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Low T and The Heart: Low T and The Heart: Testosterone Therapy & CVD RiskTestosterone Therapy & CVD Risk

Kevin Kevin L. BillupsL. Billups, , MDMD

Director, Men’s Health & Vitality ProgramDirector, Men’s Health & Vitality Program

The James Buchanan Brady The James Buchanan Brady Urological Urological InstituteInstitute

Associate Professor of Urology & Medicine Associate Professor of Urology & Medicine

Johns Hopkins Johns Hopkins Medical InstitutionsMedical Institutions

Baltimore, MDBaltimore, MD

Disclosures for Dr. BillupsDisclosures for Dr. Billups

•• Endo PharmaceuticalsEndo Pharmaceuticals•• Advisory BoardAdvisory Board

•• Clarus TherapeuticsClarus Therapeutics•• Advisory BoardAdvisory Board

PRESENTATION OUTLINEPRESENTATION OUTLINE

I. I. Introduction to Testosterone Introduction to Testosterone Deficiency and TRTDeficiency and TRT

II. Defining the relationship II. Defining the relationship between hypogonadism and between hypogonadism and CVDCVD

III. TIII. Testosterone estosterone therapy therapy and CV and CV risk: What is risk: What is the Truth?the Truth?

IV. ConclusionsIV. Conclusions

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Symptoms and Signs Suggestiveof 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):682-696.

Risk of Testosterone-Replacement Therapy and Recommendations for Monitoring

Rhoden, Morgentaler N.E.J.M. 2004; 350: 482-492

Risks of Testosterone??

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TD, TRT TD, TRT and Cardiovascular and Cardiovascular Safety ConcernsSafety Concerns

IntroductoryIntroductory StatementsStatements

•• Low levels of Total T, bioavailable T and Low levels of Total T, bioavailable T and free T are associated with increased risk of free T are associated with increased risk of mortality from all causes and CVD (LOE mortality from all causes and CVD (LOE IIa)IIa)

•• Incident CAD is associated with lower Incident CAD is associated with lower levels of total T, bioavailable T or free T levels of total T, bioavailable T or free T (LOE IIa)(LOE IIa)

•• Severity of CAD is inversely correlated Severity of CAD is inversely correlated with serum concentrations of total T, with serum concentrations of total T, bioavailable T or free T (LOE IIa)bioavailable T or free T (LOE IIa)

Morgentaler A. et al., Testosterone Therapy and Cardiovascular Risk: Advances and Controversies, Mayo Clin Proc. 2014. In Press

Introductory StatementsIntroductory Statements

•• Carotid intimaCarotid intima--media thickness and/or media thickness and/or carotid plaque volume are inversely carotid plaque volume are inversely correlated with serum concentrations of correlated with serum concentrations of total T, bioavailable T or free T (LOE IIa)total T, bioavailable T or free T (LOE IIa)

•• Testosterone therapy is associated with a Testosterone therapy is associated with a significant reduction in obesity and fat significant reduction in obesity and fat mass (LOE Ib)mass (LOE Ib)

•• Testosterone therapy is associated with Testosterone therapy is associated with small increases in serum concentrations small increases in serum concentrations of Totalof Total--C, HDLC, HDL--C and LDLC and LDL--C. No clear C. No clear effect on Triglycerides (LOE IIa)effect on Triglycerides (LOE IIa)

Morgentaler A. et al., Testosterone Therapy and Cardiovascular Risk: Advances and Controversies, Mayo Clin Proc. 2014. In Press

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IntroductoryIntroductory StatementsStatements

•• Testosterone therapy is associated with a Testosterone therapy is associated with a decrease in serum glucose concentrations, decrease in serum glucose concentrations, HbA1c and insulin resistance in diabetic HbA1c and insulin resistance in diabetic and preand pre--diabetic men (LOE Ia)diabetic men (LOE Ia)

•• Testosterone therapy is associated with an Testosterone therapy is associated with an inconsistent reduction in serum inconsistent reduction in serum concentrations of inflammatory markers concentrations of inflammatory markers (LOE Ib)(LOE Ib)

Morgentaler A. et al., Testosterone Therapy and Cardiovascular Risk: Advances and Controversies, Mayo Clin Proc. 2014. In Press

Introductory StatementsIntroductory Statements

•• Testosterone therapy improves time to Testosterone therapy improves time to onset of symptomatic angina (LOE 1b)onset of symptomatic angina (LOE 1b)

•• Testosterone therapy improves exercise Testosterone therapy improves exercise capacity and peak oxygen consumption in capacity and peak oxygen consumption in men with symptomatic CHF as defined by men with symptomatic CHF as defined by New York Heart Association functional New York Heart Association functional class II (LOE Ia)class II (LOE Ia)

Morgentaler A. et al., Testosterone Therapy and Cardiovascular Risk: Advances and Controversies, Mayo Clin Proc. 2014. In Press

Prior Articles Demonstrating Prior Articles Demonstrating Beneficial Effects of T Against CVDBeneficial Effects of T Against CVDType of Article Number of Articles

Low levels of endogenous testosterone and increased mortality

8

Low testosterone levels and increased incidence of coronary artery disease

6

Low testosterone level correlates with increased severity of coronary artery disease

4

Low endogenous testosterone level and increased carotid intima-media thickness

8

TRT decreases obesity 6

TRT improved cholesterol levels (meta- analysis) 3

TRT improves glycemic control 6

TRT decreases markers of inflammation 8

Total studies= 49Total studies= 49

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Association of Low T with Association of Low T with

MortalityMortality

Low Testosterone Levels Are Associated

With Increased All-Cause Mortality 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

Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Arch Intern Med. 2006;166:1660-1665.

Men With a NormalTestosterone Level (n=452)

Men With a EquivocalTestosterone Level (n=240)

Men With a LowTestosterone Level (n=166)

1.0

0.9

0.8

0.7

0.6

0.5

0.00 2.00 4.00 6.00 8.00 10.00

Cu

mu

lati

ve S

urv

ival

Survival, y

Malkin CJ et al. Heart 96: 18231-1825 (2010)

CUMULATIVE SURVIVAL BASED ON BIOAVAILABLE TCUMULATIVE SURVIVAL BASED ON BIOAVAILABLE T

N=930 MEN WITH CORONARY HEART DISEASE N=930 MEN WITH CORONARY HEART DISEASE

FOLLOWED FOR 6.9 FOLLOWED FOR 6.9 ±±±±±±±± 2.6 Y2.6 Y

MORTALITY: LOW T 21%, NORMAL T 12%MORTALITY: LOW T 21%, NORMAL T 12%

0.85

0.9

0.95

1

0 500 1000 1500 2000 2500 3000 3500Survival time

Cu

mu

lati

ve S

urv

ival

Bio T < 2.6 nmol/L

(n=194)

Bio T < 2.6 nmol/L

(n=194)

Bio T > 2.6 nmol/L

(n=736)

Bio T > 2.6 nmol/L

(n=736)

Log rank, p=0.007, HR 2.2 (1.2-3.9)

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Low T Low T As A As A Predictive Predictive Marker For Marker For

Cardiovascular Cardiovascular MortalityMortality

�� N = 11,606 men (no cancer N = 11,606 men (no cancer

or CVD)or CVD)

�� 825 men died matched 825 men died matched with 1489 living men in with 1489 living men in

control groupcontrol group

�� Mean followMean follow--up 7 yearsup 7 years

�� “In men, endogenous testosterone “In men, endogenous testosterone concentrations concentrations

are inversely related to are inversely related to

mortality due to cardiovascular mortality due to cardiovascular disease and all causes”disease and all causes”

Khaw KT, et al. Circulation. 2007;116:2694-2701.

0 2 4 6 8 10

1234

Multivariate-adjusted survival by quartile of endogenous T concentration (4 is highest)

Years of follow up

Testosterone group

.5

.6

.7

.8

.9

1.0

Cum

ula

tive

surv

ival

1.1

Overall mortality

P < .001 for trend after adjusting for multiple variables, including age, BMI, blood pressure, cigarette smoking, etc.

Survival of treated vs untreated Survival of treated vs untreated

TT--deficient men deficient men

�� N=1031N=1031

�� Men>40yMen>40y

�� T<250 ng/dlT<250 ng/dl

�� Mortality:Mortality:

�� 20.7% untreated20.7% untreated

�� 10.3% T treated 10.3% T treated

�� P<0.0001P<0.0001

Shores et al, JCEM 2012

T Deficiency in DM Associated With T Deficiency in DM Associated With

Increased Mortality, Reversed with T TherapyIncreased Mortality, Reversed with T Therapy

�� Muraleedharan V et alMuraleedharan V et al

Eur J Endocrin 2013Eur J Endocrin 2013

�� 581 men T2DM581 men T2DM

�� F/u 5.8yF/u 5.8y

�� Low T defined <300ng/dl Low T defined <300ng/dl (10.4 nmol/L(10.4 nmol/L

�� Men with low T untreated HR Men with low T untreated HR 2.3 (CI95% 1.32.3 (CI95% 1.3--3.5; p=0.004)3.5; p=0.004)

�� T therapyT therapy-- Reduced from Reduced from 19.2% to 8.4% mortality19.2% to 8.4% mortality

�� Normal T had 9% mortalityNormal T had 9% mortality

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Testosterone and Cardiovascular Testosterone and Cardiovascular DiseaseDisease

A Tale of Two A Tale of Two Flawed Flawed StudiesStudies

•• Retrospective, Retrospective, nonnon--randomizedrandomized, , observational studies of observational studies of unhealthy, unhealthy, already atalready at--risk risk population population

TRT Associated with Adverse TRT Associated with Adverse Cardiovascular Outcomes, DeathCardiovascular Outcomes, Death

Vigen et al:Vigen et al:11

••Medical records of 1223 men with T levels <300 ng/dL taking T vs Medical records of 1223 men with T levels <300 ng/dL taking T vs 7486 men with similar T levels, not using TST7486 men with similar T levels, not using TST

••TST associated with increased risk of heart attack, stroke, deathTST associated with increased risk of heart attack, stroke, death

Finkle Finkle et al:et al:22

••Cohort study of risk of acute nonCohort study of risk of acute non--fatal MI following initial T fatal MI following initial T prescription (N=55,593) in a large healthprescription (N=55,593) in a large health--care databasecare database••In men aged ≥65 y, TRT associated with:In men aged ≥65 y, TRT associated with:

•• 22--fold increase in risk of heart attack in first 90 days of treatmentfold increase in risk of heart attack in first 90 days of treatment

•• 22-- to 3to 3--fold increase in younger men with a history of cardiovascular diseasefold increase in younger men with a history of cardiovascular disease

TRT, testosterone replacement therapy; T, testosterone; MI, myocardial infarction

1Vigen R et al. JAMA. 2013;310:1829-1836. 2Finkle WR et al. PLOS ONE.2014;9:e85805.

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Vigen R et al. J Am Med Assoc 310(17): 1829-1836 (2013)

Original Jama Article Abstract

Proportion of All Events (Composite of AllProportion of All Events (Composite of All--cause Mortality, Myocardial cause Mortality, Myocardial Infarction and Stroke) in Hypogonadal Patients (%)Infarction and Stroke) in Hypogonadal Patients (%)

with or with or withoutwithout Testosterone Testosterone ReplacementReplacement TherapyTherapy (TRT)(TRT)

6.5

5.6

9.1

2.7

1.9

5.5

0

2

4

6

8

10

Death Myocardial infarction Stroke

no TRT TRT

Data from: Vigen R et al. J Am Med Assoc 310(17): 1829-1836 (2013)

21.2

10.1

0

5

10

15

20

25

all events

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Proportion of All Events after Statistical Proportion of All Events after Statistical ModellingModelling((StabilizedStabilized Inverse Inverse ProbabilityProbability of Treatment of Treatment WeightingWeighting*)*)

Data from: Vigen R et al. J Am Med Assoc 310(17): 1829-1836 (2013)

19.9

15.4

10.1

25.7

18.5

11.3

0

5

10

15

20

25

30

at 1 year at 2 years at 3 years

no TRT TRT

*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, eversmoker, 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, priorcatheterization, 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 computedtomography [CT], CT coronary angiography, prior myocardial perfusion imaging,,prior transthoracic echocardiogram, and

prior transesophageal echocardiogram

Vigen R et al. J Am Med Assoc 310(17): 1829-1836 (2013)

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EXCLUDED MEN EXCLUDED MEN SKEW RESULTSSKEW RESULTS

•• Once MI or stroke Once MI or stroke occurred, men were occurred, men were no longer in the riskno longer in the risk--setset

•• Irrelevant whether or Irrelevant whether or not they received Tnot they received T

•• If included, this If included, this increases number of increases number of events in noevents in no--T group T group by 71% (1132 + 1587)by 71% (1132 + 1587)

22ndnd correction published Mar 5, 2014correction published Mar 5, 2014

22ndnd correction published Mar 5, 2014correction published Mar 5, 2014

•• 1132 to 128: shift >1000 1132 to 128: shift >1000 menmen

•• 397 to 1301: shift >900 men397 to 1301: shift >900 men•• 100 women/1132= 9%100 women/1132= 9%

•• Major errors and nearly Major errors and nearly 10% contamination of 10% contamination of dataset by ineligible dataset by ineligible (wrong gender) population(wrong gender) population

•• Only identified upon postOnly identified upon post--publication review of datapublication review of data

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World’s Experts Petition World’s Experts Petition JAMA to Retract T StudyJAMA to Retract T Study

•• 25 (now 29) Societies25 (now 29) Societies-- Endocrinology, Endocrinology, Andrology, Men’s Health, Sexual Medicine Andrology, Men’s Health, Sexual Medicine submitted Apr 10, 2014submitted Apr 10, 2014

•• >160 distinguished researchers/clinicians>160 distinguished researchers/clinicians

•• 8 emeritus professors8 emeritus professors•• >60 full professors>60 full professors

•• 9 journal editors9 journal editors•• 32 countries (all continents except Antarctica)32 countries (all continents except Antarctica)

•• “Gross data mismanagement and “Gross data mismanagement and contamination”contamination”

•• Study “no longer credible”Study “no longer credible”

Vigen StudyVigen Study•• Average T levels rose from 175.5 ng/dL to 332.2 ng/dL, Average T levels rose from 175.5 ng/dL to 332.2 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

1Vigen R et al. JAMA. 2013;310:1829-1836

PLoSPLoS One TRT Study AbstractOne TRT Study Abstract

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Finkle et al, Plos OneFinkle et al, Plos One

LimitationsLimitations•• UncontrolledUncontrolled•• Unknown whether observed rate is higher, Unknown whether observed rate is higher,

lower, or unchanged for similar men without lower, or unchanged for similar men without T RxT Rx

•• Events unverified (87% accuracy)Events unverified (87% accuracy)•• Comparison with PDE5iComparison with PDE5i-- classic apples and classic apples and

oranges oranges •• Dissimilar groups (low T vs ED) treated with Dissimilar groups (low T vs ED) treated with

dissimilar meds (T vs PDE5i) dissimilar meds (T vs PDE5i)

•• PrePre-- Rx rate: 3.48 events/1000 personRx rate: 3.48 events/1000 person--yearsyears

•• PostPost--Rx rate: 4.75 events/1000 personRx rate: 4.75 events/1000 person--yearsyears

•• Difference: 1.27 events/1000 personDifference: 1.27 events/1000 person--yearsyears•• Data available, but not reported for >90d Data available, but not reported for >90d

after T Rxafter T Rx-- why??why??

Conclusion: Study is nonConclusion: Study is non--informativeinformative

TRTTRT-- ““ House Effect House Effect ””

CeilingCeiling

AtticAttic

FloorFloor

BasementBasement

PolycythemiaPolycythemiaLiver CancerLiver Cancer

EdemaEdemaHypertensionHypertension

FatigueFatigue↓ Libido↓ Libido

Insulin ResistanceInsulin ResistanceBone lossBone loss

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Summary: T and CV RiskSummary: T and CV Risk

�� No large prospective trialsNo large prospective trials

�� Numerous observational studies indicate Numerous observational studies indicate

association between low T and increased mortalityassociation between low T and increased mortality

�� Modest number of smaller RCTs indicating Modest number of smaller RCTs indicating

benefit of T benefit of T vsvs placebo in men with CVDplacebo in men with CVD

�� T therapy improves CVD risk factorsT therapy improves CVD risk factors

�� Still no direct RCT evidence that T therapy Still no direct RCT evidence that T therapy associated with increased CV risks associated with increased CV risks

Thank you for your attention…Thank you for your attention…

QuestionsQuestions