Perspective from Paresh Dandona, MD, PhD
Disclosures: Wittert reports receiving grants from the Freemasons Centre for Male Health and Wellbeing at the University of Adelaide, related to the conduct of the present study, as well as grants and honoraria from Lawley Pharmaceuticals and Elsevier, and speaker fees from Bayer and Besins, unrelated to the present study. The researchers also reported receiving grants from the Australian National Health and Medical Research Council, grants and nonfinancial support with the testosterone and matching placebo used in the study from Bayer, grants from Eli Lilly, and nonfinancial support from WW related to the present study.
February 22, 2021
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Testosterone therapy may prevent type 2 diabetes in men without hypogonadism

Perspective from Paresh Dandona, MD, PhD
Disclosures: Wittert reports receiving grants from the Freemasons Centre for Male Health and Wellbeing at the University of Adelaide, related to the conduct of the present study, as well as grants and honoraria from Lawley Pharmaceuticals and Elsevier, and speaker fees from Bayer and Besins, unrelated to the present study. The researchers also reported receiving grants from the Australian National Health and Medical Research Council, grants and nonfinancial support with the testosterone and matching placebo used in the study from Bayer, grants from Eli Lilly, and nonfinancial support from WW related to the present study.
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Compared with placebo, 2 years of testosterone therapy was associated with lower risk for type 2 diabetes among men with impaired glucose tolerance or newly diagnosed diabetes but no hypogonadism, according to trial data.

“Our findings suggest that testosterone treatment for 2 years, as an adjunct to a lifestyle program, can prevent or revert type 2 diabetes in overweight men without pathological hypogonadism,” Gary Wittert, MBBch, MD, FRACP, professor of medicine and director of the Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Australia, and colleagues wrote in a study published in The Lancet Diabetes & Endocrinology. “This effect compares favorably to that of metformin in the Diabetes Prevention Program and was accompanied by increased muscle mass, grip strength and on average, small but sustained, improvements in sexual function.”

Testosterone drawing Adobe
Source: Adobe Stock

Researchers conducted the Testosterone for Diabetes Mellitus trial, a randomized, double-blind, placebo-controlled, 2-year, phase 3b trial at six Australian tertiary care centers with participants enrolled between Feb. 5, 2013, and Feb. 27, 2017. Participants were men aged 50 to 74 years with a waist circumference of 95 cm or more and with impaired glucose tolerance or newly diagnosed type 2 diabetes. Participants also had a serum testosterone level of 14 nmol/L or lower, and a pathological cause for hypogonadism was excluded in men with testosterone of 8nmol/L or less. The screening testosterone concentration was measured using a platform chemiluminescent assay.

All participants were enrolled in a 2-year lifestyle program from WW (formerly Weight Watchers) that was deemed acceptable to men and effective at preventing type 2 diabetes. Each participant was randomly assigned to 1,000 mg testosterone undecanoate (n = 504; Reandron, Bayer) or placebo (n = 503) at baseline, 6 weeks, and then every 3 months until the end of the study. Blood samples were obtained prior to each dose, and sex steroid levels were measured by Tandem Mass Spectrophotometry at completion of the trial. A validated Active Australia Survey was used to assess whether participants performed sufficient exercise of 150 minutes or more per week.

At 2 years, fewer participants in the testosterone cohort had a 2-hour glucose level of 11.1 mmol/L (80 mg/dL) or higher compared with placebo (RR = 0.59; 95% CI, 0.43-0.8; P = .0007). The testosterone group also had a larger decrease in 2-hour glucose on oral glucose tolerance test during the study compared with placebo (mean difference, –0.75 mmol/L; 95% CI, –1.1 to –0.4; P < .0001). The treatment effect at 2 years was not associated with screening or baseline testosterone concentration.

“It would be useful to see a head-to-head comparison with metformin and a 5-year study to examine the durability of effect and cardiovascular outcomes,” Wittert told Healio.

There was no difference in program adherence between the two groups. The testosterone cohort had larger decreases in fasting glucose, waist circumference, total fat mass and abdominal fat mass. Total muscle mass, arm muscle mass and hand-grip strength increased in the testosterone treatment cohort and decreased in the placebo treated group.

“HbA1c was similar between the groups, most likely because testosterone increases red cell lifespan,” Wittert said.

Safety triggers occurred for 38% of the testosterone group and 19% of the placebo group. In the testosterone cohort, 22% had hematocrit of 54% or higher vs. 1% of the placebo group, and 23% of men receiving testosterone had an increase in prostate-specific antigen of 0.75 g/mL or more vs. 19% of the placebo group. There were serious adverse events reported in 10.9% of testosterone participants and 7.4% of the placebo group, but there were no differences in cardiovascular events or prostate cancer.

Researchers cautioned that the trial’s findings should not be generalized because it involved a low-risk population, a structured lifestyle program, frequent monitoring and support of the participants. Additionally, they said screening for preexisting risk factors, especially for an increase of hematocrit, may be necessary.

“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,” the researchers wrote. “For now, we consider it premature to treat men who do not have pathological hypogonadism with testosterone, for whom the primary approach should be assessment and management of physical and psychological conditions and risk factors known to be causally associated with functional hypogonadism.”

For more information:

Gary Wittert, MBBch, MD, FRACP, can be reached at gary.wittert@adelaide.edu.au.