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

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

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 (1987-2004). Exp Gerontol. 2004 Jul;39(7):975 984. 2. 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. 2001 Feb;86(2):724 731. 3. 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. 2012 May;97(5):1508 1516. 4. 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. 2010 Jul 8;363(2):123 135. 2

LATE-ONSET HYPOGONADISM Distinct from testicular/pituitary hypogonadism Elements of both: Decreased testicular response Decreased HP signal http://www.writeopinions.com/hypothalamic-pituitary-gonadal-axis 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 (1987-2004). Exp Gerontol. 2004 Jul;39(7):975 984. 2. 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. 2001 Feb;86(2):724 731. 3. 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. 2012 May;97(5):1508 1516. 4. 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. 2010 Jul 8;363(2):123 135. 5. Bebb, R. BCMJ 2011. 3

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, 145 7 (2014). 4

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. 2011 Oct 1;96(10):3007 3019. 2. 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

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, 2647 2653 (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, 725 733 (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, 2572 2582 (2010). 4. Dohle et al, 2015. Guidelines on Male Hypogonadism. EAU Guidelines. 2015. TESTOSTERONE TRIALS 7-armed RCT to assess efficacy of TT 3 main arms: sexual function, physical function, vitality N = 790 T gel (target: 500-800 ng/dl) vs. placebo x 1 year 6

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, 688 698 (2003). 7

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

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 http://www.facit.org/facitorg/questionnaires 9

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, 480 490 (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, 471 479 3. Resnick, S. M. et al. Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment. JAMA 317, 717 727 (2017). 4..Budoff, M. J. et al. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. JAMA 317, 708 716 (2017). 10

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

QOL CV events 12

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 http://issam.ch/ams_.asp 13

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

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

CONTROVERSY FDA Drug Safety Warnings, 2014-2015 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

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

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 0.62-0.73) TT is protective against CV events 19

Matched retrospective cohort, N = 38 340 66 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 (0.84-0.93) No difference in CV event rate 20

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 = 91 000) Men with one low T level (lab dependent) Excluded: prior MI/stroke, subsequent normal T Outcomes: MI, stroke, mortality 21

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 0.44 22

Responders MI vs. untreated: HR 0.76 CV events 23

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

Retrospective cohort (N = 71 407) Inclusion: 2 low T levels Excluded: Hx of VTE, warfarin use, cancer, coagulopathy 3 groups: Treated, adequate response (N = 38 362) Mean follow-up 6.1 years Treated, inadequate response (N = 22 191) Mean follow-up 4.5 years Untreated (N = 10 854) Mean follow-up 4.6 years No significant difference in VTE incidence 25

Retrospective case control study (n = 928 745) 19 215 confirmed VTEs (DVT or PE) 909 530 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 69/19 215 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

Flannigan R, Locke J et al. 40 081 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

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, 2015 28

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, 3007 3019 (2011). 2.Basaria, S. et al. Adverse Events Associated with Testosterone Administration. New England Journal of Medicine 363, 109 122 (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, 570 581 (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, 2536 2559 (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. 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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