While data from numerous randomized controlled trials have allowed the establishing of evidence based guidelines for statin use in the prevention of cardiovascular disease (CVD) [1], there remains considerable debate as to which patients should be treated. Indeed, as far back as 2000, we questioned whether lipid lowering treatment guidelines should be based on absolute risk reduction (ARR) or relative risk reduction (RRR) [2]. Until recently, treatment strategies have focused on high absolute risk thresholds in order to obtain maximal ARR as opposed to RRR. However, evidence for considering lifetime risk reduction as opposed to ARR is mounting and this has been highlighted in the latest Joint British Societies 3 recommendations for prevention of CVD [1].

We recently showed that hypogonadism (HG), defined as sexual symptoms and total testosterone < 12.0 nmol/l (346.1 ng/dl), in men with type 2 diabetes (T2DM) is associated with higher all-cause mortality [3]. Importantly, testosterone replacement therapy (TRT) in such men abolishes this increased risk, independently of improvements in metabolic parameters and, statin and phosphodiesterase 5-inhibitor treatments. We further characterized this benefit by showing that TRT alters the association between age and mortality [4].

Figure 1 demonstrates the discrepancy between ARR and lifetime risk reduction following a mean TRT of 3.7 years duration [3][4]. This figure shows the ARR, RRR and lifetime risk reduction that could be expected by treating these men at 55 and 65 years of age. Whilst the ARR is greater in the treated 65-year-old (8.1%) than in the 55-year-old (3.6%) man, lifetime risk reduction is significantly greater when TRT is initiated at 55 years of age. Similar to lipid lowering, the RRR associated with TRT is similar at both ages selected. Based on these results we make a case for earlier treatment and also for not using absolute risk thresholds in men with diabetes and HG. We acknowledge that we have not taken cost effectiveness into account as the underlying risk of mortality in men with HG and T2DM is very high, as evident in (Figure 1).

Laboratory testosterone measurement is recommended in men with HG (including T2DM) and obesity [5][6]. The threshold testosterone level requiring TRT should also be addressed. Quoted laboratory reference ranges (Mayo Medical Laboratories: total testosterone reference range 240–950 ng/ml (8.3–33.0 nmol/l); http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/83686 in adult men) are often inconsistent with the clinical presentation [7] . Thus, evidence exists indicating that treatment thresholds should be 8.7 nmol/l (250.9 ng/dl) in non-diabetic [8] and 10.4 nmol/l (300.0 ng/dl) in diabetic men [9], unless contraindicated. It is important that laboratories keep up with research developments and move away from reference ranges based on the population distribution of the analyte to levels more likely to be clinically useful. Hence, interaction between clinicians and laboratory personnel is essential. To further illustrate this point we turn again to cholesterol concentrations and statin treatment, a field mature in evidence based medicine. Statin treatment is tailored to the underlying risk of the individual and not a laboratory reference range. The low density lipoprotein cholesterol reference range has been replaced by a target value of 1.8 mmol/l (70 mg/dl) in secondary prevention based on evidence [10]. We conclude that it is also important that we observe developments in parallel clinical conditions and apply them when appropriate to our own field.

Keywords: Hypogonadism, Mortality risk reduction, Testosterone, Testosterone replacement therapy, Type 2 diabetes

1. Joint British Societies' consensus recommendations for the prevention of cardiovascular disease (JBS3). Heart 2014 Apr;100 Suppl 2:ii1–67.   [CrossRef]   [Pubmed]    
2. Ramachandran S, French JM, Vanderpump MP, Croft P, Neary RH. Should treatment recommendations for lipid lowering drugs be based on absolute coronary risk or risk reduction? BMJ 2000;320(7236):677–9.    
3. Hackett G, Heald AH, Sinclair A, Jones PW, Strange RC, Ramachandran S. Serum testosterone, testosterone replacement therapy and all-cause mortality in men with type 2 diabetes: Retrospective consideration of the impact of PDE5 inhibitors and statins. Int J Clin Pract 2016 Mar;70(3):244–53.   [CrossRef]   [Pubmed]    
4. Hackett G, Jones PW, Strange RC, Ramachandran S. Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes. World J Diabetes 2017 Mar 15;8(3):104–11.   [CrossRef]   [Pubmed]    
5. Dohle G, Arver S, Bettocchi C, Jones T, Kliesch S Punab M. EAU Guidelines on Male Hypogonadism. 2015. [Available at: https://uroweb.org/wp-content/uploads/18-Male-Hypogonadism_LR.pdf]    
6. Garvey WT, Mechanick JI, Brett EM, et al. American association of clinical endocrinologists and American college of endocrinology comprehensive cllnical practice guidelines for medical care of patients with obesity. Endocr Pract 2016 Jul;22 Suppl 3:1–203.   [CrossRef]   [Pubmed]    
7. Strange RC, Burdett H, Hackett G, Ramachandran S. The metabolic syndrome: A more useful prognostic marker for CVD if testosterone and urate were included? J Endocrinol Diab Res 2016;2(1):100107.    
8. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012 Jun;97(6):2050–8.   [CrossRef]   [Pubmed]    
9. Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 2013 Oct 21;169(6):725–33.   [CrossRef]   [Pubmed]    
10. Ray KK, Kastelein JJ, Boekholdt SM, et al. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: The good the bad and the uncertain: A comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur Heart J 2014 Apr;35(15):960–8.   [CrossRef]   [Pubmed]