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The Effect of Testosterone Therapy on the Mortality Rate in Men Suffering From Diabetes Mellitus Deion Tran

Follow this and additional works at: http://commons.pacificu.edu/pa Part of the Medicine and Health Sciences Commons Recommended Citation Tran, Deion, "The Effect of Testosterone Therapy on the Mortality Rate in Men Suffering From Diabetes Mellitus" (2015). School of Physician Assistant Studies. Paper 547.

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The Effect of Testosterone Therapy on the Mortality Rate in Men Suffering From Diabetes Mellitus Abstract

Background: Low testosterone level is common with aging men and is associated with many adverse outcomes like diabetes mellitus (DM). In addition, men with low testosterone and DM have increased mortality risk. This review looks at the effect of testosterone therapy on mortality in men suffering from DM. Methods: An exhaustive literature search of available databases using Medline-OVID, CINAHL and Web of Science was conducted using the following keywords: testosterone, diabetes mellitus, and mortality. Results: The initial search of the databases yielded 58 articles. A total of two articles, both observation studies, met the inclusion criteria. The articles demonstrated decreased mortality rate in treated men with low testosterone suffering from DM. Conclusion: In both observation studies, testosterone therapy is associated with decreased mortality rate in men with DM. However, due to the studies’ limitations, further studies are needed to confirm the data. Keywords: Testosterone, mortality, diabetes mellitus, therapy. Degree Type

Capstone Project Degree Name

Master of Science in Physician Assistant Studies First Advisor

Saje Davis-Risen, PA-C, MS Keywords

Testosterone, mortality, diabetes mellitus, therapy Subject Categories

Medicine and Health Sciences Rights

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The Effect of Testosterone Therapy on the Mortality Rate in Men Suffering From Diabetes Mellitus

Deion Tran

A Clinical Graduate Project Submitted to the Faculty of the School of Physician Assistant Studies Pacific University Hillsboro, OR For the Masters of Science Degree, August 8, 2015

Faculty Advisor: Saje Davis-Risen, PA-C, MS Clinical Graduate Project Coordinator: Annjanette Sommers, PA-C, MS

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Biography [Redacted for privacy]

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Abstract Background: Low testosterone level is common with aging men and is associated with many adverse outcomes like diabetes mellitus (DM). In addition, men with low testosterone and DM have increased mortality risk. This review looks at the effect of testosterone therapy on mortality in men suffering from DM. Methods: An exhaustive literature search of available databases using Medline-OVID, CINAHL and Web of Science was conducted using the following keywords: testosterone, diabetes mellitus, and mortality.

Results: The initial search of the databases yielded 58 articles. A total of two articles, both

observation studies, met the inclusion criteria. The articles demonstrated decreased mortality rate in treated men with low testosterone suffering from DM. Conclusion: In both observation studies, testosterone therapy is associated with decreased mortality rate in men with DM. However, due to the studies’ limitations, further studies are needed to confirm the data. Keywords: Testosterone, mortality, diabetes mellitus, therapy.

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Table of Contents

Cover Page .......................................................................................................................... 1 Biography............................................................................................................................ 2 Abstract ............................................................................................................................... 3 Table of Contents ................................................................................................................ 4 List of Tables ...................................................................................................................... 5 List of Abbreviations .......................................................................................................... 5 BACKGROUND ................................................................................................................ 6 METHODS ......................................................................................................................... 7 RESULTS ........................................................................................................................... 7 DISCUSSION ................................................................................................................... 10 CONCLUSION ................................................................................................................. 12 References ......................................................................................................................... 13 Tables ................................................................................................................................ 16

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List of Tables Table I:

Characteristics of Reviewed Studies and Summary of Finding

List of Abbreviations CI……………………………………………………………………………Confidential Interval DM………………………………………………………………………………Diabetes Mellitus DM type 2………………………………………………………………Diabetes Mellitus Type 2 HR.…………………………………………………………………………… ……Hazard Ratio IM……………………………………………………………………………………Intramuscular S.D.……………………………………………………………………………Standard Deviation VA………………………………………………………………………………Veterans Affairs

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The Effect of Testosterone Therapy on the Mortality Rate in Men Suffering From Diabetes Mellitus BACKGROUND Testosterone is one of the important hormones in the body. It maintains bone density, fat distribution, muscle strength and mass, red blood cells production, sex drive, and sperm production.1 A decline in testosterone level is common with aging men. As a result, diabetes, obesity, cardiovascular events, sarcopenia, osteoporosis, or a decreased libido occurs.2,3 A study4 had noted mortality rate in men with low testosterone levels is double compared to men with normal testosterone levels. A low testosterone level in men is defined as total testosterone < 300 ng/dl (10.4 nmol/L).5 Several studies6-8 have noted that low testosterone levels are associated with increase mortality risk in men with diabetes mellitus (DM). In addition, there is evidence demonstrating an increased occurrence of low testosterone in men with DM type 2,8-10 and a longitudinal cohort study11 found there is an increase in mortality associated with low testosterone in men with DM type 2. However, the direct link between low testosterone and DM is unknown.12 Since 2000, testosterone therapy prescriptions have increased astronomically from 700 000 per year to 2 700 000 in 2008.13 Some studies14-17 have shown the benefit of testosterone therapy such as increasing strength, muscle mass, bone mineral density, insulin sensitivity, and libido. In a large, multi-centre, randomized, double-blind, placebo-controlled study18 testosterone therapy was shown to improve insulin resistance, cholesterol, lipoprotein, body fat composition, sexual dysfunction in men with DM type 2. A meta-analysis19 of testosterone therapy trial on men with DM showed no increase of cardiovascular events in the treatment group; however, they

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did not measure mortality. Can testosterone therapy have an effect on the mortality rate in men suffering from DM? METHODS An exhaustive literature search of available databases using Medline-OVID, CINAHL and Web of Science was performed using the following keywords: testosterone, DM, and mortality. In both Medline-OVID and CINAHL, no further eligibility criteria were used. In Web of Science, the result was narrowed down using years 2000 to 2014, articles only, Englishlanguage only, and endocrinology. The bibliographies of the articles were then screened by relevance. All articles that contained discussion of testosterone therapy and mortality were included. Relevant studies were assessed for quality using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria.20 RESULTS The initial search of Medline-OVID, CINAHL, and Web of Science yield 4, 18, and 36 articles, respectively. After screening for relevance, a total of two articles met the inclusion criteria. These articles included one prospective cohort study5 and one retrospective cohort study.11

Muraleedharan et al In this prospective cohort study,5 the authors compared the mortality rate associated with testosterone therapy in men with DM type 2 to men that did not receive testosterone therapy with the same conditions. This study included patients that were recruited by district-wide diabetic retinopathy screening, in a hospital diabetic clinic, through the general community, or through a hospital database identifying DM type 2 patients. Of the 591 patients with DM type 2 who had 7

testosterone screened from 2002 to 2005, 238 patients were identified to have low testosterone. Low testosterone level is defined as total testosterone < 10.4 nmol/L. Of the 238 patients with low testosterone, 64 received testosterone therapy and 174 did not. The 174 patients did not receive testosterone therapy for following reasons: patient choice, declined to attend for further clinical assessment, did not response to invitation, or declined treatment. The authors noted that testosterone therapy is mainly administered to patient with total testosterone level < 8.4 nmol/L, without prostate cancer or other contraindication for testosterone therapy.5 The treatment group received either testosterone gel or testosterone intramuscularly (IM). Of the 64 patients, 55 received testosterone gel and 9 received testosterone IM. Doses were adjusted to achieve testosterone levels within the mid to upper normal range. The average duration of treatments was 41.6±20.7 (S.D.) months with 60 patients receiving testosterone therapy for ≥ 12 months and 51 patients receiving testosterone therapy ≥ 2 years. There was no significant differences in baseline characteristics between the normal testosterone group and low testosterone group. A follow-up was performed on average, 5.8±1.3 (S.D.) years later.5 The mortality rate was significantly higher in the untreated group (20.11%) compared to the treated group (9.38%). The authors used the Kaplan-Meier curves which showed improved survival rate in the treated group compared with the untreated group. The authors also used the multivariate-adjusted survival curves in the Cox regression model, which showed the hazard ratio (HR) for decreased survival for the untreated group was 2.3; 95% CI 1.3-3.9; P=0.004.5 The authors noted that several meta-analyses have not found any increase in cardiovascular events with testosterone therapy.19,21-23 They concluded that long-term testosterone therapy is safe and there was a decreased mortality rate in men with low testosterone and DM type 2. In addition, the authors encouraged careful monitoring of testosterone levels

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(also hematocrit and prostate specific antigen) when administering testosterone therapy with cautious dosing while achieving normal healthy range.5

Shores et al In this observational, retrospective cohort study,11 the authors examine the influence of testosterone therapy on mortality in men with low testosterone and whether results were modified by other factors such as DM. This study used the Veterans Affairs (VA) medical database, Consumer Health Information and Performance Set, to identify veteran men age > 40 years old who had received treatment at the seven VA medical centers in the Northwest states and had total testosterone ≤ 250 ng/d (8.7 nmol/L) between January 1, 2001 to December 31, 2002. Of the 5714 patients who had testosterone levels checked, 1090 patients were included in the final study. Of these final group, 393 patients with DM received testosterone therapy and 638 patients did not received treatment.11 The primary focus of this study was mortality. The number of patients who died was obtained from the VA Beneficiary Identification records Locator Subsystem-Death File and the Social Security Administration-Death Master File. The Kaplan-Meier survival curves were used to show unadjusted survival times for the treated group compared to the untreated group. The HR and CI were calculated based on multivariate-adjusted survival curves in the Cox regression model.11 In the treatment group, 88.6% received testosterone IM, 9.1% used the testosterone patch, and 2.3% received testosterone gel which resulted in 398 patients who were treated with testosterone. The average duration of treatment was 20.2 months. The patients in this group were younger, had lower testosterone levels, and higher BMI compared to the untreated group;

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otherwise, both groups are similar in the baseline characteristics. The average follow-up was 42.8 months with 51 patients lost to follow-up.11 In the unadjusted analyses, the mortality rate is significantly higher in the untreated group - 20.7% compared to 10.3% in the treated group. In the unadjusted Kaplan-Meier survival curves shown, survival rate in the treated group was better compared to the untreated group (p = 0.029). In the time-varying Cox-adjusted regression model, there was a 39% reduction in mortality risk (HR 0.61, 95% CI 0.42-0.88, P = 0.008) in the treated group compared to untreated group. When analyzing the mortality rate in the treated group compared to untreated group by DM, there is an association with improve survival in men with DM received testosterone therapy. The HR for treated group with DM was 0.44; 95% CI 0.23-0.84; P=0.013 compared to the untreated with DM, HR 0.72; 95% CI 0.46-1.13; P=0.155.11 As a results of a lower HR in the treated group with DM compared to untreated men with DM, the authors concluded that testosterone therapy is associated with improved survival in men with low testosterone and DM. However, because this is the first study to examining the association between testosterone therapy and mortality in men with low testosterone levels, and this is an observational study, the authors caution readers to interpret the results cautiously.11

DISCUSSION In men, low testosterone is commonly associated with many adverse outcomes such as DM. In addition, men with DM has significant lower testosterone levels than those without DM.24 The link between those two conditions are unknown, but these men are at increasing risk of mortality when they are combined. There has been increased use of testosterone therapy since 2000 which has shown to improve strength, muscle mass, bone mineral density, insulin

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sensitivity, and libido.14-17 However, there have been no studies on mortality until two studies in the Muraleedharan et al5 and Shores et alto11 demonstrated increase survival rate in low testosterone men suffering from DM compared to men who did not received treatment. Reviewing the two studies5,11 that compared testosterone treatment and mortality risk in men with DM it is clear that there is some correlation. In the Shores et al study,11 the authors demonstrated a decreased in mortality rate of men with DM who received testosterone therapy compared to men with the same condition and did not received treatment. The result can be seen in Table 1.11 In the Muraleedharan et al study,5 the authors demonstrated an increase in survival rate of low testosterone men with DM type 2 who received testosterone therapy compared to men with the same condition and did not received treatment.5 Furthermore, testosterone therapy has been shown to be safe when a patient has low levels.19 Although these two studies showed the benefit of testosterone therapy in men with low testosterone and DM, there are limitations in both studies. These two studies were evaluated using the GRADE method and the results can be seen in Table 1. Both studies5,11 were of observational study design. Moreover, both used a lower testosterone thresholds in treated patients. In the Shores et al study,11 treated patients had total testosterone levels of 8.7 nmol/L compared to the treated patient in the Muraleedharan et al study5 who had an average total testosterone level of 6.8±2.3 nmol/L. This could lead to overestimating the treatment effects, thus, limiting the interpretation of the results. Another limitation, mainly from the Shores et al study,11 is that patients were initiated into testosterone therapy based on one testosterone level check instead of the recommended two testosterone level checks from the clinical guideline. It is recommended to recheck the testosterone level because lower testosterone level can be due to serious conditions like

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cardiovascular diseases or DM.25 Lastly, the study11 contains patients with history of high risk of chronic medical morbidity including coronary heart disease and diabetes. The generalizability of the results are, therefore, limited. Because of these limitations, larger and longer studies with double-blind, placebocontrolled design will increase confidence of whether or not mortality risk is improved in men with DM who also have low testosterone. CONCLUSION Testosterone therapy has shown to decrease mortality rate in men suffering from DM in two observation studies. However, due to these studies’ limitations, the results should be cautiously interpreted but testosterone therapy may be beneficial in the long-term in improving survival rate in men with low testosterone and DM. A further long-term and large randomized controlled trial is needed to confirm this data.

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References 1. Mayo Clinic Staff. Testosterone therapy: Key to male vitality? http://www.mayoclinic.org/healthy-living/sexual-health/in-depth/testosterone-therapy/art20045728. Updated July 10, 2014. Accessed September 22, 2014. 2. Travison TG, Araujo AB, Kupelian V, O’Donnell AB, McKinlay JB 2007 The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab 92:549–555 3. Matsumoto AM 2002 Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol Med Sci A Biol Sci Med Sci 57A:M76– M99 4. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR 2006 Low serum testosterone and mortality in male veterans. Arch Intern Med 166:1660–1665 5. 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(6):725-733. Accessed 20131022. doi: http://dx.doi.org/10.1530/EJE-13-0321. 6. Farrell JB, Deshmukh A, Baghaie AA 2008 Low testosterone and the association with type 2 diabetes. Diabetes Educ 34:799–806 7. Vandenput L, Mellstro¨m D, Lorentzon M, Swanson C, Karlsson MK, Brandberg J, Lo¨nn L, Orwoll E, Smith U, Labrie F, Ljunggren O, Tivesten A, Ohlsson C 2007 Androgens and glucuronidated androgen metabolites are associated with metabolic risk factors in men. J Clin Endocrinol Metab 92:4130–4137 8. Ding EL, Song Y, Malik VS, Liu S 2006 Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 295:1288– 1299 9. 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 30 911–917. doi:10.2337/dc061426 10. Wang C, Jackson G, Jones TH, Matsumoto AM, Nehra A, Perelman MA, Swerdloff RS, Traish A, Zitzmann M & Cunningham G. Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. Diabetes Care 2011 34 1669–1675. doi:10.2337/dc10-2339

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11. 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;97(6):2050-2058. Accessed 20120607. doi: http://dx.doi.org/10.1210/jc.2011-2591 12. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men. Prospective results from the Massachusetts Male Aging Study. Diabetes Care. 2000;23:490-494. 13. Food and Drug Administration 2009 Postmarket reviews, Vol 2, No. 2. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Pedia tricAdvisoryCommittee/UCM166697.pdf 14. Srinivas-Shankar U, Roberts SA, Connolly MJ, O’Connell MD, Adams JE, Oldham JA, Wu FC 2010 Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 95:639–650 15. Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, Mammi C, Piepoli M, Fini M, Rosano GM 2009 Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol 54:919–927 16. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Berman N, Hull L, Swerdloff RS 2004 Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab 89:2085–2098 17. Malkin CJ, Jones TH, Channer KS 2007 The effect of testosterone on insulin sensitivity in men with heart failure. Eur J Heart Fail 9:44–50 18. Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, Morales AM, Volterrani M, Yellowlees A, Howell JD et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 Study). Diabetes Care 2011 34 828–837. doi:10.2337/dc10-1233 19. Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Bolon˜a ER, Sideras K, Uraga MV, Erwin PJ, Montori VM 2007 Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 82:29–39 20. GRADE working group. GRADE website. http://gradeworkinggroup.org/. Accessed August 11, 2012.

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21. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL & Bhasin S. Adverse events associated with testosterone replacement in middle-aged and older men: a metaanalysis of randomized, placebo-controlled trials. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2005 60 1451–1457. doi:10.1093/gerona/60.11.1451 22. Merce Fernandez-Balsells M, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, Elamin MB, Gallegos-Orozco JF, Wang AT et al. Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. Journal of Clinical Endocrinology and Metabolism 2010 95 2560–2575. doi:10.1210/jc.2009-2575 23. Carson CC III & Rosano G. Exogenous testosterone, cardiovascular events, and cardiovascular risk factors in elderly men: a review of trial data. Journal of Sexual Medicine 2012 9 54–67. doi:10.1111/j.1743-6109.2011.02337.x 24. Fukui M, Kitagawa Y, Ose H, Hasegawa G, Yoshikawa T, Nakamura N. Role of endogenous androgen against insulin resistance and atherosclerosis in men with type 2 diabetes. Curr Diabetes Rev. 2007;3:25-31. 25. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM 2010 Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95:2536–2559

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Table I. Characteristics of Reviewed Studies and Summary of Findings Quality Assessment

Treatment Effect

Downgrade Criteria Design

Quality HR (95% CI)

RR

NNT

Indirectness

Imprecision

Inconsistency

Publication bias likely

No serious limitations

No serious indirectness

No serious imprecision

No serious inconsistencies

No bias likely

2.3 (1.3-3.9)

0.47 RRR 0.53

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Moderatea

No serous limitations

No serious indirectness

No serious imprecision

No serious inconsistencies

No bias likely

0.61 (0.42-0.88)

0.50 RRR 0.50

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Moderatea

Limitations

Muraleedharan et al5 Prospective cohort

Shores et al11 Retrospective cohort

a

Studies were upgraded due to large treatment effect

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