Massachusetts Medical Society 12 th annual Men s Health Symposium 11 June 2014 Testosterone and Cardiovascular Disease Where Does The Real Answer Lie? Andre Guay MD, FACP, FACE, IF (Ret) Director, Center for Sexual Function/Endo Lahey Clinic Northshore, Peabody Clinical Professor of Medicine ( Endocrinology) Tufts University School of Medicine Boston, MA Disclosures Advisory Boards Endo Pharmaceuticals Repros Therapeutics 1
Low Testosterone Related To Increased Cardiac Risk And Also To Mortality Low Serum Testosterone and Mortality in Male Veterans 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 > 250 24.6% with equivocal T Equal # 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: 1660-1665 2
Recent Studies Low Testosterone and Increased Mortality (N >500) HR (95% CI) Nature Men, n Follow- Up, yrs Mortality Shores, 2006 1.88 (1.34 2.63) Retrospective 858 8 All-cause Laughlin, 2008 1.38 (1.02 1.85) Prospective 794 20 CVD Khaw, 2007 2.29 (1.60 3.26) Prospective 2314 of 11,606 10 All-cause/ CVD Haring, 2010 2.32 (1.38 3.89) Prospective 1954 7.2 All-cause 2.56 (1.15-6.52) CVD Malkin, 2010 2.27 (1.45 3.60) Prospective 930 6.9 All-cause in men with CAD Tivesten, 2009 1.65 (1.29 2.12) Prospective 3014 4.5 All-cause Menke, 2010 1.43 (1.09 1.87) Prospective 1114 9 All-cause Vikan, 2009 1.24 (1.01 1.54) Prospective 1568 11.2 All-cause Pye 2014 2.3 (1.2-4.2) 3.0 if sex sx Prospective 2599 4.3 All Cause/CVD Jones 2013 2.02 (1.2-3.4) Prospective 581 5.8 All cause Corona, 2010 7.1 (1.8 28.6) Prospective 1687 4.3 CVD HR=hazard ratio; CI=confidence interval. Risk Factor Prevalence of and Major Risk Factors for Hypogonadism Overall Prevalence of Hypogonadism in Clinical Practice: 38.9% Hypogonadism a Prevalence (95% CI) Odds Ratio (95% CI) Obesity 52.4 (47.9-56.9) 2.38 (1.93-2.93) Type 2 diabetes 50.0 (45.5-54.5) 2.09 (1.70-2.58) Hypertension 42.4 (39.6-45.2) 1.84 (1.53-2.22) Hyperlipidemia 40.4 (37.6-43.3) 1.47 (1.23-1.76) Asthma or COPD 43.5 (36.8-50.3) 1.40 (1.04-1.86) Prostate disease 41.3 (36.4-46.2) 1.29 (1.03-1.62) 6 HIM Study (N = 2085) Adapted from Mulligan T, et al. Int J Clin Pract. 2006;60:762-769. 3
Men With Erectile Dysfunction (ED) Have Hypogonadism Due to Varied Chronic Illnesses (N=990) Condition N # Hypo. ( % ) #1 o Hypo ( % ) # 2 o Hypo (% ) Diabetes mellitus 229 78 (35.6) 12 (5.2) 66 (30.4) Hypertension 354 109 (34.6) 15 (4.2) 94 (30.4) ASCAD 197 69 (35.0) 17 (8.6) 52 (26.4) Asthma 42 19 (45.2) 1 (2.4) 18 (42.8) Seizures 53 18 (34.4) 3 (5.7) 15 (28.7) OSA 42 27 (64.3) 2 (4.8) 25 (59.5) Roh 140 38 (27.1) 7 (5.0) 31 (22.1) Anxiety/Depression 208 77 (37.0) 17 (8.2) 60 (28.8) Work stress 197 86 (43.6) 6 (3.0) 80 (40.6) TOTAL (36 %) (6%) (30%) *Lahey Clinic Northshore, Peabody, MA; Case Western Reserve, Cleveland, OH. Guay AT, et al. Int J Imp Res. 2010; 22(3):9-19. Metabolic Syndrome: Defined by the Presence of Any 3 of 5 Components 1. Abnormality of blood sugar/insulin resistance 2. Enlarged waist circumference/bmi (visceral fat) 3. Elevated blood pressure 4. Elevated triglycerides 5. Decreased HDL cholesterol Androgen deficiency/ hypogonadism Obesity Hypertension Dyslipidemia Hyperglycemia Insulin resistance Metabolic syndrome 4
Can Testosterone Replacement in Hypogonadism Ameliorate Cardiometabolic Risks? T Therapy Improves Metabolic Syndrome Components FBG HbA1c Fasting insulin HOMA index of insulin resistance Waist circumference, BMI, cholesterol Prevalence of metabolic syndrome (after 1 year) Kapoor D,* et al. Eur J Endocrinol. 2006;154(6):899 906. 3 month trial Heufelder AE, et al. J Androl. 2009;30(6):726 733. 12 month trial *United Kingdom; Germany, Jones TH, et. al. Diabetes Care. 2011;34:828-837. 5
CIMT After 12 Months of Nebido Treatment (n=40) and Correlation Between Change in Testosterone and CIMT. CIMT Correlation of CIMT vs TT P<0.0001 r 5 = 0.31; P<0.0001 CIMT=carotid intima media thickness. Aversa A,* et al. J Sex Med. 2010;7(10):3495-3503 Testosterone-Treated Hypogonadal Men Have a Longer Survival Time than Untreated Men* Log Rank p = 0.029 Treated (n=398) mortality 10.3% 3.4 deaths/100 pat yrs Untreated (n=633) mortality 20.7% 5.7 deaths/100 pat yrs *in 1031 men (mean age ~ 60 years; 38% with type 2 diabetes; 22% with cardiac disease) Shores MM et al. J Clin Endocrinol Metab 97(6): 2050-2058 (2012) 6
Low Testosterone Predicts Increased Mortality and Testosterone Therapy Improves Survival in 587 Men with Type 2 Diabetes (mean Follow-up: 5.8 years) Low T treated Normal T Low T untreated Mean TRT was for 41.6 months.hr 2.3 for untreated Muraleedharan V et al. Eur J Endo 2013; 169: 725-733 Recent Meta analyses About Testosterone Therapy Related To Cardiovascular Events 7
Meta Analyses For CV Events on T Therapy 2 3 1. Calof OM et al. J Gerontology 2005;11:1451 57. 2. Haddad RM et al. Mayo Clin Proc. 2007;82:29-39. 3. Fernández-Balsells NM et al. J. Clin. Endocrinol. Metab. 2010;95:2560-2575 8
Testosterone Prescription Sales Sales in millions of dollars 500 450 400 350 300 250 200 150 100 50 0 1988 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 Year Source: IMS Sales Data, BMC Corp. Courtesy: Reed Selby, ALZA Corporation; Michael Bailey, SmithKline Beecham; Kevin Rose, Solvay-Unimed U.S. annual testosterone sales approaching $1 Billion (Year over year growth in %) 900 20% 800 20% 700 14% 600 500 400 300 Androgel Launch 87% 25% 32% 16% 8% oral (methylated-t) injectable patch/buccal gel total 200 100 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 Source: IMS 9
Why Have Testosterone Prescriptions Increased? 1. Direct to consumer advertising 2. Subliminal promise of eternal youth 2. Gyms and Athletes Not prescribed but obtained via black market 12 % of high school athletes have taken steroids 3. Anti aging Clinics Run by physicians May recommend testosterone and growth hormone therapy 4. Increased awareness of Hypogonadism (1990 s) 5. Fear of prostate cancer has been answered TOM Trial NEJM 2010 10
In Older Men an Optimal Plasma Testosterone is Associated with Reduced All Cause Mortality and Higher Dihydrotestosterone With Reduced Ischemic Heart Disease Mortality, While Estradiol Levels Do Not Predict Mortality Health in Men Study Perth Australia 4248 men studied at 5 yrs Of men that qualified: N = 2716 remained alive N = 974 died Men who died had an association with low T at baseline No relation of E2 with Mortality Normal T related to increased survival Yeap, et al (Aus) J Clin Endo Metab Epub 20 Nov 2013 doi:10.1210/jc.2013-3272 Adverse Events Associated With Testosterone Administration: TOM Study Basaria, Bhasin et al (Boston) N.E.J.M. 2010; E-pub 30 June:10.1056/NEJMoa1000485 TOM = Testosterone in Older Men with Mobility Limitation N = 209 men, > 65 years of age (of the 252 desired by power analysis) Baseline TT 100 350 ng/dl ( free T < 50 pg/ml or 170 pmol/l ) 1% testosterone gel used, 10 Gm QD, titrated to 5.0 or 15.0, 6 mo rx Aimed for TT between 500 and 1000 ng/dl Results of muscle performance and physical functionwere positive 11
Adverse Events Associated With Testosterone Administration: TOM Study More risks in T Rx group Cv disease Hypertension And HTN meds Statin therapy But not statistically significant Basaria, Bhasin et al (Boston) N.E.J.M. 2010; E-pub 30 June:10.1056/NEJMoa1000485 Adverse Events Associated With Testosterone Administration: TOM Study Placebo Group No major CV event Testosterone Group MI x2 Death, presumed MI x1 CVA x1 Acute coronary syndrome X1 Serious CHF x2 Basaria, Bhasin et al (Boston) N.E.J.M. 2010; E-pub 30 June:10.1056/NEJMoa1000485 12
Adverse Events Associated With Testosterone Administration: TOM Study Hazard Ratio of 2.0 for men who had TT levels between 512 ng/dl to 1957 ng/dl At baseline, men with lower TT levels were at greater risk Elevated Hct seems to be a great aggravating factor in men at this age at risk Interesting that BMI, smoking, the presence of DM did not increase risk..but age did Basaria, Bhasin et al (Boston) N.E.J.M. 2010; E-pub 30 June:10.1056/NEJMoa1000485 Adverse Events Associated With Testosterone Administration: TOM Study Despite all of problems int the design of the paper: Study not powered to find CV events Poor randomization (due to underpowering) T treatment group had patients at higher risk There is a signal for increased CV events: Poor inclusion criteria Class I and II CHF Creatinine levels < 3.5 ng/ml T gel not started at lowest dose before titration Did not aim for midrange T levels Aimed for T levels between 500-1000 ng/dl Reasonable assumption that men had salt and water retention and it resulted in the 7 major CV events Where there were none for the placebo group Basaria, Bhasin et al (Boston) N.E.J.M. 2010; E-pub 30 June:10.1056/NEJMoa1000485 13
In Older Men an Optimal Plasma Testosterone is Associated with Reduced All Cause Mortality and Higher Dihydrotestosterone With Reduced Ischemic Heart Disease Mortality, While Estradiol Levels Do Not Predict Mortality Optimal androgen levels are a biomarker for survival because older men with midrange levels of T and DHT had the lowest death rates from any cause Note the trend for increasing mortality with higher T and DHT levels: Especially TT > 30 nmol/l (864ng/dL) Or cft > 500 pmol/l? Explanation for TOM trial results? Yeap, et al (Aus) J Clin Endo Metab Epub 20 Nov 2013 doi:10.1210/jc.2013-3272val Do the Effects of Testosterone on Muscle strength, Physical Function, Body Composition, and Quality of Life Persist Six Months After Treatment in Intermediate-Frail and Frail Elderly Men N=274 frail men, ages 65-90 Treated for 6 months 25 75 mg/d Total T < 12 nmol/l Calculated free T < 250 pmol/l Total from 11.3 to 18.4 nmol/l Declined to 10.5 nmol/l at 12 months Calc free T went from 175 to 365 pmol/l Declined to 172 pmol/l at 12 months Need to continnue Rx NO ADVERSE CV EVENTS O Connell, Srinivas-Shankar, Wu et al (UK) J.C.E.M. 2011; 96:454-458 14
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 N=70 elderly men with stable CHF, median age 70 years Peak O2 (VO2) increased with T rx, as did muscle strength, 6MWT MVC (max vol muscle contraction) increased on T Rx EF increased but not significantly Caminiti, Rosano et al (It) J Am Coll Card 20019; 54: 919-927 Cardiorespiratory and Muscular Results before and after 3 mo of Treatment with Nebido in 64 Frail Elderly Men with Chronic Heart Failure * * * * * *p<0.05 Caminiti G et al. J Am Coll Cardiol 54: 919-927 (2009) 15
Metabolic and Hormonal Results before and after 3 mo of Treatment with Nebido in 64 Frail Elderly Men with Chronic Heart Failure * *p<0.05 * 6- Minute Walking Test (m) * Caminiti G et al. J Am Coll Cardiol 54: 919-927 (2009) Xu et al Biomedical Central On-Line Journal 2013 16
Testosterone Therapy and Cardiovascular Events Among Men: A Systematic Review and Meta-Analysis of Placebo-Controlled Randomized Trials 1,882 papers obtained; 27 used Table 1: men who had low T and/or chronic disease Search Terms: tetosterone, androgen, random, trial 12 had TT < 10.4 nmol/l Or 300 ng/dl 12 had TT > 10.4 nmol/l No Rx T levels available No correlation of CV events with any T levels Xu L, et al BMC Medicine 2013, 11:108 Testosterone Therapy and Cardiovascular Events Among Men: A Systematic Review and Meta-Analysis of Placebo-Controlled Randomized Trials o Conclusion? Biased,?Relevant: o The effects of testosterone on cardiovascular-related events varied with source of funding o Fig 4 o Upper panel sponsored by Pharma o o 3 studies had inadequate levels Lower panel, no Pharma support o 4 studies had inadequate levels o Eliminate Basaria 2010 o Would have changed the OR o If a number of men had T, then one can make the case for low T related to CV events Xu L, et al BMC Medicine 2013, 11:108 17
Vigen et al JAMA November 2013 Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels Study Population: at risk population of veterans who underwent coronary arteriography N = 8709 men with TT < 300ng/dL (<10.4 nmol/l) Of 7486 men NOT RECEIVING T Rx: 681 died, 420 had MI, 486 had CVA Incidence of AE: 21.2% Of 1223 men RECEIVING T Rx:d 67 dies, 23 had MI, 33 had CVA Incidence of AE: 10.0% Vigen, et al (VA Study in USA) J.A.M.A. 2013; 310:1829-1836 18
Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels Since population biased for CAD How to generalize this data to apply to a general population? Applied the stabilized inverse probability of treatment weighting There are no standardized method of assigning statistical weights Subjective definitions by each study group Over 50 variables were weighted, but it was not clear if there was any adjustment for multiple risk factors, or whether and how the authors took into consideration to correlations between the factors N=1132 men excluded from the study Not available for the T risk Group Should have been added to the NON T Group Could have made a separate arm Vigen, et al (VA Study in USA) J.A.M.A. 2013; 310:1829-1836 JAMA Abstracts Before and after Revision The absolute rate of events were 19.9% in the no testosterone group vs 25.7% in the testosterone therapy group, with an absolute risk difference of 5.8% at 3 years after coronary arteriography At 3 years after coronary arteriography, the Kaplan-Meier estimated cumulative percentages with events were 19.9% in the no testosterone therapy group vs 25.7% in the testosterone therapy group, with an absolute risk difference of 5.8% 19
Diagnosis and Treatment of Hypogonadism Diagnosis of Hypogonadism Total T < 300 ng/dl (10.4 nmol/l) has been the standard in the past The definition of testosterone deficiency involves a biochemical number plus consistent signs and symptoms of androgen deficiency Bhasin S, et al. J Clin Endocrinol Metab 2010; 95: 2536 2559 There is no mention in the JAMA report of any symptomotology No mention of any confirmatory blood test being done Up to 30% of low TT has been shown to be normal on retesting Brambilla DJ, et al. Clin Endocrinol (Oxf) 2007; 67: 853 862 No mention of the time of day the test was done Even many repeat TT in Am in older men were found to be normal Brambilla DJ, et al. Clin Endocrinol (Oxf) 2007; 67: 853 862 Only 60% of the men had post rx Testosterone levels The 40% with no tests should have been eliminated from the study Vigen, et al (VA Study in USA) J.A.M.A. 2013; 310:1829-1836 Diagnosis and Treatment of Hypogonadism Treatment of Testosterone Deficiency.? Inadequate 63.9% of the men were given the low, 2.5 mg, Testosterone patch The VA requires that T treatment is begun with patches Most clinicians would start at 5.0 mg Also, nearly half of the men develop dermatitis The mean number of refills was 6 So, 80% of the men were treated for about 6 months The mean treatment T level was 332 ng/dl (11.5 nmol?l) and levels of T on treatment was only carried out in 60% of the men Many feel that the cutoff for testosterone deficiency should be a TT < 350 ng/dl (12.1 nmol/l) Wang C, et al. J Androl 2009 doi: 10.2164/jandrol.108.006486 Maggi M, et al. J Sex Med 2013; 10: 661 677 Bhasin S,et al. J Clin Endocrinol Metab 2011; 95: 2430 2439 Vigen, et al (VA Study in USA) J.A.M.A. 2013; 310:1829-1836 20
Finkle et al PLOS one On line Journal January 2014 Increased Risk of Non Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men Cohort Formation 1 st Prescription for Testosterone.N = 55,593 (48,539 men < 65) Comparison population 1 st Prescription for PDE5.N = 167,279 Post Prescription F/U 90 days..then from 91 180 days because many men dropped out in the first 90 days Pre Prescription..25 months!!!!...how cam you compare 90 days and 25 months? Why PDE5 as comparison group because some indications for prescription are similar to those for T Transcription.WRONG!!! Only indication for PDE5 is ED, and ED not an indication for TT because PDE5 s not associated with cardiovascular events Makes populations quite different.. Men with multiple medical co factors may not be eligible to receive a PDE5 Finkle WD, et al PLOS/one Jan 2014/ V9/ Issue 1/ e85805 www.plosone.org 21
Increased Risk of Non Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men PDE5 patients were weighted to match the TT cohort on odds of testosterone prescription.. So a guess 141,031./. 167,279 = 84% chance of needing a prescription Without weighting there are more men with hyperlipidemia, hypertension, heart disease, asthma, SSRI s, Corticosteroids, insulin and anti-diabetic drugs in the T Rx group Putting the odds at 84% evens the groups out wonderfully well Finkle WD, et al PLOS/one Jan 2014/ V9/ Issue 1/ e85805 www.plosone.org Increased Risk of Non Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men So what is the true prevalence of hypogonadism in ED? 1. Kohler. Prevalence of And Def in ED. Urology 2008 Prevalence of 23% (TT < 300ng/dL) 2. Somani. Screening for MS and T Def in ED. BJU Int 2010 Prevalence of 27% ( with cft < 220 pmol/l) 3. Guay. Characterization of men in an endocrine clinic. Endo Prac 1999 Prevalence of 36% (TT < 300 ng/dl) 4. Wu. Identification of LOH in Eur Male Aging Study. N.E.J.M. 2010 Prevalence of 33% (with cft < 220 pmol/l) 5. Isidori. Critical analysis of Testosterone on erectile function. Eur Urol 2013 Prevalence between 23% and 36% Why bother to worry about the prevalence? There is no mention of T levels, before or after a rx for testosterone There is no assurance that the men ever took the medication Finkle WD, et al PLOS/one Jan 2014/ V9/ Issue 1/ e85805 www.plosone.org 22
Take Home Messages I would not recommend stopping testosterone therapy o the basis of the recent publicized studies There is overwhelming evidence that the opposite is true, i.e., cardiovascular risk is related to low testosterone Androgen Study Group www.androgenstudygroup.com 23