Testosterone therapy may prevent type 2 diabetes in men without hypogonadism
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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.”
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.
Perspective
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Type 2 diabetes is associated with hypogonadotropic hypogonadism in men. Hypogonadal diabetic patients have been shown to be more insulin resistant than eugonadal patients with type 2 diabetes. Previous work has shown that testosterone replacement leads to a significant reduction in insulin resistance with a loss of adipose tissue and an increase in lean body mass. In addition, testosterone treatment of hypogonadal patients with prediabetes and diabetes has recently been shown to improve or even reverse these conditions (Haider KS, et al. Diabetes Obes Metab. 2020;doi:10.1111/dom.14122).
With these facts in the background, the team led by Wittert first determined that the critical concentration of testosterone below which the incidence of hypogonadism in their type 2 diabetic population increased was 16 nmol/L. On this basis, Wittert and colleagues set up a prospective, randomized clinical trial to compare the effect of testosterone treatment and lifestyle change in early diabetic and prediabetic patients with abdominal obesity and testosterone concentrations of less than 14 mmol/L with that of lifestyle alone. Treatment with testosterone along with lifestyle modification led to a reduction in glycemia and to a greater reduction in the occurrence of diabetes (RR = 0.59) over a period of 2 years, when compared with lifestyle modification alone. Post-glucose challenge 2-hour glucose concentration fell by 1.7 mmol/L. There was an increase in muscle mass, muscle strength, reduction in total body fat and abdominal fat with an improvement in sexual function in testosterone-treated patients. These actions of testosterone were independent of the baseline testosterone concentrations.
Important as these observations are, they should trigger further investigations in this area to confirm these observations about the benefits of testosterone and to examine the mechanisms underlying these effects.
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