Testosterone Ineffective in Preventing Diabetes in Men with Hypogonadism

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Testosterone replacement therapy did not differ significantly from placebo in preventing diabetes progression in a substudy of the TRAVERSE randomized trial.

Shalender Bhasin, MBBS | Image Credit: UKMC

Shalender Bhasin, MBBS

Credit: UKMC

A substudy of the TRAVERSE trial revealed the progression from prediabetes to diabetes did not significantly differ between testosterone replacement therapy (TRT) or placebo treatment among middle-aged and older men with hypogonadism.1

The nested TRAVERSE Diabetes Study, an intention-to-treat analysis within the placebo-controlled randomized clinical trial, was conducted at 316 trial sites in the United States. Among the more than 5200 randomized participants, TRT did not improve glycemic control in those with hypogonadism and prediabetes or diabetes.

“The findings of this study suggest that TRT alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism,” wrote the investigative team led by Shalender Bhasin, MBBS, Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women’s Hospital, Harvard Medical School.

Evidence has linked low testosterone to an increased risk of prediabetes and type 2 diabetes (T2D) in men.2 Men with prediabetes and diabetes have a high prevalence of hypogonadism, while a substantial portion of individuals receiving TRT have diabetes or prediabetes.3 TRT in men with hypogonadism can reduce whole-body and visceral fat mass, increase muscle mass, and improve insulin sensitivity.

As it is not well-understood, Bhasin and colleagues suggested further knowledge on testosterone’s efficacy in preventing progression from prediabetes to diabetes or in inducing glycemic control would be beneficial for clinicians, as well as patients weighing the benefit-risk profile of TRT.1

Men aged 45 to 80 years with hypogonadism and prediabetes, or diabetes were enrolled in TRAVERSE between May 2018 and January 2023. Participants were randomized 1:1 to receive 1.62% testosterone gel or placebo gel until the end of the study. All participants, the study staff, and those assessing outcomes were blinded to randomization.

The primary endpoint of the TRAVERSE Diabetes Study was the risk of progression from prediabetes to diabetes, assessed at all post-randomization time points using repeated-measures log-binomial regression. Secondary endpoints consisted of the risk of glycemic remission in those with diabetes at baseline, defined as a hemoglobin A1c level of ≤6.5% or two fasting glucose measurements <126 mg/dL without antidiabetic medication use.

Of the 5246 individuals randomized in TRAVERSE, 5204 were included in the analysis set for the nested substudy. Among this population, 1175 had prediabetes (607 randomized to TRT), and 3880 had diabetes (1917 randomized to TRT). Baseline characteristics were similar between the testosterone- and placebo-treated cohorts with prediabetes or diabetes – the mean age was 63.8 years, and the mean HbA1c level was 5.8%.

Upon analysis, investigators found the relative risk of progression from prediabetes to diabetes did not significantly between testosterone and placebo groups. Progression risk was identified in 4 of 598 (0.7%) vs. 8 of 562 (1.4%) at six months, 45 of 575 (7.8%) vs. 57 of 533 (10.7%) at 12 months, 50 of 494 (10.1%) vs. 67 of 460 (14.6%) at 24 months, 46 of 359 (12.8%) vs. 52 of 330 (15.8%) at 36 months, and 22 of 164 (13.4%) vs. 19 of 121 (15.7%) at 48 months (omnibus test, P = .49).

Further results showed the risk of glycemic remission among those with diabetes at baseline did not significantly differ between the testosterone and placebo groups. Changes from baseline in fasting glucose or HbA1c concentrations were also similar among testosterone- and placebo-treated groups in those with either prediabetes or diabetes at baseline. Post-hoc sensitivity analysis of the primary and secondary events occurring within 30 days or 365 days after stopping treatment exhibited similar results to the primary analyses.

Based on these data, Bhasin and colleagues indicated the study results do not support the use of TRT alone in the prevention or treatment of diabetes in men with hypogonadism. Still, they could help weigh its benefit-risk profile for each individual.

“The trial’s findings may be useful in weighing the potential benefits of TRT in middle-aged and older men with hypogonadism who have prediabetes or diabetes,” investigators wrote.

References

  1. Bhasin S, Lincoff AM, Nissen SE, et al. Effect of Testosterone on Progression From Prediabetes to Diabetes in Men With Hypogonadism: A Substudy of the TRAVERSE Randomized Clinical Trial. JAMA Intern Med. Published online February 05, 2024. doi:10.1001/jamainternmed.2023.7862
  2. Ruth KS, Day FR, Tyrrell J, etal; Endometrial Cancer Association Consortium. Using human genetics to understand the disease impacts of testosterone in men and women. Nat Med. 2020; 26(2):252-258. doi:10.1038/s41591-020-0751-5
  3. Dandona P, Dhindsa S, Chandel A, Chaudhuri A. Hypogonadotropic hypogonadism in men with type 2 diabetes. Postgrad Med. 2009;121(3):45-51. doi:10.3810/pgm.2009.05.2001
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