Combining tirzepatide, testosterone, and exercise and dietary counseling was associated with weight and fat loss accompanied by increased skeletal muscle mass and grip strength despite a net decrease in lean body mass, 'likely reflecting disproportionate loss of non-muscle lean tissue relative to skeletal muscle.'
Key Findings
Results
Body weight decreased substantially over 12 months in men with obesity and testosterone deficiency receiving combined tirzepatide, testosterone, and lifestyle coaching.
Body weight decreased by 20.9–22.6 kg over 12 months
This represented an 18–20% reduction in body weight
The study included 93 men total: 45 with T2DM and 48 without T2DM
All participants had obesity, testosterone deficiency symptoms, and morning total testosterone <400 ng/dL
Treatment was delivered at a single outpatient clinic in a retrospective case series design
Results
Fat mass decreased substantially while skeletal muscle mass increased despite an overall reduction in lean body mass.
Fat mass decreased by 16.6–17.1 kg, representing a 38–40% reduction
Lean body mass (LBM) decreased by 4.0–6.1 kg overall
Bioelectrical-impedance-derived skeletal muscle mass (SMM) increased by 1.6–3.7 kg, representing a 4–12% increase
The authors attribute the divergence between LBM and SMM to 'disproportionate loss of non-muscle lean tissue relative to skeletal muscle'
Body composition was measured using multifrequency bioelectrical impedance analysis at baseline and 3, 6, and 12 months
Results
Grip strength increased meaningfully over the 12-month treatment period.
Grip strength increased by 5.7–7.1 kg over 12 months
This represented an 18–21% increase in grip strength
Grip strength was measured using dynamometry at baseline and 3, 6, and 12 months
Results
Among participants with type 2 diabetes, glycemic control improved markedly over 12 months.
HbA1c decreased from 10.1% to 5.8% in patients with T2DM
This represents an absolute reduction of approximately 4.3 percentage points
45 of the 93 participants had type 2 diabetes mellitus
Results
Cardiometabolic and inflammatory biomarkers improved over the treatment period.
LDL cholesterol decreased by 20%
High-sensitivity C-reactive protein (hs-CRP) decreased by 43–53%
These improvements occurred across the 12-month treatment period
Results
Patient-reported physical and mental health outcomes improved substantially over 12 months.
PROMIS Global Health 10 physical and mental health scores improved by 13–16%
The PROMIS Global Health 10 is a validated patient-reported outcomes measurement tool
Improvements were observed across both physical and mental health domains
Conclusions
The multimodal, uncontrolled design of the study precludes attribution of findings to any individual treatment component.
This was a retrospective case series with no control group
Three simultaneous interventions were used: weekly tirzepatide, intramuscular testosterone cypionate, and lifestyle coaching focused on resistance exercise and protein intake
The authors explicitly state: 'The uncontrolled multimodal design precludes attribution of these findings to individual components'
Weekly behavioral support was also provided alongside pharmacological and lifestyle interventions
Background
Men with obesity or T2DM and testosterone deficiency may lose skeletal muscle mass during weight reduction, raising concern about sarcopenia.
Incretin-based therapies produce robust weight loss but some weight lost is lean body mass (LBM)
This raises concern about sarcopenia and functional decline
The study specifically targeted men with testosterone deficiency symptoms and morning total testosterone <400 ng/dL
Whether a program incorporating testosterone therapy and exercise can preserve SMM during incretin-mediated weight loss was described as 'uncertain' prior to this study
What This Means
This research suggests that a combination treatment program—using the weight-loss drug tirzepatide, testosterone injections, resistance exercise coaching, and dietary guidance—was associated with significant fat loss and improvements in muscle mass and strength in men with obesity and low testosterone levels, even though overall lean body mass declined. Over 12 months, participants lost roughly 20% of their body weight and 38–40% of their fat mass, but their measured skeletal muscle mass actually increased by 4–12% and grip strength improved by 18–21%. The authors propose this apparent paradox—losing lean mass overall while gaining muscle—is explained by the loss of non-muscle tissues (such as organ tissue or connective tissue) that are also counted as 'lean mass.'
For people with type 2 diabetes in the study, blood sugar control improved dramatically, with average HbA1c falling from 10.1% to 5.8%—a level approaching normal. Markers of cardiovascular risk and inflammation also improved, and participants reported better physical and mental well-being. These findings address a concern that has arisen with popular GLP-1/GIP receptor agonist drugs like tirzepatide: that significant muscle loss alongside fat loss could lead to weakness and increased risk of falls or disability, particularly in older or already-vulnerable individuals.
However, this research has important limitations. It was a retrospective case series with no comparison group and no way to separate the effects of tirzepatide, testosterone, exercise, or dietary changes from one another. The authors themselves caution that 'the uncontrolled multimodal design precludes attribution of these findings to individual components.' This means the results are promising but should be interpreted cautiously, and randomized controlled trials would be needed to determine which elements of the program drive the muscle-related benefits.
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C. Mendias, Tariq M. Awan. (2026). Increasing skeletal muscle mass and strength during incretin-based weight loss. Obesity Pillars. https://doi.org/10.1016/j.obpill.2026.100317