Testosterone therapy for prevention and reversal of type 2 diabetes in men enrolled in a lifestyle program

28 January 2021

STUDY: Wittert G, Bracken K, Robledo KP, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. The lancet Diabetes & endocrinology. Jan 2021;9(1):32-45

Obesity and/or abdominal obesity is a more significant cause of hypogonadism (functional hypogonadism) than age per se. The prevalence of hypogonadism in men with obesity and/or abdominal obesity has been reported to be as high as 53%  1, 58%2, 64% 3 and 79%4. Hypogonadism in turn is a significant risk factor for type 2 diabetes.5-7 Weight loss achieved by either testosterone therapy 8, 9 or lifestyle intervention 10 improves glycemic control and can prevent or reverse type 2 diabetes. However, the effects of testosterone therapy combined with lifestyle interventions have not been rigorously studied.

Here we summarise the results of the Testosterone for Diabetes Mellitus (T4DM) trial, which was designed to investigate whether testosterone treatment increases the benefits of lifestyle intervention for prevention or remission of type 2 diabetes.11 The T4DM trial is the first large‐scale, randomised placebo-controlled trial (RCT) assessing testosterone treatment for preventing or reversing type 2 diabetes in men with abdominal obesity who have low testosterone levels.

For more information about the T4DM study, see "Testosterone therapy to prevent type 2 diabetes in men at risk – rationale"

KEY POINTS

In men with hypogonadism, testosterone treatment + lifestyle weight loss intervention for 2 years, compared with placebo treatment + lifestyle weight loss intervention, resulted in the following health benefits:

Lower incidence of type 2 diabetes after 2 years of treatment, in men who had newly-diagnosed type 2 diabetes at baseline: Among men with newly-diagnosed type 2 diabetes at baseline, 31.8% (28/88) of the testosterone group had type 2 diabetes, compared with 45.2% (38/84) of the placebo group.

What is known about testosterone, prediabetes and type 2 diabetes prevention?

Low testosterone levels, which are common in men who are overweight or obese, are associated with an increased risk of type 2 diabetes.5 A prospective observational study found increased incidence of diabetes in men with testosterone levels below 16 nmol/L (461 ng/dL).6 In a systematic review and meta-analysis, men with testosterone levels higher than 15.5 nmol/L (447 ng/dL) had a 42% reduced risk of type 2 diabetes compared with men with testosterone levels of 15.5 nmol/L or less.7

Diet-induced weight loss can prevent progression of prediabetes to type 2 diabetes 12 and induce remission of type 2 diabetes, i.e., normalisation of glucose tolerance,10 that is sustained for 2 years in one third of subjects.13 However, weight loss maintenance after completing structured weight-loss programs is poor, with subjects regaining half of the lost weight after 1 year and nearly three quarter during the first three years.14-16 Less than 3% of subjects maintained their weight loss at all annual visits for 4–5 years after completion of a weight-loss program.14-16

A meta-analysis of randomised controlled trials found that testosterone treatment consistently leads to significant reduction in fat mass and increase in lean mass, which are body composition changes that can be expected to have beneficial metabolic effects.17 In accordance with this, real-world evidence (RWE) studies of men with hypogonadism have shown that treatment with testosterone undecanoate injections for 8-11 years completely prevented progression of prediabetes to type 2 diabetes,8 and improved glucose metabolism in men with type 2 diabetes, of whom 34.3% experienced remission.9 For more information about these studies, see “Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes” and “Remission of type 2 diabetes during long-term treatment with testosterone undecanoate injections”.

No large-scale, placebo-controlled randomised trial has previously evaluated testosterone treatment for preventing or reversing type 2 diabetes in men with overweight or obesity who have low testosterone, and whether testosterone treatment confers benefits in addition to lifestyle intervention.

What this study adds

The aim of the T4DM trial was to determine the efficacy and safety of testosterone treatment for prevention and/or remission of type 2 diabetes, beyond the effects of a provided by WW (formerly Weight Watchers) lifestyle intervention alone.

Men aged 50–74 years, with abdominal obesity (waist circumference of 95 cm or higher), testosterone level of 14.0 nmol/L (403.8 ng/dL) or lower but without pathological hypogonadism, and impaired glucose tolerance (prediabetes, defined as oral glucose tolerance test [OGTT] 2-h glucose 7.8–11.0 mmol/L) or newly diagnosed type 2 diabetes (defined as OGTT 2-h glucose 11.1 - 15.0 mmol/L) were enrolled in a lifestyle program, and randomly assigned to receive treatment with testosterone undecanoate injection (n=504) or placebo (n=503) at baseline, 6 weeks, and then every 3 months for 2 years.

At 2 years, the prevalence of type 2 diabetes was 21% in placebo treated men and 12% in testosterone treated men (figure 1). This corresponded to a significantly reduced risk of type 2 diabetes by 41% (RR 0·59, p=0·0007) in men who had been receiving testosterone therapy.

A sub-group analysis showed that, after two years (figure 1):

Among men with pre-diabetes at baseline, 7.6% (27/355) in the testosterone group had progressed to type 2 diabetes, compared to 14.9% (49/329) of the placebo group.
Among men with newly-diagnosed type 2 diabetes at baseline, 31.8% (28/88) in the testosterone group had type 2 diabetes, compared with 45.2% (38/84) in the placebo group.

 

Figure 1: Effect of testosterone treatment on prevention, incidence and reversal of type 2 diabetes.

Figure 1: Effect of testosterone treatment on prevention, incidence and reversal of type 2 diabetes.

T2D = type 2 diabetes
Data from Wittert G, Bracken K, Robledo KP, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. The lancet Diabetes & endocrinology. Jan 2021;9(1):32-45

During the trial, medication use for diabetes, lifestyle programme engagement, and maintenance of sufficient exercise were similar between the groups. A higher proportion of men in the testosterone group had normalised 2-h glucose at 2 years from baseline, but HbA1c was similar in the two groups. However, compared with the placebo group, the testosterone group had a significantly greater reduction in fasting glucose. OGTT 2-h glucose was reduced by –0·95 mmol/L in placebo treated men and –1·70 mmol/L in testosterone treated men (mean difference between groups –0·75 mmol/L, p<0·0001).

While there was not a significant difference in weight loss between groups, treatment with testosterone undecanoate increased body fat loss and gain in muscle mass. Compared to placebo, testosterone treated men had a greater reduction in waist circumference (-6.99 vs. -4.85 cm), total fat mass (-4.60 vs. -1.89 kg) and abdominal fat mass (-3.55 vs. -1.21%). Total muscle mass, arm muscle mass and hand-grip strength declined in men receiving placebo and increased in men receiving testosterone treatment, so that after 2 years, men in the testosterone group had significantly greater total muscle mass, arm muscle mass and hand-grip strength.

Compared with the placebo group, the testosterone group had significant improvements in the International Index of Erectile Function subscales (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall sexual satisfaction). There was no between-group difference in lower urinary tract symptoms.

Safety measures were reassuring; there were no significant between-group differences in the change of systolic or diastolic blood pressure, or alanine transferase. As expected, compared to placebo, testosterone treated men had elevations in hematocrit by 4% (see below) and PSA by 0.3 ng/mL, which remained within the normal range in most men.

Commentary

The main results of the T4DM trial are that treatment with testosterone undecanoate injections plus lifestyle intervention for 2 years significantly reduced the progression of prediabetes to type 2 diabetes, and increased cases of reversal of type 2 diabetes, compared to lifestyle intervention alone.11 In other words, testosterone treatment resulted in an additional 41% reduced risk of type 2 diabetes, above the risk reduction conferred by lifestyle intervention alone. Additionally, testosterone treated men had nearly twice the reduction in postprandial glucose levels.

As of this writing, the T4DM trial is the largest testosterone treatment RCT ever conducted, and the first RCT to specifically examine whether long-term testosterone therapy increases the benefits of lifestyle intervention in men with abdominal obesity, prediabetes, type 2 diabetes and low testosterone levels.11 The T4DM trial provides high level evidence that testosterone therapy combined with lifestyle intervention, compared to lifestyle intervention alone, may be a safe and effective strategy for type 2 diabetes prevention, and possibly also type 2 diabetes treatment in men with hypogonadism.

The T4DM trial confirms findings from long-term real-world evidence (RWE) studies in men with hypogonadism, which found that uninterrupted treatment with testosterone undecanoate injections for up to 8-12 years completely prevented progression of prediabetes to type 2 diabetes,8 and resulted in remission of type 2 diabetes in 34% of men.9 In contrast, among men in the control groups who did not receive treatment with testosterone undecanoate injections, 40.2% progressed to type 2 diabetes 8 and no subject had remission of type 2 diabetes.9 The T4DM trial is a milestone study in the field of testosterone therapy and men’s health, for a number of reasons, as explained below.

    Testosterone therapy benefits men with low-normal testosterone levels

    A particularly notable aspect of the T4DM trial is that it was conducted in men with testosterone levels up to 14 nmol/L (404 ng/dL), which is higher than the clinical guideline recommended threshold of 12.1 nmol/L (350 ng/dL) for making the diagnosis of hypogonadism (which also require presence of symptoms and/or signs).

    The rationale for this is that the risk of type 2 diabetes rises markedly in men with testosterone levels below 14 nmol/L.6 The finding that testosterone treated men had a significant improvement in erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall sexual satisfaction, suggests that the traditional diagnostic threshold of 12.1 nmol/L (350 ng/dL) for hypogonadism may be too conservative in men with abdominal obesity who have functional hypogonadism.

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

    Compared to placebo, testosterone treatment also resulted in greater reduction in fasting glucose levels, but there was no significant difference in HbA1c. Discordance between HbA1c and blood glucose has also been seen in other studies of testosterone treatment.18, 19 Similarly, an unexplained discordance between HbA1c and the progression of diabetes has been observed in clinical practice.20

    There are at least two possible explanations for the discordance between blood glucose and HbA1c findings in the T4DM trial. Firstly, HbA1c was only 5.7% at baseline, and hence there was not a lot of room for improvement. Similarly, previous RCTs of testosterone therapy in men with well-controlled diabetes (by diabetes drugs) did not show improvement in HbA1c, despite improvement in insulin sensitivity.19, 21 In contrast, significant reduction in HbA1c has been shown in men with poorly controlled type 2 diabetes, with baseline HbA1c greater than 7.5%.22 The 2021 ADA (American Diabetes Association) Standards of Medical Care in Diabetes recommend an HbA1c target between 6.0% and 7.0%.23

    Secondly, HbA1c is linearly related to blood glucose and red blood cell (RBC) lifespan. At any given average blood glucose, decreased RBC lifespan decreases HbA1c and increased RBC lifespan increases HbA1c.20 One study found that type 2 diabetes patients with poor glycemic control have reduced RBC lifespan.20 The decrease in RBC lifespan in patients with hyperglycemia was not associated with HbA1c. Thus, a decrease in RBC lifespan will lead to an underestimation of the actual level of hyperglycemia and the progression of disease by HbA1c. It has been demonstrated that men with low testosterone have a significant reduction in aldolase and pyruvate kinase activity in red blood cells, which may decrease RBC lifespan and cause spuriously low HbA1C values.24 In accordance with this, another study found that testosterone therapy increased RBC lifespan.25

    Weight loss alone does not lead to maximal improvement in hypogonadism symptoms

    Compared to placebo, testosterone treated men had significant improvements in erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall sexual satisfaction. This confirms findings from previous studies that the small elevation in testosterone levels achieved by diet and exercise interventions is not enough to improve symptoms that are associated with low testosterone.26, 27 In a previous small RCT, men with obesity who had mild to moderate symptoms and modest reductions in testosterone levels, testosterone treatment improved testosterone deficiency symptoms over and above the improvement associated with weight loss alone, and more severely symptomatic men achieved a greater benefit.26 Likewise, in the European Male Ageing Study (EMAS), comprising 3369 community-dwelling men aged 40–79 years, weight loss induced elevation in testosterone levels was not accompanied by symptomatic improvement during a follow-up of 4.3 years.27 Based on these data, the British Society for Sexual Medicine (BSSM) Guidelines on Adult Testosterone Deficiency underscore that lifestyle modification and weight loss alone have failed to demonstrate effective improvement in clinical symptoms, and that patients need to be informed of this.28 The T4DM trial provides strong evidence to support this position.

    Weight loss vs. fat loss

    It is well-established that weight loss reduces risk of type 2 diabetes and improves glycemic control in men with established type 2 diabetes.13, 29, 30 For instance, meta-analyses have concluded that a weight loss of >5% at 12 months appears necessary for beneficial effects on glycemic control,30 and that every kilogram of weight lost is associated with an additional 7% decrease in risk of progression to type 2 diabetes.29 However, the T4DM trial shows that improvement in body composition may be of greater importance than weight loss per se.

    In the T4DM trial, lifestyle intervention alone (placebo group) resulted in a weight loss of -3.53 kg (3.3%) while lifestyle intervention combined with testosterone treatment resulted in a 4.45 kg (4.2%) weight loss.11 The difference in weight loss between groups (-0.92 kg) did not reach statistical significance. Despite similar weight loss, the incidence of type 2 diabetes was nearly twice as high in the placebo group. This suggests that weight loss is not an accurate predictor of intervention effectiveness for diabetes prevention.

    The reason for the lack of significant difference in weight loss between placebo and testosterone groups is that in the testosterone group, the reduction in total and abdominal fat mass was offset by an increase in muscle mass.11 Increased muscle mass is a well-documented effect of testosterone treatment,17, 31 and smaller studies have shown that testosterone treatment may attenuate weight loss-induced reduction in muscle mass.31, 32

    The increase in muscle mass seen in testosterone treated men is particularly noteworthy, considering that a concern with traditional weight loss interventions is that they cause a significant loss of muscle mass.33 A decrease in muscle mass and concomitant decrease in strength, as seen in the placebo group in the T4DM trial, is a detrimental consequence of weight loss induced by lifestyle interventions, which can only be partly counteracted by an increase in physical activity.34 For instance, in the Look AHEAD trial, which is the longest duration intensive lifestyle intervention with body composition data, from baseline to year 1, men and women in the intervention group had a weight loss of 9.4 and 7.0 kg, of which 6.6 kg (70%) and 5.0 kg (71%) was body fat mass, respectively.35 In other words, lean mass made up 30% of the weight loss. From year 1 to 8, there was minimal change in lean mass; the weight gain was nearly exclusively body fat gain. In a sex-specific analysis, differences in fat mass among men in the intervention group and control group (standard diabetes education) were not significant at year 8, however, men in the intervention group had a significantly greater loss of lean mass at all time points.35

    Preservation of lean (muscle) mass during weight loss is critical, as loss of muscle mass may increase risk for weight regain and increased fatness over time, by lowering maintenance energy requirement and triggering increased hunger/appetite.36 Furthermore, muscle tissue is important for maintenance of metabolic health,37 bone mass/skeletal integrity,38 as well as quality of life.39 Higher muscle mass is associated with a significantly reduced risk of the metabolic syndrome,40 nonalcoholic fatty liver disease 41 and, as shown in the T4DM trial, type 2 diabetes.42 Furthermore, higher muscle mass is associated with lower mortality risk, independently of body fat mass, cardiovascular and metabolic risk factors.43-46

    It has been suggested that in healthy weight loss, the fraction of weight loss attributed to lean body mass should not exceed 25%.47 A meta-analysis of lifestyle interventions for weight loss (minimum intervention period including follow-up ≥12 months) found that 25% of weight loss commonly constitutes lean body mass.48 A systematic review found that the mean lean body mass loss as a percentage of weight loss after dietary and drug based weight loss interventions (resulting in a weight loss of >10 kg) is 27% and 31%, respectively.49 While the composition of weight loss is influenced by variables such as physical activity, diet composition, degree of caloric restriction, and - as shown in the T4DM trial - testosterone treatment, weight loss comprising less than 25% lean body mass may be a reasonable reference point for examination of the degree to which different weight loss interventions achieve preservation of muscle mass and healthy weight loss.

    In the T4DM trial, loss of muscle mass in the placebo group was -37.4% (1.32/3.53 = 0.3739), which is alarmingly high.11 In contrast, in testosterone treated men, all weight loss was fat loss, which was accompanied by a small but significant increase in muscle mass. Hence, the T4DM trial provides evidence that testosterone therapy in conjunction with lifestyle intervention results in a significant improvement in body composition, which likely underlies the significantly larger reduction in incidence of type 2 diabetes, compared to men undergoing lifestyle intervention alone. Support for this comes from several studies showing that lower muscle mass is associated with higher fasting and postprandial blood glucose, as well as elevated insulin levels,50 and that higher muscle mass is associated with improved insulin sensitivity and reduced risk for prediabetes and type 2 diabetes.50, 51 After adjusting for age, ethnicity, sex, obesity and waist circumference, each 10% increase in muscle mass index (calculated as muscle mass divided by height squared) has been shown to be associated with 14% reduced insulin resistance and 23% reduced prediabetes risk 50. Muscle, together with the liver, is the main site for storage of glucose (as glycogen) after meals, and therefore plays a central role in glucose disposal.52 Therefore, it is crucial that future studies of interventions for type 2 diabetes prevention/reversal analyse not only weight loss, which can mask important changes in body composition, but also actual fat loss and change in muscle mass.

    Safety

    The T4DM trial confirmed the safety profile of treatment with testosterone undecanoate injections. There was no difference in incident cardiovascular events or prostate cancer between groups. The increase in benign prostate hyperplasia-related hospital admissions with testosterone treatment compared with placebo (eight vs. three) is consistent with the label information for testosterone products, which indicates a risk for acute urinary retention due to benign prostate hyperplasia.

    Testosterone product labels also indicate a risk for worsening lower urinary tract symptoms; however, in the T4DM trial there was no worsening lower urinary tract symptoms (measured by the International Prostate Symptom Score). Meta-analyses of randomized trials have also demonstrated that testosterone treatment has no effect on lower urinary tract symptoms.53, 54

    Testosterone treatment has been associated with venous thrombosis.55 In 2014, the US Food and Drug Administration (FDA) 56 and Health Canada 57 mandated a requirement for manufacturers to add a warning about potential risks of venous thromboembolism and deep vein thrombosis to the label of all testosterone products. This warning was based on data from post-marketing surveillance. In contrast, a meta-analysis of 6 RCTs (n = 2236) and 5 observational studies (n = 1,249,640) did not find a significant association between testosterone and venous thromboembolism.58 For more information, see “Risk of venous thromboembolism in men receiving testosterone therapy”. In the T4DM trial, there were two instances of venous thrombotic complications, both in men in the testosterone group. However, this is lower than the incidence of venous thrombotic complications in other studies with similar populations in terms of risk profile, in which treatment with testosterone was not provided.59

    Elevation in hematocrit is a common physiological response to testosterone treatment.54 Although the elevation in hematocrit stays within normal range in most men who receive testosterone treatment, and despite lack of direct evidence that testosterone-induced hematocrit elevations could be harmful, due to theoretical plausibility, hematocrit needs to be monitored during testosterone therapy. In line with clinical guidelines on testosterone treatment, the T4DM trial had specified an increase in hematocrit to 54% or higher as a safety trigger, which occurred in 106 (22%) of 491 participants treated with testosterone. This proportion is within the range of treatment-limiting increases in hematocrit in other studies of testosterone treatment.60 This trigger led to the cessation of treatment for 26 participants (25 in the testosterone group). One man in the placebo group was also withdrawn from the study due to excessive increase in hematocrit, which could have been caused by insufficient fluid intake during hot weather periods (Australia). The remaining 86 participants either did not have raised hematocrit when blood draw was repeated in a non-fasting state, or they had already received their final study treatment injection. It should be pointed out that no adjustments were made in the injection interval of testosterone undecanoate in the T4DM trial. In clinical practice, excessive elevation in hematocrit could be prevented by periodic venesection 28 and/or increasing the injection interval from every 12 weeks to for example every 14 or 16 weeks in men who develop higher than average elevations in hematocrit.

    Durability of type 2 diabetes prevention

    A dilemma with lifestyle interventions and obesity medications is declining effectiveness over time and high drop-out rates.29 For instance, in a 3-year RCT investigating liraglutide versus placebo for type 2 diabetes risk reduction, the proportion of individuals regressing to normoglycemia during the treatment period decreased during the last interventional year, and similarly, the initial liraglutide-induced weight loss decreased after the first year of treatment.61 In trials of liraglutide, orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion, the 1-year dropout rates were 24%, 29%, 35%, 41%, 49%, respectively.62 In contrast, in the T4DM trial, adherence was 76.5% (dropout 23.5%) in the testosterone group and 73.9% (dropout 26.1%) in the placebo group.

    Several aspects of testosterone treatment make it unique among currently available drugs for diabetes and obesity. Firstly, the effects of testosterone treatment on weight loss, glycemic control and reduction in cardiovascular risk factors progressively improve over time and are sustained with continued treatment.8, 9, 63, 64 A likely explanation for this is the marked improvement in body composition seen during testosterone treatment. Secondly, testosterone treatment reduces both insulin resistance 19 and beta-cell dysfunction,65 the root causes of prediabetes and type 2 diabetes.66-70 Finally, in contrast to diabetes drugs, testosterone treatment significantly improves sexual symptoms.

    In conclusion, the T4DM trial shows that testosterone treatment for 2 years, as an adjunct to a lifestyle program, can prevent or revert type 2 diabetes in men with overweight or obesity who do not have pathological hypogonadism. This effect was accompanied by increased muscle mass, grip strength and sexual function. The T4DM trial provides high level evidence that testosterone treatment provides significant health benefits to men with obesity or abdominal obesity who are at high risk for, or have, type 2 diabetes.

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    References

    1. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. Jul 2006;60(7):762-9.
    2. Hofstra J, Loves S, van Wageningen B, Ruinemans-Koerts J, Jansen I, de Boer H. High prevalence of hypogonadotropic hypogonadism in men referred for obesity treatment. Neth J Me. Mar 2008;66(3):103-9.
    3. Escobar-Morreale HF, Santacruz E, Luque-Ramírez M, Botella Carretero JI. Prevalence of 'obesity-associated gonadal dysfunction' in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis. Hum Reprod Update. Jul 1 2017;23(4):390-408.
    4. Pellitero S, Olaizola I, Alastrue A, et al. Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery. Obes Surg. Dec 2012;22(12):1835-42.
    5. Gyawali P, Martin SA, Heilbronn LK, et al. The role of sex hormone-binding globulin (SHBG), testosterone, and other sex steroids, on the development of type 2 diabetes in a cohort of community-dwelling middle-aged to elderly men. Acta Diabetol. Aug 2018;55(8):861-872.
    6. Atlantis E, Fahey P, Martin S, et al. Predictive value of serum testosterone for type 2 diabetes risk assessment in men. BMC endocrine disorders. May 27 2016;16(1):26.
    7. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. Mar 15 2006;295(11):1288-99.
    8. Yassin A, Haider A, Haider KS, et al. Testosterone Therapy in Men With Hypogonadism Prevents Progression From Prediabetes to Type 2 Diabetes: Eight-Year Data From a Registry Study. Diabetes Care. Jun 2019;6(42):1104-1111.
    9. Haider KS, Haider A, Saad F, et al. Remission of type 2 diabetes following long-term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11-year data from a real-world registry study. Diabetes, obesity & metabolism. Jun 19 2020;
    10. Lean ME, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. Feb 10 2018;391(10120):541-551.
    11. Wittert G, Bracken K, Robledo KP, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. The lancet Diabetes & endocrinology. Jan 2021;9(1):32-45.
    12. Diabetes Prevention Program Research G, Knowler WC, Fowler SE, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. Nov 14 2009;374(9702):1677-86.
    13. Lean MEJ, Leslie WS, Barnes AC, et al. Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. The lancet Diabetes & endocrinology. May 2019;7(5):344-355.
    14. Anderson JW, Vichitbandra S, Qian W, Kryscio RJ. Long-term weight maintenance after an intensive weight-loss program. J Am Coll Nutr. Dec 1999;18(6):620-7.
    15. Kramer FM, Jeffery RW, Forster JL, Snell MK. Long-term follow-up of behavioral treatment for obesity: patterns of weight regain among men and women. Int J Obes. 1989;13(2):123-36.
    16. Curioni CC, Lourenço PM. Long-term weight loss after diet and exercise: a systematic review. Int J Obes (Lond). Oct 2005;29(10):1168-74.
    17. Corona G, Giagulli VA, Maseroli E, et al. Testosterone supplementation and body composition: results from a meta-analysis study. Eur J Endocrinol. Mar 2016;174(3):R99-116.
    18. Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. Apr 2011;34(4):828-37.
    19. Dhindsa S, Ghanim H, Batra M, et al. Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes. Diabetes Care. Jan 2016;39(1):82-91.
    20. Huang Z, Liu Y, Mao Y, Chen W, Xiao Z, Yu Y. Relationship between glycated haemoglobin concentration and erythrocyte survival in type 2 diabetes mellitus determined by a modified carbon monoxide breath test. J Breath Res. Jan 9 2018;12(2):026004.
    21. Gianatti EJ, Dupuis P, Hoermann R, et al. Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: a randomized controlled trial. Diabetes Care. Aug 2014;37(8):2098-107.
    22. Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P. Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study. The journal of sexual medicine. Mar 2014;11(3):840-56.
    23. 6. Glycemic Targets: Standards of Medical Care in Diabetes - 2021. Diabetes Care. 2021;44(Supplement 1):S73-S84.
    24. Medras M, Checińska E, Silber-Kasprzak D, Gwóźdź K. Decrease of aldolase and pyruvate kinase activity in erythrocytes of individuals with male hypogonadism as an expression of lack of androgen influence on the bone marrow. Andrologia. Jan-Feb 1983;15(1):44-9.
    25. Solomon LR, Hendler ED. Androgen therapy in haemodialysis patients. II. Effects on red cell metabolism. Br J Haematol. Feb 1987;65(2):223-30.
    26. Ng Tang Fui M, Hoermann R, Prendergast LA, Zajac JD, Grossmann M. Symptomatic response to testosterone treatment in dieting obese men with low testosterone levels in a randomized, placebo-controlled clinical trial. Int J Obes (Lond). Mar 2017;41(3):420-426.
    27. Rastrelli G, Carter EL, Ahern T, et al. Development of and Recovery from Secondary Hypogonadism in Aging Men: Prospective Results from the EMAS. J Clin Endocrinol Metab. Aug 2015;100(8):3172-82.
    28. Hackett G, Kirby M, Edwards D, et al. British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice. The journal of sexual medicine. Dec 2017;14(12):1504-1523.
    29. Haw JS, Galaviz KI, Straus AN, et al. Long-term Sustainability of Diabetes Prevention Approaches: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA internal medicine. Dec 1 2017;177(12):1808-1817.
    30. Franz MJ, Boucher JL, Rutten-Ramos S, VanWormer JJ. Lifestyle weight-loss intervention outcomes in overweight and obese adults with type 2 diabetes: a systematic review and meta-analysis of randomized clinical trials. Journal of the Academy of Nutrition and Dietetics. Sep 2015;115(9):1447-63.
    31. Ng Tang Fui M, Prendergast LA, Dupuis P, et al. Effects of testosterone treatment on body fat and lean mass in obese men on a hypocaloric diet: a randomised controlled trial. BMC medicine. Oct 07 2016;14(1):153.
    32. Barnouin Y, Armamento-Villareal R, Celli A, et al. Testosterone Replacement Therapy added to Intensive Lifestyle Intervention in Older Men with Obesity and Hypogonadism. J Clin Endocrinol Metab. Dec 22 2020;
    33. Marks BL, Rippe JM. The importance of fat free mass maintenance in weight loss programmes. Sports Med. Nov 1996;22(5):273-81.
    34. Weinheimer EM, Sands LP, Campbell WW. A systematic review of the separate and combined effects of energy restriction and exercise on fat-free mass in middle-aged and older adults: implications for sarcopenic obesity. Nutr Rev. Jul 2010;68(7):375-88.
    35. Pownall HJ, Bray GA, Wagenknecht LE, et al. Changes in body composition over 8 years in a randomized trial of a lifestyle intervention: the look AHEAD study. Obesity (Silver Spring). Mar 2015;23(3):565-72.
    36. Dulloo AG, Jacquet J, Miles-Chan JL, Schutz Y. Passive and active roles of fat-free mass in the control of energy intake and body composition regulation. Eur J Clin Nutr. Mar 2017;71(3):353-357.
    37. Wolfe RR. The underappreciated role of muscle in health and disease. Am J Clin Nutr. Sep 2006;84(3):475-82.
    38. Bano G, Pigozzo S, Piovesan F, et al. Influence of serum 25-hydroxyvitamin D levels, fat-free mass, and fat mass on bone density, geometry and strength, in healthy young and elderly adults. Exp Gerontol. Nov 2018;113:193-198.
    39. Trombetti A, Reid KF, Hars M, et al. Age-associated declines in muscle mass, strength, power, and physical performance: impact on fear of falling and quality of life. Osteoporos Int. Feb 2016;27(2):463-71.
    40. Park BS, Yoon JS. Relative skeletal muscle mass is associated with development of metabolic syndrome. Diabetes Metab J. Dec 2013;37(6):458-64.
    41. Kim G, Lee SE, Lee YB, et al. Relationship Between Relative Skeletal Muscle Mass and Nonalcoholic Fatty Liver Disease: A 7-Year Longitudinal Study. Hepatology. Nov 2018;68(5):1755-1768.
    42. Kalyani RR, Metter EJ, Xue QL, et al. The Relationship of Lean Body Mass With Aging to the Development of Diabetes. J Endocr Soc. Jul 1 2020;4(7):bvaa043.
    43. Srikanthan P, Karlamangla AS. Muscle mass index as a predictor of longevity in older adults. Am J Med. Jun 2014;127(6):547-53.
    44. Wannamethee SG, Shaper AG, Lennon L, Whincup PH. Decreased muscle mass and increased central adiposity are independently related to mortality in older men. Am J Clin Nutr. Nov 2007;86(5):1339-46.
    45. Bigaard J, Frederiksen K, Tjonneland A, et al. Body fat and fat-free mass and all-cause mortality. Obes Res. Jul 2004;12(7):1042-9.
    46. Chuang SY, Chang HY, Lee MS, Chia-Yu Chen R, Pan WH. Skeletal muscle mass and risk of death in an elderly population. Nutrition, metabolism, and cardiovascular diseases : NMCD. Jul 2014;24(7):784-91.
    47. Heymsfield SB, Gonzalez MC, Shen W, Redman L, Thomas D. Weight loss composition is one-fourth fat-free mass: a critical review and critique of this widely cited rule. Obesity reviews : an official journal of the International Association for the Study of Obesity. Apr 2014;15(4):310-21.
    48. Schwingshackl L, Dias S, Hoffmann G. Impact of long-term lifestyle programmes on weight loss and cardiovascular risk factors in overweight/obese participants: a systematic review and network meta-analysis. Systematic reviews. Oct 30 2014;3:130.
    49. Chaston TB, Dixon JB, O'Brien PE. Changes in fat-free mass during significant weight loss: a systematic review. Int J Obes (Lond). May 2007;31(5):743-50.
    50. Kalyani RR, Metter EJ, Ramachandran R, Chia CW, Saudek CD, Ferrucci L. Glucose and insulin measurements from the oral glucose tolerance test and relationship to muscle mass. J Gerontol A Biol Sci Med Sci. Jan 2012;67(1):74-81.
    51. Srikanthan P, Karlamangla AS. Relative muscle mass is inversely associated with insulin resistance and prediabetes. Findings from the third National Health and Nutrition Examination Survey. J Clin Endocrinol Metab. Sep 2011;96(9):2898-903.
    52. Abdul-Ghani MA, DeFronzo RA. Pathogenesis of insulin resistance in skeletal muscle. Journal of biomedicine & biotechnology. 2010;2010:476279.
    53. Kohn TP, Mata DA, Ramasamy R, Lipshultz LI. Effects of Testosterone Replacement Therapy on Lower Urinary Tract Symptoms: A Systematic Review and Meta-analysis. Eur Urol. Jun 2016;69(6):1083-90.
    54. Ponce OJ, Spencer-Bonilla G, Alvarez-Villalobos N, et al. The efficacy and adverse events of testosterone replacement therapy in hypogonadal men: A systematic review and meta-analysis of randomized, placebo-controlled trials. J Clin Endocrinol Metab. Mar 17 2018;
    55. Martinez C, Suissa S, Rietbrock S, et al. Testosterone treatment and risk of venous thromboembolism: population based case-control study. BMJ. Nov 30 2016;355:i5968.
    56. Testosterone products: FDA/CDER statementdrisk of venous blood clots. US Food and Drug Administration website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm402054.htm Published June 20, 2014. Accessed July 26, 2015.
    57. Summary safety review - testosterone replacement products - cardiovascular risk. Health Canada website. http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/testosterone-eng.php Published July 15, 2014. Accessed July 26, 2015.
    58. Houghton DE, Alsawas M, Barrioneuvo P, et al. Testosterone therapy and venous thromboembolism: A systematic review and meta-analysis. Thromb Res. Dec 2018;172:94-103.
    59. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. Nov 26 2005;366(9500):1849-61.
    60. Coviello AD, Kaplan B, Lakshman KM, Chen T, Singh AB, Bhasin S. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab. Mar 2008;93(3):914-9.
    61. le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet. Apr 8 2017;389(10077):1399-1409.
    62. Dong Z, Xu L, Liu H, Lv Y, Zheng Q, Li L. Comparative efficacy of five long-term weight loss drugs: quantitative information for medication guidelines. Obesity reviews : an official journal of the International Association for the Study of Obesity. Dec 2017;18(12):1377-1385.
    63. Saad F, Doros G, Haider KS, Haider A. Differential effects of 11 years of long-term injectable testosterone undecanoate therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight, overweight and obesity in comparison with untreated controls: real-world data from a controlled registry study. Int J Obes (Lond). Jun 2020;44(6):1264-1278.
    64. Saad F, Caliber M, Doros G, Haider KS, Haider A. Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality. The aging male : the official journal of the International Society for the Study of the Aging Male. Mar 2020;23(1):81-92.
    65. Dimitriadis GK, Randeva HS, Aftab S, et al. Metabolic phenotype of male obesity-related secondary hypogonadism pre-replacement and post-replacement therapy with intra-muscular testosterone undecanoate therapy. Endocrine. Apr 2018;60(1):175-184.
    66. Chiasson JL, Rabasa-Lhoret R. Prevention of type 2 diabetes: insulin resistance and beta-cell function. Diabetes. Dec 2004;53 Suppl 3:S34-8.
    67. Kasuga M. Insulin resistance and pancreatic beta cell failure. J Clin Invest. Jul 2006;116(7):1756-60.
    68. Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care. May 2006;29(5):1130-9.
    69. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia. Jan 2003;46(1):3-19.
    70. Cerf ME. Beta cell dysfunction and insulin resistance. Frontiers in endocrinology. 2013;4:37.
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