therapy. Australian New Zealand Clinical Trials Registry identifier: ACTRN12623001236684 .
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Nov 11, 2026 | 43003902 first ingestion |