Increasing skeletal muscle mass and strength during incretin-based weight loss

Incretin-based therapies produce robust weight loss in obesity and type 2 diabetes mellitus (T2DM), but some weight lost is lean body mass (LBM), raising concern about sarcopenia and functional decline. Men with obesity or type 2 diabetes (T2DM) and testosterone deficiency may lose skeletal muscle mass (SMM) during weight reduction. Whether a program incorporating testosterone therapy and exercise can preserve SMM during incretin-mediated weight loss remains uncertain.

This retrospective case series included 93 men with obesity, testosterone deficiency symptoms and morning total testosterone <400 ng/dL, with (n = 45) or without (n = 48) type 2 diabetes mellitus, treated at a single outpatient clinic. Participants received weekly tirzepatide, intramuscular testosterone cypionate, and lifestyle coaching focused on resistance exercise and protein intake. Body composition was measured using multifrequency bioelectrical impedance analysis and grip strength using dynamometry at baseline and 3, 6, and 12 months. Laboratory measures included hemoglobin A1c (HbA1C), high-sensitivity C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C), and trough total testosterone. Patient-reported outcomes used the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health 10.

Over 12 months, body weight decreased by 20.9-22.6 kg (18-20%) and fat mass by 16.6-17.1 kg (38-40%). LBM decreased by 4.0-6.1 kg, whereas bioelectrical-impedance-derived SMM increased by 1.6-3.7 kg (4-12%) and grip strength increased by 5.7-7.1 kg (18-21%). Among patients with type 2 diabetes, HbA1c decreased from 10.1% to 5.8%. LDL-C decreased by 20%, hs-CRP decreased by 43-53%, and physical and mental health PROMIS scores improved by 13-16%.

Combining tirzepatide, testosterone, and execise and dietary counseling, along with weekly behavioral support was associated with weight and fat loss accompanied by increased SMM and grip strength despite a net decrease in LBM, likely reflecting disproportionate loss of non-muscle lean tissue relative to skeletal muscle. The uncontrolled multimodal design precludes attribution of these findings to individual components.