Hypogonadism markedly increases risk of type 2 diabetes and death

01 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 an increasingly common metabolic disorder 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 increased mortality.4 

Men with hypogonadism, also known as testosterone deficiency, are at increased risk for developing insulin resistance and type 2 diabetes.5,6 In men with existing type 2 diabetes, low testosterone levels are associated with a significantly increased mortality risk compared to men without testosterone deficiency.7,8 Here we summarise the results of recent studies that aimed to quantify the relationship between testosterone, diabetes and mortality.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 laboratory measurement of testosterone levels should be part of routine clinical management of men with type 2 diabetes.

What is known about testosterone and type 2 diabetes

The global prevalence of type 2 diabetes and impaired glucose tolerance in adults has been increasing over past decades,11-14 and emerged as the fourth leading cause of disability globally.15 Type 2 diabetes confers a two-fold excess risk for a wide range of vascular diseases and cardiovascular mortality, independently from other conventional risk factors such as age, sex, and other traditional cardiovascular risk factors.16,17Persistently high blood glucose levels cause generalized vascular damage affecting the heart, eyes, kidneys and nerves, resulting in various complications.18 Nevertheless, while hyperglycemia is the major risk factor for microvascular complications, cardiovascular disease is the principal cause of death in patients with type 2 diabetes.19

Men with type 2 diabetes have lower testosterone levels 18 and higher prevalence of hypogonadism than men without type 2 diabetes; up to 81% of men with type 2 diabetes have hypogonadism.20-24 Importantly, low testosterone levels may be a reversible risk factor for type 2 diabetes.25,26 For instance, a 2006 meta-analysis showed that men with testosterone levels >15.6 nmol/L (450 ng/dL) have a 42% reduced risk of developing type 2 diabetes compared to men with testosterone levels ≤15.6 nmol/L.25

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 prospective population studies with 16,709 participants showed that higher total and free testosterone levels significantly decrease the risk of type 2 diabetes in men by 38% and 23%, respectively.10 This is the first meta-analysis of prospective population studies to investigate the association between testosterone levels and type 2 diabetes risk in men. The large sample size allowed for a reliable assessment of the causal relationship between testosterone and risk of type 2 diabetes, and provides strong epidemiological evidence for a causal role of low testosterone in the development of type 2 diabetes.

A 14‐year follow‐up study collected health record data of 550 men with type 2 diabetes to evaluate the influence of baseline testosterone levels on type 2 diabetes outcomes.9 Mean baseline total testosterone for the entire cohort was 13.7 nmol/L (395 ng/dL). Lower baseline total testosterone levels were significantly associated with a higher BMI and increased risk of stroke at follow‐up. Mortality rate was nearly twice as high in patients with lower total testosterone compared to normal baseline total testosterone (5.0% vs 2.8% per year). During the 14-year follow‐up period, 36.1% of men with normal baseline testosterone died vs 55.8% of men with hypogonadism at baseline (figure). The age‐adjusted hazard ratio for higher mortality associated with low total testosterone corresponded to 3.2 years 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.

2019-Malipatil-mortality

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 total testosterone and BMI, HDL‐cholesterol and triglycerides; 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 all‐cause 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 cardiovascular events/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.27 This, combined with the data 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.

While the meta-analysis presented above shows that hypogonadism is a strong risk factor for development of type 2 diabetes,10 it has also been suggested that type 2 diabetes may be a risk factor for the development of hypogonadism.28 For instance, one prospective study showed that the

development of type 2 diabetes is a major driver of the age-related testosterone decline.29 Hence, it appears that the link between low testosterone and type 2 diabetes is bidirectional. A notable prospective cohort study including 1,400 men aimed to investigate the possible bidirectional relationship between testosterone and insulin resistance by analyzing if a low level of testosterone could predict the development of insulin resistance and vice versa.30 Results showed a significant longitudinal association between lower testosterone levels and the development of insulin resistance, which remained significant even after adjustment for confounding factors, including waist-hip ratio. However, degree of insulin resistance at baseline did not predict low testosterone levels at follow-up. This suggests that testosterone itself might have an important and independent effect on the development of insulin resistance over time. However, this was not the case for baseline insulin resistance. Hence, this study did not confirm the suggested bidirectional link between testosterone and insulin resistance/type 2 diabetes.30 The study authors acknowledged that the lack of association between baseline insulin resistance and testosterone levels at follow-up may be due to methodological differences. However, even though there may be a bidirectional association, the direction where insulin resistance decreases testosterone levels appears to be much weaker than the other direction where low testosterone increases insulin resistance.30

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) prospective study, aimed to determine whether low testosterone levels add clinically meaningful information beyond current type 2 diabetes risk prediction models.31 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 available for use in routine clinical practice, including the AUSDRISK (Australian Type 2 Diabetes Risk Assessment) tool. Testosterone levels below <16 nmol/L (461 ng/dL), which was prevalent in nearly half of the MAILES population of 2563 community-dwelling men aged 35-80 years in Adelaide, Australia, was best for predicting incident type 2 diabetes.31

The threshold of 16 nmol/L for defining low testosterone that is predictive of type 2 diabetes is higher than that reported in a previous systematic review of prospective cohort studies on type 2 diabetes risk in men (15.5 nmol/L or 447 ng/dL).25 It is also higher than the threshold of 12 nmol/L (350 ng/dL) for making the diagnosis of hypogonadism, as suggested by clinical guidelines.32-36 Another recent study found that the risk for diabetes already starts below 20 nmol/L (577 ng/dL), which is the mid-normal testosterone range.37 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 a causal role of low testosterone in the development of type 2 diabetes comes from a notable study published in Diabetes Care, showing that testosterone therapy in men with hypogonadism and prediabetes completely prevents progression to frank type 2 diabetes, and even restores normoglycemia.38

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.31 This could have important implications for clinical 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 diabetes who have symptoms or signs of hypogonadism, such as decreased sexual desire (libido) or sexual activity and/or erectile dysfunction.39

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 suggests that testosterone therapy may increase longevity in men with hypogonadism and type 2 diabetes, with increasing benefit with age.7,8,40 This is an area of active research in the field of men’s health.

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