Testosterone treatment may help prevent type 2 diabetes in overweight and obese men beyond the effects of diet and exercise, according to new trial results. However, it’s premature to recommend testosterone for this use in clinical practice.
In the Testosterone for Diabetes Mellitus (T4DM) trial, investigators randomly assigned 1007 men aged 50 to 74 years with a waist circumference of 95 cm or higher, a serum testosterone concentration of 14.0 nmol/L or less (but without pathological hypogonadism), and impaired glucose tolerance or newly diagnosed type 2 diabetes to receive intramuscular testosterone undecanoate (1000 mg) or placebo. All men also participated in a WW (formerly Weight Watchers) lifestyle program involving group meetings and online access to diet and activity guidelines and self-monitoring tools. Men with an estimated glomerular filtration rate of 30 mL/min/1.73 m² or less or high cardiovascular risk were among those excluded from the trial.
Testosterone treatment was associated with a significant 41% decline in type 2 diabetes risk, Gary Wittert, MD, of South Australian Health and Medical Research Institute in Adelaide, Australia, reported in Lancet Diabetes & Endocrinology. At 2 years, fewer patients treated with testosterone than placebo had a 2-hour oral glucose tolerance of 11.1 mmol/L or more: 12% vs 21%, respectively. From baseline, 2-hour glucose declined a significant 0.75 mmol/L more in the testosterone than placebo group (-1.70 vs –0.95 mmol/L, respectively), independent of baseline testosterone levels.
Testosterone replacement also correlated with modest increases in skeletal muscle mass, grip strength, and sexual function compared with placebo. But it did not improve health-related quality of life. During the trial, medication use for diabetes, lifestyle program engagement, and exercise maintenance were similar between groups.
With respect to safety, hematocrit greater than 54% (22% vs 1%) and a PSA increase of 0.75 μg/mL or more (23% vs 19%) occurred in greater proportions of the testosterone than placebo group. Prespecified serious adverse events occurred in 10.9% vs 7.4%, respectively, and 2 patients in each group died.
“Although these data might inform decisions about testosterone as a pharmacotherapy for diabetes prevention, the minimum dose exposure, duration of treatment, durability of effect, and long-term safety remain to be determined,” according to Dr Wittert’s team. For now, they consider it premature to use testosterone in men without pathologic hypogonadism.
“We agree: one of the key goals in preventing diabetes is to slow progression to cardiovascular pathology, and in view of the major uncertainties about the vascular effects of testosterone, outcome trials are necessary before any conclusions can be drawn,” Naveed Sattar, MD, PhD, of the University of Glasgow in Glasgow, UK, and coauthors commented in an accompanying editorial. “Concerns about prostate safety also need longer-term trials.”
Disclosure: This clinical trial was supported by the Australian National Health and Medical Research Council, Bayer, Eli Lilly, University of Adelaide, and WW. 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 Diab Endocrinol. doi:10.1016/S2213-8587(20)30367-3
Sattar N, Boyle JG, Al-Ozairi E, et al. Testosterone replacement to prevent type 2 diabetes? Not just yet. Lancet Diab Endocrinol. doi:10.1016/S2213-8587(20)30373-9