Post on 11-Oct-2020
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Cardiovascular Risk and Testosterone
Fact vs Fiction
Professor Robert I McLachlan AM, FRACP, PhD
Hudson Institute of Medical Research, Monash University
Department of Endocrinology, Monash Health
Director, Andrology Australia
Consultant Andrologist, Monash IVF Group
Health Ed Brisbane Saturday 27th October 2018
Outline
1. Background: organic vs ‘late onset’ hypogonadism
2. CV risk: current evidence and limitationsEpidemiological studies
Retrospective prescription database studies
Randomised controlled trials
3. Practical implications
Courtesy of
H. Newnham,
Melbourne
Eugonadism Organic Hypogonadism*Fatigue, Low libido, Erectile dysfunction
Infertility, Small testes
Height lossSpinal fractures
Osteoporosis
Muscle Wasting
Central
Adiposity
Diabetes
Preservation
of scalp hair
Gynecomastia
Loss of body hair
Weakness
disease of hypothalamic-
pituitary-testicular axis
‘Classic’ Testosterone Deficiency
Defined testicular or hypothalamo-pituitary disease
Can occur at all ages
• Testis failure - 95%
• Pituitary failure - 5%
Testosterone replacement is marvellous
Restores all the things testosterone does
Classic Androgen deficiency
Primary (high LH) impaired testis function
Secondary (low LH) hypothalamo-pituitary
2
Classic Androgen deficiency
Primary (high LH) impaired testis function
Klinefelter’s syndrome
Infertile men
Testicular damage vascular, cancer Rx
Secondary (low LH) hypothalamo-pituitary
Prolactinoma
Iron deposition
Kallmann’s syndrome
Commonest chromosomal disorder 1:600 males
Commonest cause of undiagnosed androgen deficiency
Almost all androgen deficient as adults: benefit from TRT
Only 25-50% Klinefelter’s are diagnosed in their lifetime
Bojesen JCEM 2003; Herlihy MJA 2011
Detection strategies a major challenge
Reject your stereotypical images of KS
Klinefelter’s Syndrome – 47XXY
From: Nieschlag and Behre, 2007
gynecomastia
abdominal obesity
small testes
reduced body hair
horizontal pubic
hairline
varicose veins
narrow shoulders
Classical KS
in textbooks
Profound learning
difficulties
From: Nieschlag and Behre, 2007
abdominal obesity
small testes
reduced body hair
horizontal pubic
hairline
varicose veins
narrow shouldersNot always!!
may appear entirely normal and adequately virilised when
clothed
Classical KS
in textbooks
Profound learning
difficulties
gynecomastia <50%
From: Nieschlag and Behre, 2007
gynecomastia
abdominal obesity
small testesr volume
reduced body hair
horizontal pubic
hairline
varicose veins
narrow shoulders
Classical KS
in textbooks
Profound learning
difficulties
~12,000 missed KS males in USA
Failure to systemically examine male genitalia : flaw
in education & practice
Klinefelter’s syndrome: The most overlooked cause of
androgen deficiency. St John B & McLachlan RI
Endocrinology Today 2015; 4(1): 8-14
Physical examination is pivotal
Courtesy of M Zitzmann, Munster
The testis is the most accessible endocrine organ
3
Testosterone replacement in men with organic hypogonadism has marked benefits*
Serum Testosterone
3.5 nmol/L
Sexual Function
+40% +20%
Energy
Hemoglobin
+2g/dl
Muscle Mass
+3kg
Fat Mass
-2kg
+7.5%
Bone Density
Think of hypogonadism:
e.g. unexplained
psychosexual complaints,
osteoporosis, anemia, sarcopenia *except fertility
Serum Testosterone
25 nmol/L
Aging and Hypogonadism
have Overlapping Features
Grossmann et al, JCEM 2008
Testosterone Levels Decline
Gradually During Male Aging
1. Is low testosterone causally related to the aging phenotype?
2. Is testosterone therapy in aging men beneficial or harmful?
Central Adiposity, Muscle Wasting, Osteoporosis
‘Late Onset Hypogonadism’
Largest Testosterone RCT: 790 men randomized for 12 months Snyder NEJM 2016
Controversy: androgens in health & aging
Low testosterone levels are common
Is this a pathological states in which androgen Rx is effective
and safe?
‘Age-related’... or ‘Late onset hypogonadism (LOH)’
‘Andropause’
‘Low T’
“Obesity-related HH’
Massive increase in testosterone prescribing
USA - 9 fold over 2000-2011
WHY?
Recognition of real entity
or
Wishful thinking + marketing (direct to consumer)
T
Symptoms
Age
1
2
Barometer of
Health
hypothesis
2
1 2
1
Andropause
hypothesis
Disease
1 2
Courtesy D Handelsman
4
>60%
population
Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)
European Male Aging Study (EMAS) Relationship between Age and Testosterone in 3220 Men
40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79
ng/ml
5.8
4.6
3.5
Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)
European Male Aging Study (EMAS) Relationship between Age and Testosterone in 3220 Men
40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79
BMI <25
BMI 25-29
BMI ≥30
ng/ml
5.8
4.6
3.5
Healthy Man Study
Sartorius G et al Clin Endocrinol 2012 ;77:755
Serum T did not
vary with age
Serum T
>60%
population
Lose weight → testosterone rises
Successful weight loss combined with
optimization of comorbidities can be sufficient to
Improve symptoms
Normalize testosterone levels and
Reduce cardiovascular risk
in men with “Late Onset Hypogonadism”
30% 9nM
10% 3nM
5
‘Symptomatic’ diabetic with low serum T, normal LH and replete with co-morbibities, CV risk
• Lifestyle• Diet• Exercise
• Medical • diabetes, hypertension, cholesterol
• Psychosexual issues• Judicious use of PDE5 inhibitors
T
Symptoms
Age
2
Barometer of
Health hypothesis
2
2
Disease
2 A
2 B
T
Symptoms
Age
2
Barometer of
Health hypothesis
2
2
Disease
2 A
2 B? Testosterone
as adjunct
in management
Risks and benefits of TRT in middle aged and older men with low T and co-morbidities
Placebo-controlled RCT data is limited…
Testosterone Trials: 7 coordinated trials of T treatment in elderly men
• Cauley JA et al J Gerontol A Biol Sci Med Sci. 2015 Sep;70(9):1105
• Snyder PJ et al. Clin Trials. 2014;11:362
• Abd alamira M et al Coron Artery Dis. 2016 ; 27: 95
• Snyder PJ et al; N Engl J Med. 2016;374:611
• Resnick SM et al JAMA 2017 ;317:717
• Snyder PJ et al JAMA Intern Med. 2017 ;177:471
• Budoff MJ et al JAMA. 2017 ;317:708
T Trial population
• Men > 65 years
• Serum total T <9.5nM
• One or more symptoms potentially related to low testosterone
6
What to do know about the impacts of testosterone
on such men?
Physical Function Trial
Sexual Function Trial
Vitality Trial
Cognitive Function Trial
Anemia Trial
Cardiovascular Trial
Bone Trial
Testosterone target range 18-27nM 500-800 ng/dL
USA ‘T Trials’ placebo–controlled RCT ~800 men
Snyder P Clin Trials 2014, 11:362
Outcomes of T Trial in Aging (co-morbid) Men
Sexual Function - Modest & transient benefits in some aspects
ED: PDE5 inhibitors are more effective.
Cognition and memory - not improved
Vitality and fatigue - in the vitality trial sub study -no benefits
Physical function - some benefits in some testing procedures
Bone - density improved: not compared to established therapies
Medication Adherence to Topical Testosterone Therapy:
Schoenfeld MJ et al J Sex Med 2013;10:1401
15,435 hypogonadal men
Persistence = time to last script OR gap of >30 days OR to at 12 months.
6 months, 34.7% 12 months, 15.4%.
Over time, dose escalation ~ 50% of men resumed therapy
Conclusions. High discontinuation rates irrespective of age, diagnosis, and index dose.
Outline
1. Background: organic vs ‘late onset’ hypogonadism
2. CV risk: current evidence and limitationsEpidemiological studies
Retrospective prescription database studies
Randomised controlled trials
3. Practical implications
Lack of adequately
designed and powered
randomized controlled
clinical trials with
cardiovascular events
as the primary outcome
Current data inconclusive, confusing & contradictory
due to inherent limitations of existing studies
Testosterone and CV Risk
Outline
1. Background: organic vs ‘late onset’
hypogonadism
2. CV risk: current evidence and limitationsEpidemiological studies
Retrospective prescription database studies
Randomised controlled trials
3. Practical implications
7
Percentage of Diabetic
Men with Low* TestosteroneMelbourne Cohort (n=580)
In Men with Type 2 Diabetes Low Testosterone is Common
and Associated with an Adverse Cardiovascular Risk Profile
Diabetic Men with Low
Testosterone have
Increased
ObesityInsulin
Resistance
Dyslipidemia Inflammation
%
Grossmann et al, JCEM 93:1834, 2008
*Relative to reference ranges based on healthy young men
HOMA-IR
Low Testosterone Independently Predicts
Mortality in Men with Type 2 DiabetesMelbourne Cohort: 572 men with T2D: Age 66 y, BMI 29.2 kg/m2, Total T 10.5 nmol/L, HbA1c 7.3%
Observation Time (years)206
247
119
197
229
108
191
212
93
162
182
66
181
196
79
Numbers
at risk
0 2 4 6 8
100
80
60
40
20
Su
rviv
al
(%)
*
Free Testosterone (normal range > 230 pmol/L)
>230 pmol/L
>160-230 pmol/L
<160 pmol/L
p<0.001*
*independent of age, BMI, micro- and macro-vascular disease, duration of T2DM,
hemoglobin, CRP, renal function, HOMA-IR Tint et al, Eur J Endocrinol 2016
Cardiovascular mortality p=0.001
Dr. Aye
TintDr. Emily
Gianatti
1.25 (0.97-1.60)1.35 (1.13-1.62)
Mortality
IncreasedDecreased
No effect
Meta-Analysis of Epidemiological Studies:Low serum testosterone predicts increased mortality
16,184 community-dwelling men (US, Europe) mean age 61 years, 9.7 years follow-up
All-Cause Mortality Cardiovascular Mortality
Araujo et al, JCEM 2011
‘between study heterogeneity suggests that
low testosterone may be a marker of poor health’
Non-causation: low T and poor health share common risk factors
Causation: low T poor health
Reverse causation: poor health low T + earlier death
Observational studies-by design-can never prove causality
Outline
1. Background: organic vs ‘late onset’
hypogonadism
2. CV risk: current evidence and limitationsEpidemiological studies
Retrospective prescription database studies
Randomised controlled trials
3. Practical implications
T treatment associated with increased, decreased or unchanged risk
Inconclusive Cardiac Effects of T Treatment in Retrospective Database Analyses
Shores AJA 2018
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T treatment associated with increased, decreased or unchanged risk
Inconclusive Cardiac Effects of T Treatment in Retrospective Database Analyses
Limitations
Inadequate outcome validation
incomplete covariate ascertainment
confounding due to lack of randomisation: e.g. preferential
treatment of healthier men
? indication for T treatment dose and duration
?hypogonadal symptoms
Baseline and on treatment T levels
Outline
1. Background: organic vs ‘late onset’
hypogonadism
2. CV risk: current evidence and limitationsEpidemiological studies
Retrospective prescription database studies
Randomised controlled trials
3. Practical implications
Small number and broad array of “cardiovascular-related” events*
RCT not powered to evaluate cardiovascular events
n=23 Testosterone
TOM trial:
RCT older men
with preexisting
cardiovascular
Disease
N = 209; age 74 y
Basaria et al, NEJM 2010
n=5 Placebo
Increased Risk of
CVS events
with Testosterone
*including oedema, blood pressure increase, arrhythmia, self reported chest pain & syncope
Men (n)
Treated
Untreated
CV events (n)
Treated
Untreated
Xu1 1733
1261
115
65
Haddad2 161
147
14
7
Calof3 651
433
18
16
Albert4 3019
2290
116
91
Corona5 1895
1341
31
20
Fernandez-
Bassels6715
456
47
30
1BMC Med 2013; 2Mayo Clin Proc 2007; 3J Geront A Biol Sci Med Sci 2005; 4Clin Endo 2016; 5Expert Opin Drug Safety 2014; 6JCEM 2010
Limitations of RCTs: low number of events, CVD events heterogeneous,
RCTs small, short-term, not designed or powered for CVD outcomes,
heterogenous populations/ inclusion criteria
Inconclusive Cardiac Effects of T Treatment in
Meta-Analyses of RCTs in Older Men
Odds ratio (95 CI%)
Increased Risk in the first 12 months of T treatment
• Labeling change to inform of possible increased risk
of heart attacks and strokes with testosterone therapy
• Labeling change to clarify that testosterone therapy
approved only for medical disorders of the HPT* axis
• Benefit and safety not established for the treatment of
low testosterone levels due to aging *hypothalamic-pituitary-testicular
see also
ESA Position statement
Yeap et al MJA 2016
PBS testosterone prescribing
criteria (updated 2015)
Testosterone Treatment: Risks?• No definitive outcome data regarding long-term CV events
• Non-randomized studies (epidemiologic, prescription database)
-Subject to confounding, bias and reverse causality
• Existing RCTs: Underpowered, short-term, CVD events not pre-specified
Need > 10,000 men
• No evidence for risk if testosterone 1) for approved indications (organic hypogonadism)* 2) contraindications observed*3) treatment monitored in line with guideline recommendations*
• Possibly increased CVS risk: Older men (>65 years) within the first few months after testosterone initiation, especially if pre-existing cardiovascular disease
*Yeap et al, MJA 2016
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Testosterone Treatment: Risks?• No definitive outcome data regarding long-term CV events
• Non-randomized studies (epidemiologic, prescription database)
-Subject to confounding, bias and reverse causality
• Existing RCTs: Underpowered, short-term, CVD events not pre-specified
Need > 10,000 men
• No evidence for risk if testosterone 1) for approved indications (organic hypogonadism)* 2) contraindications observed*3) treatment monitored in line with guideline recommendations*
• Possibly increased CVS risk: Older men (>65 years) within the first few months after testosterone initiation, especially if pre-existing cardiovascular disease
*Yeap et al, MJA 2016
Outline
1. Background: organic vs ‘late onset’
hypogonadism
2. CV risk: current evidence and limitationsEpidemiological studies
Retrospective prescription database studies
Randomised controlled trials
3. Practical implications
Testosterone Treatment and Vascular Risk:
Clinical Implications
• No evidence that testosterone replacement
in men with organic^ hypogonadism is harmful: testosterone
maintain virilisation and optimal health*.
• Vascular risk an important factor in decision making in men
without organic hypogonadism#:especially if pre-existing CV disease or risk of venous thromboembolism
^established organic hypothalamic-pituitary-testicular axis pathology
*unless fertility desired
#Routine T treatment in ‘Late Onset Hypogonadism’ not recommended by Australian Guidelines
(Yeap et al MJA 2016) or by the US Federal Drug Administration (FDA)
Concern Testosterone effect 1st line therapy
Sexual Modest increase in overall function,
if TT<9.5-12nmol/L1,2. Libido > erectile function.PDE5 inhibitor No added benefit of T3
Muscle 1.6-2.7 kg increase in mass4
Modest performance rise in some RCTs5,6
Exercise
Fat 1.6 to 2.0 kg decrease7 Weight loss
Glucose Modest fall in insulin resistance. No fall HbA1c8 Lifestyle, anti-diabetic medications
Bone 2-7% increase in BMD lumbar spine9 Anti-resorptives
Mood/Cognition
No consistent effects1,10 e.g. Counseling, anti-depressants
Testosterone Treatment: Benefits in older men with low T
Not powered for clinically important health outcomes:
mortality, quality of life, physical function, falls or fractures
1Isidori Clin Endo 2005a; 2Snyder NEJM 2016; 3Spitzer Ann Int Med 2012; 4Bhasin NCPEM 2006; 5Basaria NEJM 2010; 6Srinivas-Shankar JCEM 2010 7Isidori Clin Endo 2005b; 8Grossmann Clin Endo 2015; 9Snyder JAMA Int Med 2017; 10Snyder NEJM 2016
Take Home Messages (1)
◼ Underdiagnosed and undertreated
◼ Benefits of testosterone replacement clearly outweigh
cardiovascular (and other) risks
◼ Think of hypogonadism: e.g. unexplained psychosexual
complaints, osteoporosis, anemia, sarcopenia
Organic Hypogonadism
Take Home Messages (2)
◼ In older men, low T is often a marker of poor health →
holistic focus on lifestyle and optimization of comorbidities
◼ Long term risks of T treatment are unknown: some evidence for
increased CV risks, esp. with pre-existing CVD
◼ Benefits of T treatment are relatively modest:
the benefit : risk profile is overall unconvincing
◼ Current Australian guidelines* recommend against T treatment
(more research)
Older men ‘Late Onset Hypogonadism’ =
Chronic disease-associated low testoterone
* Yeap et al, MJA 2016
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“Men with organic hypogonadism^ should be identified and
given testosterone replacement*, but further research is
needed to clarify whether there is a role for testosterone in
other settings” (such as ‘late onset hypogonadism’)
15 August, 2016; part 2; 5 Sept, 2016
*unless fertility is desired^medical disease of the hypothalamic-pituitary-testicular axis
such as pituitary tumor, Klinefelter’s ect.
www.andrologyaustralia.org
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