The results of the TIMES2 study indicate that a transdermal testosterone regiment improves glucose control, insulin resistance, lipid parameters, and sexual health in hypogonadal men with type 2 diabetes and metabolic syndrome (1). The idea of improving metabolic profile with a bonus of increased libido must be charming for all the physicians working in the field. However, after winnowing the busy data, we noticed several critical problems with the interpretation of the results.
The effects of testosterone on glycemic control and insulin sensitivity seem to be overemphasized. The abstract states a better glycemic control in the 9th month of testosterone treatment. Yet, it is evident that the HbA1c levels do not decrease, and even get worse in the first 6 months. The “improvement” begins only after concomitant medications were allowed and do not last till the 12th month. Another point is that the improvement of the insulin sensitivity is seen only in the intention-to-treat population (ITT), which includes patients with protocol violations and alterations of the treatment regiments. However, there were no improvements in the per-protocol (PP) or the modified PP (mPP) groups, which were free of the effects of the above confounders. The authors mention that these later groups were not large enough to make any alteration statistically significant. However, this does not seem to be the case because according to the data, 118 patients in the ITT group who completed the study were analyzed along with 95 patients in the PP group and 130 patients in the mPP group.
The authors also underemphasize the effects of testosterone on HDL cholesterol levels. The significant decline in HDL cholesterol levels were neither mentioned in the abstract nor addressed in the discussion sections. However, among all alterations of lipid parameters, the decline in the HDL cholesterol levels was the most significant and consistent one that was present both in the PP and ITT groups and in the ITT subgroups. Instead, the authors bring to the fore the lowering of lipoprotein a (Lpa), LDL cholesterol, and total cholesterol levels in the metabolic syndrome subgroup, and the lowering of Lpa in the total group. So far, the decrement of HDL cholesterol and the Lpa levels were commonly reported as the metabolic results of testosterone replacement therapy (2,3), and none of these alterations has been shown to reduce (or increase) the cardiovascular risk of these patients. These alterations in lipid profiles may only illustrate the complex multifaceted actions of testosterone on lipid metabolism.
Finally, the authors mention that cardiovascular events occurred more commonly in the placebo group, although there was no significant difference between the two groups (P = 0.095). To our knowledge, no randomized, prospective, controlled study has been performed to show beneficial effects of testosterone replacement on cardiovascular outcomes. On the other hand, tendency toward increased cardiovascular events has been reported (4), and a prospective randomized testosterone study has been terminated as the result of increased cardiovascular mortality (5). Therefore, until we get robust cardiovascular safety data, clinicians should be meticulous on prescribing testosterone regiments to patients with increased cardiovascular disease risks.
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