Effect of Testosterone on Progression From Prediabetes to Diabetes in Men With Hypogonadism: A Substudy of the TRAVERSE Randomized Clinical Trial - PubMed (original) (raw)

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. 2024 Apr 1;184(4):353-362.

doi: 10.1001/jamainternmed.2023.7862.

A Michael Lincoff 2, Steven E Nissen 2, Kathleen Wannemuehler 3, Marie E McDonnell 4, Anne L Peters 5, Nader Khan 6, Michael C Snabes 6, Xue Li 6, Geng Li 3, Kevin Buhr 3, Karol M Pencina 1, Thomas G Travison 7 8

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Effect of Testosterone on Progression From Prediabetes to Diabetes in Men With Hypogonadism: A Substudy of the TRAVERSE Randomized Clinical Trial

Shalender Bhasin et al. JAMA Intern Med. 2024.

Abstract

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

Main outcomes and measures: 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 A1c 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: 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 A1c 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 = .49). The proportions of participants with diabetes who experienced glycemic remission and the changes in glucose and hemoglobin A1c levels were similar in testosterone- and placebo-treated men with prediabetes or diabetes.

Conclusions and relevance: 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: ClinicalTrials.gov Identifier: NCT03518034.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bhasin reported grants to the institution from Metro International Biotech and Function Promoting Therapies, LLC; receiving consulting fees from Varsenis One and OPKO; having equity in Xyone outside the submitted work; and having a patent for a free T algorithm issued. Dr Lincoff reported receiving personal fees from Novo Nordisk, Eli Lilly and Company, Recor, Medtronic, Ardelyz, GlaxoSmithKline, Akebia, Endologix, Fibrogen, Provention, and Becton Dickson and receiving grants from Esperion, CSL, AstraZeneca, and Novartis outside the submitted work. Dr Snabes reported being a shareholder in AbbVie during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.

Figure 1.. CONSORT Diagram Showing the Flow of Study Participants Through Different Phases of the Study

All participants who were classified as having prediabetes or diabetes at baseline and who had at least 1 postbaseline value were included in the analyses. Because this was an event-driven trial, the randomized participants were followed up until accrual of at least 256 major adverse cardiovascular events. Thus, the follow-up duration varied for different participants. HbA1c indicates hemoglobin A1c.

Figure 2.

Figure 2.. Progression From Prediabetes to Diabetes Among Participants Who Had Prediabetes at Baseline

The risk ratio of progression to diabetes in the testosterone replacement therapy (TRT) vs placebo group was estimated by repeated-measures log-binomial generalized estimating equations regression with fixed effects for treatment, visit, treatment-visit interaction, and preexisting cardiovascular disease and an unstructured correlation matrix to account for repeated measures. A simpler compound symmetric matrix was used due to the algorithm’s inability to estimate the covariance function needed for the omnibus test when an unstructured matrix was assumed. The omnibus test P value was .49 for a test of the null hypothesis of no difference between TRT and placebo groups across all time points. RR indicates relative risk.

Figure 3.

Figure 3.. Glycemic Remission Among Men Who Had Diabetes at Baseline by Treatment Group and Time Point

The risk of glycemic remission in the testosterone replacement therapy (TRT) vs placebo group was estimated by repeated-measures log-binomial generalized estimating equations regression with fixed effects for treatment, visit, treatment-visit interaction, and preexisting cardiovascular disease and an unstructured correlation matrix to account for repeated measures. The omnibus test P value was .95 for a test of the null hypothesis of no difference between TRT and placebo groups across all time points. RR indicates relative risk.

Figure 4.

Figure 4.. Estimated Changes From Baseline in Fasting Glucose and Hemoglobin A1c (HbA1c) Levels for Participants Who Had Prediabetes or Diabetes at Baseline

A linear mixed model was fit with fixed effects for treatment, visit, and treatment-visit interaction, baseline value, and preexisting cardiovascular disease and a random per-participant repeated-measures effect with an unstructured covariance matrix. Omnibus test P values were derived separately for participants with prediabetes and diabetes from a test of the null hypothesis of no difference between the testosterone replacement therapy (TRT) and placebo groups across all time points. To convert glucose to mmol/L, multiply by 0.0555; and hemoglobin A1c to proportion of hemoglobin, multiply by 0.01. Error bars indicate 95% CIs.

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