Can testosterone prevent type 2 diabetes in men?

T4DM was a two-year randomised, double blind, placebo controlled clinical trial, conducted across six Australian specialist centres. The aim was to identify whether treatment with testosterone can prevent progression of impaired glucose tolerance to type 2 diabetes (T2D) or reverse newly diagnosed T2D in men.

Background

Levels of serum testosterone are lower than normal in obese men, particularly if they are carrying visceral fat and are insulin resistant. These low testosterone levels are independently associated with an increased risk of developing T2D.

Weight loss, achieved by a healthy diet and exercise, prevents the progression of insulin resistance to diabetes and reverses newly diagnosed T2D. Weight loss and it’s beneficial metabolic effects also increase serum testosterone, with the magnitude of effect depending on the amount of weight lost.

Testosterone treatment alone decreases fat mass and increases muscle mass in men, but it is unknown if testosterone can also prevent, or reverse newly diagnosed, diabetes. Whether testosterone treatment can augment the known benefits of a healthy diet and exercise is similarly unknown.

In previous randomised controlled trials, testosterone treatment:

• Did not lower glycated haemoglobin in men with T2D, and
• Did improve insulin resistance in men with T2D or the metabolic syndrome.

In a registry-based study, testosterone treatment prevented progression of insulin resistance to T2D and, in men with T2D, improved glucose metabolism.

The T4DM trial

In the trial, 1,007 men (aged 50-74 years; waist circumference ≥95 cm; with impaired glucose tolerance or newly diagnosed T2D; and with serum testosterone concentrations ≤14 nmol/l) were enrolled in a diet and exercise program, and randomised to receive 3-monthly intramuscular injections of either testosterone undecanoate (1000mg) or placebo. Men with hypogonadism or high cardiovascular risk were excluded.

Primary outcome measures were:

1. The proportion of participants with T2D defined as a 2-hour OGTT result of glucose ≥11.1 mmol/l, and
2. The change in glucose concentration from baseline, with the study powered to find a difference of at least 0.6mmol/l between groups. 

Results

The risk of T2D after two years was 60% lower in the men treated with testosterone relative to the placebo group. The change in glucose from baseline was 0.75 mmol/l lower in men treated with testosterone than in the placebo group. The magnitude of both effects was independent of baseline serum testosterone concentration.  

At two-years, normal glucose tolerance was observed in 43% and 52% of men, respectively, in the placebo and testosterone groups. Reductions in fasting serum glucose (0.17mmol/l) and fat mass (-4.6 vs -1.9 kg), and increases in skeletal muscle mass (+ 0.39 vs -1.32 kg) and hand grip strength, as well as small improvements in sexual function, were observed in men treated with testosterone, compared to those who received placebo. Glycated haemoglobin levels, lower urinary tract symptoms, adherence with the lifestyle program, and overall change in quality of life and mood, were similar in the two groups of men.

Testosterone did not result more adverse cardiovascular events or prostate cancer diagnoses compared to placebo. However, changes in haematocrit (0.04) and prostate specific antigen (0.3ng/ml) during the study were greater in the testosterone group. An increase in haematocrit to 0.54 or higher was observed in 22% men who received testosterone — 25 ceased treatment early as a result.

What does this mean for practice?

Testosterone treatment for two years, in combination with a diet and lifestyle program, prevented or reverted newly diagnosed T2D in overweight men without pathological hypogonadism.

The magnitude of the effect of testosterone on glucose metabolism is like that of metformin (without diet and exercise intervention) in the Diabetes Prevention Program. Metformin and testosterone have comparable effects when it comes to decreasing fat mass, but metformin does not increase skeletal muscle mass or strength. However, metformin has cardiovascular benefits and may improve erectile function, whereas testosterone suppression of gonadal function is protracted and without benefit.

It is premature to advocate widespread use of testosterone for diabetes prevention or reversal in men without pathological hypogonadism. The minimum effective dose, duration of treatment, durability of effect, and long-term safety, including cardiovascular outcomes, are all unknown.

Writing a prescription might be quicker and easier than providing a comprehensive and holistic approach to care but it represents an abdication from our duty of care to men’s health.