Hypogonadism markedly increases risk of type 2 diabetes and death

August 2019

STUDIES:

Yao QM, Wang B, An XF, Zhang JA, Ding L. Testosterone level and risk of type 2 diabetes in men: a systematic review and meta-analysis. Endocr Connect. 2018;7(1):220-231.

Malipatil NS, Yadegarfar G, Lunt M, et al. Male hypogonadism: 14-year prospective outcome in 550 men with type 2 diabetes. Endocrinology, Diabetes & Metabolism.0(0):e00064.

 

Type 2 diabetes is increasingly common in men,1,2 mirroring the increasing prevalence of obesity and reduced testosterone levels.3 Type 2 diabetes increases the risk of developing a number of serious health problems, resulting in higher medical care costs, reduced quality of life and premature death.4

Men with hypogonadism, also known as testosterone deficiency, are at increased risk for developing metabolic risk factors and type 2 diabetes.5,6 In men with existing type 2 diabetes, low testosterone levels are associated with a significantly increased risk of death compared to men without testosterone deficiency.7,8 Here we summarise the results of two recent studies that aimed to further investigate the relationship between testosterone, diabetes and death.9,10

 

 

KEY POINTS

  • Low testosterone levels increase risk for developing type 2 diabetes by nearly 40%.
  • Low testosterone levels are associated with higher all-cause mortality in men with type 2 diabetes over a 14‐year follow‐up period.
  • Men with type 2 diabetes who also have hypogonadism should be considered at very high risk for cardiovascular death.
  • Screening for hypogonadism by blood testing of testosterone levels should be part of regular health checkups in men with type 2 diabetes.

What is known about testosterone and type 2 diabetes

The prevalence of type 2 diabetes in men has been increasing over past decades,11-14 and is the fourth leading cause of disability.15 Type 2 diabetes confers a two-fold excess risk for cardiovascular disease and death, independently from other conventional risk factors such as age, sex, cholesterol and blood pressure.16,17

Men with type 2 diabetes have lower testosterone levels18 and higher prevalence of hypogonadism than men without type 2 diabetes; up to 81% of men with type 2 diabetes have hypogonadism.19-23 Importantly, low testosterone levels may be a reversible risk factor for type 2 diabetes.24,25 For instance, it has been shown that men with testosterone levels above 15.6 nmol/L (450 ng/dL) have a 42% reduced risk of developing type 2 diabetes compared to men with testosterone levels below 15.6 nmol/L.24 It is notable that 15.6 nmol/L (450 ng/dL) is higher than the thresholds recommended by clinical guidelines to make the diagnosis of hypogonadism.

 

What new studies show

A large meta-analysis of 13 population studies with 16,709 participants showed that higher testosterone levels significantly decrease the risk of type 2 diabetes in men by 38%.10 This is the first meta-analysis of population studies that measured testosterone levels in men and then followed these men for up to 29 years to see if more men with low testosterone developed type 2 diabetes than men with higher testosterone levels. The large number of men and the long follow-up provides strong evidence that low testosterone is a risk factor for the development of type 2 diabetes.

A 14‐year follow‐up study collected health record information about 550 men with type 2 diabetes to evaluate the influence of baseline testosterone levels on type 2 diabetes outcomes.9 Mean baseline testosterone level was 13.7 nmol/L (395 ng/dL). It was found that lower baseline total testosterone levels were significantly linked to obesity (estimated by BMI), increased risk of stroke and death at follow‐up. During the 14-year follow‐up period, 36% of men with normal baseline testosterone died vs 56% of men with hypogonadism at baseline (figure). The higher mortality linked to low testosterone corresponded to 3.2 years of reduced life expectancy for men who have both hypogonadism and type 2 diabetes, compared to men who only have type 2 diabetes.

Figure: Mortality in men with type 2 diabetes who have hypogonadism compared to men with type 2 diabetes who have normal testosterone levels.

Figure: Mortality in men with type 2 diabetes who have hypogonadism compared to men with type 2 diabetes who have normal testosterone levels.

Data from: Malipatil NS, Yadegarfar G, Lunt M, et al. Male hypogonadism: 14-year prospective outcome in 550 men with type 2 diabetes. Endocrinology, Diabetes & Metabolism.0(0):e00064.

This study also found a significant association between testosterone and BMI, HDL (the “good” cholesterol) and triglycerides (blood fats); men with higher testosterone levels had higher HDL and lower BMI and triglyceride levels. It was concluded that low testosterone levels are associated with higher mortality in men with type 2 diabetes.9 Men who have both hypogonadism and type 2 diabetes should be considered to be at a very high risk for heart disease and death.

 

Commentary

The average life expectancy of a 50-year-old individual with diabetes is 6 years shorter than it would be without the disease.26 This, combined with the study results presented above, suggests that men with both hypogonadism and type 2 diabetes have a life expectancy that is 10 years shorter compared to men who are free of hypogonadism and type 2 diabetes.

Effective prevention of type 2 diabetes requires early identification of high-risk individuals who might benefit from intervention. A notable study, the MAILES (Men Androgen Inflammation Lifestyle Environment and Stress) study, aimed to determine whether low testosterone levels add meaningful information beyond current type 2 diabetes risk prediction models.27 It was found that testosterone levels predict risk of developing type 2 diabetes over the next 5 years, independent of all risk factors included in type 2 diabetes risk assessment tools. Testosterone levels below <16 nmol/L (461 ng/dL), which was prevalent in nearly half of the MAILES population of 2563 men aged 35–80 years, was best for predicting future type 2 diabetes.27

The threshold of 16 nmol/L for defining low testosterone that is predictive of type 2 diabetes is higher than the threshold of 12 nmol/L (350 ng/dL) for making the diagnosis of hypogonadism, as suggested by clinical guidelines.28-32 Another recent study found that the risk for diabetes already starts below 20 nmol/L (577 ng/dL) , i.e. in the mid-normal testosterone range.33 This suggests that men with symptoms of hypogonadism who have testosterone levels that are higher than the diagnostic threshold of 12 nmol/L (350 ng/dL) may derive health benefits from testosterone therapy. Support for the possibility that low testosterone is a risk factor underlying the development of type 2 diabetes comes from a notable study published in the prestigious journal Diabetes Care, which showed that testosterone therapy in men with hypogonadism and prediabetes completely prevents progression to frank type 2 diabetes and restores normal glucose metabolism.34

The finding that testosterone remains a significant predictor for development of type 2 diabetes even after correction for all other diabetes risk factors suggests that screening for low serum testosterone would identify a large group of men at-risk who would otherwise not been detected by current risk assessment tools.27 This could have important implications for medical decision making and prognosis for a large and growing population of men with low testosterone levels. Accordingly, in 2018 the American Diabetes Association added the recommendation to measure testosterone in men with type 2 diabetes who have symptoms or signs of hypogonadism, such as decreased sexual desire (libido) or sexual activity and/or erectile dysfunction.35

The second study summarised above confirms that men with type 2 diabetes who are also hypogonadal have worse health outcomes, including increased risk of stroke and a mortality rate that is nearly twice as high compared to men with type 2 diabetes without hypogonadism.9 A growing number of studies suggest that testosterone therapy may increase longevity in men with hypogonadism and type 2 diabetes, with increasing benefit with age.7,8,36 This is an area of active research in the field of men’s health.

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