Treatment with testosterone over 2 years was associated with a reduction in the risk of type 2 diabetes that was beyond the effects of lifestyle interventions alone in men who were overweight or obese, according to a study in The Lancet Diabetes & Endocrinology.
This is the first-known large-scale, placebo-controlled randomized trial designed to assess testosterone treatment for preventing or reversing type 2 diabetes in overweight or obese men. “We aimed to determine the efficacy and safety of testosterone treatment to prevent progression of impaired glucose tolerance to type 2 diabetes or to reverse newly diagnosed type 2 diabetes beyond the effects of a lifestyle intervention,” wrote the authors who were led by Gary Wittert, MD, of the South Australian Health and Medical Research Institute in Australia.
This multicenter, double-blind, phase 3b Australian trial enrolled 1,007 men between the ages of 50 to 74 years who had a waist circumference of ≥95 cm, serum testosterone concentration of ≤140 nmol/L but without pathological hypogonadism, and impaired glucose tolerance or newly diagnosed type 2 diabetes. These patients were enrolled in a lifestyle program that was designed to prevent type 2 diabetes through diet and exercise.
All patients were randomized to either an intramuscular injection of 1,000 mg testosterone undecanoate (n=504) or placebo (n=503). Treatments were administered at baseline, 6 weeks, and then every 3 months for a total of 2 years. The 2-year incidence of type 2 diabetes, defined as a 2-hour oral glucose tolerance test (OGTT) glucose ≥11.1 mmol/ and mean change from baseline in 2-hour OGTT glucose, comprised the primary outcome.
A significantly lower proportion of patients in the testosterone group had type 2 diabetes at 2 years compared with patients in the placebo arm (12% vs 21%, respectively; relative risk, 0.59, 95% CI, 0.43-0.80; P =.0007). Patients randomized to testosterone also had a significantly greater mean change from baseline 2-hour glucose (–1.70 vs –0.95 mmol/L; mean difference, –0.75 mmol/L; 95% CI, –1.10 to –0.40; P <.0001). According to the investigators, this treatment effect was independent of serum testosterone at baseline.
Approximately 1% of patients in the placebo arm and 22% of patients in the testosterone group experienced an increase in hematocrit to >54%. An increase of ≥0.75 μg/mL in prostate-specific antigen was observed in 23% of participants in the testosterone arm vs 19% of patients in the placebo group.
There was an overall total of 55 prespecified serious adverse events in this study, including 37 (7.4%; 95% CI, 5.4-10.0) in the placebo group and 55 (10.9%; 95% CI, 8.5-13.9) in the testosterone arm. A total of 2 deaths were reported in each treatment group.
Limitations of this study included the self-reported nature of physical activity and adherence with the lifestyle program as well as the exclusion of patients with pathological hypogonadism. The investigators added that “neither benefit nor safety can be generalized beyond the relatively low-risk population enrolled.”
“We consider it premature to advocate for the widespread use of testosterone for diabetes prevention in men without pathological hypogonadism. Identification of subgroups of men more likely to benefit or most at risk of adverse outcomes might aid treatment decisions, but, if testosterone treatment is considered, there must be a concomitant lifestyle programme and careful monitoring of haematocrit, cardiovascular risk factors, and prostate health,” the authors wrote.
Disclosure: This clinical trial was supported by Bayer, Eli Lilly and WW (formerly Weight Watchers). Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Wittert G, Bracken K, Robledo KP, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. Lancet Diabetes Endocrinol. 2021;9(1):32-45. doi:10.1016/S2213-8587(20)30367-3