NEW DEVELOPMENTS: T & CVD FDA & THE T TRIALS

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1 NEW DEVELOPMENTS: T & CVD FDA & THE T TRIALS 2017 UPDATE FDUS Martin Miner MD Clinical Professor of Family Medicine and Urology Co-Director The Men s Health Center The Miriam Hospital Warren Albert School of Medicine Brown University Providence, RI

2 NY TIMES EDITORIAL 2/5/14 substantial risks in prescribing testosterone to middleage & 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.

3 WHAT IS TESTOSTERONE DEFICIENCY? T levels decline with age = Normal Aging Secondary Hypogonadism = symptoms = Disease Mongering...loss of energy, libido and spontaneous erections, and ED Is hormone repletion without long-term safety studies appropriate? T Trials: Included older men with declining levels for no apparent reason other than age Obesity 62%; HTN 72%; h/o of MI 15%; DM 37% Target levels were the normal range for men age years ( ng/dl) a numerical endpoint, not consistent with clinical practice focused on symptom relief Goal: to implement the IOM 2003 recommendation- coordinated set of clinical trials to determine efficacy of T therapy in older men with low levels for no other reason than age.

4 FDA ADVISORY BOARD (SEP 17, 2014) Voted in favor for the FDA to impose stricter limitations on the T drug industry, particularly the language in product labels; this would clarify the appropriate therapeutic indications for TRT. With regards to the risk of CV events, the panelists confirmed that evidence linking T therapy to an increased risk of heart attack, stroke & death is inconclusive. The panel further advised that the FDA should require drug manufacturers to conduct comprehensive studies to better assess the potential cardiovascular risks with TRT.

5 Testosterone: Age Trends Longitudinal Study: 890 healthy men with the comorbidities of aging Proportion of Patients (%) Total Testosterone <11.3 nmol/l (325.6 ng/dl) Free Testosterone Index <0.153 Total T/SHBG 49% 28% 12%-20% Age Harman SM et al. J Clin Endocrinol Metab. 2001;86:

6 Query #1 IS A LOW SERUM TESTOSTERONE LEVEL ASSOCIATED WITH CARDIOVASCULAR RISK FACTORS?

7 PREVALENCE OF MAJOR RISK FACTORS FOR HYPOGONADISM Overall Prevalence of Biochemical Hypogonadism in Clinical Practice: 38.9% HIM Study N = 2085 Presenting to the physician for any problem Risk Factor Hypogonadism * Prevalence (95% CI) Odds Ratio (95% CI) Obesity 52.4 ( ) 2.38 ( ) Type 2 diabetes 50.0 ( ) 2.09 ( ) Hypertension 42.4 ( ) 1.84 ( ) Hyperlipidemia 40.4 ( ) 1.47 ( ) Asthma or COPD Prostate disease 43.5 ( ) 1.40 ( ) 41.3 ( ) 1.29 ( ) *Total Testosterone (TT) < 300 ng/dl] Adapted from Mulligan T, et al. Int J Clin Pract. 2006;60:

8 LOW SERUM TESTOSTERONE AND MORTALITY IN MALE VETERANS Retrospective Study N=858 men > age of 40 Low T = total T < 250 ng/ ml < 8.7 nmol/l Mortality over 5 years 20.1% with normal T 2 levels > % with equivocal T N and low Odds Ratio 1.38 (P=0.06) 34.9% with low T 2 levels < 250 Odds Ration 1.88 (P<0.001) Shores et al (Seattle) Arch Int Med 2006; 166:

9 LOW TESTOSTERONE AND INCREASED MORTALITY (N >500) Studies HR (95% CI) Nature Men, n Follow-Up, yrs Mortality Shores, ( ) Retrospective All-cause Laughlin, ( ) Prospective CVD Khaw, ( ) Prospective Haring, ( ) 2.56 ( ) 2314 of 11,606 Prospective Malkin, ( ) Prospective All-cause/ CVD All-cause CVD All-cause in men with CAD Tivesten, ( ) Prospective All-cause Menke, ( ) Prospective All-cause Vikan, ( ) Prospective All-cause Pye ( ) 3.0 if sex sx Prospective All Cause/CVD Jones ( ) Prospective All cause Corona, ( ) Prospective CVD Muraleedharan et al, 2013 Hyde et al, 2012 Lerchbaum et al, ( ) prospective All-cause 1.62 ( ) All-cause prospective ( ) CVD 2.11 ( ) All-cause 1.77 ( ) prospective CVD

10 Query #2 CAN TRT DECREASE CARDIOMETABOLIC RISKS FOR HYPOGONADAL MALES?

11 SURVIVAL OF TREATED VERSUS UNTREATED TESTOSTERONE-DEFICIENT MEN IN VA POPULATION: DOES TRT IMPROVE MORTALITY? Observational Study of mortality testosterone-treated compared with untreated men 1031 men aged >40 years, T <250 ng/dl Mortality: 10.3% treated, 20.7% untreated (P<.0001) Survival by Testosterone Treatment, % At risk, n Untreated Treated Untreated Treated Log rank P= Time Since Testosterone Test Date, mo VA, US Department of Veterans Affairs. Shores MM et al. J Clin Endocrinol Metab ;97(6):

12 TRT IMPROVES SURVIVAL IN MEN WITH T2DM Prospective Study 581 men with T2 DM over 5.8 y Muraleedharan V, et al. Eur J Endocrinol

13 SO, HOW DID THE BELIEF OCCUR AND IT IS BASED ON WHAT? Testosterone Increases CVD Risk! The beginning: RPCT TOM Study: Testosterone in Older Men with Mobility Limitation N=209 men >65 years of age (of the 252 desired by power analysis) Baseline TT ng/dl (free T <50 pg/ml or 170 pmol/l) 1% testosterone gel 10 g QD, titrated to 5.0g-15.0g, 6 mo rx Target TT ng/dl Results of muscle performance and physical function were positive AE not dutifully recorded and minor in scope: i.e. dizziness, swelling, etc Trial stopped at 9 mo by DSMB: 5 serious CVS events in T; 2 in P groups TOM TRIAL: Basaria S. NEJM 2010

14 Vigen Finkle

15 3 Cross-sectional Clinical Trials in Older Men & 1 Meta- Analysis Showing increase in CVS Events with T Use Basaria et al NEJM 2010 Vigen et al JAMA 2013 RPCT frail elderly men 15 grams of testosterone CVD not an endpoint Treatment arm greater CV risks 5 vs 2 major CV events (ie MI) No difference if exclude CHF No randomization or placebo No control group or clinical info Health insurance database 90 days after start testosterone PDE5I Control Group inherently healthier (no nitrates) Pre-prescription MI rate 3.48/1000 Post-prescription MI rate 4.75/1000 Finkle et al PLoS One 2014 TRT Causes CVD No randomization or placebo 2 major corrections Absolute risk of MI (19.9 vs 25.7%) vs (21 vs 10%) Exclusion of 1132 men RETRACTION 29 societies Meta- analysis of CV events in 27 PC studies of >12 weeks Just 2 studies provided 1/3 of all CV events in T treat arm If exclude 2 studies CV events in T and placebo are identical Xu et al BMC 2013 Retrospective Analyses of EMR Also Show Conflicting Results (Inc CVS events)

16 EFFECTS OF TESTOSTERONE ON MUSCLE STRENGTH, PHYSICAL FUNCTION, BODY COMPOSITION, AND QUALITY OF LIFE IN INTERMEDIATE-FRAIL AND FRAIL ELDERLY MEN: RPCT N=274 frail men, ages Treated for 6 months DBRPCT mg/d 1% T gel vs PBO Muscle function improved on T Rx (A) Lean mass increased and fat mass decreased (B) Somatic scales and sexual dysfunction scales decreased on Rx No Adverse CV events Almost identical study to Basaria 2010 European Study Aging Male Srinivas_Shankar, Wu et al. (Australia) J.C.E.M. 2010

17 A recently published meta-analysis of 75 placebo-controlled studies THE LARGEST META-ANALYSIS TO DATE, FOUND NO EVIDENCE OF INCREASED CV RISK WITH T THERAPY AND CLEAR EVIDENCE OF IMPROVED METABOLIC PROFILES CORONA G, MASEROLI E, RASTRELLI G, ISIDORI AM, SFORZA A, MANNUCCI E, MAGGI M.CARDIOVASCULAR RISK ASSOCIATED WITH TESTOSTERONE-BOOSTING MEDICATIONS:A SYSTEMATIC REVIEW AND META-ANALYSIS.EXPERT OPIN DRUG SAF. 2014;13:

18 CORONA META-ANALYSIS CONCLUSIONS Available evidence does not support a causal role between testosterone supplementation and adverse CV events when hypogonadism is properly diagnosed and replacement therapy correctly performed. Corona G, et al. Expert Opin Drug Saf. 2014;13:

19 RISK OF MYOCARDIAL INFARCTION IN OLDER MEN RECEIVING TESTOSTERONE THERAPY 6355 Medicare pts treated with at least one injection of T between 1997 and 2005 Retrospective Cohort Study Matched to 19,065 T non-users 1:3 ratio based on composite MI prognostic score Results: TRT was not associated with increased risk of MI In men at high risk of MI, TRT was associated with a reduced risk of MI No difference in risk for pts at lower CV risk Baillargeon J, et al. Ann Pharmocother, 2014 Jul 2;48(9):

20 CONCLUSIONS TRT has not been associated with significantly increased cardiovascular risk at least up to 36 months Low T levels are associated with poor cardiovascular health and known risk factors for cardiovascular disease, such as obesity, diabetes, and the metabolic syndrome. The body of evidence supports the need for long term placebo controlled randomized trials of T replacement in hypogonadal men with regard to morbidity and mortality

21 FDA Drug Safety Communication March 2015 FDA CAUTIONS ABOUT USING TESTOSTERONE PRODUCTS FOR LOW TESTOSTERONE DUE TO AGING; REQUIRES LABELING CHANGE TO INFORM OF POSSIBLE INCREASED RISK OF HEART ATTACK AND STROKE WITH USE

22 NEW EVIDENCE SINCE THE FDA S 2015 COMMUNICATION TRT DOES NOT INCREASE RATES OF ADVERSE CARDIOVASCULAR EVENTS WHEN USED APPROPRIATELY

23 NORMALIZATION OF TESTOSTERONE LEVEL IS ASSOCIATED WITH REDUCED INCIDENCE OF MI AND MORTALITY IN MEN AIM: Study of hypogonadal men without MI or CVA after TRT evaluating for CV events and all cause morality. METHODS: Retrospective 83, 010 vets with low TT ( ) Gp1 TRT with normalization of TT Gp2 TRT without normalization of TT Gp3 no TRT RESULTS: All-cause morality Gp1<Gp2<Gp3 MI and CVA Gp1<Gp2=Gp3 Treated men 56% Dec Mortality & 24% Dec MI (Gp1 vs Gp3) CONCLUSIONS: Largest observational cohort with extended follow-up (15 yrs) Normalization of TT after TRT significantly reduced all-cause mortality MI, and stroke Sharma R, et al. European Heart J, 2015, 100(3):36;

24 T EFFECTS ON ATHEROSCLEROSIS IN AGING MEN (TEAAM) 2015 AIM: To determine the effect of testosterone administration on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels. METHODS: N = 308 men > 60 yo with low or low normal T levels TT ng/dl; FT < 50 pg/ml Mean Age: 67.6 yo; 42% HTN; 15% DM; 15% CVD; 27% Obese 3-year DBPCT: 156 men 7.5 gm 1% T 152 placebo gel daily x 3yrs Dose adjusted to achieve levels ng/dl Co Primary Outcomes: CIMT and CAC Secondary Outcomes: Sexual Function & HR QOL RESULTS: Rate of change of CIMT Placebo 0.010mm/yr and in T mm/yr p=0.89 Rate of change of CAC Placebo 41.4 Agatston units/year T 31.4 Agatston units/year p=0.54 CONCLUSIONS: No Changes in intima-media thickness or calcium scores associated with TRx Sexual desire, erectile function, overall sexual function scores, partner intimacy, health-related quality of life did not differ significantly between groups Lack of CVD events is most significant & reassuring but again, not powered for safety When T given in appropriate dosages there is no serious morbidity/mortality Basaria S, Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. JAMA.2015; 314:

25 EFFICACY OF T WITH SEXUAL FUNCTION, VITALITY, & PHYSICAL FUNCTION OF SYMPTOMATIC OLDER MEN WITH LOW T AT BASELINE: T TRIALS AIM: Test hypothesis that baseline TT, FT, E 2 and SHBG are independently associated with sexual functions, vitality, and physical functions in older hypogonadal men (Anemia; Bone Mass; Cognitive Function also studied). METHODS: 12 U.S. centers 788 symptomatic men >65 yrs with TT<275 RDBPCT Highest Quality RESULTS: TT and FT had statistically significant associations with measures of sexual desire, EF, and sexual activity, Not vitality and sexual function. Slightly better mood, less depression in T arm CONCLUSIONS: Statistically significant improvements in older men with T in some parameters of sexual function and mood No increase in CVD events with T vs P (Study not powered for safety). Some improvement in strength utilized as walking distance though did not reach target Sexual Function: 10 of 12 Domains increased PDQ, greatest in libido Snyder et al. T Trials JAMA 2016 Validated by Cunningham et al. J Clin Endo Metab 2016

26 TESTOSTERONE TREATMENT AND CORONARY ARTERY PLAQUE VOLUME: T TRIAL AIM: Test the hypothesis that testosterone treatment of older men with low testosterone slows the progression of noncalcified coronary artery plaque volume in men with low testosterone METHODS: Men >65 y/o with only age related decline in T RDBPCT 9 centers 170/788 men >65 years 2 am levels <275 ng/dl (82P, 88T) Men allocated to treatment by minimization: computerized technique provides best balance across groups on specific baseline characteristics RESULTS: 138 completed study (73T, 65P) Mean age 71.2 years Rx vs. Pbo showed increase in non-calcified plaque volume from baseline to 12 months 204mm 3 to 232mm 3 vs 317mm 3 to 321mm 3; (T vs Pbo) Est diff 41mm 3 ; 95% CI 14-67mm 3 ; p=.003 T group Budoff MJ, Ellenberg SS, Lewis CE, Mohler ER 3rd, Wenger NK, Bhasin S, Barrett-Connor E, Swerdloff RS, Stephens-Shields A, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Gill TM, Matsumoto AM, Molitch ME, Nakanishi R, Nezarat N, Matsumoto S, Hou X, Basaria S, Diem SJ, Wang C, Cifelli D, Snyder PJ. JAMA Feb 21;317(7): doi: /jama

27 TESTOSTERONE TREATMENT AND CORONARY ARTERY PLAQUE VOLUME: T TRIAL OUTCOMES: Primary outcome was Non-calcified Plaque Volume=sum of 4 types of plaque: low attenuation, fibrous-fatty, fibrous and dense calcium Secondary outcomes: Total Plaque Volume = sum of all 4 types and Coronary Artery Calcium Score (CAC) RESULTS: Baseline: 61% BMI>30; 31% DM; 67% HTN; 63% Dyslipidemia; 66% Hx Cig abuse; 19% OSA Mean ACC/AHA ASCVD Risk Score: 24% T; 27% P 50.7% had CAC> 300 (severe atherosclerosis) Men in P group had somewhat greater mean non-calcificed plaque volume by CCTA and somewhat greater CAC score T Treatment associated with a significant increase in fibrous plaque volume (change 25 mm 3 ) vs placebo (change 1 mm 3 ) Fibrous Plaque protective capping of Vulnerable Plaque= More Stable Budoff MJ, Ellenberg SS, Lewis CE, Mohler ER 3rd, Wenger NK, Bhasin S, Barrett-Connor E, Swerdloff RS, Stephens-Shields A, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Gill TM, Matsumoto AM, Molitch ME, Nakanishi R, Nezarat N, Matsumoto S, Hou X, Basaria S, Diem SJ, Wang C, Cifelli D, Snyder PJ. JAMA Feb 21;317(7): doi: /jama

28 TESTOSTERONE TREATMENT & CORONARY ARTERY PLAQUE VOLUME: T TRIAL COMMENTS: Among the 170 men in the CVS Trial in TRx group and in Pbo group NONE reported MACE (NOT POWERED FOR SAFETY) Few studies have examined the effect of T on atherosclerosis in men: TEEAM study in older men showed TRx did not affect the change from baseline CAC or CIMT over 3 years. 1 Increase in non-calcified and total plaque volumes in men on TRx are concerning because any limitation of the vascular lumen could be considered deleterious 2 Fibrous plaque is more stable & protective 3 Single review suggests that total plaque burden may be more important than ind plaque type 2 1. Basaria S. JAMA 2015; 314(6) Samady H, Circulation 2011;124(7) Arbab-Zadeh A, et al. J Am Coll Cardiol 2015;65(8):

29 TESTOSTERONE TREATMENT AND CORONARY ARTERY PLAQUE VOLUME The coronary luminal narrowing observed over 12 months in this study is an unprecedented drug effect and appears ominous in signifying accelerated atherosclerosis, and is perhaps a harbinger of increased cardiac ischemic events. Early plaque growth may explain previous reports suggesting an association between testosterone use and cardiovascular harm in older men as well as transient cardiovascular harms confined to the first 6 to 12 months after commencing testosterone treatment. These findings may provide a possible mechanistic basis of an adolescent head start in atherogenesis to explain the earlier onset and greater severity of atherosclerosis in men compared with age- matched women despite parallel age-specific risks of men and women. Editorial Handelsman DJ. Testosterone and Male Aging Faltering Hope for Rejuvenation. JAMA 2017;317:

30 TESTOSTERONE TREATMENT AND CORONARY ARTERY PLAQUE VOLUME LIMITATIONS Non-randomization = Minimization of 170 men Different baseline groups due baseline plaque volume? Prognostic studies of non-calificied plaque volume non-existent Assumptions about composition of plaque components as detected by CCTA not confirmed by direct radiologic-pathologic studies Plaque volume and radiologic characteristics of plaque: surrogate outcomes; other factors that influence thrombosis and plaque rupture Another interpretation: T increases fibrous component of plaque = stability Thus, testosterone therapy resulted in stabilization of coronary plaque? What is the meaning of this study? Stabilization is consistent with many retrospective/prospective reports of decreased major adverse cardiovascular events (MACE) after testosterone therapy.

31 SYSTEMATIC REVIEW & META-ANALYSIS CARDIOVASCULAR RISKS OF EXOGENOUS TESTOSTERONE 39 RCTS and 10 Observational Studies Included Compared with Placebo Exogenous T Treatment did not show any significant increase in risk of myocardial infarction, stroke or mortlity Observational studies showed marked clinical and methodological heterogeneity The evidence was rated as low quality; high risk of bias, imprecision, and inconsistency Low quality of evidence precludes definitive conclusion Alexander GC, Iyer G, Lucas E et al. Am J Med 2017; 130:

32 TESTOSTERONE AND CARDIOVASCULAR DISEASE

33 T TODAY: A CLIMATE OF LITIGATION Class Action Suit initiated against T manufacture rs in 2015 Purported that T manufactures both conspired to limit knowledge of T s known thrombotic risks and participated in ad campaign targeted to aging men with diminished libido and fatigue making most prescribing of T off label First bellwether trial trial decided July 24, 2017 found Abbvie guilty of misleading Abbvie found not guilty of its product not causing CVS event and jurors awarded no compensation for injuries Abbvie found liable for misleading plaintiff and his physician about safety and Androgel s propensity for causing blood clots and fined $150 million in damages by jury Award likely to be appealed and overturned due to US Supreme Court ruling that such awards need be based on actual damages. Both sides claim victory

34 CONCLUSIONS Low T associated with increased atherosclerosis & MACE Meta-analyses show TRT has neutral (or possible beneficial) effect on CV risk factors and cardiac events Current evidence about the safety of TRT is hampered by the small n, brief study follow up and soft end points The TOM trial suggested possible increased CV risks of T therapy in elderly and very frail individuals Caution is warranted in interpreting & extrapolating findings to other doses and formulations of T or to other populations, particularly men with hypogonadism w/o CVD or mobility limitations. Serious limitations of recent JAMA (Vigen), Plos One(Finkel), and BMC (Xu) Retrospective and Meta-analysis studies as pointed out by many investigators and FDA No black box warning regarding MI, stroke or death; FDA says weak signal may exist. No association or causal basis. T Trials: soft support for T improving sexual function and mood No improvement in cognitive function and frailty Increase in non-calcified plaque of unknown significance