Question听 Does testosterone replacement therapy (TRT) prevent progression from prediabetes to diabetes or induce glycemic remission in middle-aged and older men with hypogonadism?

Findings听 In this randomized clinical trial of 5204 participants aged 45 to 80 years with hypogonadism and prediabetes (n鈥�=鈥�1175) or diabetes (n鈥�=鈥�3880), the risk of progression from prediabetes to diabetes did not differ significantly between a group that received TRT and a placebo group and TRT did not improve glycemic control in men with prediabetes or diabetes.

Meaning听 This study did not provide evidence of TRT鈥檚 efficacy in preventing progression from prediabetes to diabetes or improving glycemic control in men with hypogonadism.

Importance听 The effect of testosterone replacement therapy (TRT) in men with hypogonadism on the risk of progression from prediabetes to diabetes or of inducing glycemic remission in those with diabetes is unknown.

Objective听 To evaluate the efficacy of TRT in preventing progression from prediabetes to diabetes in men with hypogonadism who had prediabetes and in inducing glycemic remission in those with diabetes.

Design, Setting, and Participants听 This nested substudy, an intention-to-treat analysis, within a placebo-controlled randomized clinical trial (Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men [TRAVERSE]) was conducted at 316 trial sites in the US. Participants included men aged 45 to 80 years with hypogonadism and prediabetes or diabetes who were enrolled in TRAVERSE between May 23, 2018, and February 1, 2022.

Intervention听 Participants were randomized 1:1 to receive 1.62% testosterone gel or placebo gel until study completion.

Main Outcomes and Measures听 The primary end point was the risk of progression from prediabetes to diabetes, analyzed using repeated-measures log-binomial regression. The secondary end point was the risk of glycemic remission (hemoglobin A_1c level <6.5% [to convert to proportion of total hemoglobin, multiply by 0.01] or 2 fasting glucose measurements <126 mg/dL [to convert to mmol/L, multiply by 0.0555] without diabetes medication) in men who had diabetes.

Results听 Of 5204 randomized participants, 1175 with prediabetes (mean [SD] age, 63.8 [8.1] years) and 3880 with diabetes (mean [SD] age, 63.2 [7.8] years) were included in this study. Mean (SD) hemoglobin A_1c level in men with prediabetes was 5.8% (0.4%). Risk of progression to diabetes did not differ significantly between testosterone and placebo groups: 4 of 598 (0.7%) vs 8 of 562 (1.4%) at 6 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鈥�=鈥�.49). The proportions of participants with diabetes who experienced glycemic remission and the changes in glucose and hemoglobin A_1c levels were similar in testosterone- and placebo-treated men with prediabetes or diabetes.

Conclusions and Relevance听 In men with hypogonadism and prediabetes, the incidence of progression from prediabetes to diabetes did not differ significantly between testosterone- and placebo-treated men. Testosterone replacement therapy did not improve glycemic control in men with hypogonadism and prediabetes or diabetes. These findings suggest that TRT alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism.

Trial Registration听 ClinicalTrials.gov Identifier: