Resistance exercise to attenuate lean mass loss during tirzepatide therapy for obesity: a randomized controlled trial

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 .