Gianatti et al. (1) have investigated the effect of testosterone therapy on insulin resistance in men with type 2 diabetes with testosterone levels below 12 nmol/L, with the primary outcome measure of insulin resistance by HOMA (HOMA-IR). Several studies have demonstrated an improvement in insulin resistance with testosterone replacement, but this study did not (2). The cut-off value for HOMA-IR to define insulin resistance is generally accepted as being greater >2.5 (3). The mean values for HOMA-IR in the current study at baseline were 2.11 (range 1.69–2.94) in the testosterone arm and 2.78 (1.76–3.93) in the placebo arm. Furthermore, the C-peptide and fasting insulin levels were not elevated or even within the upper normal range. This clearly demonstrates that a significant proportion of the men in the study did not have insulin resistance. So, it is not surprising that no effect was observed. Even if the cohort had had insulin resistance, it is likely the study would have been underpowered and also not shown an effect. The TIMES2 (Testosterone Replacement in Hypogonadal Men With Type 2 Diabetes and/or Metabolic Syndrome) study (4), the first large trial to examine the effect of testosterone replacement on insulin resistance in men with metabolic syndrome and/or type 2 diabetes, studied men (n = 220) with combined mean HOMA-IR value of both arms being 5.4 ± 3.6 (range 1–21). This study did show a significant reduction in insulin resistance with treatment (−15.2%).
It is also not surprising that there was no effect on HbA1c after 40 weeks, especially with a small study population. In addition to the majority of subjects not having insulin resistance, the study group, on the whole, had good glycemic control at baseline (HbA1c 6.8% [51 mmol/mol] treatment arm and 7.1% [54 mmol/mol] in the placebo arm). The study population in TIMES2 also had a mean baseline HbA1c levels showing a reasonably well-controlled population (treatment arm 7.27% [56 mmol/mol]; placebo arm 7.2% [55 mmol/mol]) with no significant change in HbA1c after 30 weeks (4). Conventionally, studies involving the investigation of new glucose-lowering drugs recruit men with uncontrolled diabetes with HbA1c values >6.5% (48 mmol/mol) or 7% (53 mmol/mol). These studies also recruit large numbers, usually >500 subjects.
No data are included as to whether or not the subjects had hypogonadism, which by definition should have included symptoms as well as biochemical evidence of testosterone deficiency. So, it is conceivable that some patients in the current study with testosterone levels in the lower range were testosterone replete. However, the study did show small but significant reductions in total cholesterol and subcutaneous fat consistent with other studies (2).
HOMA-IR is an accepted method for the evaluation of insulin resistance that correlates closely with the gold-standard euglycemic clamp method (5). The key issue with the study by Gianatti et al. (1) is that one must have insulin resistance in the baseline study cohort to be able to assess the effect of any agent on this parameter. This was not the case in this study, so no conclusion can be drawn on an absent effect on insulin resistance—the primary outcome of the study.
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Duality of Interest. T.H.J. has received research grants and honoraria for nonpromotional educational lectures from Bayer Healthcare; has served on advisory boards for Bayer Healthcare, Besins Healthcare, ProStrakan, Lilly, and Merck; and has provided consultancy for Clarus Therapeutics. No other potential conflicts of interest relevant to this article were reported.
