Call Us Today!   702-838-1994

Testosterone levels, testosterone therapy and all-cause mortality in men with type 2 diabetes - impact of PDE5 inhibitors and statins

The prevalence of testosterone deficiency is higher in men with type 2 diabetes than among non-diabetic men [1-6], and testosterone deficiency is associated with increased mortality.[7, 8]
 
Type 2 diabetic men often have dyslipidemia [9] and erectile dysfunction [10, 11], and hence statins and phosphodiesterase 5 inhibitors (PDE5I) are widely used in these men.
 
Here I summarize the results of a study published in International Journal of Clinical Practice, which investigated the impact of testosterone levels and testosterone therapy on mortality, and assessed if this was affected by concomitant statin and PDE5I use.[12] 
 
 
 
 
 
 
 
 
Key Points
 
- Mortality is higher in men who are not on testosterone therapy or PDE5I.
 
- Men who are eugonadal or on testosterone therapy have a 38% and 62% reduced risk of mortality, compared to hypogonadal men not receiving testosterone therapy.
 
- Use of PDE5I reduces mortality rates to a greater degree in eugonadal men and hypogonadal men not on testosterone therapy, than in testosterone treated men. 
 
- Statin use is not significantly associated with mortality.
 
- Mortality rates in the Low T/untreated, Normal T and Low T/treated groups were 19.74%, 13.31% and 3.64%, respectively.
 

What is known

 
It is well documented that testosterone deficiency is associated with cardiovascular disease [13] and increased mortality risk.[7, 8] Low testosterone levels are also associated with the number and severity of components of the metabolic syndrome, and may predict the onset of diabetes even in younger men.[14] In line with this, among men with type 2 diabetes low levels of free testosterone are associated with carotid atherosclerosis (measured by CIMT and plaque score) [15], and diabetic men with low testosterone levels  have an almost 2-fold higher mortality rate compared to those with normal testosterone levels, 17.2% vs. 9% respectively.[16]
 
Testosterone deficiency is more common in men with comorbidities, such as diabetes. The prevalence of testosterone deficiency in primary care/screening studies ranges from 19.3% [17] to 38.7% [18]. In other studies, testosterone deficiency affects 43 to 50% of diabetic men.[5, 6] The prevalence of low free testosterone levels (calculated) in diabetic men is even higher, close to 60%.[5] This raises the possibility that low testosterone levels in diabetic men may be of greater clinical importance in these patients than non-diabetic patients.
 
Notably, in men with type 2 diabetes or the metabolic syndrome testosterone therapy has beneficial effects on obesity parameters (body weight, waist circumference and BMI) and metabolic parameters, such as the total: HDL cholesterol ratio, insulin levels, insulin resistance and CRP (C-Reactive Protein).[19-22]
 
While improvements in established risk factors support the efficacy of a treatment, the ultimate proof is hard clinical endpoints, such as cardiac events and mortality. Currently, only two intervention studies – one in type 2 diabetic men - have investigated the effect of testosterone therapy on mortality.[16, 23] Both studies showed that testosterone therapy reduced mortality by half.[16, 23] Specifically, mortality in diabetic men receiving testosterone treatment for a mean duration of 42 months was 8.4%, compared with 19.2% in the untreated group.[16] However, these studies did not examine the possible impact of co-treatment with statins or PDE5Is.
 

What this study adds

 
This study  expands previous research by prospectively examining the association between mortality and testosterone levels in men with type 2 diabetes, and evaluating the impact of concomitant statin or PDE5I use on testosterone treatment outcomes.[12] 
 
857 men with type 2 diabetes, 58 to 65 years old, were screened from five primary care practices during 2007 to 2009. Of the 857 men, 175 of 637 men with total testosterone levels ≤ 12 nmol/L (346 ng/dL) or free testosterone ≤ 0.25 nmol/L received testosterone treatment with injectable testosterone undecanoate for a mean duration of 3.8 years. PDE5I and statins were prescribed to 175 of 857 and 662 of 857 men, respectively.
 
In 2014, after a mean follow-up of 4 years, demographic, concomitant treatment (statin and PDE5I) and mortality, major adverse cardiac events and prostate-related events data were collected from the most recent follow-up visit.
 
Adverse Events and Mortality risk
 
It was found that there were no differences in major adverse cardiac events and prostate-related events among groups.
 
Mortality risk was higher in men who were not on testosterone therapy or PDE5I. When analysis was adjusted for age at initial visit, men in the Normal T/untreated and Low T/treated groups had a 38% and 62% reduced risk of mortality, compared to the Low T/untreated group.
 
When additionally adjusting for PDE5I and statin use, the association between testosterone therapy and mortality lost significance, but the association of age at initial visit and baseline testosterone levels remained significant. 
 
Among the 682 men not given a PDE5I, when compared to the Low T/untreated group, mortality in the Normal T/untreated and Low T/treated groups was significantly lower, 38% an 67% respectively.
 
Statin treatment was not significantly associated with mortality in any analyses. Blood pressure, BMI and lipids were also not significantly associated with mortality.
 
Among men with Low T who were not receiving testosterone therapy, use of PDE5I was associated with a 94% reduced mortality risk, and statin treatment appeared protective. In contrast, PDE5I treatment was not associated with mortality in the 175 patients on testosterone therapy.
 
Actual deaths
 
There were 103 deaths during the study period, primarily due to cardiovascular, respiratory and cancer causes. There were marked differences in mortality in the treated groups. Use of PDE5I reduced mortality rates to a greater degree in the Normal T and Low T/untreated groups, than in the Low T/treated group. Mortality rates were 19.74%, 13.31% and 3.64% in the Low T/untreated, Normal T and Low T/treated groups, respectively, as illustrated in figure 1.
 
Figure 1: Mortality Rates in Testosterone Treated vs. Untreated Hypogonadal men with Type 2 Diabetes. Data based on men not receiving PDE5I.
 

This study concluded that testosterone therapy is independently associated with reduced mortality in men with type 2 diabetes, and that use of PDE5I use was associated with decreased mortality in all patients, suggesting it has an independent protective effect.
 

Comments

 
This is the first study that investigated the independence of testosterone therapy, PDE5I and statin use, and shows that testosterone therapy and PDE5I confer independent protection against mortality in men with type 2 diabetes, while statins do not. 
 
This study confirms previous findings that testosterone therapy reduces mortality [16, 23] by showing that mortality was higher in men who were not on testosterone therapy.[12] A particularly noteworthy finding in this study is that hypogonadal men with type 2 diabetes who received testosterone treatment (without PDE5I or statins) had a 3.7-fold reduced mortality rate than type 2 diabetic men without testosterone deficiency (who were not on PDE5I or statins). 
 
Another interesting - and provocative - finding in this study is that statins do not reduce mortality.
 
The markedly reduced mortality confirms results from previous studies, which I have covered in previous artciles:
 
References:

1.            Haring, R., et al., Prevalence, incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania. Aging Male, 2010. 13(4): p. 247-57.

2.            Corona, G., et al., Association of hypogonadism and type II diabetes in men attending an outpatient erectile dysfunction clinic. Int J Impot Res, 2006. 18(2): p. 190-7.

3.            Dhindsa, S., et al., Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab, 2004. 89(11): p. 5462-8.

4.            Grossmann, M., et al., Low testosterone and anaemia in men with type 2 diabetes. Clin Endocrinol (Oxf), 2009. 70(4): p. 547-53.

5.            Grossmann, M., et al., Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab, 2008. 93(5): p. 1834-40.

6.            Dhindsa, S., et al., Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care, 2010. 33(6): p. 1186-92.

7.            Pye, S.R., et al., Late-onset hypogonadism and mortality in aging men. J Clin Endocrinol Metab, 2014. 99(4): p. 1357-66.

8.            Yeap, B.B., et al., In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality. J Clin Endocrinol Metab, 2014. 99(1): p. E9-18.

9.            Wu, L. and K.G. Parhofer, Diabetic dyslipidemia. Metabolism, 2014. 63(12): p. 1469-79.

10.          Malavige, L.S. and J.C. Levy, Erectile dysfunction in diabetes mellitus. J Sex Med, 2009. 6(5): p. 1232-47.

11.          Maiorino, M.I., G. Bellastella, and K. Esposito, Diabetes and sexual dysfunction: current perspectives. Diabetes Metab Syndr Obes, 2014. 7: p. 95-105.

12.          Hackett, G., et al., 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. 70(3): p. 244-53.

13.          Corona, G., et al., Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol, 2011. 165(5): p. 687-701.

14.          Oh, J.Y., et al., Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care, 2002. 25(1): p. 55-60.

15.          Fukui, M., et al., Association between serum testosterone concentration and carotid atherosclerosis in men with type 2 diabetes. Diabetes Care, 2003. 26(6): p. 1869-73.

16.          Muraleedharan, V., et al., Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol, 2013. 169(6): p. 725-33.

17.          Schneider, H.J., et al., Prevalence of low male testosterone levels in primary care in Germany: cross-sectional results from the DETECT study. Clin Endocrinol (Oxf), 2009. 70(3): p. 446-54.

18.          Mulligan, T., et al., Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract, 2006. 60(7): p. 762-9.

19.          Francomano, D., A. Lenzi, and A. Aversa, Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. Int J Endocrinol, 2014. 2014: p. 527470.

20.          Haider, A., et al., Effects of long-term testosterone therapy on patients with "diabesity": results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. Int J Endocrinol, 2014. 2014: p. 683515.

21.          Jones, T.H., et al., Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care, 2011. 34(4): p. 828-37.

22.          Kalinchenko, S.Y., et al., Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin Endocrinol (Oxf), 2010. 73(5): p. 602-12.

23.          Shores, M.M., et al., Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab, 2012. 97(6): p. 2050-8.

Last modified on Thursday, 31 March 2016 22:50
Monica Mollica

Medical Writer & Nutritionist

MSc in Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

back to top

Dr. Pierce's Medical Organization Affiliations

  • 1-a4m.jpg
  • 2-ACAM.jpg
  • 3-AMMG.jpg
  • 4-American-Board-Anti-Aging-Regenerative-Medicine.jpg
  • 5-AAPMR.jpg
  • 6-acoep.jpg
  • 7-ISSM.jpg
Subscribe to our newsletter for the latest anti-aging news and special promotions.