Risks of Testosterone?? Symptoms and Signs Suggestive of Hypogonadism

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1 Low T and The Heart: Testosterone Therapy & CVD Risk Kevin L. Billups, MD Director, Men s Health & Vitality Program The James Buchanan Brady Urological Institute Associate Professor of Urology & Medicine Johns Hopkins Medical Institutions Baltimore, MD Disclosures for Dr. Billups Endo Pharmaceuticals Advisory Board Clarus Therapeutics Advisory Board PRESENTATION OUTLINE I. Introduction to Testosterone Deficiency and TRT II. Defining the relationship between hypogonadism and CVD III. Testosterone therapy and CV risk: What is the Truth? IV. Conclusions 1

2 Symptoms and Signs Suggestive of Hypogonadism No symptoms are unique to hypogonadism Main symptoms and signs: low sexual desire, ED, ejaculatory dysfunction, low energy, low mood, decreased mental concentration, low muscle mass, decreased muscle strength, high fat mass, osteoporosis, anemia, and others Testing for serum testosterone level is appropriate when presented with symptoms Total T of < 300 ng/dl considered low; also may consider bioavailable T and free T levels for overall evaluation Diagnosis of hypogonadism is made when one or more symptoms are combined with low testosterone concentration Dandona P, Rosenberg M.. Int J Clin Pract. 2010;64(6): Risk of Testosterone-Replacement Therapy and Recommendations for Monitoring Rhoden, Morgentaler N.E.J.M. 2004; 350: Risks of Testosterone?? 2

3 TD, TRT and Cardiovascular Safety Concerns Introductory Statements Low levels of Total T, bioavailable T and free T are associated with increased risk of mortality from all causes and CVD (LOE IIa) Incident CAD is associated with lower levels of total T, bioavailable T or free T (LOE IIa) Severity of CAD is inversely correlated with serum concentrations of total T, bioavailable T or free T (LOE IIa) Morgentaler A. et al., Testosterone Therapy and Cardiovascular Risk: Advances and Controversies, Mayo Clin Proc In Press Introductory Statements Carotid intima-media media thickness and/or carotid plaque volume are inversely correlated with serum concentrations of total T, bioavailable T or free T (LOE IIa) Testosterone therapy is associated with a significant reduction in obesity and fat mass (LOE Ib) Testosterone therapy is associated with small increases in serum concentrations of Total-C, HDL-C and LDL-C. No clear effect on Triglycerides (LOE IIa) Morgentaler A. et al., Testosterone Therapy and Cardiovascular Risk: Advances and Controversies, Mayo Clin Proc In Press 3

4 Introductory Statements Testosterone therapy is associated with a decrease in serum glucose concentrations, HbA1c and insulin resistance in diabetic and pre-diabetic men (LOE Ia) Testosterone therapy is associated with an inconsistent reduction in serum concentrations of inflammatory markers (LOE Ib) Morgentaler A. et al., Testosterone Therapy and Cardiovascular Risk: Advances and Controversies, Mayo Clin Proc In Press Introductory Statements Testosterone therapy improves time to onset of symptomatic angina (LOE 1b) Testosterone therapy improves exercise capacity and peak oxygen consumption in men with symptomatic CHF as defined by New York Heart Association functional class II (LOE Ia) Morgentaler A. et al., Testosterone Therapy and Cardiovascular Risk: Advances and Controversies, Mayo Clin Proc In Press Prior Articles Demonstrating Beneficial Effects of T Against CVD Type of Article Low levels of endogenous testosterone and increased mortality Low testosterone levels and increased incidence of coronary artery disease Low testosterone level correlates with increased severity of coronary artery disease Low endogenous testosterone level and increased carotid intima-media thickness Number of Articles TRT decreases obesity 6 TRT improved cholesterol levels (meta- analysis) 3 TRT improves glycemic control 6 TRT decreases markers of inflammation 8 Total studies=

5 Association of Low T with Mortality Low Testosterone Levels Are Associated With Increased All-Cause Mortality Cumulative Survival Men With a Normal Testosterone Level (n=452) Men With a Equivocal Testosterone Level (n=240) Men With a Low Testosterone Level (n=166) VA 8-year study of 858 men Low T <250 ng/dl or a 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 Survival, y Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Arch Intern Med. 2006;166: CUMULATIVE SURVIVAL BASED ON BIOAVAILABLE T N=930 MEN WITH CORONARY HEART DISEASE 1 FOLLOWED FOR 6.9 ± 2.6 Y MORTALITY: LOW T 21%, NORMAL T 12% Cumulative Survival Bio T > 2.6 nmol/l (n=736) Bio T < 2.6 nmol/l (n=194) Log rank, p=0.007, HR 2.2 ( ) Survival time Malkin CJ et al. Heart 96: (2010) 5

6 Low T As A Predictive Marker For Cardiovascular Mortality N = 11,606 men (no cancer or CVD) 825 men died matched with 1489 living men in control group Mean follow-up 7 years In men, endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes Cumulative survival Multivariate-adjusted survival by quartile of endogenous T concentration (4 is highest) Years of follow up Testosterone group Overall mortality P <.001 for trend after adjusting for multiple variables, including age, BMI, blood pressure, cigarette smoking, etc. Khaw KT, et al. Circulation. 2007;116: Survival of treated vs untreated T-deficient men N=1031 Men>40y T<250 ng/dl Mortality: 20.7% untreated 10.3% T treated P< Shores et al, JCEM 2012 T Deficiency in DM Associated With Increased Mortality, Reversed with T Therapy Muraleedharan V et al Eur J Endocrin men T2DM F/u 5.8y Low T defined <300ng/dl (10.4 nmol/l Men with low T untreated HR 2.3 (CI95% ; 3.5; p=0.004) T therapy-reduced from 19.2% to 8.4% mortality Normal T had 9% mortality 6

7 Testosterone and Cardiovascular Disease A Tale of Two Flawed Studies Retrospective, non-randomized, observational studies of unhealthy, already at-risk population TRT Associated with Adverse Cardiovascular Outcomes, Death Vigen et al: 1 Medical records of 1223 men with T levels <300 ng/dl taking T vs 7486 men with similar T levels, not using TST TST associated with increased risk of heart attack, stroke, death Finkle et al: 2 Cohort study of risk of acute non-fatal MI following initial T prescription (N=55,593) in a large health-care database In men aged 65 y, TRT associated with: 2-fold increase in risk of heart attack in first 90 days of treatment 2-to 3-fold increase in younger men with a history of cardiovascular disease TRT, testosterone replacement therapy; T, testosterone; MI, myocardial infarction 1 Vigen R et al. JAMA. 2013;310: Finkle WR et al. PLOS ONE.2014;9:e

8 Vigen R et al. J Am Med Assoc 310(17): (2013) Original Jama Article Abstract Proportion of All Events (Composite of All-cause Mortality, Myocardial Infarction and Stroke) in Hypogonadal Patients (%) with or without Testosterone Replacement Therapy (TRT) no TRT TRT Death Myocardial infarction Stroke 0 all events Data from: Vigen R et al. J Am Med Assoc 310(17): (2013) 8

9 Proportion of All Events after Statistical Modelling (Stabilized Inverse Probability of Treatment Weighting*) no TRT TRT at 1 year at 2 years at 3 years *adjusting for: age, race, comorbidities: (prior MI, congestive heart failure, diabetes, renal failure, depression, posttraumatic stress disorder, hyperlipidemia, peripheral vascular disease, chronic pulmonary disease, chronic obstructive pulmonary disease, obstructive sleep apnea, hypertension, cerebrovascular disease, overweight, dialysis, ever smoker, alcohol, anemia, blood loss anemia, coagulation disorder, complicated diabetes, uncomplicated diabetes, drug abuse, fluid electrolyte disorder, human immunodeficiency syndrome or AIDS, hypothyroidism, liver disease, lymphoma, metastatic cancer, neurological disorder, paralysis, peptic ulcer disease, psychoses, pulmonary circulatory disorder, renal failure, rheumatoid arthritis, nonmetastatic tumor, and weight loss), and procedures (prior revascularization, prior catheterization, prior percutaneous coronary intervention [PCI], prior coronary artery bypass graft surgery, cardiac transplant, prior stress test, prior cardiac blood pool imaging, cardiac magnetic resonance imaging, cardiac computed tomography [CT], CT coronary angiography, prior myocardial perfusion imaging,,prior transthoracic echocardiogram, and prior transesophageal echocardiogram Data from: Vigen R et al. J Am Med Assoc 310(17): (2013) Vigen R et al. J Am Med Assoc 310(17): (2013) 9

10 EXCLUDED MEN SKEW RESULTS Once MI or stroke occurred, men were no longer in the risk- set Irrelevant whether or not they received T If included, this increases number of events in no-t group by 71% ( ) 2 nd correction published Mar 5, nd correction published Mar 5, to 128: shift >1000 men 397 to 1301: shift >900 men 100 women/1132= 9% Major errors and nearly 10% contamination of dataset by ineligible (wrong gender) population Only identified upon post- publication review of data 10

11 World s Experts Petition JAMA to Retract T Study 25 (now 29) Societies- Endocrinology, Andrology, Men s Health, Sexual Medicine submitted Apr 10, 2014 >160 distinguished researchers/clinicians 8 emeritus professors >60 full professors 9 journal editors 32 countries (all continents except Antarctica) Gross data mismanagement and contamination Study no longer credible Vigen Study Average T levels rose from ng/dl to ng/dl, The percentage of men who suffered an MI event was actually lower by one half for the testosterone group compared with the no-testosterone group (10.1% vs 21.2%) Significantly lower baseline testosterone levels in the T group The authors excluded 1132 men who suffered stroke or heart attack prior to receiving a testosterone prescription These men all had events during the study period and all should have been included in the no-testosterone group 1 Vigen R et al. JAMA. 2013;310: PLoS One TRT Study Abstract 11

12 Finkle et al, Plos One Limitations Uncontrolled Unknown whether observed rate is higher, lower, or unchanged for similar men without T Rx Events unverified (87% accuracy) Comparison with PDE5i- classic apples and oranges Dissimilar groups (low T vs ED) treated with dissimilar meds (T vs PDE5i) Pre- Rx rate: 3.48 events/1000 person- years Post-Rx rate: 4.75 events/1000 person- years Difference: 1.27 events/1000 person-years Data available, but not reported for >90d after T Rx- why?? Conclusion: Study is non-informative TRT- House Effect Attic Polycythemia Liver Cancer Edema Hypertension Ceiling Basement Fatigue Libido Insulin Resistance Bone loss Floor 12

13 Summary: T and CV Risk No large prospective trials Numerous observational studies indicate association between low T and increased mortality Modest number of smaller RCTs indicating benefit of T vsplacebo in men with CVD T therapy improves CVD risk factors Still no direct RCT evidence that T therapy associated with increased CV risks Thank you for your attention Questions 13