Testosterone for prevention and reversal of diabetes in men with low T

[madman]

Abstract

Men with obesity and/or type 2 diabetes (T2D) have a high prevalence of testosterone deficiency (TD). Similarly, men with TD has an increased risk of developing obesity and/or T2D, and further body fat accumulation and deterioration of glycemic control create a vicious cycle. The landmark testosterone for diabetes mellitus trial, the largest randomized controlled trial of testosterone therapy (TTh) to date, confirm the beneficial effects of TTh on fat loss and gain in muscle mass, and that TTh for 2 years significantly reduces the risk of incident T2D, and may also reverse T2D. The testosterone for diabetes mellitus trial suggests that TTh reduces the risk of T2D and results in greater improvement in sexual function and wellbeing, beyond lifestyle intervention alone.





Introduction

Type 2 diabetes (T2D) is one of the fastest-growing chronic diseases worldwide [1], in large part driven by (abdominal) obesity. Obesity is a strong risk factor for testosterone deficiency (TD), which further increases fat accumulation, insulin resistance (IR), and deterioration of glycemic control creating a vicious circle. Due to the common co-occurrence of obesity and T2D, the term ‘diabesity’ was proposed to describe this condition [2].

Weight loss by lifestyle intervention is a cornerstone treatment for obesity and/or T2D. However, a profound weight loss of about 10% - and maintenance of reduced body weight - is required to prevent diabetes [3,4]. The problem is that long-term weight loss maintenance is poor, with subjects regaining half of the lost weight after 1 year and nearly three quarter during the first three years [5-7]. Less than 3% of subjects maintain their weight loss at all annual visits for 4-5 years after completion of a weight-loss program [5-7]. Hence, lifestyle intervention alone is not sufficient to treat or prevent obesity/T2D, as demonstrated by the ongoing and increasing prevalence of these dysmetabolic conditions.




Low testosterone and IR

Men with low testosterone have increased IR [8-11], which is one of the root causes of T2D [12-17]. The significant graded inverse association between testosterone and IR is independent of age [18] and low testosterone is associated with IR even in relatively young non-obese men [8,9,11]. A positive correlation has been shown between serum testosterone levels in men and insulin sensitivity, across the full spectrum of glucose tolerance regardless of age [19] Box 1.




*Randomized trials of TTh in men with T2D

*Real-world evidence studies of TTh for prevention of T2D

*Testosterone for diabetes mellitus trial – TTh for prevention T2D in men with low-normal T

*HbA1c may not be an accurate marker of glycemic control in men with low testosterone




Discussion

The T4DM trial, which is the first large-scale RCT examining the efficacy and safety of TTh for the prevention of T2D in men with low testosterone levels, provides high-level evidence that TTh increases the benefits of lifestyle intervention for prevention of T2D, as well as reversal of T2D [45]. Hence, the T4DM trial confirms findings from previous RWE studies in men with TD, which showed that treatment with testosterone undecanoate injections for 8-11 years completely prevented progression of prediabetes to T2D [41] and resulted in T2D remission in 34.3% of men [42].




*The T4DM trial provides high-level evidence that TTh, as an adjunct to a lifestyle program, significantly reduces incidence of T2D in men with low testosterone and may also, reverse T2D in newly diagnosed patients. This may inform clinical decisions about the use of TTh as a pharmacotherapy for T2D prevention and healthcare cost-savings.

 

[madman]

Box 1. The bidirectional link between low testosterone, obesity and type 2 diabetes.

The bidirectional link between TD and obesity/T2D on the one hand, and between obesity/T2D and TD on the other hand, is well established. Observational studies suggest that low testosterone is associated with both current and future IR, obesity, metabolic syndrome, and T2D [20]. Importantly, the risk of T2D seems to increase at a higher testosterone threshold than previously thought. The Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study found a significantly increased incidence of T2D in men with testosterone levels below 16 nmol/L (461 ng/dL) during a follow-up of 5 years, independent of T2D risk prediction models used in routine clinical practice [21]. The MAILES study concluded that screening for low testosterone in addition to risk factors included in T2D risk assessment tools would identify a large subgroup of distinct men who might benefit from targeted preventive interventions [21].

A meta-analysis showed that men with testosterone levels above 15.5 nmol/L (447 ng/dL) had a 42% reduced risk of T2D compared to men with testosterone levels below 15.5 nmol/L [22]. Another large meta-analysis of 13 prospective population studies including 16,709 men showed that higher testosterone levels were associated with a significantly reduced risk of T2D by 38% [23]. A 14-year follow-up study collected health record data of 550 men with T2D to evaluate the influence of baseline testosterone levels on T2D outcomes [24]. 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. The 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 TD at baseline. 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 T2D, compared to men who only have T2D.

A topic of scientific debate is the relative strength of the bidirectional link between low testosterone and diabesity, i.e., whether obesity (and to a lesser extent T2D, especially if poorly controlled) has a greater effect on reducing testosterone, or whether low testosterone has a greater effect on body fat accumulation and IR [20]. However, this is irrelevant for clinical practice. The bidirectional link between low testosterone and diabesity creates a vicious cycle, in which one condition worsens the other, regardless of which came first. In clinical practice, the important question is how to most effectively and sustainably break this vicious cycle.

 

[madman]

Table 1 RCT showing the importance of long-term TTh to achieve maximal improvement in insulin resistance and glycemic control [28,35]].

 

[madman]

Effect of TTh on incidence and reversal of type 2 diabetes (T2D). T2D = type 2 diabetes. Data from Wittert G, Bracken K, Robledo KP, et al. TTh to prevent or revert type 2 diabetes in men enrolled in a lifestyle program (T4DM): a randomized, double-blind, placebo-controlled, 2-year, phase 3b trial. The Lancet Diabetes & Endocrinology. Jan 2021; 9(1):32–45.

 

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