Testosterone replacement therapy gel is effective, safe in men with diabetes

San Francisco-Low levels of testosterone in men have been shown to be associated with cardiovascular disease, type II diabetes, visceral adiposity, dyslipidemia, fatigue, sexual dysfunction, and metabolic syndrome, and are more commonly seen in aging men. Data from a 1-year study presented at The Endocrine Society's ENDO 08 meeting here show that testosterone replacement therapy in hypogonadal men suffering from these symptoms can be effective in significantly improving insulin sensitivity and sexual function, with durable results.

"The hope is that the longer-term replacement of testosterone in hypogonadal men with type II diabetes or metabolic syndrome will improve their insulin sensitivity and also their long-term glycemic control, ultimately leading to a reduction in the effects of type II diabetes, especially improvement in cardiovascular risk," said Julian Howell, MD, head of clinical development at ProStrakan Pharmaceuticals Ltd., Galashiels, United Kingdom. "Our goal is also to improve the quality of life of these patients by improving their symptoms of hypogonadism."

ProStrakan sponsored the TIMES 2 testosterone replacement study, which evaluated the effect of topical 2% testosterone gel, 20 mg/mL (Tostran [not available in the U.S. market]) on insulin resistance, glycemic control, lipids, erectile function, and quality of life in hypogonadal men with type II diabetes or metabolic syndrome. Eight centers in Europe enrolled 221 hypogonadal men (mean age, 60 years; mean weight, 97 kg; mean BMI, 32), of whom 80%, 64%, and 44% were diagnosed with metabolic syndrome, type II diabetes, or both, respectively.

The primary endpoint of the double-blind study was an improvement in insulin sensitivity as measured by the homeostasis model assessment of insulin resistance (HOMA-IR), a formula that uses fasting serum insulin and glucose levels, at 6 and 12 months. Secondary endpoints included changes in the measurements of study participants' morphology, as measured by the percentage of body fat, waist-hip ratio, and body mass index; cardiovascular events; and safety and tolerability.

In order to measure long-term glycemic control, HbA1c values also were examined, as were erectile function and the symptoms of hypogonadism.

At 6 months, mean change from baseline in HOMA-IR index improved significantly in the men using the testosterone gel compared with the placebo group (-0.54 vs. 0.14; p=.018). At 12 months, improvement in HOMA-IR index was maintained: -0.41 versus 0.24 (p=.006). Among those men with diabetes (with or without metabolic syndrome) who used testosterone gel, mean improvement in HOMA-IR index from baseline was -0.62 versus 0.16 for placebo (p=.049) at 6 months and -0.58 versus 0.33 for placebo (p=.010) at 12 months.

Regardless of whether they had diabetes, men with metabolic syndrome who used the testosterone gel had reduced insulin resistance (mean change from baseline vs. placebo at 6 months, -0.56 vs. 0.12 [p=.069]) that approached statisical significance at 12 months (-0.41 vs. 0.14, respectively [p=.054]). Among diabetic men, improvement was not reflected in a significant change from baseline at 1 year in HbA1c, which the investigators attributed to prohibited changes in diabetic medication as a confounding factor.

Compared with the placebo group, men in the testosterone gel group experienced significant improvement in erectile function from baseline at both 6- and 12-month time points (p<.05), according to the International Index of Erectile Function.

Sixty-two percent of patients reported adverse events over the 12-month period, albeit 60% were determined by investigators to have been unrelated to the study drug and 92% of events were classified as mild or moderate, Dr. Howell said. The most frequently reported adverse events were dermal, occurring in 25% of those using the study drug and 17% of the placebo group.

Building on research

Dr. Howell explained that the decision to support the TIMES 2 study was spawned from a double-blind, placebo-controlled, crossover study performed at the University of Sheffield, UK, by Kapoor et al (Eur J Endocrinol 2006; 154:899-906). This study of 24 men with type II diabetes and hypogonadism who were treated with intramuscular injections of testosterone or placebo showed an improvement in insulin sensitivity and glycemic control following testosterone replacement.

"The TIMES 2 study was designed to further evaluate these original results with a gel formulation and over a longer period of time, and also take treatment a step further and include patients with metabolic syndrome," Dr. Howell said.

"The TIMES 2 study shows that testosterone replacement has wider benefits for men than improvement in fatigue or erectile dysfunction. It is very exciting to see that this treatment has the potential to improve glycemic control and reduction in cardiovascular risk."

A completed phase III study in the United States known as FORTIFY uses an identical formulation of the testosterone gel (Fortigel). This study has met all FDA pre-agreed pharmacokinetic endpoints, and ProStrakan plans to file for FDA approval of the formulation later this year.