Testosterone- Should we be considering it as a risk factor for CVD?

And should we be measuring & addressing it?

Professor Mike Kirby FRCP University of Hertfordshire & The

Prostate Centre London

Disclosures

• Professor Mike Kirby has received funding for research, conference

attendance, lecturing and advice from the pharmaceutical industry

including Astellas, Pfizer, Takeda, Bayer, Besins, MSD, BI, Lilly,

GSK, AZ, Ipsen and Menarini.

• Editor PCCJ

• Also on several NHS advisory boards including the Prostate cancer

Risk Management Programme and the Prostate Cancer advisory

Group

• Member of the National Prostate Cancer Audit Group

Hodges Kirby et al Int J Clin. Pract 2007;61:2019-25

In half the men there were missed opportunities

to assess CVD risk and treat to goal

“Men with ED should be specifically targeted for CVD

preventative strategies in terms of lifestyle changes and

pharmacological treatments” Nitrates!!

The temporal relationship between ED and CVD & why don’t men talk about it ?

• 207 CVD men attending cardiac rehab

• 165 age matched controls

• ED in 66% with CVD – discussed in 53%

• ED in 37% controls – discussed in 43%

• ED on average 5 years before CVD

Testosterone levels are lower at all ages in

Men with ED

0

5

10

15

20

25

30

18-35 35-55 56-70

Age Group

Te

sto

ste

ron

e (

nm

ol/

l)

Patient Control

Janini Int J Androl 1999 22 385-392

1400 men aged 40-49 ED associated with 50 fold risk of CAD

Age Group ED at baseline No baseline ED

40-49 48.52 (1.23-269.26) 0.94 (0.02-5.21)

50-59 27.15 (7.40-69.56) 5.09 (3.38-7.38)

60-69 23.97 (11.49-44.10) 10.72 (7.62-14.66)

70+ 29.63 (19.37-43.75) 23.30 (17.18-30.89)

Inman et al Mayo Clin Pr 2009

CAD events per 1000 pt years with CI interval

What is the difference between QRISK®3 and QRISK®2?

• QRISK®3 includes more factors than QRISK®2 to help enable doctors

to identify those at most risk of heart disease and stroke. • These are

• Chronic kidney disease, which now includes stage 3 CKD • Migraine • Corticosteroids • Systemic lupus erythematosus (SLE) • atypical antipsychotics • severe mental illness

• erectile dysfunction • a measure of systolic blood pressure variability

Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease:

prospective cohort study

BMJ 2017;357:j2099 doi: 10.1136/bmj.j2099 (Published 24 May 2017)

• Testosterone Deficiency Syndrome (TDS) is inadequate function of the testes

• Prevalence: Over 8% of men between age 50 and 79 years1

• Characterised by low serum testosterone (total testosterone <12nmol/l) + clinical symptoms2

– <8nmol/l - usually require treatment

– 8-12nmol/l – consider 3 months trial if appropriate or refer to specialist

• Prompt diagnosis, treatment or referral are key factors in avoiding serious long-term consequences for health

1. British Society for Sexual Medicine, Guidelines on the Management of Sexual Problems in Men:

the Role of Androgens 2010.

2. Wang C et al. Eur J Endocrinol 2008;159:507-514.

20%

31%

49%

Total T<8 nmol/L

Total T 8.0-12 nmol/L

Total T>12 nmol/L

T; Testosterone

1. Kapoor D et al. Diabetes Care 2007;30:911-917.

• 355 UK men (mean age, 58 yrs) with type 2 diabetes

51%

Testosterone

≤12 nmol/L

Less than 8nmol/L

8-12nmol/L

A self-perpetuating pathogenic cycle

Metabolic syndrome

Insulin resistance

Dyslipidemia

Arterial hypertension

Obesity

Hypogonadism

Depression

Other adverse

psychotropic effects

Osteoporosis

Anaemia

Late outcomes

Hyperinsulinemia/disturbed

Endothelial function

Type 2 diabetes mellitus

Cardiovascular events

Stroke

Erectile dysfunction

Hypothalamic-pituitary-

gonadal axis

Testicular

function Visceral

adipose tissue

+

+

+

+

+

-

+

Zitzmann Nature Endo Rev 2009

Insulin Inflammatory

cytokines

Leptin

Probability of Symptoms on the Basis of Levels of Total Testosterone

and Free Testosterone

Wu FCW et al. N Engl J Med 2010;363:123-135

0.75

0.50

0.25

0.00

Pro

babili

ty

0 10 20 30 40

Total testosterone (nmol/L)

Sexual symptoms and total testosterone

Decreased frequency of

morning erection Erectile dysfunction Decreased frequency of

sexual thoughts 11 nmol/L

8.5 nmol/L 8 nmol/L

0.75

0.50

0.25

0.00

Pro

babili

ty

0 10 20 30 40

Total testosterone (nmol/L)

Physical symptoms and total testosterone

Decreased vigerous

activity Difficulty walking >1km Decreased bending

13 nmol/L

0.75

0.50

0.25

0.00

Pro

babili

ty

0 10 20 30 40

Total testosterone (nmol/L)

Psychological symptoms and total testosterone

Fatigue Loss of energy Sadness

Hypogonadism – A combination of abnormal biochemistry and clinical symptoms

•DIMINISHED SEXUAL DESIRE

•ED

LOSS OF MORNING ERECTIONS

•Diminished energy

•Reduced vitality /well-being

•Increased fatigue

•Depressed mood

•Impaired cognition

•Diminished muscle mass and

Strength (3Kg of lean muscle/decade over 30)

•Diminished bone density

•Anaemia

•PATIENTS EXPECT BOTHERSOME

•SYMPTOMS TO BE TREATED!

•(NOT JUST STATISTICAL RISK)

Circadian rhythm of testosterone

1. Adapted from Diver M et al. Clin Endocrinol 2003;58:710-717.

15

12

10

8

0

Loss of libido p<0.001

Loss of vigour p<0.001

Obesity p<0.001

Feeling depressed p=0.001

Disturbed sleep p=0.004

Lack concentration p=0.002

Type 2 diabetes p<0.001

Hot flushes p<0.001

Erectile dysfunction p=0.003

N

84

65

67

75

Increasing

prevalence of

symptoms with

decreasing

androgen

concentrations

Zitzmann M et al. JCEM 2006;91:4335-4343.

Total testosterone nmol/L

MM Shores Arch Int Med 2006 166 1660-5

Testosterone and Survival

Benefits of Testosterone Replacement

• Increases lean body mass

• Decreases fat mass

• Increases muscle strength

• Increases libido

• Increases well being

• Decreased total cholesterol, LDL cholesterol and triglycerides

• Increases bone mineral density

• (Restores fertility)

The estimated mortality probability and 95% CI from the fitted logistic regression: Men on all and none of the above treatments

Not on any treatment Not on any treatment + 95% CI Not on any treatment – 95% CI All 3 treatments All 3 treatments + 95% CI All 3 treatments – 95% CI

World Journal of Diabetes 2017 March 15; 8(3): 104-111

Multivariate Regression model for risk of mortality (N=7860): (Anderson et al Heart 2016 )

21

Adjusted HRs and 95% CIs for the association between treatment for erectile

dysfunction, compared with no treatment for erectile dysfunction, and

outcomes after a first myocardial infarction in : 43,145 men.

Daniel P Andersson et al. Heart doi:10.1136/heartjnl-2016-

310746

Copyright © BMJ Publishing Group Ltd & British Cardiovascular Society. All rights reserved.

Dose dependent effect

How would the recognition of ED and low T work when integrated into current screening regimes?

• Matthew is 52 and has not seen a doctor for 22 years. He has become tired and lethargic and has given up physical activity, for over 5 years because of reduced strength and endurance.

• He is now longer engaging in any sort of physical activity. He feels tired at work as a factory worker and often needs to sleep in the afternoon. He falls asleep easily and has not initiated sex for 3 years and has lost his morning erections.

• His wife Tracy is concerned and makes an appointment for him to have an over-40 medical check

• He sees his GP, who takes his history • but does not ask about his erections or sexual function. • Matthew is too embarrassed to raise the issue as his doctor is running late and seems stressed. Some routine measurements and blood tests are arranged.

Matthew - Results • Weight 101 Kg, BMI 28kg/m2. Waist 102cms

• Total Cholesterol 6.6 LDL-Cholesterol 5.4, HDL-cholesterol 0.95 mmol/l TGs 2.78mmol/l. HbA1c 46mmol/mol.

• The data used in the JBS3 calculator confirms that he has a heart age 60 with a 4.7% 10 year risk of a cardiovascular event. He has metabolic syndrome and pre-diabetes.

• An exercise and dietary regime is advised with follow up in 3 months.

• Matthew returns home and tells his wife that the doctor said that he is “overweight”, but his heart is not too bad.

• He decides not to attend for the follow-up visit

Highest risk of mortality

• Had the GP asked about his erections, she would have found that he had severe ED with a SHIM score of 7.

• This would have led to mandatory measurement of his testosterone level which would have shown a level of 7.2 nmol/l with SHBG 19nmol/l. LH 2.0 iu/l.

• This would have led to the recognition that his multiple symptoms were due to testosterone deficiency.

• Traditional teaching that men such as Matthew should be managed by weight loss in the first instance

• A recent RCT showed that men treated with diet alone lose lean substantial lean muscle mass compared with men

treated with diet plus testosterone.

Fui MNT, Prendergast LA, Dupuis P. et al Effects of testosterone treatment on body fat and lean mass in obese men on a hypocaloric diet: a randomised controlled trial BMC Medicine 2016; 14:153 DOI: 10.1186/s12916-016-0700-9

Preservation of lean muscle is an important component in cardiovascular performance and in the prevention of frailty in ageing

men (Kloner).

As loss of physical strength was a major complaint, the optimal treatment for George would be lifestyle advice, testosterone therapy

plus a PDE5 inhibitor and a statin, as the presence of ED increases risk by 50% ( Araujo).

Recognition and treatment of his ED would also guarantee attendance at follow –up medical assessments.

Kloner RA, Carson C 3rd, Dobs A, Kopecky S, Mohler ER 3rd. Testosterone and Cardiovascular Disease. J Am Coll Cardiol. 2016; 67 (5): 545-57. Araujo AB, Hall SA, Ganz P, et al. Does erectile dysfunction contribute to cardiovascular disease risk prediction beyond the Framingham Risk Score? J Am Coll Cardiol. 2010; 55(4): 350-356.

The Pleomorphic effects of testosterone on Cardiovascular risk and Frailty.

Total T Free T

Consider trial of treatment if other causes

of symptoms have been excluded

8 nmol/L*

12 nmol/L* 225 pmol/L*

180 pmol/L*

Testosterone substitution required

Testosterone substitution not required

BSSM and ISSM 2017

Thresholds for T Therapy

Regarding the thresholds for treatment intervention in symptomatic men, BSSM and ISSM guidelines recommend the following:

• TT level <8 nmol/L or FT <180 pmol/L (<0.180nmol/L) (based on two separate 8–11 am levels), usually requires T Therapy • TT level >12 nmol/L, or FT of >225 pmol/L (>0.225nmol/L), does not require T Therapy • Levels between 8-12nmol/L may require a trial of T Therapy for a minimum of 6 months, based on symptoms (LoE = 3, Grade = C )

Additional recommendations include:

• Raised LH levels and testosterone below normal or in the lower quartile range, indicates testicular failure, so T Therapy should be considered

• Raised LH levels in men with normal testosterone levels but symptoms of TD, should be considered as TD

• Recent data from EMAS found that clinical symptoms were more closely related to calculated free testosterone (cFT). (LoE 2 Grade = B)

• T Calc for Free T

Treatment Risks • Serious adverse events related to T Therapy are relatively rare. They are more

significant in elderly patients and often dependent on the method of delivery.

• The intramuscular injections , (monthly or 3 monthly) are associated with pain at the injection site, changes in mood, energy and sexual desire, and rarely, coughing straight after the injection

• Transdermal gels carry a risk of interpersonal transfer, skin irritation and fluctuations in absorption.

Follow Up

For risk reduction programmes to be practical, consideration should be given to factors that are relevant, easily assessed and measured, be quantifiable and be modifiable.

There is now strong evidence that both ED and testosterone deficiency fulfil these

criteria and that both should, at the very least, now be considered as predisposing risk factors for cardiovascular disease.

ED and low testosterone are symptomatic conditions that patients would expect to be fully assessed and treated. Motivation to comply with ED and T therapy is relatively high, in contrast with other risk factors modification regimes. The reality is that, unless risk “markers” are not reclassified as “risk factors” then they will not be seen as relevant in every day practice. These issues are particularly important in younger men where current risk calculators are

of less value.

Conclusions

Less heart attacks & less strokes

Lower pulse rate

Lower BP

Longer marriage & Less divorce

Longer life

Take Home Message

Sexual activity

Global CV Risk Perspective

Vascular Disease is an Interplay of Risk Factors

Poulter N. Am J Hypertens. 1999;12:92S-95S.

age sex

Lipids BP

DM

smoking

ED LOW

T

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