Background: Intensive lifestyle intervention(ILI) in type 2 diabetes(T2D) improves cardiometabolic risk factors. Sex differences in these responses may be driven by the sex hormones testosterone(T), estradiol(E2), and sex hormone binding globulin(SHBG). We evaluated whether baseline sex hormone levels modify ILI effects on cardiometabolic risk factors ie, heterogeneity of treatment effect(HTE), and whether these modifications differ by sex. Methods: Study included 2,260 Look AHEAD participants(1,093 postmenopausal females; 1,167 males, mean age 60 years) randomized to ILI or diabetes support and education with sex hormone measurements. We used linear mixed-effects models, stratified by sex and adjusted for age, race, study site, medications and baseline weight, to examine the association between baseline T, E2, and SHBG with change in lipids, hemoglobin A1c(HbA1c), systolic and diastolic blood pressure(BP), weight, and waist circumference(WC) over an 8-year follow-up. HTE was assessed using a three way interaction term between baseline hormone levels, time and randomization arm. Permutation tests controlled for multiple comparisons. Results: In males, lower baseline E2 and total T significantly augmented ILI-induced triglyceride reductions(p=0.019 and 0.008, respectively) throughout follow up. Higher SHBG enhanced LDL-C lowering in females(p=0.018) and HDL-C increases in males(p=0.043). Higher baseline total T predicted greater long-term weight(p=0.013 females; 0.003 males) and WC loss(p=0.061 females; 0.035 males), while fewer hormone interactions were observed for BP and HbA1c. Conclusions: Males with greater endogenous total T achieved larger reductions in triglycerides, weight, and WC, whereas females with higher total T had greater HDL-C improvements and those with higher SHBG experienced more BP lowering. Hormone profiling may guide personalized lifestyle prescriptions to improve long term cardiometabolic benefits.

The authors have declared no competing interest.

The Look AHEAD (Action for Health in Diabetes) trial's ClinicalTrials.gov number is NCT00017953.

This work was funded by NIH-NIDDK grants: R01DK127222 and U01DK57149

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