Testosterone therapy reduces insulin resistance in men with adult-onset testosterone deficiency and metabolic syndrome. Results from the Moscow Study, a randomized controlled trial with an open-label phase.

Testosterone undecanoate (TU) therapy significantly reduced median HOMA-IR at almost every time point after 18 weeks compared to baseline in both the study and confirmatory cohorts.

• The randomized controlled trial comprised 184 men with MetS and hypogonadism (TU: 113 men, placebo: 71 men).
• Analysis focused on men not receiving antiglycaemic agents (TU: 81 men; placebo: 54 men) to avoid confounding effects on HOMA-IR.
• Significant HOMA-IR reductions were observed starting at 18 weeks and continued through the open-label phase up to 138 weeks.
• Placebo was not associated with significant change in HOMA-IR (ΔHOMA-IR).

TU treatment was associated with significant decreases in both fasting glucose and fasting insulin levels.

• Fasting glucose decreased by -2.1% at 30 weeks and -4.9% at 138 weeks following TU treatment.
• Fasting insulin decreased by -10.5% at 30 weeks and -35.5% at 138 weeks following TU treatment.
• The percentage change in insulin was greater than the percentage change in fasting glucose.
• These findings suggest that HOMA-IR improvements may be greater than suggested by change in fasting glucose alone in men with MetS/T2DM not on antiglycaemic therapy.

Baseline HOMA-IR was the only consistent predictor of HOMA-IR decrease following TU treatment.

• Regression analysis was performed to identify factors associated with change in HOMA-IR (ΔHOMA-IR).
• Baseline HOMA-IR accounted for r² ≥ 0.64 of the variance in ΔHOMA-IR.
• No other variables were identified as consistent predictors of HOMA-IR reduction.
• Men with higher baseline HOMA-IR showed greater absolute reductions in HOMA-IR with TU treatment.

The study design included a double-blind randomized controlled trial phase followed by an open-label phase, allowing both inter-group and intra-group comparisons.

• The double-blind RCT phase lasted 30 weeks, and the open-label phase extended follow-up to 138 weeks.
• Inter-group comparison of HOMA-IR was restricted to the RCT (30 weeks).
• Intra-group comparison was carried out on the study cohort (TU throughout) and a confirmatory cohort (placebo during RCT, then switched to TU during open-label phase).
• The confirmatory cohort design allowed assessment of whether TU effects observed in the RCT phase could be replicated upon switching from placebo.

The authors concluded that hypogonadism screening should be included in the management of men with metabolic syndrome and type 2 diabetes.

• Improvements in insulin resistance as measured by HOMA-IR in men with MetS/T2DM not on antiglycaemic therapy may be greater than suggested by change in fasting glucose alone.
• The study population included men with both hypogonadism and metabolic syndrome, representing a clinically relevant overlap population.
• The long follow-up period (138 weeks) demonstrated sustained improvements in insulin resistance metrics with TU therapy.