Transcript Nitric Oxide and Its Effect Throughout the Body

Hormone Replacement Therapy
and Cardiovascular Events –
What’s True?
Arthur L. (Bud) Burnett, M.D., M.B.A., F.A.C.S.
Patrick C. Walsh Professor of Urology
The James Buchanan Brady Urological Institute
Johns Hopkins Medicine
Baltimore, Maryland
Disclosure Statement: In accordance with
ACCME policy on relevant financial
disclosure, I disclose financial relationships
with the following entities: Acorda
Therapeutics, American Medical Systems,
Astellas, Auxilium Inc, Coloplast, Endo
Pharmaceuticals, Genomic Health Inc,
Medispec, National Institutes of Health, New
England Research Institute, Pfizer Inc,
Reflexonic LLC, Urology Times Editorial
Council, Vivus Inc.
Overview
Review the concept of testosterone
deficiency: clinical syndrome?
– association with cardiovascular disease
Discuss the role and objectives of
testosterone replacement therapy (TRT)
– cardiovascular disease implications
Testosterone Deficiency
Is it just an aging issue?
or
Are chronic diseases in play?
Androgen Deficiency
Association with Cardiovascular Disease:
Postulated Mechanism
Traish AM et al. J Androl 2009; 30: 477-94
Adult Onset Hypogonadism
Not classical primary (testicular failure) or secondary (pituitary
or hypothalamic failure) hypogonadism because it may have
elements of both presentations.
May occur commonly in middle-age and older men, many of
whom have concomitant metabolic disease (i.e. obesity, type 2
diabetes, or metabolic syndrome)
In a subgroup of 4,220 men presenting to a sexual dysfunction clinic, only 11% of those
diagnosed with secondary hypogonadism had a diagnosable medical cause for the condition
and of the remaining 89% the majority (70.7%) had concomitant metabolic disease.
Khera M et al Mayo Clin Proc 2016; 91:908-26.
Clinical Implication of Testosterone Deficiency
Insulin
Resistance/
Diabetes
Inflammation
Metabolic
Syndrome
Sexual
Dysfunction
TESTOSTERONE
DEFICIENCY
Dyslipidemia
Vascular
Stiffness
Hypertension
Atherosclerosis
MORTALITY
Adapted from Maggio M and Basaria S Int J Impot Res 21: 261-264 (2009)
Low Testosterone Levels Are
Associated
With Increased All-Cause Mortality
1.0
Men With a Normal
Testosterone Level (n=452)
0.9
Cumulative Survival
VA 8-year study of
858 men
Men With a Equivocal
Testosterone Level (n=240)
Men With a Low
Testosterone Level (n=166)
0.8
Low T <250 ng/dL or a
free T <0.75 ng/dL
0.7
0.6
0.5
0.00
2.00
4.00
6.00
Survival, y
8.00
10.00
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.
CUMULATIVE SURVIVAL BASED ON BIOAVAILABLE T
N=930 MEN WITH CORONARY HEART DISEASE
FOLLOWED FOR 6.9 ± 2.6 Y
MORTALITY: LOW T 21%, NORMAL T 12%
Cumulative Survival
1
Bio T > 2.6 nmol/L
(n=736)
0.95
Bio T < 2.6 nmol/L
(n=194)
0.9
Log rank, p=0.007, HR 2.2 (1.2-3.9)
0.85
0
500
1000
1500
2000
Survival time
2500
3000
3500
Malkin CJ et al. Heart 96: 18231-1825 (2010)
Low T As A Predictive Marker For
Cardiovascular Mortality
N = 11,606 men (no cancer
or CVD)
Multivariate-adjusted survival by quartile of
endogenous T concentration (4 is highest)
1.1
– 825 men died matched
with 1489 living men in
control group
Cumulative survival
Mean follow-up 7 years
“In men, endogenous
testosterone concentrations
are inversely related to
mortality due to cardiovascular
disease and all causes”
1.0
.9
.8
Testosterone
group
.7
4
3
2
1
.6
.5
0
2
4
6
8
10
Years of follow up
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;116:2694-2701.
Testosterone Replacement?
Update in Testosterone Therapy in Men
Corona, Maggi, et al. J Sex Med 2011; 8: 639-654
Goals of Testosterone Replacement
Therapy
Improve libido
Improve erectile function
Improve psychologic well-being and mood
Increase muscle mass
Improve strength and stamina (prevent falls)
Preserve or strengthen bone mass (prevent fractures)
Possibly decrease cardiovascular disease risk
- Decrease in total cholesterol and low-density
lipoprotein (LDL)
Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987
T Deficiency in DM Associated With
Increased Mortality, Reversed with T Therapy
Muraleedharan V et al
Eur J Endocrin 2013
581 men T2DM
F/u 5.8y
Low T defined <300ng/dl
(10.4 nmol/L)
Men with low T untreated
HR 2.3 (CI95% 1.3-3.5;
p=0.004)
T therapy- Reduced from
19.2% to 8.4% mortality
Normal T had 9% mortality
Testosterone and Cardiovascular
Disease
Vigen et al
JAMA 2013
Basaria et al
NEJM 2010
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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
•
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•
•
•
No randomization or placebo
No control group or clinical info
Health insurance database
90 days after start testosterone
•
•
Pre-prescription MI rate 3.48/1000
Post-prescription MI rate 4.75/1000
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
TRT Causes CVD
Finkle et al
PLoS One 2014
•
•
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
Xu Meta-Analysis
27 published RPC trials
2,994 mid-aged and older men
– 1,773 with TRT
– 1,261 with Placebo
Found TRT associated with increased risk
of CV adverse events
Just 2 studies provided 1/3 of all CV events
in the TRT arm
– If studies excluded no differences seen
Methodological issues limit conclusions
Xu L et al. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebocontrolled randomized trials. BMC Med, 11, 108. 2013
Corona Meta-Analysis
75 trials
3,016 with TRT
2,446 with Placebo
Mean treatment duration = 34 weeks
Study did not find significant increased risk
of CV events associated with TRT
Methodological issues that limit conclusion
Corona G, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert
Opin Drug Saf. 13(10), 1327-1351. 2014
FDA Drug Safety Communication
FDA Drug Safety Communication
– Required Label Changes
Clarify the approved uses of testosterone meds
Add information about a possible increased risk
of heart attacks and strokes in patients taking
testosterone
– FDA concerned about TRT to relieve symptoms
in men who have low T for no apparent reason
other than aging
– Requiring manufacturers of approved TRT
products to conduct well-designed trial
FDA Drug Safety Communication
TRT Approved for Use
– Primary Testis Failure
Genetics or Chemotherapy Damage
– Secondary Hypogonadism
Hypothalamus or Pituitary Failure
Safety and Efficacy of TRT for Age-Related
Hypogonadism not established
Diagnosis of Hypogonadism
– At least 2 separate morning lab tests
FDA Drug Safety Communication
Weigh potential risk of major adverse CV
outcome and other risks against benefit
for each patient
Inform patients of potential increased
CV risk
Encourage patients to read Medication
Guide
Report adverse events involving TRT to
FDA
TRT Objectives and Monitoring
Inadequate data exists to determine the optimal serum T
level for efficacy and safety; mid to lower young adult male
levels seem appropriate as the therapeutic goal; no
evidence exists for or against the need to maintain a
circadian rhythm
Monitoring should occur at 3-6 months during the first year
and annually thereafter, and include a careful clinical and
andrological evaluation (DRE, PSA, hematocrit, metabolic
parameters such as glycemia and lipid profile)
Bhasin S et al. J Clin Endocrinol Metab 95:2536-59, 2010.
Risk of Testosterone-Replacement Therapy
and Recommendations for Monitoring
Rhoden, Morgentaler N.E.J.M. 2004; 350: 482-492
Thank you for your attention…