Disclosures. Faculty 3/5/18. Testosterone, the FDA and CVD Risk Controversies. Matt Rosenberg, MD Director of Mid-Michigan Health Centers Jackson, MI

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1 Testosterone, the FDA and CVD Risk Controversies Faculty Matt Rosenberg, MD Director of Mid-Michigan Health Centers Jackson, MI 2 Disclosures Matt Rosenberg, MD serves on the advisory board for Bayer, Janssen, OPKO and Purdue. Dr. Rosenberg also serves on the advisory board and as a speaker for Astellas. 3 1

2 Learning Objectives 1. Recognize patient populations at risk for testosterone deficiency 2. Discuss the relationship between testosterone deficiency, metabolic syndrome and vascular disease 3. Understand the controversy surrounding testosterone replacement and risk for cardiovascular disease 4 PRE-TEST QUESTIONS 5 Pre-test ARS Question 1 How confident are you in your ability to identify male patients who would benefit from testosterone replacement therapy? 1.Not at all confident 2.Slightly confident 3.Moderately confident 4.Pretty much confident 5.Very confident 6 2

3 Pre-test ARS Question 2 How often do you consider testosterone replacement therapy for male patients with signs or symptoms of hypogonadism? 1. Never 2. Rarely 3. Sometimes 4. Often 5. Always 7 Part 1 8 Testosterone Deficiency Well established medical condition Confirmed by low serum concentrations of total T (eg, < 200 ng/ml) drawn in early AM Negatively impacts Male sexuality General health Quality of life Symptoms include: Decreased libido Erectile dysfunction Decreased energy Depressed mood Irritability Decreased sense of well being 9 3

4 Testosterone Deficiency High-risk populations CHF Type 2 diabetes Obese COPD HIV Chronic opioid use Associated comorbidities Condition Odds Ratio Obesity 2.38 Diabetes 2.09 Hypertension 1.84 Hyperlipidemia 1.47 Osteoporosis 1.41 Asthma/COPD Prevalence of Low Testosterone Increases with Age (<300 ng/dl) Prevalence of Low Testosterone % 40% 40% 46% 50% 39% 0 45() 54 55() 64 65() 74 75() Total Patient Age Range Adapted from Mulligan T, Frick MF, Zuraw QC, et al. Int J Clin Pract. 2006;60(7): Reality Check High testosterone levels are associated with decreased cardiovascular events Low testosterone levels are associated with increased cardiovascular events 12 4

5 Higher Testosterone Associated with Decreased Risk of CV events 19 eligible articles looking at population-based cohorts and case control studies testosterone and atherosclerosis stroke myocardial infarction ischemic heart disease death from coronary heart disease or mortality Evidence in older population (>70), not younger Ruige JB1, Mahmoud AM, De Bacquer D, Kaufman JM. Heart Jun;97(11): doi: /hrt Epub 2010 Dec Araujo et al. Meta-analysis 18 studies (N=22,000): lower T significantly associated with overall and strongly associated with CV mortality Araujo AB, Dixon JM, Suarez EA, Murad M, Guey LT, Wittert GA. J Clin Endocrinol Metab Oct; 96(10): Low Testosterone Levels are Associated with Increased Mortality VA Puget Sound 8 year study of 858 men Low T <250 ng/dl or free T <0.75 ng/dl All-cause mortality was 34.9% in men with low T and 20.1% in men with normal T Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Arch Intern Med. 2006;166(15):

6 Testosterone Levels are Related to All-Cause and CVD Mortality (EPIC) Khaw KT, Dowsett M, Folkerd F, et al. Circulation. 2007;116(23): What is the Connection? 17 Part

7 ARS Question How aware are you of current study data regarding the cardiovascular safety of testosterone replacement therapy? 1. Not at all aware 2. Not very aware 3. Somewhat aware 4. Pretty much aware 5. Very aware The Bad News for Testosterone? 21 7

8 Study Design Population TOM Trial: Basaria et al Effect of TRT on lower-extremity strength and physical function in older, hypogonadal men with mobility limitations Randomized, 6-month trial T gel vs. placebo 209 men (mean age 74 y) with serum TT ng/dl or FT <50 pg/ml Testosterone gel titrated from 50 to 150 mg/d Mean serum testosterone levels achieved: 574 (403) ng/dl with T and 292 (160) ng/dl with placebo Both groups had high prevalence of hypertension, obesity, diabetes, hyperlipidemia, and CVD T: testosterone; TRT: testosterone replacement therapy; CVD: cardiovascular disease. FT: free testosterone; TT: total testosterone Basaria S et al. N Engl J Med. 2010;363(2): TOM Trial: Benefits of Therapy Testosterone preferred Leg-press strength Chest-press strength Leg-press power Chest-press power Total lean mass ALST Grip strength Unloaded gait speed Loaded gait speed Unloaded stair climb Loaded stair climb Lift and lower Treatment Effect, SD Units Absolute treatment differences (testosterone vs placebo arms) are plotted for primary and secondary outcomes in units normalized to baseline standard deviation of measurement. Data are point estimates with 95% confidence intervals. ALST = appendicular lean soft tissue. SD = standard deviation. Adapted from: Travison TG, et al. J Gerontol A Biol Sci Med Sci. 2011;66(10): TOM Trial: Safety and Limitations Safety More CV AEs: 23 with TRT vs 5 with placebo Terminated in December 2009 based on significantly increased incidence of CV AEs with TRT Limitations Not designed for CV AEs Did not evaluate baseline CV function or preexisting conditions Did not account for confounding effect of possible sudden increase in physical activity due to supratherapeutic testosterone supplementation Elkhoury FF, et al. Urology. 2017; (epub ahead of print). 24 8

9 Vigen, et al. JAMA November Vigen et al Study Design Retrospective VA study of men with low T (<300 ng/dl) who underwent coronary angiography Population 1223 patients started TRT at median of 531 days after angiography 7486 patients received no TRT Results 3 years after angiography, Kaplan-Meier cumulative percentages with CV events: 19.9% control vs 25.7% TRT Absolute risk difference of 5.8% No difference in effect among those with and without coronary artery disease MI: myocardial infarction;; TRT: testosterone replacement therapy Vigen R, et al. J Am Med Assoc. 2013;;310(17): Proportion of All Events after Statistical Modeling: Vigen Study Proportion of events (%) Vigen R, et al. J Am Med Assoc. 2013;310(17):

10 Vigen Study: Limitations TRT dosage, duration of treatment, and follow up levels not disclosed No randomization or placebo control Using propensity score weighting to minimize residual confounding Absolute risk of death, MI or stroke: 19.9% PBO vs 25.7% TRT Raw data showed opposite effect Absolute risk of death, MI or stroke: 21.2% PBO vs 10% TRT Exclusion of 1132 men RETRACTION 29 societies Elkhoury FF, et al. Urology. 2017; (epub ahead of print). 28 Proportion of All Events in Patients with Hypogonadism +/- TRT: Vigen Study Proportion of events (%) Proportion of events (%) Vigen R, et al. J Am Med Assoc. 2013;310(17): Study Design Population Results Limitations Frinkle et al Retrospective cohort study Risk of acute non-fatal MI in 90 days following TRT prescription 55,593 patients started TRT 167,279 prescribed PDE5 inhibitors <65 years, excess risk with TRT only if prior CVD history, RR 2.9 ( ) >65 years, 2-fold increased risk associated with TRT regardless of CVD history Non-randomized, retrospective study, no placebo or control Serum T before/after treatment unknown TRT dosages unknown CV risk factors not discussed PDE5 = phosphodiesterase type 5. Frinkle WD, et al. PLoS One Jan 29;9:e Elkhoury FF, et al. Urology. 2017; (epub ahead of print)

11 Xu et al. 2013: TRT and CV events Study Design Population Meta-analysis of 27 placebo-controlled TRT studies to assess CV events Men receiving TRT for 12+ weeks reporting CVrelated events Results TRT increased risk of CV events (OR 1.54) Limitations 2 studies provided 1/3 of all CV events in TRT arm (1 was the TOM trial) If exclude 2 studies, CV events in TRT and placebo arms identical Xu L, et al. BMC Med. 2013; Published online 2013 Apr 18. doi: / Elkhoury FF, et al. Urology. 2017; (epub ahead of print). 31 Xu et al. 2013: Not All What it Seems Xu L, et al. BMC Med. 2013; Published online 2013 Apr 18. doi: / NY Times Editorial 2/5/14 substantial risks in prescribing testosterone to middle-age & older men for a variety of ailments. testosterone doubled the risk of CV disease in more than 7,000 men who were 65 years + testosterone tripled risk of heart attacks in a group of more than 48,000 middle-age men with previous histories of heart disease. the study provides the most compelling evidence yet that many American men have embarked on a perilous course of overtreatment testosterone is now being prescribed to men who are simply reluctant to accept the fact that they are getting older

12 FDA Actions 2014: Voted to impose stricter limitations on TRT industry, esp. language in product labels, to clarify appropriate therapeutic indications for TRT Panelists confirmed that evidence linking TRT to an increased risk of heart attack, stroke, and death is inconclusive Advised FDA to require manufacturers to conduct comprehensive studies to assess potential CV risks of TRT 2015: FDA cautions about using TRT products for low T due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke 34 Part 3 35 The Good News for Testosterone? 36 12

13 Treated vs. Untreated Testosterone-Deficient Men: Does TRT Improve Mortality? 1031 men aged >40 years, T <250 ng/dl Mortality: 10.3% treated, 20.7% untreated (P<.0001) VA, US Department of Veterans Affairs. Shores MM et al. J Clin Endocrinol Metab ;97(6): Study Design Population Results Sharma et al. 2015: Normalization of T Associated with Reduced MI and Mortality Retrospective observational cohort study 83,010 vets with low T, no history of MI or stroke All-cause mortality, MI, stroke, and composite Group 1: TRT with normalization of total T (n=43931) Group 2: TRT no normalization of total T (n=25701) Group 3: Did not receive TRT (n=13378) All-cause mortality (HR 0.44), MI (HR 0.76), and stroke (HR 0.64) significantly lower Gp1 vs. Gp3 All-cause mortality (HR 0.53), MI (HR 0.82), and stroke (HR 0.70) significantly lower Gp1 vs. Gp2 No difference in MI or stroke between Gp2 and Gp3 Sharma R, et al. Euro Heart J. 2015;36(40); Sharma et al. 2015: All-cause Mortality in Propensity-matched Groups From: Eur Heart J. 2015;36(40): doi: /eurheartj/ehv

14 Myocardial infarction-free survival among different propensity-matched study groups From: Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men Eur Heart J. 2015;36(40): doi: /eurheartj/ehv346 Eur Heart J Published by Oxford University Press on behalf of the European Society of Cardiology This work is written by (a) US Government employee(s) and is in the public domain in the US. 40 Sharma et al. 2015: Normalization of T Associated with Reduced MI and Mortality Normalization of total T after TRT associated with significant reduction in all-cause mortality, MI, and stroke in men with no prior CV history Conclusion Additional studies needed to identify mechanisms responsible for these outcomes Non-randomized, observational study No control of when blood T levels drawn Limited clinical data regarding indications for Limitations therapy or withholding therapy No data on why some patients had subtherapeutic TRT (quality of care) 41 Sharma R, et al. Euro Heart J. 2015;36(40); Cheetham et al. 2017: TRT and CV Outcomes in Men with Androgen Deficiency Study Design Retrospective cohort study at integrated system Composite CV end point (acute MI, coronary revascularization, UA, stroke, TIA, and SCD) Population Men 40 years with androgen deficiency (coded diagnosis and/or morning total T <300 ng/dl) Any TRT (injection, oral, or topical) Results Median follow up: 3.2 never-trt group (n=35,526) vs 4.2 years ever-trt group (n=8808) Composite end point: 23.9 vs per 1000 person-years in the never-trt and ever-trt groups Cheetham TC, et al. Jama Intern Med. 2017;177(4):

15 Cheetham et al. 2017: TRT and CV Outcomes in Men with Androgen Deficiency Conclusion Among men with androgen deficiency, TRT associated with lower risk of CV outcomes over median of 3.4 years Raw data consistent with propensity scoring Limitations Observational design Identification of T deficiency did not follow guidelines (ie, only 1 level) Unmeasured confounding issues (ie, healthier patients received TRT) Dose and duration of TRT not controlled Cheetham TC, et al. Jama Intern Med. 2017;177(4): Traish et al. 2017: Long-Term TRT Reduces CV Risk in Men with Hypogonadism Study Design Population Observational, prospective, cumulative registry study N=656, mean 60.7 years, total T 12.1 nmol/l and symptoms of hypogonadism Treatment group (n=360): parenteral T undecanoate 1000 mg/12 weeks for up to 10 years Controls (n=296): men who opted against TRT Median follow-up in both groups 7 years Results 2 deaths in TRT group, none related to CV events 21 deaths in control group, 19 related to CV events Estimated mortality reduction with TRT: 66%- 92% 30 nonfatal strokes and 26 nonfatal MI in the control group, none in TRT group 44 Traish AM, et al. J Cardiovasc Pharmacol Ther. 2017;22(5): Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease in Men with Hypogonadism Traish AM, et al. J Cardiovasc Pharmacol Ther. 2017;22(5):

16 Traish et al. 2017: Long-Term TRT Reduces CV Risk in Men with Hypogonadism Reductions in A1C and serum glucose also demonstrated Traish AM, et al. J Cardiovasc Pharmacol Ther. 2017;22(5): Traish et al. 2017: Long-Term TRT Reduces CV Risk in Men with Hypogonadism Conclusion Long-term TRT well tolerated, excellent adherence Significant improvement in anthropometric parameters, cardiometabolic functions, and risk of CV events Mortality related to CVD significantly reduced with TRT Limitations Not designed to address effect of TRT on mortality No adjudication of previous CV events Not randomized Single urologist Selection bias (low income) No monitoring of concomitant medications Traish AM, et al. J Cardiovasc Pharmacol Ther. 2017;22(5): Study Design Corona et al. 2014: CV Risk with TRT: A Systematic Review and Meta-analysis Meta-analysis of all placebo-controlled RCTs on TRT and CV-related problems 75 studies (3016 TRT, 2448 placebo), mean duration of 34 weeks Results TRT not related to increase in CV risk In subjects with metabolic derangements, protective effect of TRT on CV risk was observed Conclusion Corona G, et al. Expert Opin Drug Saf. 2014;13(10): Data do not support causal relationship between TRT and adverse CV events Results support treatment of hypogonadal men to improve metabolic profile, reduce body fat and increase lean muscle mass, which could reduce risk of heart disease Corona G, et al. Expert Opin Drug Saf. 2014;13(10):

17 Baillargeon et al. 2014: Risk of MI in Older Men Receiving TRT Study Design Examine the risk of MI in population-based cohort of older men receiving intramuscular TRT Materials N=6355 treated with 1 injection of TRT Matched cohort to 19,065 TRT nonusers Results TRT not associated with increased risk of MI Men in the highest quartile of MI risk, TRT associated with reduced risk of MI No difference in risk for the 1 st, 2 nd, and 3 rd quartiles 49 Baillargeon J, et al. Ann Pharmacother. 2014;48(9): Baillargeon et al. 2014: Risk of MI in Older Men Receiving TRT Conclusion Limitations Older men were treated with TRT testosterone did not appear to have increased risk of MI For men with high MI risk, TRT modestly protective against MI Information on outcomes and risk factors came from diagnosis codes (accuracy?) Medicare claims during the study period provided no data on other formulations No assessment of comorbidities or other medications (ie, lipid-lowering) No baseline information Retrospective study with possible selection bias Baillargeon J, et al. Ann Pharmacother. 2014;48(9): What About Precursors of Cardiac Disease? 51 17

18 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 Study Design To determine the effect of testosterone administration on subclinical atherosclerosis progression in older men with low or low-normal levels Placebo-controlled, double-blind, parallel-group randomized trial involving Materials 308 men 60 years or older with low or low-normal testosterone levels ( ng/dl; free testosterone <50 pg/ml) 156 randomized to receive 7.5 g of 1% testosterone 152 randomized to receive placebo gel packets daily for 3 years Dose adjusted to achieve levels between 500 and 900 ng/dl. Results Rate of change in intima-media thickness was mm/year in the placebo group and mm/year in the testosterone group (P =.89) Rate of change in the coronary artery calcium score was 41.4 Agatston units/year in the placebo group and 31.4 Agatston units/year in the testosterone group (P =.54) Basaria S, et al. JAMA 2015:314(6): 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 Conclusion Testosterone administration for 3 years vs placebo did not result in a significant difference in the rates of change in either common carotid artery intima-media thickness or coronary artery calcium Limitations Sexual desire, erectile function, overall sexual function scores, partner intimacy, and health-related quality of life did not differ significantly between groups Because this trial was only powered to evaluate atherosclerosis progression, these findings should not be interpreted as establishing cardiovascular safety of testosterone use in older men Basaria S, et al. JAMA 2015:314(6): Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. Study Design Double-blinded, placebo-controlled trial at 9 US academic centers testing hypothesis that testosterone treatment of older men slows progression of noncalcified coronary artery plaque volume Materials Results 170 pts 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dl 82 men assigned to placebo 88 to testosterone gel adjusted to maintain therapeutic level Testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively P =.003) Median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (P =.006) Median coronary artery calcification score changed from 255 to 244 Agatston units in the T group vs 494 to 503 Agatston units in placebo No major adverse cardiovascular events occurred in either group Budoff MJ, et al. JAMA 2017;317(7):

19 Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. Conclusions Among older symptomatic hypogonadal men treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume Larger studies are needed to understand the clinical implications of this finding Limitations Non-randomization Different baseline groups as see by different baseline plaque volume Prognostic studies of noncalcified plaque volume non-existent Questions if increase of fibrous component of plaque increases stability Budoff MJ, et al. JAMA 2017;317(7): Summary 56 Three Sides to Every Story My side Your side The truth 57 19

20 The Risk of Not Knowing the Absolute Truth Class Action Suits 58 Summary Keep track of the literature Be vigilant and pick the right patient Assess risk of cardiac disease Discuss risks and benefits with: The patient Primary care, cardiology, urology Document Document Document 59 POST-TEST QUESTIONS 60 20

21 Post-test ARS Question 1 After completing this activity, how confident are you in your ability to identify male patients who would benefit from testosterone replacement therapy? 1.Not at all confident 2.Slightly confident 3.Moderately confident 4.Pretty much confident 5.Very confident 61 Post-test ARS Question 2 After completing this activity, how often do you intend to consider testosterone replacement therapy for male patients with signs or symptoms of hypogonadism? 1. Never 2. Rarely 3. Sometimes 4. Often 5. Always 62 21