Testosterone therapy to prevent type 2 diabetes in men at risk−rationale
STUDY: Wittert G, Atlantis E, Allan C, et al. Testosterone therapy to prevent type 2 diabetes mellitus in at-risk men (T4DM): Design and implementation of a double-blind randomised controlled trial. Diabetes, obesity & metabolism. 2018.
Obesity is a well-established cause of low testosterone that is potentially reversible with weight loss.1-3 While theoretically obesity is a reversible cause of low testosterone, a very large amount of weight loss is necessary to raise endogenous testosterone levels enough to achieve resolution of hypogonadal symptoms. For the vast majority of men, it is extremely hard to achieve this amount of weight loss, and even harder to maintain it long-term.
Low testosterone in turn is associated with an increased risk of incident type 2 diabetes in men.4
A high proportion of men with type 2 diabetes have low testosterone that is associated with obesity, insulin resistance and hyperglycemia.5,6 A systematic review with meta-analysis showed that men with testosterone levels above 15.5 nmol/L (447 ng/dL) have a 42% reduced risk of type 2 diabetes compared to men with testosterone below 15.5 nmol/L.7
Here we summarise the rationale of the notable upcoming T4DM “Testosterone 4 Diabetes Mellitus” study, which is investigating whether testosterone treatment combined with lifestyle change can prevent type 2 diabetes in men who have low testosterone levels and prediabetes.8
- It is well documented that low testosterone is associated with elevated glucose levels and type 2 diabetes.
- Multiple studies have shown that testosterone therapy significantly reduces fasting glycemia and insulin resistance.
- The benefits of testosterone therapy are greatest when combined with lifestyle interventions.
- The “Testosterone 4 Diabetes Mellitus” study, also known as the T4DM trial, is a randomised, double-blind, placebo-controlled trial – the gold standard study method - designed to find out if testosterone therapy with Nebido®/Reandron® combined with lifestyle intervention (Weight Watchers®) for 2 years versus lifestyle intervention alone, improves glucose tolerance and reduces incidence of type 2 diabetes.
- The first results from the T4DM trial are expected to get published end of 2019. The T4DM trial is a milestone study because it may have significant implications for clinical practice, both in regards to treatment of men with type2 diabetes or impaired glucose tolerance and the diagnosis of hypogonadism.
What is known about testosterone, insulin sensitivity / resistance and diabetes
Low testosterone can cause hyperglycemia both directly and indirectly. Low testosterone increases body fat and reduces lean body (muscle) mass, which in turn results in insulin resistance followed by elevated glucose levels.9 Hence, the effect of testosterone on insulin resistance is partly mediated by changes in body composition.10 Several direct mechanisms exist that explain how low testosterone acutely contributes to hyperglycemia in the absence of changes in body composition. Testosterone modulates the expression of the glucose transporter Glut4 and activities of glycolytic enzymes (phosphofructokinase and hexokinase)11, as well as inflammatory cytokines (TNF-alpha and IL-1beta).12,13 Testosterone is also associated with mitochondrial function in muscle tissue14, and data suggest that the age-associated decline in mitochondrial function contributes to insulin resistance.15 Reduced mitochondrial function is also a hallmark of obesity and type 2 diabetes.16,17
Several studies with long follow-up periods of up to 15 years show that low testosterone levels significantly increased risk for development of insulin resistance, the metabolic syndrome and type 2 diabetes, even in men who were not obese at baseline.18-20 Among men with low testosterone, half already have prediabetes.21,22 A comprehensive analysis found that a testosterone level below 16 nmol/L predicts 5 year risk of developing type 2 diabetes in men, independently of age, ethnicity/country of birth, family history of diabetes, impaired fasting glucose, blood pressure medications, smoking, physical inactivity, waist circumference, pre-diabetes, BMI, diagnosed cardiovascular disease, high blood pressure, high triglycerides, low HDL-C, and income.23 This suggests that screening for low testosterone would identify a large group of men at risk who otherwise would get missed by use of current type 2 diabetes risk assessment tools.23
Several long-term prospective observational “real life” studies of testosterone therapy for up to 6 years in hypogonadal men with the metabolic syndrome or type 2 diabetes show marked improvement in glycemic control (reduction in fasting glucose and HbA1c), weight loss and reduced overall cardiovascular risk.24-26 A meta-analysis of 7 placebo-controlled randomised controlled trials (RCTs) found that testosterone therapy in men with the metabolic syndrome or type 2 diabetes reduced insulin resistance (HOMA-IR), but had no effect on HbA1c.27 The contradictory data in RCTs is likely due to inclusion of subjects with varying degrees of baseline testosterone deficiency, as well as failure to achieve large enough elevations in testosterone levels that are sustained long enough for a reduction in HbA1c to manifest.28,29 In the meta-analysis, the study with the longest duration of testosterone therapy lasted only 12 months.9 This is in stark contrast to observational studies where testosterone therapy was provided continuously for at least 6 years.24-26
The beneficial effects of testosterone have been confirmed in numerous randomized controlled trials which demonstrate that testosterone therapy significantly reduces fasting glycemia and insulin resistance.10 There is international consensus among medical organizations supporting lifestyle intervention for prevention and management of type 2 diabetes.30,31 In this regard, it is particularly notable that the benefits of testosterone therapy are greatest when combined with lifestyle intervention.32 Addition of testosterone therapy to a supervised diet and exercise program results in greater improvements in HbA1c, fasting plasma glucose, high-density lipoprotein cholesterol, triglyceride and waist circumference than that achieved with the supervised diet and exercise program alone.32
However, up to this point no large-scale trial has evaluated the effect of testosterone therapy combined with lifestyle intervention versus lifestyle intervention alone. Therefore, the “Testosterone 4 Diabetes Mellitus” study, also known as the T4DM trial, was undertaken.
What the “Testosterone 4 Diabetes Mellitus” study will teach us
The T4DM study is a randomised, double-blind, placebo-controlled trial designed to find out if testosterone treatment combined with lifestyle intervention (Weight Watchers®) for 2 years versus lifestyle intervention alone, improves glucose tolerance and reduces incidence of type 2 diabetes.8
Subjects included approximately 1000 overweight or obese men aged 50-74 years with testosterone levels of 14nmol/L or less and with impaired glucose tolerance or newly diagnosed type 2 diabetes (diagnosed by oral glucose tolerance test, OGTT). All men had abdominal obesity (waist circumference ≥ 95 cm).
Participants were randomized to receive treatment with testosterone undecanoate injections (Nebido®, tradename in Australia Reandron®, Bayer, 1000mg/4ml) or placebo injections (4ml castor oil), at baseline, 6 weeks and 3-monthly thereafter for 2 years.
The lifestyle intervention was provided by Weight Watchers®, with an interactive website providing diet and activity guidelines, and self-monitoring tools allowing men to log food, physical activity and weigh-in details. Men were encouraged to achieve a 5% reduction in body weight each year and to monitor and record their own body weight weekly. Adherence with the overall lifestyle program was monitored via website logins and activity, meeting attendance and information collected at 3-monthly clinic visits.
Besides the primary endpoints of incident type 2 diabetes (diagnosed as 2-hour glucose in the diabetic range, ≥11.1mmol/L on 75g OGTT), and change in post-prandial 2-hour glucose after 2 years of treatment with testosterone undecanoate injections vs. placebo, the following secondary endpoints will be examined:
- Normalised blood glucose (2-hour glucose < 7.8mmol/L)
- Initiation of antidiabetic pharmacotherapy
- Glucose metabolism: fasting plasma glucose, insulin and HbA1c
- Anthropometrics: body weight, waist circumference
- Body composition: DEXA measurements of whole-body and regional fat and lean body mass
- Muscle strength: handgrip
- Sex steroid hormone profile: testosterone, DHT, estrone, estradiol and SHBG
- Sexual function and lower urinary tract symptoms (LUTS)
- Biomarkers for metabolic function: lipids (total cholesterol, LDL, triglycerides, HDL)
- Psychosocial function
- Compliance with the lifestyle intervention program
- Health care expenditure
The reasons for measuring these outcomes are described below.
Additional markers of glycemic status
The percentage of men with normal glucose levels (2-hour glucose < 7.8 mmol/L), initiation of antidiabetic pharmacotherapy, fasting plasma glucose, insulin and HbA1c.
Mechanisms underlying the effects of testosterone therapy
a. Improved body composition reflected by a decrease in total and/ or abdominal fat mass and increase in lean mass (DXA). Two outcomes related to body composition improvement will also be analysed: muscle strength (measured by hand grip dynamometry) and insulin resistance (by HOMA-IR, based on fasting plasma glucose and insulin).
b. Enhanced adherence to the Weight Watchers® program, as reflected by attendance at groups, use of the online program, or both, and its relationship to weight loss.
c. Increase in physical activity as assessed by the Active Australia questionnaire.
The effects of testosterone therapy may be attributable either to testosterone treatment, improvement in health behaviours and weight loss, or an interaction between testosterone therapy, health behaviours and weight loss.
These outcomes include: erectile function, sexual desire and LUTS, assessed by the International Index of Erectile Function (IIEF-5), Sexual Desire Inventory, and IPSS respectively. These questionnaires were chosen because they were used in the Men in Australia Inflammation Lifestyle, Environment and Stress (MAILES) study.33
Treatment impact on psychosocial factors
a. Health-related quality of life will be assessed by the Short-Form Health Survey (SF-12) to test the hypotheses that Health-related quality of life will improve over time and be greater at study completion for men who had received testosterone therapy vs. placebo for 2 years.
b. Psychosocial function and motivation for lifestyle change will be assessed by the MacArthur Scale of Subjective Social Status, Pearlin’s Personal Mastery Scale, and Sense of Coherence (a factor in determining how well a person manages stress and stays healthy), to test the hypothesis that subjective social status, mastery, and sense of coherence will improve over time in men and be greater at study completion for men who had received testosterone therapy vs. placebo for 2 years.
To determine whether psychosocial measures mediate the impact of testosterone on glycemic status
The hypothesis being tested is that improvements in subjective social status, mastery, and sense of coherence will partially or fully mediate (account for, in the causal pathway) the impact of T on glycaemia.
To determine whether the relationship between testosterone and glycemic status varies by sociodemographic measures
The hypothesis being tested is that greater education, greater household income, higher status occupation, or being married or cohabitating will strengthen the relationship between testosterone and glycemic status and, conversely, lesser values for these measures will be associated with a lesser strength of the relationship between testosterone and glycemic status.
Association of treatment effects with baseline and change in sex steroid concentrations
Circulating testosterone, DHT, estradiol and estrone will be measured by LC-MS/MS at baseline, 18, 66, and 102 weeks. Serum SHBG, follicle stimulating hormone (FSH) and luteinising hormone (LH) will be measured by immunoassay.
Treatment impact on health care expenditure
Costs of prescribed testosterone therapy (Reandron®), costs of hospitalisations, and costs of general practitioner visits will be used to analyse impact of testosterone therapy on health care expenditure.
Cost-effectiveness per incident type 2 diabetes prevented, per death prevented, life year gained and quality-adjusted life year (QALY) gained will be analysed.
Three sub-studies of T4DM will be conducted to determine the effects of testosterone therapy on:
- Bone micro-architecture (measured by peripheral quantitative computed tomography, pQCT), and bone mineral density (measured by DXA) (T4Bone).
- Motivation and behaviour (T4M&B).
- Telomere length (T4Telomeres).
Two additional sub-studies will investigate the effects of extended testosterone therapy for up to 4 years (T4DM run-on), and rate of HPT axis recovery at the end of the initial 2-year treatment period (T4DM run-off), respectively.
The first results from the T4DM trial are expected to get published end of 2019. With 1000 subjects, the T4DM trial is the largest RCT investigating the effects of testosterone therapy. The Testosterone Trials (TTrials) had 790 subjects and lasted 1 year. The TEAAM (Testosterone’s Effects on Atherosclerosis Progression in Aging Men) trial lasted 3 years, but only included 156 subjects.
A particularly notable aspect of the T4DM trial is that it includes men with a baseline testosterone level of ≤14 nmol/L (404 ng/dL). This threshold is higher than the threshold recommended by most clinical guidelines for the diagnosis of hypogonadism, which is 12 nmol/L (345 ng/dL). The higher threshold of 14 nmol/L was chosen because the association of low testosterone levels and insulin resistance in men with type 2 diabetes remains present within the “normal” testosterone level range, and does not have a clear cutoff point.5 The T4DM research team settled on a testosterone threshold of 14 nmol/L somewhat below 16 nmol/L (461 ng/dL)) where incident type 2 diabetes began to increase in an analysis of longitudinal data from the Florey Adelaide Male Aging Study (FAMAS)6, and 15.5 mmol/L (447 ng/dL) in the prospectively followed cohorts in a large meta-analysis.7
The T4DM run-on part of the study will investigate the effects of testosterone therapy for 4 years. This will become a milestone in testosterone therapy research; the longest duration RCT data currently available is the TEAAM trial, which examined the effects of testosterone therapy for 3 years in 156 men. The T4DM run-on sub-study will surpass the TTrials and TEAAM trial in both duration, size and comprehensiveness (a wider range of effects and mechanisms investigated).
A recent prospective study with a follow-up of nearly 10 years showed for the first time that low testosterone levels at baseline predicted higher insulin resistance (assessed by HOMA-IR) at follow-up, but high insulin resistance at baseline did not predict low testosterone at follow-up.34Even if insulin resistance contributes to or causes low testosterone levels, this link may be weaker than the reverse direction where low testosterone contributes to or causes insulin resistance. The T4DM study, by measuring fasting plasma glucose and insulin, which are variables included in the HOMA-IR calculation of insulin resistance, will be able to shed light on the nature of the association between low testosterone and insulin resistance.
The T4DM trial will be the first ever RCT to investigate the effects of testosterone therapy on motivation for physical activity and telomere length, a biomarker of aging, in humans.35Experimental data show that testosterone can protect telomeres36, and in mice treated with long-term physiological testosterone therapy there was amelioration of cardiomyocyte aging, as indicated by increased telomere length in cardiomyocytes.37 A case-report of a patient with acquired aplastic anemia showed that long-term testosterone therapy resulted in sustained telomere elongation in hematopoietic stem cells.38 In a prospective study, higher baseline waist circumference and glucose levels, and lower HDL levels, were consistently associated with shorter telomere length after a 6-year follow-up.39 Also, greater 6-year increase in waist circumference was associated with larger telomere attrition. Similar but nonsignificant associations were observed for increases in triglycerides and glucose levels.39 The potential effect of testosterone therapy on motivation is also an emerging research area. Subjective reports from prior studies suggested that testosterone therapy increases motivation for exercise, and a recent experimental study showed that testosterone treatment stimulates physical activity behavior (wheel running) in male mice by acting on central dopaminergic pathways.40 Sub-studies of T4DM will specifically investigate whether testosterone therapy in men with low testosterone levels does have an effect on telomere length and motivation, as well as bone mineral density.
The upcoming year will be a milestone in testosterone science. Stay tuned for the first T4DM results, which are expected get published end of 2019 and will be reported here on www.nebido.com