Higher testosterone levels Linked to Lower CV Risk in Men With Type 2 Diabetes: Study

Cardiovascular disease continues to be the principal cause of morbidity and mortality in people with T2D. Although established risk factors include hypertension, dyslipidemia, obesity, and glycemic control, emerging evidence also suggests that endogenous sex hormones could be involved in the regulation of cardiometabolic risk. Testosterone, estradiol, and sex hormone-binding globulin (SHBG) have been shown to be involved in metabolic pathways such as insulin sensitivity, inflammation, fat distribution, and endothelial function. However, there has been a lack of prospective information on their relationship with major adverse CV outcomes in T2D, especially in the context of lifestyle changes and weight loss.

The aim of the current study was to determine whether baseline hormone concentrations and changes at 1 year following a lifestyle intervention were related to CV outcomes, and whether weight loss modified these associations. This prospective study included 2,260 adults with T2D in the LookAHEAD trial. The LookAHEAD trial was a large multicenter randomized clinical trial designed to determine the impact of intensive lifestyle intervention on cardiovascular outcomes in overweight or obese individuals with T2D.

Baseline levels of hormones and changes at 1 year were categorized into sex-specific tertiles. Researchers analyzed associations of these tertiles with the development of CV events (n = 488). These analyses also tested interaction with weight loss, stratified by ≥7% vs <7% weight loss at 1 year.

Key findings

• Higher baseline levels of total testosterone were significantly associated with lower CV risk.

• The hazard ratio (HR) was 0.74 (95% CI 0.56–0.97), corresponding to a 26% relative reduction in CV risk for men with higher levels of total testosterone.

• In men who achieved ≥7% weight loss, higher levels of SHBG over 1 year were inversely associated with CV risk.

• The HR was 0.47 (95% CI 0.26–0.85), corresponding to a 53% reduction in CV risk in this subgroup.

• In contrast, in men who lost <7% of body weight, higher levels of estradiol were associated with increased CV risk.

Compared with the lowest estradiol tertile:

• Second tertile: HR 1.64 (95% CI 1.13–2.38)

• Third tertile: HR 1.88 (95% CI 1.29–2.73)

In women with T2D:

• No significant associations were found between baseline hormone levels, 1-year changes in sex hormones, and CV events.

In men with type 2 diabetes, but not women, sex hormones were significantly associated with CVD events. Greater baseline testosterone and SHBG with ≥7% weight loss were associated with lower CVD risk, while increasing estradiol in men without significant weight loss was associated with higher risk. These results underscore the role of sex-specific endocrine variables in CVD risk stratification in patients with T2D and suggest that endocrine profiling may improve personalized preventive approaches.

Reference:

Teresa Gisinger, Jiahuan Helen He, Chigolum P. Oyeka, Jianqiao Ma, Nityasree Srialluri, Mark Woodward, Erin D. Michos, Rita R. Kalyani, Jeanne M. Clark, Alexandra Kautzky-Willer, Dhananjay Vaidya, Wendy L. Bennett; Sex Hormones and Cardiovascular Risk in Type 2 Diabetes: Cohort Study of the LookAHEAD Trial. Diabetes Care 2026; dc252465. https://doi.org/10.2337/dc25-2465