Health Ed Brisbane Saturday 27th Outline Cardiovascular ... · Lose weight → testosterone rises...

1

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


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%


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





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





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


hypogonadism





T treatment associated with increased, decreased or unchanged risk

Inconclusive Cardiac Effects of T Treatment in Retrospective Database Analyses

Shores AJA 2018

8

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


hypogonadism





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

9

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


hypogonadism





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

10

“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

• Resources– Clinical Summary Guides on male reproductive health

– Patient resources

– Orchidometer

– Position statements and guidelines

• Support– Accredited online education (GPs, Nurses & other HPs)

– A&TSI health education (GPs, Nurses, AHWs)

– Speakers for health professional events

• Activities– Presenting and attending professional conferences

• Future doctors– Andrology training

Health professionals Clinical summary guides

Health Ed Brisbane Saturday 27th Outline Cardiovascular ... · Lose weight → testosterone rises...

Documents

Transcript of Health Ed Brisbane Saturday 27th Outline Cardiovascular ... · Lose weight → testosterone rises...