Cardiovascular benefits and risks of testosterone replacement therapy in hypogonadal men with type 2 diabetes mellitus and/or the metabolic syndrome: a systematic review

Authors

  • Le Minh Quang CARDIFF DIABETES CENTRE FV HOSPITAL
  • Atul Kalhan South Wales University Royal Glamorgan Hospital

DOI:

https://doi.org/10.15277/bjd.2018.192

Keywords:

testosterone replacement, diabetes, cardiovascular events, men, hypogonadal

Abstract

Background: Because of the paucity of large randomised controlled trials (RCTs) in men with type 2 diabetes mellitus (T2DM) and/or the metabolic syndrome (MS), the majority of evidence for use of testosterone replacement therapy (TRT) on the cardiovascular (CV) system in such men is derived from observational studies and systematic reviews.

Methods: We carried out an extensive retrospective review of the literature, comparing the major comparative trials that involved TRT in hypogonadal men with T2DM and/or MS and focused on CV outcomes.

Results: Of 311 studies initially identified, 25 studies (12 RCTs and 13 non-RCTs) with a total number of 729,927 participants were deemed eligible for further review. Three RCTs and one non-RCT were excluded as these had not measured all-cause mortality and CV events as primary outcomes. Benefits of TRT on myocardial infarction were observed in two RCTs which were reviewed, while the rest demonstrated a neutral effect on CV events. In the non-RCTs, seven studies observed reduced all-cause mortality and/or major adverse CV events in the TRT group compared with the placebo group.

Conclusions: This retrospective and systematic review of the literature suggests protective effects of TRT against all-cause mortality and major adverse cardiac events in hypogonadal men with T2DM and/or MS, although these results need to be interpreted cautiously.

Author Biography

Le Minh Quang, CARDIFF DIABETES CENTRE FV HOSPITAL

DIABETOLOGIST

SENIOR PHYSICIAN CONSULTANT

References

Kapoor D, Aldred H, Clark S, Channer KS, Jones TH. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Diabetes Care 2007;30:911–17.

Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab 2004;89:5462–8.

Shores MM, Smith NL, Forsberg CW, et al. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012;97:2050–8. https://doi.org/10.1210/jc.2011-2591

Muraleedharan V, Marsh H, Kapoor D, et al. Testosterone treatment is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 2013; 169:725–33. https://doi.org/10.1530/EJE-13-0321

English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation 2000;102:1906–11.

Rosano GM, Leonardo F, Pagnotta P, et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 1999; 99:1666–70.

Webb CM, Adamson DL, de Zeigler D, Collins P. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am J Cardiol 1999;83:437–9.

Jones TH. Testosterone deficiency: a risk factor for cardiovascular disease? Trends Endocrinol Metab 2010;21:496–503. https://doi.org/10.1016/j.tem.2010.03.002

Traish AM, Saad F, Feeley RJ, Guay A. The dark side of testosterone deficiency: III. Cardiovascular disease. J Androl 2009;30:477–94. https://doi.org/10.2164/jandrol.108.007245

Khaw KT, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) prospective population study. Circulation 2007;116:2694–701. https://doi.org/10.1161/CIRCULATIONAHA.107.719005

Haring R, Völzke H, Steveling A, et al. Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20–79. Eur Heart J 2010;31:1494–501. https://doi.org/10.1093/eurheartj/ehq009

Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008;93:68–75. https://doi.org/10.1210/jc.2007-1792

Zhao SP, Li XP. The association of low plasma testosterone level with coronary artery disease in Chinese men. Int J Cardiol 1998;63:161–4.

Rosano G, Sheiban I, Massaro R, et al. Low testosterone levels are associated with coronary artery disease in male patients with angina. Int J Impot Res 2007;19:176–82. https://doi.org/10.1038/sj.ijir.3901504

Li L, Guo CY, Jia EZ, et al. Testosterone is negatively associated with the severity of coronary atherosclerosis in men. Asian J Androl 2012;14:875–8. https://doi.org/10.1038/aja.2012.95

Jankowska EA, Biel B, Majda J, et al. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation 2006;114:1829–37. https://doi.org/10.1161/CIRCULATIONAHA.106.649426

Xu L, Freeman G, Cowling B, Schooling C. Testosterone and cardiovascular related events in men: a meta-analysis of randomized controlled trials. BMC Med 2013;11:108. https://doi.org/10.1186/1741-7015-11-108

Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomised, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005;60:1451–7.

Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed1000097.

Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from http://handbook.cochrane.org

Anderson JL, May HT, Lappe DL, et al. Impact of testosterone replacement therapy on myocardial infarction, stroke, and death in men with low testosterone concentrations in an integrated health care system. Am J Cardiol 2016;117:794–9. https://doi.org/10.1016/j.amjcard.2015.11.063

Aversa A, Bruzziches R, Francomano D, et al. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. J Sexual Med 2010;7:3495–503. https://doi.org/10.1111/j.1743-6109.2010.01931.x

Baillargeon J, Urban RJ, Kuo YF, et al. Risk of myocardial infarction in older men receiving testosterone therapy. Ann Pharmacother 2014;48:1138–44. https://doi.org/10.1177/1060028014539918

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 2016;39:82–91. https://doi.org/10.2337/dc15-1518

Francomano D, Lenzi A, Aversa A. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. Int J Endocrinol 2014; 2014:527470. https://doi.org/10.1155/2014/527470.

Giagulli VA, Carbone MD, Ramunni MI, et al. Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism. Andrology 2015;3:1094–103. https://doi.org/10.1111/andr.12099

Hackett G, Cole N, Bhartia M, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract 2014;68:203–15. https://doi.org/10.1111/ijcp.12235

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;70:244–53. https://doi.org/10.1111/ijcp.12779

Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: an observational study. Obes Res Clin Pract 2014;8:e339–49. https://doi.org/10.1016/j.orcp.2013.10.005

Haider A, Yassin A, Haider KS, Doros G, Saad F, Rosano GM. Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy: observational, real-life data from a registry study. Vasc Health Risk Manage 2016;12:251–61. https://doi.org/10.2147/VHRM.S108947

Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 2009;30:726–33. https://doi.org/10.2164/jandrol.108.007005

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 2011;34:828–37. https://doi.org/10.2337/dc10-1233

Kalinchenko SY, Tishova YA, Mskhalaya GJ, Gooren LJ, Giltay EJ, Saad F. 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 2010;73:602–12. https://doi.org/10.1111/j.1365-2265.2010.03845.x

Li H, Benoit K, Wang W, Motsko S. Association between use of exogenous testosterone therapy and risk of venous thrombotic events among exogenous testosterone treated and untreated men with hypogonadism. J Urol 2016;195(4 Pt 1):1065–72. https://doi.org/10.1016/j.juro.2015.10.134

Malkin CJ, Pugh PJ, Morris PD, et al. Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life. Heart 2004;90:871–6. https://doi.org/10.1136/hrt.2003.021121

Martinez C, Suissa S, Rietbrock S, et al. Testosterone treatment and risk of venous thromboembolism: population based case-control study. BMJ 2016;355:i5968. https://doi.org/10.1136/bmj.i5968

Mathur A, Malkin C, Saeed B, Muthusamy R, Jones TH, Channer K. Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men. Eur J Endocrinol 2009;161:443–9. https://doi.org/10.1530/EJE-09-0092

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;169:725–33. https://doi.org/10.1530/EJE-13-0321

Sharma R, Oni OA, Chen G, et al. Association between testosterone replacement therapy and the incidence of DVT and pulmonary embolism: a retrospective cohort study of the Veterans Administration Database. Chest 2016;150:563–71. https://doi.org/10.1016/j.chest.2016.05.007

Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J 2015;36:2706–15. https://doi.org/10.1093/eurheartj/ehv346

Stanworth RD, Akhtar S, Channer KS, Jones TH. The role of androgen receptor CAG repeat polymorphism and other factors which affect the clinical response to testosterone replacement in metabolic syndrome and type 2 diabetes: TIMES2 sub-study. Eur J Endocrinol 2014;170:193–200. https://doi.org/10.1530/EJE-13-0703

Tan WS, Low WY, Ng CJ, et al. Efficacy and safety of long-acting intramuscular testosterone undecanoate in aging men: a randomised controlled study. BJU Int 2013;111:1130–40. https://doi.org/10.1111/bju.12037

Tong SF, Ng CJ, Lee BC, et al. Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial. Asian J Androl 2012;14:604–11. https://doi.org/10.1038/aja.2011.178

Vigen R, O'Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829–36. https://doi.org/10.1001/jama.2013.280386

Dhindsa S, Ghanim H, Batra M, Dandona P. Hypogonadotropic hypogonadism in men with diabesity. Diabetes Care 2018;41:1516–25. https://doi.org/10.2337/dc17-2510

Grossman M. Hypogonadism and male obesity: focus on unresolved questions. Clin Endocrinol 2018;89:11–21. https://doi.org/10.1111/cen.13723

Dudek M, Ziamiak K, Sliwowska JH. Kisspeptin and metabolism: the brain and beyond. Front Endcrinol (Lausanne) 2018;9:145. https://doi.org/10.3389/fendo.2018.00145

Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013;11:108. https://doi.org/10.1186/1741-7015-11-108

Corona G, Maseroli E, Rastrelli G, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf 2014;13:1327–51. https://doi.org/10.1517/14740338.2014.950653

Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 2007;82:29–39. https://doi.org/10.4065/82.1.29

Fernández-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010;95:2560–75. https://doi.org/10.1210/jc.2009-2575

Ponce OJ, Spencer-Bonilla G, Alvarez-Villalobos N, et al. The efficacy and adverse events of testosterone replacement therapy in hypogonadal men: a systemic review of randomised, placebo controlled trials. J Clin Endocrinol Metab 2018;103:1745–54. https://doi.org/10.1210/jc.2018-00404

Menke A, Guallar E, Rohrmann S, et al. Sex steroid hormone concentrations and risk of death in US men. Am J Epidemiol 2010;171:583–92. https://doi.org/10.1093/aje/kwp415

Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008;93:68–75. https://doi.org/10.1210/jc.2007-1792

Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH, Channer KS. Low serum testosterone and increased mortality in men with coronary heart disease. Heart 2010;96:1821–5. https://doi.org/10.1136/hrt.2010.195412

Downloads

Published

2018-12-12