Testosterone therapy does not slow progression to diabetes, increase odds for remission
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Key takeaways:
- Men with prediabetes receiving testosterone therapy had similar rates for progression to diabetes as placebo.
- No difference between the testosterone and placebo groups was seen in diabetes remission odds.
Testosterone replacement therapy alone did not lower risk for progression from prediabetes to diabetes or increase the likelihood of type 2 diabetes remission among men with hypogonadism, according to study data.
In the TRAVERSE trial, men aged 45 to 80 years with hypogonadism were randomly assigned, 1:1, to transdermal 1.62% testosterone gel (AbbVie) or placebo until the end of the study. In findings from a substudy of the TRAVERSE trial published in JAMA Internal Medicine, researchers found testosterone therapy did not result in differences in glycemic outcomes compared with placebo.
“The findings of this study suggest that testosterone replacement therapy alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism,” Shalender Bhasin, MD, professor of medicine at Harvard Medical School, director of the research program in Men’s Health: Aging and Metabolism and director of the Boston Claude D. Pepper Older Americans Independence Center at Brigham and Women’s Hospital, and colleagues wrote.
The TRAVERSE diabetes study consisted of two subgroups. The prediabetes subgroup included men with an HbA1c between 5.7% and 6.4% or a fasting glucose level between 100 mg/dL and 125 mg/dL. The primary endpoint within the prediabetes group was the risk for progression from prediabetes to diabetes. The diabetes subgroup included TRAVERSE participants with an HbA1c of 6.5% or higher, two fasting glucose levels of more than 125 mg/dL, a current diagnosis of diabetes or use of diabetes medication. The endpoint among those with diabetes was the likelihood of diabetes remission.
There were 1,175 men with prediabetes in TRAVERSE (mean age, 63.8 years), of whom 607 received testosterone therapy and 568 were randomly assigned placebo. The mean follow-up was 32.1 months for the testosterone group and 31.5 months for men receiving placebo. The risk for progression from prediabetes to diabetes was similar in the testosterone and placebo groups at all follow-up points.
TRAVERSE included 3,880 men with diabetes (mean age, 63.2 years), of whom 1,917 received testosterone therapy and 1,963 received placebo. Mean follow-up was 33.5 months for the testosterone group and 33.3 months for placebo. Rates of diabetes remission did not differ between the testosterone and placebo groups during all follow-up timepoints. Change in fasting glucose and HbA1c did not differ between the testosterone and placebo groups among both the prediabetes and diabetes groups.
In the full TRAVERSE trial, men receiving testosterone therapy had a higher incidence of venous thromboembolism, atrial fibrillation and acute kidney injury than the placebo group. There were no additional differences in safety data within the prediabetes and diabetes subgroups.
“Lifestyle modification, metformin, acarbose, pioglitazone and GLP-1 analogs reduce the incidence of progression from prediabetes to diabetes,” the researchers wrote. “The findings of this study do not support the use of testosterone replacement therapy alone to prevent or to treat diabetes in men with hypogonadism. The trial’s findings may be useful in weighing the potential benefits of testosterone replacement therapy in middle-aged and older men with hypogonadism who have prediabetes or diabetes.”
Perspective
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T. Hugh Jones, BSc, MBChB, MD, FRCP
The primary outcome of the TRAVERSE study was reported in the New England Journal of Medicine last year. Testosterone therapy was not associated with an increased risk for a major adverse cardiovascular event compared with placebo in this large study that included men with either known CVD or high CV risk, which comprised approximately 70% of men with diabetes.
The current publication in JAMA reports the results of a substudy among men in TRAVERSE who had prediabetes and diabetes. The effect of testosterone therapy on these groups is not the primary outcome for which the TRAVERSE study was designed. Importantly, there are major issues in the interpretation of the results of the substudy and the conclusions drawn that should be considered.
Firstly, the main paper from the TRAVERSE in the New England Journal of Medicine states subjects were given testosterone gel to maintain testosterone between 350 ng/dL and 750 ng/dL. That paper stated that 25% of men on testosterone therapy did not achieve therapeutic testosterone levels as the median increase was 268 ng/dL to 372 ng/dL. Furthermore, 61% in each of the testosterone and placebo groups ceased treatment during the study. This large group of subjects who have not had therapy optimized will have an effect on results, and therefore, should not be included in the analysis when studying the effect of testosterone therapy.
Secondly, the optimal assessment in prediabetes research should use 2-hour glucose in a glucose tolerance test and not HbA1c. HbA1c does not have high enough assay accuracy at lower levels including in the HbA1c range. The T4D study (n = 1,007), in which the primary outcome was progression of diabetes, did achieve therapeutic testosterone levels and did demonstrate a decrease in the development of overt diabetes (Wittert G, et al. Lancet Diabetes Endocrinol. 2021;doi:10.1016/S2213-8587(20)30367-3). In addition, the effect of testosterone on hematocrit is known to affect HbA1c levels.
Thirdly, in the TRAVERSE study there was no evidence of consistent lifestyle intervention in either the prediabetes or diabetes cohorts. In addition, no data on changes in diabetes medications were recorded. These factors also will clearly have an impact on prediabetes and diabetes.
In type 2 diabetes the response to different drugs, including insulin, may be different between individuals. The same is also true for testosterone replacement therapy. In view of the factors described above and the fact that the T4D study reported a reduction in the progression of prediabetes, it is not clear how the authors can make a conclusion that “testosterone replacement therapy alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism.”
It should also be remembered that the major clinical reason to treat hypogonadism in men with prediabetes and type 2 diabetes is improvement in their symptoms of hypogonadism.
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