Testosterone Gel Improves Diabetes in Men with Low Levels

Insulin resistance as measured by the HOMA-IR standard was cut by about 15% in hypogonadal men with overt type 2 diabetes or metabolic syndrome in the placebo-controlled trial, although the results were marred by a high dropout, according to Hugh Jones, MD, MBChB, of the University of Sheffield in England.

Moreover, glycated hemoglobin levels were cut by half a percentage point after six months of treatment, Jones said during a presentation here at at the Society for Endocrinology annual meeting.

Low testosterone is a known risk factor for type 2 diabetes in men. Up to one-third of men with type 2 diabetes are testosterone-deficient, due to aging or treatment for prostate or testicular cancer.

Jones reported results from a randomized, international, multicenter trial of a 2% topical testosterone gel.

A number of previous, smaller studies had suggested that testosterone replacement was beneficial in hypogonadal men with or at risk for type 2 diabetes, he said.

The investigators recruited 220 patients with a serum testosterone level below 11 nmol/L or calculated free serum testosterone less than 255 pmol/L, along with at least two symptoms of testosterone deficiency and no replacement therapy within the previous six months.

Participants also had to meet International Diabetes Federation criteria for metabolic syndrome and/or type 2 diabetes.

They were randomized to receive either a placebo gel or the testosterone product (Tostran) at 60 mg/day. Serum levels were monitored and doses were adjusted to meet a target of at least 17 nmil/L. Treatment lasted one year.

Importantly, no changes in preexisting glucose- or lipid-lowering medications were permitted during the first six months of treatment unless absolutely necessary, Jones said.

The primary study outcome was the change in HOMA-IR values. Secondary endpoints included changes in glycated hemoglobin, blood lipids, body composition, and sexual function.

Compared with placebo, the group receiving the active treatment had declines in HOMA-IR of 0.85 points on an intent-to-treat basis (P=0.018) at six months and 0.84 points (P=0.06) at 12 months, Jones reported.

That reduction, approximately 15%, is less than what is typically seen with thiazolidinedione drugs (around 25%), he said.

The loss of significance in the second half of the study was the result of discontinuation rates of 54% in both study arms, Jones indicated.

Eleven patients in the placebo group and 17 receiving the testosterone gel withdrew because of adverse effects.

The vast majority of discontinuations were for other reasons, such as consent withdrawal and loss to follow-up, which Jones attributed to the large number of clinical sites involved in the study (40 in eight countries).

Nevertheless, the study produced statistically significant results for several outcomes in the intent-to-treat sample:

• Patients with type 2 diabetes, with or without metabolic syndrome: HOMA IR reduction at six months, 15% versus placebo (P<0.05); -20% at 12 months versus placebo (P<0.01)
• Patient with metabolic syndrome, with or without type 2 diabetes: Waist circumference reduced 1.1 cm versus placebo (P<0.05) at 12 months
• Patients with type 2 diabetes: HbA1c reduced 0.58% at six months (P=0.002) and 0.50% at 12 months (P=0.035) relative to placebo
• Total sample: Lipoprotein-a levels reduced by 0.06 mmol/L at six months (P<0.05) and by 0.05 at 12 months (P<0.01)

Jones also reported that sexual desire, intercourse satisfaction, and overall sexual satisfaction on the International Index of Erectile Function scale were also significantly improved in the intent-to-treat sample with testosterone replacement. There were trends toward better erectile and orgasmic function as well.

Several other outcomes were significantly improved in patients who completed treatment, including cholesterol and percentage body fat.

Adverse events were largely related to irritation caused by the gel -- and were nearly as common with the placebo agent as with the active treatment. Symptoms such as erythema and pruritus were reported. Nasopharyngitis and arthralgia were also common.

Serious adverse events were rare, leading to withdrawal of two patients from each group. One fatal myocardial infarction occurred in the placebo group.

"This was the first large placebo-controlled study to show that testosterone replacement in hypogonadal men with metabolic syndrome or diabetes improves insulin resistance and glycemic control," Jones concluded.

Medpage Today, March 16, 2010