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Authors Atlantis E, Fahey P, Martin S, et al.
Review Date August 2016
Citation BMC Endocrine Disorders 2016; 16: 26 (open access)
Given the high rates of type 2 diabetes (T2D) in Australia and around the world, identifying those at risk of developing diabetes in the future is important so that intervention may be implemented to prevent progression of impaired glucose tolerance. The progression from pre-diabetes to T2D is likely to be influenced by non-modifiable risk factors such as older age and male sex as well as modifiable risk factors such as smoking and obesity. Large scale trials have shown that lifestyle interventions are effective in reducing the risk of developing T2D by as much as 50% over 3 to 6 years. There are at least seven risk models to identify those at risk of developing T2D but novel biomarkers have emerged since the models were developed. Observational data suggest that testosterone levels in men may be a reversible risk factor for T2D and therefore inclusion of testosterone may enhance the risk models and testosterone may help explain the sex differences in risk.
To determine whether low serum testosterone levels add clinically useful information to current T2D risk models.
The Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) prospective cohort study includes 2563 community-dwelling men aged 35–80 years from Adelaide (from two existing cohort studies). Of the MAILES participants, 2038 (80.0 %) provided information at baseline (2002–2006) and follow-up (2007–2010). After excluding participants with diabetes (n = 317), underweight (n = 5), and unknown BMI status (n = 11) at baseline, and unknown diabetes status (n = 50) at follow-up, 1655 participants were followed for 5 years.
T2D at baseline and follow-up was defined by self-reported diabetes, or fasting plasma glucose (FPG) ≥7.0 mmol/L (126.1 mg/dL), or glycated haemoglobin (HbA1c) ≥6.5 %, or diabetes medication.
Seven risk models (including the Australian AUSDRISK) were tested using logistic regression models. Sensitivity, specificity and positive predictive values (PPV) were used to identify the optimal cut-off point for low serum testosterone for incident T2D and the area under the receiver operating characteristic (AROC) curve was used to summarise the predictive power of the model. Missing data on predictor variable (15.5% of men) were replaced through multiple imputation.
The incidence of T2D was 8.9 % (147/1655) over a median follow-up of 4.95 years (interquartile range: 4.35-5.00). Serum testosterone level (continuous variable) predicted incident T2D (relative risk 0.96 [95 % CI: 0.92,1.00], P = 0.032) independent of current risk models including the AUSDRISK, but did not improve corresponding AROC statistics. A cut-off point of <16 nmol/L for low serum testosterone, which classified about 43% of men, had equal sensitivity (61.3 % [95 % CI: 52.6,69.4]) and specificity (58.3 % [95 % CI: 55.6,60.9) for predicting T2D risk, with a PPV of 12.9 % (95 % CI: 10.4,15.8).
Low serum testosterone predicts an increased risk of developing T2D in men over 5 years independent of current T2D risk models used in clinical practice. A cut-of point of age-adjusted serum testosterone <16 nmol/L was best for optimizing the balance between sensitivity and specificity and the PPV was comparable to that of the risk models. Although including serum testosterone does not improve the performance of current risk models it remains an independent predictor of incident T2D. Screening for low serum testosterone in addition to risk factors from current T2D risk assessment tools, including the AUSDRISK, could identify a large subgroup of distinct men who might benefit from targeted preventive interventions.
Points to Note
- In this study, serum testosterone in men predicted an increased risk of developing T2D over 5 years independent of current risk models.
- Screening for low testosterone (in addition to variables in current risk models) could identify an important sub-group of men who might benefit from targeted interventions.
- Results from short-term RCTs suggest testosterone supplementation may improve glucose control in men with low testosterone through improvement of insulin resistance and may be most beneficial when combined with lifestyle intervention.
- The safety of testosterone therapy in this scenario needs to be adequately tested.
- If the results of a current trial show that testosterone therapy is effective in preventing development of T2D in men with pre-diabetes, in addition to lifestyle intervention, screening for low testosterone in addition to current risk tools could identify men who could benefit from targeted pharmacotherapy and lifestyle interventions.
- The results reported here need to be confirmed in other studies before the value of screening for low testosterone in addition to existing risk assessments for T2D can be determined.