Response to Comment on: Jones et al. Testosterone Replacement in Hypogonadal Men With Type 2 Diabetes and/or Metabolic Syndrome (the TIMES2 Study). Diabetes Care 2011;34:828–837

The primary outcome of the TIMES2 study was to determine if testosterone replacement improved insulin resistance in hypogonadal men with metabolic syndrome and/or type 2 diabetes. There is substantial evidence that hypogonadism is associated with reduced insulin sensitivity and that testosterone replacement increases sensitivity as assessed by hyperinsulinemic-euglycemic clamp and homeostasis model assessment of insulin (HOMA-IR). TIMES2 showed a significant benefit on reduction in insulin resistance (−15%), similar to that reported with metformin. Changes in HOMA-IR in the per-protocol group did not reach significance, but in the type 2 diabetes cohort after 12 months approached significance (P = 0.067; n = 50). In the total modified per-protocol population, changes in HOMA-IR almost reached significance at 6 (P = 0.053) and 12 months (P = 0.055), with a significant reduction in modified per-protocol type 2 diabetic subjects completing 12 months (P = 0.037). These results suggest that statistical power was lost because of insufficient numbers. The beneficial effect of testosterone on HOMA-IR was confirmed in a study of hypogonadal men with metabolic syndrome (n = 220) (1).

The TIMES2 study was not designed or powered to investigate the effect of testosterone replacement on glycemic control, since the majority of subjects had HbA_1c levels that were <7% (HbA_1c mean ± SD: metabolic syndrome 6.62 ± 1.22%; type 2 diabetes 7.16 ± 1.39%). Inclusion criteria for trials investigating hypoglycemic drug action usually have HbA_1c >7% with large subject numbers. We did not expect to find an effect on HbA_1c; however, a significant difference was detected between placebo and treatment at 9 months. A deterioration in HbA_1c with placebo is not an uncommon observation. We stated that “no clear conclusion can be made.” Evidence that testosterone improves glycemic control required a dedicated study sufficiently powered in uncontrolled diabetes. Some studies have demonstrated improvements in HbA_1c.

Studies have found conflicting effects of testosterone on HDL cholesterol with either small decreases, no effect, or increases in levels. Testosterone may stimulate reverse cholesterol transport back to the liver, and this could lead to early consumption of HDL cholesterol. In TIMES2, the effect of testosterone on HDL cholesterol becomes nonsignificant after 9 months. The effects of testosterone on cholesterol and LDL cholesterol are important, especially because many subjects were treated with statins or other lipid-lowering agents (n = 139). Reducing lipoprotein (a) in diabetes is a novel finding. Until a 5-year outcome study of testosterone versus placebo has been performed, the evidence for testosterone on reducing cardiovascular risk, events, and mortality cannot be firmly established.

Cardiovascular events did occur more frequently in the placebo group. Again, the study was not powered to investigate this definitively, and we agree that larger studies are required, but safety data in TIMES2 study is reassuring. We are confused by the comments (2) in relation to cardiovascular events and mortality because the referenced study was epidemiological, not interventional.

In summary, the effect of testosterone on insulin resistance was not overemphasized, and those on secondary outcomes were reported and discussed appropriately.