T4DM: can testosterone help prevent type 2 diabetes?

Background: low testosterone and insulin resistance are linked both ways

Men with overweight and abdominal obesity often have low testosterone, and low testosterone is associated with a higher risk of type 2 diabetes. The relationship probably runs both ways. Fat tissue and insulin resistance dampen the brain's signal to the testes, and low testosterone means less muscle and more belly fat, which in turn worsens insulin sensitivity. About one in three men with type 2 diabetes had low testosterone in Dhindsa and colleagues' survey (JCEM 2004). T4DM was designed to test whether testosterone on top of a lifestyle programme can prevent or reverse early type 2 diabetes.

Trial design

T4DM was a randomised, double-blind, placebo-controlled phase 3b trial lasting two years at six Australian tertiary centres.

• Participants: 1,007 men aged 50–74, selected from 19,022 pre-screened.
• Entry criteria: waist of at least 95 cm, total testosterone of 14 nmol/L or lower without pathological hypogonadism (no known pituitary or testicular disease), and either impaired glucose tolerance (2-hour glucose 7.8–11.0 mmol/L on an oral glucose tolerance test) or newly diagnosed type 2 diabetes.
• Everyone joined the same lifestyle programme (WW, formerly Weight Watchers).
• Treatment: testosterone undecanoate 1,000 mg or placebo by injection at baseline, at 6 weeks and then every 3 months for two years.
• Primary outcomes: type 2 diabetes on a glucose tolerance test at two years (2-hour glucose of 11.1 mmol/L or higher) and change in 2-hour glucose.

Results

At two years, 55 of 443 men (12%) in the testosterone group had type 2 diabetes on the glucose tolerance test versus 87 of 413 (21%) in the placebo group. That is a relative risk of 0.59 (95% confidence interval 0.43–0.80; p = 0.0007), or about 41% lower risk. 2-hour glucose fell by 1.70 mmol/L on testosterone and 0.95 mmol/L on placebo. The effect did not depend on how low testosterone was at baseline.

What does it mean for you?

T4DM shows that testosterone on top of a structured lifestyle programme reduced the share with type 2 diabetes after two years in men with abdominal obesity, low-normal testosterone and prediabetes. It is one of the few large randomised trials with a hard metabolic outcome.

It does not show that testosterone is a shortcut. Every participant had the lifestyle programme, and the placebo group also improved its glucose. Testosterone is not a replacement for lifestyle, but in selected cases it may be an addition.

What do the guidelines say?

The American Diabetes Association (ADA) recommends in its Standards of Care measuring morning testosterone in men with diabetes who have symptoms or signs of low testosterone. The Endocrine Society (Bhasin et al., JCEM 2018) recommends a fasting morning sample, repeated to confirm a low result before a diagnosis is made. T4DM does not change the fact that treatment is only relevant for symptomatic deficiency.

Caveats

• Haematocrit: a safety trigger for haematocrit above 54% occurred in 22% of the testosterone group versus 1% on placebo. This may limit treatment and must be monitored.
• PSA: a rise of 0.75 ng/mL or more was recorded in 23% on testosterone versus 19% on placebo.
• Serious adverse events: prespecified serious adverse events occurred in 10.9% on testosterone versus 7.4% on placebo. There were two deaths in each group.
• Heart and vessels: the trial was not powered to assess cardiovascular events, and the long-term effect is unknown.
• Selected group: participants did not have classic hypogonadism. The result cannot be transferred directly to all men.
• Funding: the trial was partly funded by industry (Bayer, Eli Lilly) and WW.

Treatment should therefore only be considered for symptomatic deficiency and always with a doctor who follows the blood tests.

Conclusion

In men aged 50–74 with abdominal obesity, low-normal testosterone and prediabetes, testosterone on top of a lifestyle programme reduced the share with type 2 diabetes after two years from 21% to 12%. On the other hand, haematocrit rises were common, and long-term safety is not settled. Read more about the link in our article on testosterone, insulin resistance and type 2 diabetes, and about why the prevalence of low testosterone depends on the criteria in the note on the EMAS study page.

First step

If you are in one of the relevant groups and are worried that low testosterone may be a contributing factor, a screening may be an option. Talk to your own doctor about the options. If you want fast action via a private clinic, you are welcome to take the free AMS test on this site, or, if you are in Denmark, order a blood test.