madman
Super Moderator
Testosterone, Diabetes Risk, and Diabetes Prevention in Men (2022)
Bu B. Yeap, MBBS, Ph.D. *, Gary A. Wittert, MBBCh, MD
INTRODUCTION
Obesity is increasingly prevalent in developed and developing countries and contributes to increasing rates of type 2 diabetes (T2D) globally.1,2 In addition, obesity is a central component of metabolic syndrome, a cluster of risk factors for T2D and cardiovascular disease, which includes hypertension, elevated triglyceride, reduced high-density lipoprotein cholesterol (HDL-C) concentrations, and abnormalities of glucose metabolism.3 The presence of T2D in itself is associated with increased mortality risk, which is additive to the risk attributable to prevalent cardiovascular disease.4 Intensive lifestyle interventions generally comprising weight loss, nutrition management, and increased physical activity reduce T2D risk.5–7 However, such interventions are difficult to implement and sustain in the general population, thus the global diabetes prevalence is estimated to increase to 10.2% (578 million people) by 2030.2 Therefore, new therapeutic approaches are needed to prevent T2D and reduce its associated therapeutic and disease burdens.8
*TESTOSTERONE AND ITS RELATIONSHIP WITH OBESITY AND INSULIN RESISTANCE
Testosterone and Obesity
In cross-sectional studies of middle-aged and older men, circulating testosterone is inversely associated with body mass index (BMI).9–13 Total testosterone concentrations are greater than 20% lower in men with a BMI of 30 kg/m2 or more, compared with those with BMI in the normal range.9,10 In a cross-sectional analysis of 208,677 men from the UK Biobank aged 40 to 69 years, in whom median total testosterone measured using immunoassay was 11.6 nmol/L (334 ng/dL), the inverse association of serum testosterone with BMI was stronger than with age. Compared with 50- year-olds, in 70-year-old men serum testosterone level was ~0.5 nmol/L (~14 mg/ dL) lower, whereas it was ~1.5 nmol/L (~43 ng/dL) lower in men with a BMI of 30 versus 25 kg/m2 and ~3 nmol/L (~86 ng/dL) lower in men with BMI 40 versus 25 kg/m2 . 13 In longitudinal studies, obesity, weight gain, or increases in waist circumference, rather than age itself, were associated with decreases in testosterone concentrations.14–16 In 2736 men aged 40 to 79 years from the European Male Aging Study, with mean total testosterone concentration measured using mass spectrometry of 16.9 nmol/L (487 mg/dL), a loss of 10% or more to less than 15% of body weight was associated with a 2.0 nmol/L (58 ng./dL) increase and a loss of 15% or more with a 5.8 nmol/L (167 ng/dL) increase in testosterone concentrations.15 In interventional studies of diet and/or exercise, loss of 6% to 17% of total weight resulted in total testosterone concentration increasing by 1.2 to 5.1 nmol/L (35–147 ng/dL), whereas bariatric surgery with loss of 29% to 36% of total weight resulted in total testosterone concentration increasing by 7.8 to 10.7 nmol/L (225–308 ng/dL).17 Therefore, men who successfully reduce excess weight can expect to increase their endogenous testosterone concentrations, proportionate to the degree of weight loss.
Testosterone, Obesity, and Sex Hormone-Binding Globulin
Testosterone, Obesity, and Sex Hormone-Binding Globulin Differences in total testosterone concentrations in relation to obesity are mediated in part via the association of obesity with lower circulating sex hormone-binding globulin (SHBG) concentrations.9,10,13 SHBG is the major carrier protein for testosterone in the circulation, and concentrations of total testosterone and SHBG are correlated with coefficients of ~0.5 to 0.6.9,18,19 Of note, the association may not be linear across the range of SHBG concentrations, with the increase in total testosterone concentrations leveling off with SHBG greater than 80 nmol/L in UK Biobank men.13 Thus, men who are obese or insulin-resistant can have low SHBG and testosterone concentrations, in the absence of pathologic hypogonadism.20
Circulating SHBG is primarily synthesized in the liver, and low SHBG concentrations are associated with the presence of insulin resistance and metabolic syndrome.21,22 Earlier experiments suggested a direct role of insulin to inhibit SHBG production in hepatoma cells.23 More recent studies suggest that SHBG is a marker of de novo hepatic lipogenesis. Increasing de novo hepatic lipogenesis is associated with a lower SHBG and vice versa.19,24 Although lower SHBG contributes to lower total testosterone concentrations in overweight or obese men, men with more severe obesity also show reductions in luteinizing hormone (LH) concentrations and LH pulse amplitude, consistent with functional inhibition of the hypothalamic-pituitary-testicular (HPT) axis25,26; this is consistent with the observation that when men lose 15% or more of body weight, the increase in total testosterone is proportionately higher than the increase in SHBG concentrations compared with lesser degrees of weight loss.15
Testosterone and Insulin Resistance
Men with lower total testosterone or SHBG concentrations are more likely to have metabolic syndrome and to manifest insulin resistance.27–29 These associations are likely to be mediated in large part by the underlying relationship of low circulating total testosterone and SHBG with central obesity and excess adiposity.9–16 Whether or not there is a direct association of lower testosterone concentrations with insulin resistance, independently of body composition, is more difficult to discern. Observational studies have reported that apparent associations of lower testosterone concentrations with insulin resistance (assessed by calculations based on circulating glucose and insulin concentrations, either the quick insulin sensitivity check index or the homeostatic model assessment of insulin resistance [HOMA-IR]) may be abrogated by adjustment for SHBG.30–33 However, in one study of older men, after adjusting for age, BMI, waist circumference, and HDL-C and triglyceride levels, lower total testosterone concentrations were independently associated with HOMA-IR, whereas SHBG concentrations were not.34 In a study of 21 men with normal glucose tolerance, impaired glucose tolerance, and diabetes, insulin sensitivity was assessed using hyperinsulinemic-euglycemic clamps correlated with testosterone concentrations and with testicular responses to human chorionic gonadotropin, suggesting an effect of insulin resistance to decrease Leydig cell testosterone secretion.35 In another study of 74 men, undergoing a 75-g oral glucose tolerance test (OGTT) was associated with a decrease in total testosterone concentrations at 30, 60, 90, and 120 minutes, without any change in SHBG or LH concentrations.36 Furthermore, in a study of 12 men diagnosed with idiopathic hypogonadotropic hypogonadism based on serum total testosterone levels less than 3.47 nmol/L (<100 ng/dL) in association with inappropriately low gonadotropin concentrations, suspension of testosterone treatment for 2 weeks resulted in increased fasting insulin concentrations and HOMA-IR without changes in BMI, indicating an acute effect of testosterone withdrawal on insulin sensitivity.37 In a study of 94 men with T2D, 44 had calculated free testosterone levels less than 226 pmol/L and were randomly allocated to testosterone or placebo treatment.38 Glucose infusion rates during hyperinsulinemic-euglycemic clamp did not change when assessed at 3 weeks, but after 6 months of testosterone treatment glucose infusion rates increased by 32%, associated with favorable changes in body composition.38
Summary: Testosterone, Obesity, and Insulin Resistance
Thus obesity, manifesting with central and visceral adiposity and insulin resistance, can inhibit the function of the HPT axis at multiple levels (Fig. 1).13–16,19,22,24–35 Higher degrees of obesity, visceral adiposity, and insulin resistance are associated with both reduced HPT axis activity and lower SHBG concentrations, hence lower circulating total testosterone (see Fig. 1).
*TESTOSTERONE AND THE RISK OF METABOLIC SYNDROME AND DIABETES
Testosterone and Risk of Metabolic Syndrome
Several epidemiologic studies have associated lower total testosterone or SHBG concentrations with a higher risk of metabolic syndrome in men in both cross-sectional and longitudinal analyses.27–29,39–45 An individual participant data meta-analysis of 20 observational studies involving 14,025 men aged 18 years or older not using hormone therapy documented inverse associations of both total testosterone and SHBG with risk of prevalent and incident metabolic syndrome.45 In the cross-sectional analysis, a quartile decrease in total testosterone concentration was associated with ~40% higher odds of metabolic syndrome, across categories of BMI, after adjusting for age, smoking, alcohol consumption, and physical activity. A quartile decrease in baseline total testosterone was associated with an ~25% higher risk of developing metabolic syndrome during follow-up, after adjusting for age and lifestyle factors, reducing to a 14% higher risk after further adjustment for BMI.45 Similarly, in that meta-analysis lower SHBG concentrations were associated with a higher risk of both prevalent and incident metabolic syndrome. Thus, whereas obesity and central adiposity predispose to lower total testosterone and SHBG concentrations, the converse is also true, because men with lower total testosterone or SHBG concentrations are at increased risk of having or developing the metabolic syndrome.
Testosterone and Risk of Diabetes
Epidemiologic studies have consistently associated lower total testosterone or SHBG concentrations not only with insulin resistance21,22,30–34 but also with a higher risk of T2D in men.31,43,46–50 In a systematic review and meta-analysis that included 43 observational studies with 6427 men, lower total testosterone concentrations were associated with a higher risk of prevalent and incident T2D.51 Men with T2D had a mean total testosterone concentration of 2.7 nmol/L (78 ng/dL) lower than those of nondiabetic men. Furthermore, in prospective studies, men who developed diabetes had a baseline mean total testosterone concentration of 2.5 nmol/L (72 ng/dL) lower than those of men who did not.51 In that meta-analysis, men who had baseline total testosterone concentrations of 15.6 to 21.0 nmol/L (450–605 ng/dL) had a relative risk of developing T2D of 0.58, compared with men with baseline total testosterone concentrations of 7.4 to 15.5 nmol/L (213–447 ng/dL).51 Other studies have further reinforced the finding of lower total testosterone concentrations in men with T2D, compared with nondiabetic men.17,52,53 This association likely reflects inhibition of HPT axis function in the presence of central adiposity, a reduction in SHBG concentrations, and possible effects of insulin resistance or hyperglycemia on testicular function.9,10,13–16,19,21–24,35,36 Of note, in a study of 195 men aged 70 years or older the presence of metabolic syndrome, but not lower total testosterone concentration in the absence of metabolic syndrome, was predictive of incident T2D.54 Thus, in older men, obesity and metabolic syndrome, in association with lower testosterone concentrations and worsening body composition, may be the key predisposing factors for T2D.
*EFFECTS OF TESTOSTERONE TREATMENT ON BODY COMPOSITION AND GLUCOSE CONCENTRATIONS
Effect of Testosterone Treatment on Body Composition
Some, but not all, studies have reported an inverse association of muscle mass or strength with diabetes risk in men.55–59 Therefore, a potential mechanism by which testosterone treatment might reduce the risk of T2D would be via its anabolic effects to increase lean mass.60–64 Together with increasing lean mass, testosterone treatment also reduces fat mass, potentially an important mechanism to reduce the risk of T2D.64–66 In men with BMI 30 kg/m2 or more and total testosterone concentrations 12 nmol/L or less (346 ng/dL), testosterone treatment given in conjunction with calorie restriction mitigated the loss of lean mass while potentiating the loss of fat mass.67 A meta-analysis by Isidori and colleagues68 of 29 testosterone randomized controlled trials (RCTs) involving 625 testosterone-treated men and 458 controls with durations ranging from 1 to 36 months with baseline mean total testosterone concentrations ranging from 7.5 to 19.0 nmol/L (216–548 ng/dL) indicated an effect of testosterone treatment to increase lean mass by 1.6 kg (+2.7%) and decrease fat mass by 1.6 kg (-6.2%). A more recent meta-analysis by Corona and colleagues69 included 59 RCTs with 3029 testosterone-treated men and 2049 controls with duration ranging from 1 to 48 months with baseline mean total testosterone concentrations ranging from 2.3 to 21.1 nmol/L (66–608 ng/dL) confirmed the effect of testosterone to increase lean mass and reduce fat mass (standardized mean difference, +0.51 and -0.32 respectively). In an analysis of observational studies, testosterone supplementation was associated with a reduction of waist circumference of 6.2 cm at 24 months.70
Effect of Testosterone Treatment on Glucose Concentrations
Several RCTs have investigated the effect of testosterone treatment on fasting or post-challenge glucose concentrations, or measures of insulin sensitivity, with mixed results.66,71–73 The previous analysis of observational studies reported that testosterone-treated men had a 0.47 mmol/L lower fasting glucose concentration and a HOMA-IR 2.8 lower.70 However, these estimates were smaller, particularly for HOMA-IR, in the meta-analysis of RCTs by Corona and colleagues69 in which testosterone treatment reduced fasting glucose concentrations by 0.34 mmol/L and HOMAIR by 0.80. A review of 3 RCTs conducted specifically in men with T2D with baseline mean total testosterone concentrations of 12 to 15 nmol/L (346–432 ng/dL), suggested a mean reduction of fasting glucose of 1.2 mmol/L with testosterone treatment over durations of 3 to 12 months in that population.74 A more recent meta-analysis of testosterone RCTs in men with T2D and/or metabolic syndrome included 7 RCTs involving 833 men with baseline mean total testosterone concentrations ranging from 6.7 to 10.1 nmol/L (193–291 ng/dL).75 In that meta-analysis, testosterone treatment improved measures of insulin resistance, but did not lower hemoglobin A1c (HbA1c) values.
Summary: Testosterone and Risk of Type 2 Diabetes
Obesity, metabolic syndrome, low testosterone concentrations, and the risk of T2D are closely interrelated (Fig. 2). Obesity per se, and the presence of metabolic syndrome, predispose to both lower testosterone concentrations and diabetes risk, with diabetes risk amplified by the presence of lower testosterone concentrations resulting in unfavorable changes to body composition (loss of lean mass and gain of fat) and alterations in insulin sensitivity (see Fig. 2A). This is consistent with lower testosterone concentrations being predictive of incident T2D in men.46–51,76 In older men, obesity and metabolic syndrome, in association with lower testosterone concentrations and worsening body composition, may be the major contributors to the risk of T2D (see Fig. 2B).
Testosterone treatment by increasing lean mass, reducing fat mass, and reducing glucose concentrations would thus be expected to reduce the risk of T2D.60–70 An uncontrolled, registry-based observational study of 316 men with baseline total testosterone concentrations 12.1 nmol/L or less (~350 ng/dL) followed for 8 years reported an improvement in HbA1c in 229 testosterone-treated men, none of whom progressed to T2D, compared with 40% of the 87 untreated men who developed HbA1c greater than 6.5%.77 Collectively, these existing data on testosterone, obesity, metabolic syndrome, and T2D justify a large-scale, high-quality RCT to determine whether testosterone treatment prevents the development of T2D in men at high risk.
*TESTOSTERONE FOR THE PREVENTION OF TYPE 2 DIABETES MELLITUS
Overview
Testosterone for the Prevention of Type 2 Diabetes Mellitus (T4DM) was a randomized, double-blind, placebo-controlled, 2-year, phase 3b trial to determine whether testosterone treatment prevents or reverts T2D in men enrolled in a lifestyle program.78 Important features of T4DM are summarized (Box 1). The trial randomized 1007 men across 6 centers in Australia, with a 2-year duration of intervention; all participating men also received a lifestyle intervention.79 T4DM represents the largest testosterone RCT completed to date, with the key outcome of T2D and 2 years of safety data.
The T4DM Study Population
As T4DM was conceived as a prevention trial; only men without a previous history of diabetes were recruited. Eligible participants were men aged 50 to 74 years, with a waist circumference of 95 cm or more, who had either impaired glucose tolerance (OGTT 2- hour glucose ≥7.8 to <11.1 mmol/L) or newly diagnosed T2D (OGTT 2-hour glucose ≥11.1 to ≤15.0 mmol/L), for whom the primary intervention could reasonably be a lifestyle program, and who were willing to participate in such a program.78,79 In addition, eligible participants were required to have a screening serum total testosterone concentration of 14.0 nmol/L (403 ng/dL) or less.76 Exclusion criteria are reported.78,79 Of note, men with major medical comorbidities, or with recent cardiovascular events or symptomatic cardiovascular disease, were excluded from T4DM.
Intervention
All participating men were enrolled in a free Weight Watchers program, with face-to-face participation via group sessions and online options available.79 A lifestyle intervention was regarded as the expected standard of care for men with impaired glucose tolerance or newly diagnosed T2D without marked hyperglycemia.5,6 Men were randomly allocated 1:1 to receive testosterone undecanoate 1000 mg or matching placebo, via intramuscular injection, at baseline, 6 weeks, and every 3 months thereafter for 2 years (9 injections in total). Of the participants, 20% of each arm had newly diagnosed T2D based on the entry OGTT result. In 503 men randomized to placebo, 370 completed 2 years of treatment, and 413 had outcome data available for primary analysis at 2 years. In the testosterone arm, 386 completed 2 years of treatment and 443 had outcome data for primary analysis at 2 years.79
Outcomes
At the end of the 2-year intervention, 55 of 443 (12%) testosterone-treated men and 87 of 413 (21%) men in the placebo arm had 2-hour glucose on OGTT of 11.1 mmol/L or more (relative risk, 0.59; 95% confidence interval [CI], 0.43–0.80; P 5 .0007). For the second primary outcome, mean change from baseline in 2-hour glucose on OGTT was -1.70 mmol/L (SD 2.47) in the testosterone arm and -0.95 mmol/L (SD 2.78) in the placebo arm (mean difference -0.75 mmol/L; 95% CI, -1.10 to -0.40; P < .0001).79
Testosterone treatment resulted in a mean increase of 0.39 kg of total muscle mass, and a mean decrease of 4.60 kg of fat mass, whereas men in the placebo group had a mean reduction of 1.32 kg of muscle mass and 1.89 kg of fat mass, after 2 years. Handgrip strength improved with testosterone treatment. Testosterone treatment also resulted in a greater likelihood of having normal 2-hour glucose on OGTT (<7.8 mmol/L; odds ratio, 1.20; 95% CI, 1.04–1.38; P 5 .012) and a lower fasting glucose concentration (-0.17 mmol/L; 95% CI, -0.29 to -0.06; P = .0036) at 2 years.79 However, HbA1c was not different between the 2 groups at 2 years (treatment effect -0.02%; 95% CI, -0.07–0.03; P = .42). Rates of participation in the Weight Watchers program were similar in both arms of the trial. Testosterone treatment increased on study testosterone concentrations, and suppressed LH, with a small reduction in SHBG concentrations.79 In a sensitivity analysis, the benefit of testosterone treatment was similar for men with baseline testosterone concentrations less than 11 nmol/L and 11 nmol/L or more (317 ng/dL), confirming that this was a pharmacologic effect of testosterone treatment.
Adverse Events
At least one safety trigger occurred for 19% of participants in the placebo arm and 38% of participants in the testosterone arm, including triggers for a hematocrit of 54% or higher (1% in placebo versus 22% in the testosterone arm), and increase in the level of the prostate-specific antigen of 0. 75 ng/mL or more (19% of the placebo and 23% of the testosterone arm). In most cases in which a trigger for raised hematocrit occurred, men were retested nonfasting, and some had study injections deferred, with one man in the placebo arm and 25 in the testosterone arm permanently discontinuing treatment. Serious adverse events (SAEs) were recorded in 7.4% of the placebo and 10.9% of the testosterone groups, in a total of 41 of 503 placebo recipients and 55 of 504 testosterone-treated men; these included 21 (4.2%) and 26 (5.2%) cardiovascular SAEs in placebo and testosterone arms, respectively. As noted earlier, men at high risk of cardiovascular adverse events were excluded from the study, leaving a lower risk population. In the placebo arm, 3 men had hospital admissions related to benign prostate hyperplasia and 5 men were diagnosed with prostate cancer, compared with 8 and 4 in the testosterone arm, respectively.
Significance of T4DM
The main result of T4DM, demonstrating an unequivocal effect of testosterone treatment to reduce the likelihood of having T2D in men at high risk is important conceptually and practically. First, in the context of the prior discussion of testosterone, obesity, metabolic syndrome, and diabetes risk (see Figs. 1 and 2), T4DM provides evidence of the bidirectional association. In this large, multicenter, double-blind, placebo-controlled RCT, with a background lifestyle intervention, the 2-year testosterone intervention reduced the risk of T2D, by preventing the progression of impaired glucose tolerance or reverting to newly diagnosed diabetes. The effect size was large, with a relative risk reduction of 40% for the outcome of T2D. Therefore, although obesity, metabolic syndrome, and T2D are associated with lower testosterone concentrations, the association is bidirectional, because low testosterone concentrations predispose to metabolic syndrome and T2D, and testosterone intervention improves body composition, reduces glucose concentrations, and reduces the risk of T2D in the context of a concomitant lifestyle program.
Second, in the context of the worldwide increase in the prevalence of obesity and T2D, T4DM offers a new therapeutic option, that of testosterone pharmacotherapy in combination with readily available lifestyle intervention. The lifestyle program was an intrinsic component of the study. Men who have pathologic hypogonadism merit testosterone treatment.20,80–82 For these men, the metabolic benefits of testosterone now clearly include improvements in glucose tolerance and prevention of T2D. With regard to men with obesity and metabolic syndrome-related reductions in serum testosterone concentrations in the absence of pathologic hypogonadism, our findings suggest that testosterone treatment for 2 years, as an adjunct to a lifestyle program, can prevent or revert T2D. However, increases in hematocrit might be treatment-limiting, and the minimum dose exposure, duration of treatment, the durability of effect, and long-term safety and cardiovascular outcomes of testosterone treatment remain to be determined.83 Thus, the benefit of testosterone treatment on the outcome of T2D as demonstrated in T4DM, needs to be carefully weighed against the limitations of the study, and the potential side effects that may be encountered. If such treatment is considered, a concomitant lifestyle program should be implemented, and there must be careful monitoring of hematocrit, cardiovascular risk factors, and prostate health.
Cardiovascular Effects of Testosterone Treatment
Whether testosterone treatment has beneficial, neutral, or adverse effects on the cardiovascular system remains a complex and debated issue (for review, see84). In brief, one RCT of testosterone in older men aged 65 years or more with baseline total testosterone of 3.5 to 12.1 nmol/L (100–350 ng/dL) or calculated free testosterone less than 173 pmol/L with mobility limitations showed an excess of broadly defined cardiovascular adverse events; another similar RCT in frail or intermediate-frail older men aged 65 years or more with baseline total testosterone of 12 nmol/L or less (345 ng/dL) or calculated free testosterone of 250 pmol/L or less showed no such signal.85,86 There was no excess of cardiovascular adverse events in T Trials, which recruited men with symptoms suggesting hypogonadism aged 65 years or more with baseline total testosterone levels less than 9.54 nmol/L (<275 ng/dL), and T4DM, the 2 largest testosterone RCTs.79,87 Furthermore, recent large meta-analyses of testosterone RCTs have not shown evidence of excess cardiovascular adverse events.88–90 Of note, the cardiovascular substudy of T Trials involving 138 men reported an increase in coronary atheroma measured as noncalcified plaque volume using cardiac computed tomography angiography in testosterone-treated men.91 However, the groups were unbalanced: men in the placebo group (N = 65) had substantially more calcified and noncalcified plaque volume at baseline and at the end of the study compared with men in the testosterone group (N = 73), making the findings challenging to interpret.84,92 Therefore, additional studies are needed to clarify the effect of testosterone on the cardiovascular system. Pending the outcomes of such studies, careful monitoring of cardiovascular risk factors and disease would be appropriate.
Holistic Evaluation and Optimizing Lifestyle, Behavioral, and Medical Factors
All men expressing concerns over their risk of obesity or T2D, whether or not there is concomitant concern over low testosterone concentrations related to these, should be offered a careful assessment and optimal management of medical risk factors and comorbidities.93 Pathologic disorders affecting the HPT axis need to be excluded, or if identified, treated appropriately.20,81,82 Men without HPT axis pathology who are overweight can be advised on losing excess weight, eating healthily, and exercising regularly. Depression and sleep disturbances, if present, should be managed appropriately.94 As discussed earlier, losing excess weight should improve HPT axis function and raise endogenous testosterone levels, and thus represents an attractive nonpharmacologic approach with the potential to capture multiple health benefits. Only after a holistic evaluation and optimization of lifestyle and medical factors have been achieved should further discussion on testosterone pharmacotherapy be considered.79
SUMMARY
There is an intimate and bidirectional association of lower testosterone concentrations with obesity and the risk of T2D risk in middle-aged and older men. Men who are obese, or have metabolic syndrome or T2D, are more likely to have lower testosterone concentrations; conversely, lower testosterone concentrations predispose men to develop metabolic syndrome or T2D. Testosterone pharmacotherapy is effective in preventing or reverting newly diagnosed T2D in men at high risk, reducing the risk of T2D by 40% beyond the effect of lifestyle intervention. However, the first step for improving men’s health must remain a holistic evaluation of lifestyle, behavioral and medical factors, engagement in healthy dietary choices and physical activity, and optimal treatment of existing medical risk factors and comorbidities. Subsequently, men at high risk of diabetes can be counseled on the benefits versus risks of testosterone pharmacotherapy on top of a lifestyle program to prevent diabetes, based on the findings and also realizing the limitations of T4DM. In this context, it could be noted that neither metformin nor the glucagon-like peptide-1 receptor agonist class of drugs increases muscle mass nor do they improve bone and sexual health, as testosterone does.79,87,95,96 If testosterone treatment is considered for the prevention of T2D, a concomitant lifestyle program is necessary as is careful monitoring of hematocrit, cardiovascular risk factors, and prostate health. Further research is needed to clarify the effects of testosterone on the cardiovascular system.
Bu B. Yeap, MBBS, Ph.D. *, Gary A. Wittert, MBBCh, MD
INTRODUCTION
Obesity is increasingly prevalent in developed and developing countries and contributes to increasing rates of type 2 diabetes (T2D) globally.1,2 In addition, obesity is a central component of metabolic syndrome, a cluster of risk factors for T2D and cardiovascular disease, which includes hypertension, elevated triglyceride, reduced high-density lipoprotein cholesterol (HDL-C) concentrations, and abnormalities of glucose metabolism.3 The presence of T2D in itself is associated with increased mortality risk, which is additive to the risk attributable to prevalent cardiovascular disease.4 Intensive lifestyle interventions generally comprising weight loss, nutrition management, and increased physical activity reduce T2D risk.5–7 However, such interventions are difficult to implement and sustain in the general population, thus the global diabetes prevalence is estimated to increase to 10.2% (578 million people) by 2030.2 Therefore, new therapeutic approaches are needed to prevent T2D and reduce its associated therapeutic and disease burdens.8
*TESTOSTERONE AND ITS RELATIONSHIP WITH OBESITY AND INSULIN RESISTANCE
Testosterone and Obesity
In cross-sectional studies of middle-aged and older men, circulating testosterone is inversely associated with body mass index (BMI).9–13 Total testosterone concentrations are greater than 20% lower in men with a BMI of 30 kg/m2 or more, compared with those with BMI in the normal range.9,10 In a cross-sectional analysis of 208,677 men from the UK Biobank aged 40 to 69 years, in whom median total testosterone measured using immunoassay was 11.6 nmol/L (334 ng/dL), the inverse association of serum testosterone with BMI was stronger than with age. Compared with 50- year-olds, in 70-year-old men serum testosterone level was ~0.5 nmol/L (~14 mg/ dL) lower, whereas it was ~1.5 nmol/L (~43 ng/dL) lower in men with a BMI of 30 versus 25 kg/m2 and ~3 nmol/L (~86 ng/dL) lower in men with BMI 40 versus 25 kg/m2 . 13 In longitudinal studies, obesity, weight gain, or increases in waist circumference, rather than age itself, were associated with decreases in testosterone concentrations.14–16 In 2736 men aged 40 to 79 years from the European Male Aging Study, with mean total testosterone concentration measured using mass spectrometry of 16.9 nmol/L (487 mg/dL), a loss of 10% or more to less than 15% of body weight was associated with a 2.0 nmol/L (58 ng./dL) increase and a loss of 15% or more with a 5.8 nmol/L (167 ng/dL) increase in testosterone concentrations.15 In interventional studies of diet and/or exercise, loss of 6% to 17% of total weight resulted in total testosterone concentration increasing by 1.2 to 5.1 nmol/L (35–147 ng/dL), whereas bariatric surgery with loss of 29% to 36% of total weight resulted in total testosterone concentration increasing by 7.8 to 10.7 nmol/L (225–308 ng/dL).17 Therefore, men who successfully reduce excess weight can expect to increase their endogenous testosterone concentrations, proportionate to the degree of weight loss.
Testosterone, Obesity, and Sex Hormone-Binding Globulin
Testosterone, Obesity, and Sex Hormone-Binding Globulin Differences in total testosterone concentrations in relation to obesity are mediated in part via the association of obesity with lower circulating sex hormone-binding globulin (SHBG) concentrations.9,10,13 SHBG is the major carrier protein for testosterone in the circulation, and concentrations of total testosterone and SHBG are correlated with coefficients of ~0.5 to 0.6.9,18,19 Of note, the association may not be linear across the range of SHBG concentrations, with the increase in total testosterone concentrations leveling off with SHBG greater than 80 nmol/L in UK Biobank men.13 Thus, men who are obese or insulin-resistant can have low SHBG and testosterone concentrations, in the absence of pathologic hypogonadism.20
Circulating SHBG is primarily synthesized in the liver, and low SHBG concentrations are associated with the presence of insulin resistance and metabolic syndrome.21,22 Earlier experiments suggested a direct role of insulin to inhibit SHBG production in hepatoma cells.23 More recent studies suggest that SHBG is a marker of de novo hepatic lipogenesis. Increasing de novo hepatic lipogenesis is associated with a lower SHBG and vice versa.19,24 Although lower SHBG contributes to lower total testosterone concentrations in overweight or obese men, men with more severe obesity also show reductions in luteinizing hormone (LH) concentrations and LH pulse amplitude, consistent with functional inhibition of the hypothalamic-pituitary-testicular (HPT) axis25,26; this is consistent with the observation that when men lose 15% or more of body weight, the increase in total testosterone is proportionately higher than the increase in SHBG concentrations compared with lesser degrees of weight loss.15
Testosterone and Insulin Resistance
Men with lower total testosterone or SHBG concentrations are more likely to have metabolic syndrome and to manifest insulin resistance.27–29 These associations are likely to be mediated in large part by the underlying relationship of low circulating total testosterone and SHBG with central obesity and excess adiposity.9–16 Whether or not there is a direct association of lower testosterone concentrations with insulin resistance, independently of body composition, is more difficult to discern. Observational studies have reported that apparent associations of lower testosterone concentrations with insulin resistance (assessed by calculations based on circulating glucose and insulin concentrations, either the quick insulin sensitivity check index or the homeostatic model assessment of insulin resistance [HOMA-IR]) may be abrogated by adjustment for SHBG.30–33 However, in one study of older men, after adjusting for age, BMI, waist circumference, and HDL-C and triglyceride levels, lower total testosterone concentrations were independently associated with HOMA-IR, whereas SHBG concentrations were not.34 In a study of 21 men with normal glucose tolerance, impaired glucose tolerance, and diabetes, insulin sensitivity was assessed using hyperinsulinemic-euglycemic clamps correlated with testosterone concentrations and with testicular responses to human chorionic gonadotropin, suggesting an effect of insulin resistance to decrease Leydig cell testosterone secretion.35 In another study of 74 men, undergoing a 75-g oral glucose tolerance test (OGTT) was associated with a decrease in total testosterone concentrations at 30, 60, 90, and 120 minutes, without any change in SHBG or LH concentrations.36 Furthermore, in a study of 12 men diagnosed with idiopathic hypogonadotropic hypogonadism based on serum total testosterone levels less than 3.47 nmol/L (<100 ng/dL) in association with inappropriately low gonadotropin concentrations, suspension of testosterone treatment for 2 weeks resulted in increased fasting insulin concentrations and HOMA-IR without changes in BMI, indicating an acute effect of testosterone withdrawal on insulin sensitivity.37 In a study of 94 men with T2D, 44 had calculated free testosterone levels less than 226 pmol/L and were randomly allocated to testosterone or placebo treatment.38 Glucose infusion rates during hyperinsulinemic-euglycemic clamp did not change when assessed at 3 weeks, but after 6 months of testosterone treatment glucose infusion rates increased by 32%, associated with favorable changes in body composition.38
Summary: Testosterone, Obesity, and Insulin Resistance
Thus obesity, manifesting with central and visceral adiposity and insulin resistance, can inhibit the function of the HPT axis at multiple levels (Fig. 1).13–16,19,22,24–35 Higher degrees of obesity, visceral adiposity, and insulin resistance are associated with both reduced HPT axis activity and lower SHBG concentrations, hence lower circulating total testosterone (see Fig. 1).
*TESTOSTERONE AND THE RISK OF METABOLIC SYNDROME AND DIABETES
Testosterone and Risk of Metabolic Syndrome
Several epidemiologic studies have associated lower total testosterone or SHBG concentrations with a higher risk of metabolic syndrome in men in both cross-sectional and longitudinal analyses.27–29,39–45 An individual participant data meta-analysis of 20 observational studies involving 14,025 men aged 18 years or older not using hormone therapy documented inverse associations of both total testosterone and SHBG with risk of prevalent and incident metabolic syndrome.45 In the cross-sectional analysis, a quartile decrease in total testosterone concentration was associated with ~40% higher odds of metabolic syndrome, across categories of BMI, after adjusting for age, smoking, alcohol consumption, and physical activity. A quartile decrease in baseline total testosterone was associated with an ~25% higher risk of developing metabolic syndrome during follow-up, after adjusting for age and lifestyle factors, reducing to a 14% higher risk after further adjustment for BMI.45 Similarly, in that meta-analysis lower SHBG concentrations were associated with a higher risk of both prevalent and incident metabolic syndrome. Thus, whereas obesity and central adiposity predispose to lower total testosterone and SHBG concentrations, the converse is also true, because men with lower total testosterone or SHBG concentrations are at increased risk of having or developing the metabolic syndrome.
Testosterone and Risk of Diabetes
Epidemiologic studies have consistently associated lower total testosterone or SHBG concentrations not only with insulin resistance21,22,30–34 but also with a higher risk of T2D in men.31,43,46–50 In a systematic review and meta-analysis that included 43 observational studies with 6427 men, lower total testosterone concentrations were associated with a higher risk of prevalent and incident T2D.51 Men with T2D had a mean total testosterone concentration of 2.7 nmol/L (78 ng/dL) lower than those of nondiabetic men. Furthermore, in prospective studies, men who developed diabetes had a baseline mean total testosterone concentration of 2.5 nmol/L (72 ng/dL) lower than those of men who did not.51 In that meta-analysis, men who had baseline total testosterone concentrations of 15.6 to 21.0 nmol/L (450–605 ng/dL) had a relative risk of developing T2D of 0.58, compared with men with baseline total testosterone concentrations of 7.4 to 15.5 nmol/L (213–447 ng/dL).51 Other studies have further reinforced the finding of lower total testosterone concentrations in men with T2D, compared with nondiabetic men.17,52,53 This association likely reflects inhibition of HPT axis function in the presence of central adiposity, a reduction in SHBG concentrations, and possible effects of insulin resistance or hyperglycemia on testicular function.9,10,13–16,19,21–24,35,36 Of note, in a study of 195 men aged 70 years or older the presence of metabolic syndrome, but not lower total testosterone concentration in the absence of metabolic syndrome, was predictive of incident T2D.54 Thus, in older men, obesity and metabolic syndrome, in association with lower testosterone concentrations and worsening body composition, may be the key predisposing factors for T2D.
*EFFECTS OF TESTOSTERONE TREATMENT ON BODY COMPOSITION AND GLUCOSE CONCENTRATIONS
Effect of Testosterone Treatment on Body Composition
Some, but not all, studies have reported an inverse association of muscle mass or strength with diabetes risk in men.55–59 Therefore, a potential mechanism by which testosterone treatment might reduce the risk of T2D would be via its anabolic effects to increase lean mass.60–64 Together with increasing lean mass, testosterone treatment also reduces fat mass, potentially an important mechanism to reduce the risk of T2D.64–66 In men with BMI 30 kg/m2 or more and total testosterone concentrations 12 nmol/L or less (346 ng/dL), testosterone treatment given in conjunction with calorie restriction mitigated the loss of lean mass while potentiating the loss of fat mass.67 A meta-analysis by Isidori and colleagues68 of 29 testosterone randomized controlled trials (RCTs) involving 625 testosterone-treated men and 458 controls with durations ranging from 1 to 36 months with baseline mean total testosterone concentrations ranging from 7.5 to 19.0 nmol/L (216–548 ng/dL) indicated an effect of testosterone treatment to increase lean mass by 1.6 kg (+2.7%) and decrease fat mass by 1.6 kg (-6.2%). A more recent meta-analysis by Corona and colleagues69 included 59 RCTs with 3029 testosterone-treated men and 2049 controls with duration ranging from 1 to 48 months with baseline mean total testosterone concentrations ranging from 2.3 to 21.1 nmol/L (66–608 ng/dL) confirmed the effect of testosterone to increase lean mass and reduce fat mass (standardized mean difference, +0.51 and -0.32 respectively). In an analysis of observational studies, testosterone supplementation was associated with a reduction of waist circumference of 6.2 cm at 24 months.70
Effect of Testosterone Treatment on Glucose Concentrations
Several RCTs have investigated the effect of testosterone treatment on fasting or post-challenge glucose concentrations, or measures of insulin sensitivity, with mixed results.66,71–73 The previous analysis of observational studies reported that testosterone-treated men had a 0.47 mmol/L lower fasting glucose concentration and a HOMA-IR 2.8 lower.70 However, these estimates were smaller, particularly for HOMA-IR, in the meta-analysis of RCTs by Corona and colleagues69 in which testosterone treatment reduced fasting glucose concentrations by 0.34 mmol/L and HOMAIR by 0.80. A review of 3 RCTs conducted specifically in men with T2D with baseline mean total testosterone concentrations of 12 to 15 nmol/L (346–432 ng/dL), suggested a mean reduction of fasting glucose of 1.2 mmol/L with testosterone treatment over durations of 3 to 12 months in that population.74 A more recent meta-analysis of testosterone RCTs in men with T2D and/or metabolic syndrome included 7 RCTs involving 833 men with baseline mean total testosterone concentrations ranging from 6.7 to 10.1 nmol/L (193–291 ng/dL).75 In that meta-analysis, testosterone treatment improved measures of insulin resistance, but did not lower hemoglobin A1c (HbA1c) values.
Summary: Testosterone and Risk of Type 2 Diabetes
Obesity, metabolic syndrome, low testosterone concentrations, and the risk of T2D are closely interrelated (Fig. 2). Obesity per se, and the presence of metabolic syndrome, predispose to both lower testosterone concentrations and diabetes risk, with diabetes risk amplified by the presence of lower testosterone concentrations resulting in unfavorable changes to body composition (loss of lean mass and gain of fat) and alterations in insulin sensitivity (see Fig. 2A). This is consistent with lower testosterone concentrations being predictive of incident T2D in men.46–51,76 In older men, obesity and metabolic syndrome, in association with lower testosterone concentrations and worsening body composition, may be the major contributors to the risk of T2D (see Fig. 2B).
Testosterone treatment by increasing lean mass, reducing fat mass, and reducing glucose concentrations would thus be expected to reduce the risk of T2D.60–70 An uncontrolled, registry-based observational study of 316 men with baseline total testosterone concentrations 12.1 nmol/L or less (~350 ng/dL) followed for 8 years reported an improvement in HbA1c in 229 testosterone-treated men, none of whom progressed to T2D, compared with 40% of the 87 untreated men who developed HbA1c greater than 6.5%.77 Collectively, these existing data on testosterone, obesity, metabolic syndrome, and T2D justify a large-scale, high-quality RCT to determine whether testosterone treatment prevents the development of T2D in men at high risk.
*TESTOSTERONE FOR THE PREVENTION OF TYPE 2 DIABETES MELLITUS
Overview
Testosterone for the Prevention of Type 2 Diabetes Mellitus (T4DM) was a randomized, double-blind, placebo-controlled, 2-year, phase 3b trial to determine whether testosterone treatment prevents or reverts T2D in men enrolled in a lifestyle program.78 Important features of T4DM are summarized (Box 1). The trial randomized 1007 men across 6 centers in Australia, with a 2-year duration of intervention; all participating men also received a lifestyle intervention.79 T4DM represents the largest testosterone RCT completed to date, with the key outcome of T2D and 2 years of safety data.
The T4DM Study Population
As T4DM was conceived as a prevention trial; only men without a previous history of diabetes were recruited. Eligible participants were men aged 50 to 74 years, with a waist circumference of 95 cm or more, who had either impaired glucose tolerance (OGTT 2- hour glucose ≥7.8 to <11.1 mmol/L) or newly diagnosed T2D (OGTT 2-hour glucose ≥11.1 to ≤15.0 mmol/L), for whom the primary intervention could reasonably be a lifestyle program, and who were willing to participate in such a program.78,79 In addition, eligible participants were required to have a screening serum total testosterone concentration of 14.0 nmol/L (403 ng/dL) or less.76 Exclusion criteria are reported.78,79 Of note, men with major medical comorbidities, or with recent cardiovascular events or symptomatic cardiovascular disease, were excluded from T4DM.
Intervention
All participating men were enrolled in a free Weight Watchers program, with face-to-face participation via group sessions and online options available.79 A lifestyle intervention was regarded as the expected standard of care for men with impaired glucose tolerance or newly diagnosed T2D without marked hyperglycemia.5,6 Men were randomly allocated 1:1 to receive testosterone undecanoate 1000 mg or matching placebo, via intramuscular injection, at baseline, 6 weeks, and every 3 months thereafter for 2 years (9 injections in total). Of the participants, 20% of each arm had newly diagnosed T2D based on the entry OGTT result. In 503 men randomized to placebo, 370 completed 2 years of treatment, and 413 had outcome data available for primary analysis at 2 years. In the testosterone arm, 386 completed 2 years of treatment and 443 had outcome data for primary analysis at 2 years.79
Outcomes
At the end of the 2-year intervention, 55 of 443 (12%) testosterone-treated men and 87 of 413 (21%) men in the placebo arm had 2-hour glucose on OGTT of 11.1 mmol/L or more (relative risk, 0.59; 95% confidence interval [CI], 0.43–0.80; P 5 .0007). For the second primary outcome, mean change from baseline in 2-hour glucose on OGTT was -1.70 mmol/L (SD 2.47) in the testosterone arm and -0.95 mmol/L (SD 2.78) in the placebo arm (mean difference -0.75 mmol/L; 95% CI, -1.10 to -0.40; P < .0001).79
Testosterone treatment resulted in a mean increase of 0.39 kg of total muscle mass, and a mean decrease of 4.60 kg of fat mass, whereas men in the placebo group had a mean reduction of 1.32 kg of muscle mass and 1.89 kg of fat mass, after 2 years. Handgrip strength improved with testosterone treatment. Testosterone treatment also resulted in a greater likelihood of having normal 2-hour glucose on OGTT (<7.8 mmol/L; odds ratio, 1.20; 95% CI, 1.04–1.38; P 5 .012) and a lower fasting glucose concentration (-0.17 mmol/L; 95% CI, -0.29 to -0.06; P = .0036) at 2 years.79 However, HbA1c was not different between the 2 groups at 2 years (treatment effect -0.02%; 95% CI, -0.07–0.03; P = .42). Rates of participation in the Weight Watchers program were similar in both arms of the trial. Testosterone treatment increased on study testosterone concentrations, and suppressed LH, with a small reduction in SHBG concentrations.79 In a sensitivity analysis, the benefit of testosterone treatment was similar for men with baseline testosterone concentrations less than 11 nmol/L and 11 nmol/L or more (317 ng/dL), confirming that this was a pharmacologic effect of testosterone treatment.
Adverse Events
At least one safety trigger occurred for 19% of participants in the placebo arm and 38% of participants in the testosterone arm, including triggers for a hematocrit of 54% or higher (1% in placebo versus 22% in the testosterone arm), and increase in the level of the prostate-specific antigen of 0. 75 ng/mL or more (19% of the placebo and 23% of the testosterone arm). In most cases in which a trigger for raised hematocrit occurred, men were retested nonfasting, and some had study injections deferred, with one man in the placebo arm and 25 in the testosterone arm permanently discontinuing treatment. Serious adverse events (SAEs) were recorded in 7.4% of the placebo and 10.9% of the testosterone groups, in a total of 41 of 503 placebo recipients and 55 of 504 testosterone-treated men; these included 21 (4.2%) and 26 (5.2%) cardiovascular SAEs in placebo and testosterone arms, respectively. As noted earlier, men at high risk of cardiovascular adverse events were excluded from the study, leaving a lower risk population. In the placebo arm, 3 men had hospital admissions related to benign prostate hyperplasia and 5 men were diagnosed with prostate cancer, compared with 8 and 4 in the testosterone arm, respectively.
Significance of T4DM
The main result of T4DM, demonstrating an unequivocal effect of testosterone treatment to reduce the likelihood of having T2D in men at high risk is important conceptually and practically. First, in the context of the prior discussion of testosterone, obesity, metabolic syndrome, and diabetes risk (see Figs. 1 and 2), T4DM provides evidence of the bidirectional association. In this large, multicenter, double-blind, placebo-controlled RCT, with a background lifestyle intervention, the 2-year testosterone intervention reduced the risk of T2D, by preventing the progression of impaired glucose tolerance or reverting to newly diagnosed diabetes. The effect size was large, with a relative risk reduction of 40% for the outcome of T2D. Therefore, although obesity, metabolic syndrome, and T2D are associated with lower testosterone concentrations, the association is bidirectional, because low testosterone concentrations predispose to metabolic syndrome and T2D, and testosterone intervention improves body composition, reduces glucose concentrations, and reduces the risk of T2D in the context of a concomitant lifestyle program.
Second, in the context of the worldwide increase in the prevalence of obesity and T2D, T4DM offers a new therapeutic option, that of testosterone pharmacotherapy in combination with readily available lifestyle intervention. The lifestyle program was an intrinsic component of the study. Men who have pathologic hypogonadism merit testosterone treatment.20,80–82 For these men, the metabolic benefits of testosterone now clearly include improvements in glucose tolerance and prevention of T2D. With regard to men with obesity and metabolic syndrome-related reductions in serum testosterone concentrations in the absence of pathologic hypogonadism, our findings suggest that testosterone treatment for 2 years, as an adjunct to a lifestyle program, can prevent or revert T2D. However, increases in hematocrit might be treatment-limiting, and the minimum dose exposure, duration of treatment, the durability of effect, and long-term safety and cardiovascular outcomes of testosterone treatment remain to be determined.83 Thus, the benefit of testosterone treatment on the outcome of T2D as demonstrated in T4DM, needs to be carefully weighed against the limitations of the study, and the potential side effects that may be encountered. If such treatment is considered, a concomitant lifestyle program should be implemented, and there must be careful monitoring of hematocrit, cardiovascular risk factors, and prostate health.
Cardiovascular Effects of Testosterone Treatment
Whether testosterone treatment has beneficial, neutral, or adverse effects on the cardiovascular system remains a complex and debated issue (for review, see84). In brief, one RCT of testosterone in older men aged 65 years or more with baseline total testosterone of 3.5 to 12.1 nmol/L (100–350 ng/dL) or calculated free testosterone less than 173 pmol/L with mobility limitations showed an excess of broadly defined cardiovascular adverse events; another similar RCT in frail or intermediate-frail older men aged 65 years or more with baseline total testosterone of 12 nmol/L or less (345 ng/dL) or calculated free testosterone of 250 pmol/L or less showed no such signal.85,86 There was no excess of cardiovascular adverse events in T Trials, which recruited men with symptoms suggesting hypogonadism aged 65 years or more with baseline total testosterone levels less than 9.54 nmol/L (<275 ng/dL), and T4DM, the 2 largest testosterone RCTs.79,87 Furthermore, recent large meta-analyses of testosterone RCTs have not shown evidence of excess cardiovascular adverse events.88–90 Of note, the cardiovascular substudy of T Trials involving 138 men reported an increase in coronary atheroma measured as noncalcified plaque volume using cardiac computed tomography angiography in testosterone-treated men.91 However, the groups were unbalanced: men in the placebo group (N = 65) had substantially more calcified and noncalcified plaque volume at baseline and at the end of the study compared with men in the testosterone group (N = 73), making the findings challenging to interpret.84,92 Therefore, additional studies are needed to clarify the effect of testosterone on the cardiovascular system. Pending the outcomes of such studies, careful monitoring of cardiovascular risk factors and disease would be appropriate.
Holistic Evaluation and Optimizing Lifestyle, Behavioral, and Medical Factors
All men expressing concerns over their risk of obesity or T2D, whether or not there is concomitant concern over low testosterone concentrations related to these, should be offered a careful assessment and optimal management of medical risk factors and comorbidities.93 Pathologic disorders affecting the HPT axis need to be excluded, or if identified, treated appropriately.20,81,82 Men without HPT axis pathology who are overweight can be advised on losing excess weight, eating healthily, and exercising regularly. Depression and sleep disturbances, if present, should be managed appropriately.94 As discussed earlier, losing excess weight should improve HPT axis function and raise endogenous testosterone levels, and thus represents an attractive nonpharmacologic approach with the potential to capture multiple health benefits. Only after a holistic evaluation and optimization of lifestyle and medical factors have been achieved should further discussion on testosterone pharmacotherapy be considered.79
SUMMARY
There is an intimate and bidirectional association of lower testosterone concentrations with obesity and the risk of T2D risk in middle-aged and older men. Men who are obese, or have metabolic syndrome or T2D, are more likely to have lower testosterone concentrations; conversely, lower testosterone concentrations predispose men to develop metabolic syndrome or T2D. Testosterone pharmacotherapy is effective in preventing or reverting newly diagnosed T2D in men at high risk, reducing the risk of T2D by 40% beyond the effect of lifestyle intervention. However, the first step for improving men’s health must remain a holistic evaluation of lifestyle, behavioral and medical factors, engagement in healthy dietary choices and physical activity, and optimal treatment of existing medical risk factors and comorbidities. Subsequently, men at high risk of diabetes can be counseled on the benefits versus risks of testosterone pharmacotherapy on top of a lifestyle program to prevent diabetes, based on the findings and also realizing the limitations of T4DM. In this context, it could be noted that neither metformin nor the glucagon-like peptide-1 receptor agonist class of drugs increases muscle mass nor do they improve bone and sexual health, as testosterone does.79,87,95,96 If testosterone treatment is considered for the prevention of T2D, a concomitant lifestyle program is necessary as is careful monitoring of hematocrit, cardiovascular risk factors, and prostate health. Further research is needed to clarify the effects of testosterone on the cardiovascular system.
