EFFICACY AND SAFETY OF TESTOSTERONE THERAPY FOR LATE-ONSET HYPOGONADISM: AN UPDATE

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1 EFFICACY AND SAFETY OF TESTOSTERONE THERAPY FOR LATE-ONSET HYPOGONADISM: AN UPDATE Matthew Ho, PGY-2 Department of Urologic Sciences University of British Columbia OBJECTIVES 1. Review the characteristics of late-onset hypogonadism (LOH) 2. Review recent evidence on the efficacy of testosterone therapy (TT) 3. Discuss the controversies surrounding TT 4. Review recent evidence on cardiovascular risk associated with TT 5. Review recent evidence on VTE risk associated with TT 1

2 OBJECTIVES 1. Review the characteristics of late-onset hypogonadism (LOH) 2. Review recent evidence on the efficacy of TT 3. Discuss the controversies surrounding testosterone therapy (TT) 4. Review recent evidence on cardiovascular risk associated with TT 5. Review recent evidence on VTE risk associated with TT LATE-ONSET HYPOGONADISM Multiple population studies demonstrate gradual decrease in serum total/free T 0.4% T, 1.2% ft per year 0.1 nmol/l per year 1. O Donnell AB, Araujo AB, McKinlay JB. The health of normally aging men: The Massachusetts Male Aging Study ( ). Exp Gerontol Jul;39(7): Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR, Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab Feb;86(2): Tajar A, Huhtaniemi IT, O Neill TW, Finn JD, Pye SR, Lee DM, Bartfai G, Boonen S, Casanueva FFF, Forti G, Giwercman A, Han TS, Kula K, Labrie F, Lean MEJ, Pendleton N, Punab M, Vanderschueren D, Wu FCW, EMAS Group. Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). J Clin Endocrinol Metab May;97(5): Wu FCW, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean MEJ, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huhtaniemi IT. Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men. New England Journal of Medicine Jul 8;363(2):

3 LATE-ONSET HYPOGONADISM Distinct from testicular/pituitary hypogonadism Elements of both: Decreased testicular response Decreased HP signal LATE-ONSET HYPOGONADISM Prevalence depends on definition 20% - 50%, increasing with age (BLSA) T < 325 ng/dl (11.4 nmol/l) 2.1% (EMAS) T < 11 nmol/l AND 3 sexual symptoms LOH = Symptoms + Low T + Improvement supplementation 1. O Donnell AB, Araujo AB, McKinlay JB. The health of normally aging men: The Massachusetts Male Aging Study ( ). Exp Gerontol Jul;39(7): Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR, Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab Feb;86(2): Tajar A, Huhtaniemi IT, O Neill TW, Finn JD, Pye SR, Lee DM, Bartfai G, Boonen S, Casanueva FFF, Forti G, Giwercman A, Han TS, Kula K, Labrie F, Lean MEJ, Pendleton N, Punab M, Vanderschueren D, Wu FCW, EMAS Group. Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). J Clin Endocrinol Metab May;97(5): Wu FCW, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean MEJ, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huhtaniemi IT. Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men. New England Journal of Medicine Jul 8;363(2): Bebb, R. BCMJ

4 TREATMENT THRESHOLDS Endocrine Society T < 10.4 nmol/l (300 ng/dl) + symptoms EAU, International Society of Andrology T < 12.1 nmol/l (350 ng/dl) + symptoms SYMPTOMS OF HYPOGONADISM 1.Grober, E. D. Testosterone deficiency and replacement: Myths and realities. Canadian Urological Association Journal 8, (2014). 4

5 LATE-ONSET HYPOGONADISM Low T associated with Metabolic syndrome (OR 3.0 for T < 8 nmol/l) All-cause mortality (HR 2.2) CVD mortality (HR 1.2) Sexual dysfunction, decreased energy/mobility, decreased mood 1. Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA. Endogenous Testosterone and Mortality in Men: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab Oct 1;96(10): Wu FCW, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean MEJ, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huh 3. Traish AM, Haider A, Haider KS, Doros G, Saad F. Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease in Men with Hypogonadism: A Real-Life Observ OBJECTIVES 1. Review the characteristics of late-onset hypogonadism (LOH) 2. Review recent evidence on the efficacy of TT 3. Discuss the controversies surrounding testosterone therapy (TT) 4. Review recent evidence on cardiovascular risk associated with TT 5. Review recent evidence on VTE risk associated with TT 5

6 TT BENEFITS Decreased fat mass Increased lean mass Increased bone mineral density (BMD) Improved glycemic, lipid control Mood Sexual function 1.Snyder, P. J. et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J. Clin. Endocrinol. Metab. 84, (1999). 2. Muraleedharan, V., Marsh, H., Kapoor, D., Channer, K. S. & Jones, T. H. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 169, (2013). 3. Giltay, E. J. et al. Effects of Testosterone Supplementation on Depressive Symptoms and Sexual Dysfunction in Hypogonadal Men with the Metabolic Syndrome. The Journal of Sexual Medicine 7, (2010). 4. Dohle et al, Guidelines on Male Hypogonadism. EAU Guidelines TESTOSTERONE TRIALS 7-armed RCT to assess efficacy of TT 3 main arms: sexual function, physical function, vitality N = 790 T gel (target: ng/dl) vs. placebo x 1 year 6

7 Included TESTOSTERONE TRIALS >65 years old Average T < 275 ng/dl (9.5 nmol/l) Symptoms of decreased sexual function, physical function or vitality Excluded PCa, PIN, PCRC > 35% or HG > 7%, MI/stroke within past 3 months, BP > 160/100 IPSS > 19, untreated OSA, meds affecting [T] SEXUAL FUNCTION Primary outcome: score on question 4 of PDQ Secondary outcomes: sexual desire, IIEF score 1.Lee, K. K. et al. A Simple Self-Report Diary for Assessing Psychosexual Function in Hypogonadal Men. Journal of Andrology 24, (2003). 7

8 SEXUAL FUNCTION Significant increase in sexual activity Treatment effect (TE) 0.58 in SF group 0.62 in all patients Improved erection scores (TE: 2.64) Inferior to PDE-5 Increased sexual desire (TE: 2.93) PHYSICAL FUNCTION Primary outcome: 50 m improvement in 6-minute walk test Secondary outcomes: 6 minute walk test improvement from baseline Improvement in PF-10 score 8

9 PHYSICAL FUNCTION Among PF-enrolled patients: No difference in walk test Among all patients: OR 1.76 for increase of 50 m in 6 min walk test 6.7 m mean difference in walk test Improvement in pt s perception of walking ability VITALITY Primary outcome: 4 point increase in FACIT Fatigue scale Secondary outcomes: SF-36, PANAS, PHQ-9 score improvements 9

10 VITALITY No improvement in FACIT Fatigue score Small improvements in PANAS, PHQ-9 More likely to report better energy levels TESTOSTERONE TRIALS Anemia: 10 pt Hgb increase 54% T vs. 15% placebo for anemia NYD Bone density Significant increases in BMD and strength (TE 0.07, 0.085) Cognitive function No improvement Coronary plaque Increased non-calcified plaque 1.Roy, C. N. et al. Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial. JAMA Intern Med 177, (2017). 2. Snyder, P. J. et al. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA Intern Med 177, Resnick, S. M. et al. Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment. JAMA 317, (2017). 4..Budoff, M. J. et al. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. JAMA 317, (2017). 10

11 META-ANALYSES 70 RCT, 19 NRS most at high or unclear risk of bias Median treatment duration 6 months Outcomes: QOL, depression, libido, erectile function, ADLs AEs: CV events, PCa, erythrocytosis Efficacy of TT as a class TT modalities head to head QOL improvement (SMD 0.26) Improved depression scores (SMD -0.23) Improved libido (SMD 0.33), erectile function (0.25) No difference in CV events or PCa 11

12 QOL CV events 12

13 16 RCTs, median treatment duration 6 months Score on Aging Men s Symptoms (AMS) questionnaire, BMI, weight, lean body mass, fat mass, total cholesterol AGING MEN S SYMPTOMS QUESTIONNAIRE 13

14 Significant improvement AMS score (1.7/85 pts) Increased lean body mass (1.2 kg) No decrease in weight or BMI No change in BMD Decreased total cholesterol (0.16 mg/dl) No increase in PSA or IPSS 5 RCTs incorporating use of AMS Significant decrease in score (3/85 points) 14

15 SUMMARY- EFFICACY Mild-moderate improvements Sexual function Mood QOL Lean body mass BMI BMD OBJECTIVES 1. Review the characteristics of late-onset hypogonadism (LOH) 2. Review recent evidence on the efficacy of TT 3. Discuss the controversies surrounding testosterone therapy (TT) 4. Review recent evidence on cardiovascular risk associated with TT 5. Review recent evidence on VTE risk associated with TT 15

16 CONTROVERSY FDA Drug Safety Warnings, Designed to test effects of TT on mobility Stopped early due to significantly increased adverse CV events Not designed or powered to detect CV outcomes 16

17 Sampled men receiving angiography Pre-adjusted risk favoured the treatment group 9% of sample was female Identified treatment group by Rx records No testing of T levels (Vigen et al., 2013) Self-controlled 90 days of follow-up Identified treatment group by Rx records 17

18 OBJECTIVES 1. Review the characteristics of late-onset hypogonadism (LOH) 2. Review recent evidence on the efficacy of TT 3. Discuss the controversies surrounding testosterone therapy (TT) 4. Review recent evidence on cardiovascular risk associated with TT 5. Review recent evidence on VTE risk associated with TT CV RISK Retrospective cohort study n = T < 300 ng/dl OR diagnosis hypogonadism Excluded: testis/prostate Ca, AIS, Klinefelter, pituitary disorder Outcome: MI/revascularization, stroke/tia, unstable angina, sudden cardiac death 18

19 Ever-T group: 8808 with filled T prescription 76% filled >1 Rx Mean duration 925 d Median follow-up 3.2 years untreated, 4.2 years treated Baseline T 212 ng/dl 318 on treatment 10.2% event rate untreated population vs. 8.2% treated population HR 0.67 (95% CI ) TT is protective against CV events 19

20 Matched retrospective cohort, N = years or older Treatment group: men receiving any TT (N = 10, 331) 5.3 (treated) vs. 5.1 (untreated) years follow-up Outcomes: mortality, CV event (MI/CVA/VTE), PCa dx Mortality benefit with treatment (19% vs 21%) HR 0.88 ( ) No difference in CV event rate 20

21 Stratification based on duration of T exposure Lowest tertile (median 2 months) Increased mortality (HR 1.11) Increased CV events (HR 1.26) Middle tertile Decreased mortality (HR 0.9) Highest tertile Decreased mortality (HR 0.67) Decreased CV events (HR 0.84) Retrospective VA cohort (N = ) Men with one low T level (lab dependent) Excluded: prior MI/stroke, subsequent normal T Outcomes: MI, stroke, mortality 21

22 3 analysis groups Untreated (18.5%) Treated, inadequate response (30.1%) Treated, adequate response (51.4%) Median follow-up 4.7 years untreated, 6.2 years treated Responders Mortality vs. untreated: HR

23 Responders MI vs. untreated: HR 0.76 CV events 23

24 SUMMARY- CV RISK According to recent evidence, multiple studies show a mortality benefit to TT At worst, CV event risk is similar; several studies show a protective event of TT OBJECTIVES 1. Review the characteristics of late-onset hypogonadism (LOH) 2. Review recent evidence on the efficacy of TT 3. Discuss the controversies surrounding testosterone therapy (TT) 4. Review recent evidence on cardiovascular risk associated with TT 5. Review recent evidence on VTE risk associated with TT 24

25 Retrospective cohort (N = ) Inclusion: 2 low T levels Excluded: Hx of VTE, warfarin use, cancer, coagulopathy 3 groups: Treated, adequate response (N = ) Mean follow-up 6.1 years Treated, inadequate response (N = ) Mean follow-up 4.5 years Untreated (N = ) Mean follow-up 4.6 years No significant difference in VTE incidence 25

26 Retrospective case control study (n = ) confirmed VTEs (DVT or PE) matched controls Current T use (<6 months vs. > 6 months) Recent within 2 years Not within 2 years RR =1.63 within 6 months of TT initiation 69/ VTEs while on TT (0.36%) 91/2107 TT users (within 2 years) developed PE (4%) RR = 1.00 after 6 months of TT 26

27 Flannigan R, Locke J et al testosterone users 135 PEs No association between TT and PE Regardless of duration of exposure or T level at entry SUMMARY- VTE Conflict in recent literature If TT increases risk of VTE, absolute increases and overall risk likely low 27

28 SUMMARY Mild-modest benefits Possible mortality benefit No increased CV risk Possible increase in VTE, but low overall EAU Guidelines GUIDELINES AUA Guidelines Endocrine Society Guidelines We recommend testosterone therapy for symptomatic men with classical androgen deficiency syndromes aimed at inducing and maintaining secondary sex characteristics and at improving their sexual function, sense of well-being, and bone mineral density. AUA Board of Directors. AUA Position Statement on Testosterone Therapy. AUA,

29 ACKNOWLEDGEMENTS Dr. Ryan Flannigan Dr. Larry Goldenberg Dr. Jenn Locke BIBLIOGRAPHY 1.Araujo, A. B. et al. Endogenous Testosterone and Mortality in Men: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab 96, (2011). 2.Basaria, S. et al. Adverse Events Associated with Testosterone Administration. New England Journal of Medicine 363, (2010). 3.Basaria, S. et al. Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. JAMA 314, (2015). 4.Bhasin, S. et al. Testosterone Therapy in Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 95, (2010). 5.Brambilla, D. J., O Donnell, A. B., Matsumoto, A. M. & McKinlay, J. B. Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men. Clin. Endocrinol. (Oxf) 67, (2007). 6.Budoff, M. J. et al. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. JAMA 317, (2017). 7.Cheetham, T. C. et al. Association of Testosterone Replacement With Cardiovascular Outcomes Among Men With Androgen Deficiency. JAMA Intern Med 177, (2017). 8.Dhindsa, S. et al. Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes. Diabetes Care 39, (2016). 9.Elliott, J. et al. Testosterone therapy in hypogonadal men: a systematic review and network meta-analysis. BMJ Open 7, e (2017). 10.Finkle, W. D. et al. Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men. PLOS ONE 9, e85805 (2014). 11. Flannigan, R et al. Pulmonary Emboli in The Setting of Testosterone Therapy. A Nested Case Control Study Among 40,081 Testosterone Users. Abstract (2017) 11.Giltay, E. J. et al. Effects of Testosterone Supplementation on Depressive Symptoms and Sexual Dysfunction in Hypogonadal Men with the Metabolic Syndrome. The Journal of Sexual Medicine 7, (2010). 12.GUO, C. et al. Efficacy and safety of testosterone replacement therapy in men with hypogonadism: A meta-analysis study of placebo-controlled trials. Exp Ther Med 11, (2016). 13.Haring, R. Meta-Epidemiology of Testosterone s Risks and Benefits Will We Ever Know the Answer? JAMA Intern Med 177, (2017). 14.Harman, S. M. et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J. Clin. Endocrinol. Metab. 86, (2001). 15.Huhtaniemi, I. Late-onset hypogonadism: current concepts and controversies of pathogenesis, diagnosis and treatment. Asian J. Androl. 16, (2014). 16.Kelsey, T. W. et al. A Validated Age-Related Normative Model for Male Total Testosterone Shows Increasing Variance but No Decline after Age 40 Years. PLoS One 9, (2014). 17.Lee, K. K. et al. A Simple Self-Report Diary for Assessing Psychosexual Function in Hypogonadal Men. Journal of Andrology 24, (2003). 18.Martinez, C. et al. Testosterone treatment and risk of venous thromboembolism: population based case-control study. BMJ 355, i5968 (2016). 19.Muraleedharan, V., Marsh, H., Kapoor, D., Channer, K. S. & Jones, T. H. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 169, (2013). 20.Nian, Y. et al. Testosterone replacement therapy improves health-related quality of life for patients with late-onset hypogonadism: a meta-analysis of randomized controlled trials. Andrologia 49, n/a-n/a (2017). 21.O Donnell, A. B., Araujo, A. B. & McKinlay, J. B. The health of normally aging men: The Massachusetts Male Aging Study ( ). Exp. Gerontol. 39, (2004). 22.Ohlsson, C. et al. High Serum Testosterone Is Associated With Reduced Risk of Cardiovascular Events in Elderly Men: The MrOS (Osteoporotic Fractures in Men) Study in Sweden. Journal of the American College of Cardiology 58, (2011). 23.Orwoll, E. et al. Testosterone and Estradiol among Older Men. J Clin Endocrinol Metab 91, (2006). 24.Piszczek, J., Mamdani, M., Antoniou, T., Juurlink, D. N. & Gomes, T. The Impact of Drug Reimbursement Policy on Rates of Testosterone Replacement Therapy among Older Men. PLOS ONE 9, e98003 (2014). 25.Resnick, S. M. et al. Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment. JAMA 317, (2017). 26.Roy, C. N. et al. Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial. JAMA Intern Med 177, (2017). 27.Saad, F., Haider, A., Doros, G. & Traish, A. Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring) 21, (2013). 28.Sharma, R. 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 150, (2016). 29.Sharma, R. et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J 36, (2015). 30.Snyder, P. J. et al. Effects of Testosterone Treatment in Older Men. New England Journal of Medicine 374, (2016). 31.Snyder, P. J. et al. The Testosterone Trials: Seven coordinated trials of testosterone treatment in elderly men. Clinical Trials (2014). 32.Snyder, P. J. et al. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA Intern Med 177, (2017). 33.Snyder, P. J. et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J. Clin. 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30 Prospective observational study (N = 656) Symptomatic, T <12.1 nmol/l Patients self-selected treatment Outcomes: mortality, weight/wc/bmi, Hgb, FBG/A1C, BP/HR, lipids, prostate volume/psa, IPSS/AMS/IIEF Mean follow-up 73 months control, 74 months treatment 66-92% mortality benefit (8% ARR incidence of death/10 years) A1C reduced in treatment group (1.7%), vs increased in control (0.3%) BP reduced in treatment group (SBP 21/DBP 16) vs. stable in control Weight loss in treated (19.3 kg) vs gain in control (1.6 kg) 30