Androgens and CVD. Brandon Orr- Walker April 2014

Transcription

1 Androgens and CVD Brandon Orr- Walker April 2014

2

3 Agenda What is normal physiology of Aging? Hypogonadism and disease If some is good is more becer? CVD safety

4

5

6 Clinical features of Androgen Deficiency If testosterone deficiency occurs during the first trimester, male sexual differenjajon may be incomplete. Complete lack of testosterone during this period results in female external genitalia (clitoris and labia). Incomplete testosterone deficiency causes parjal virilizajon, ranging from posterior labial fusion when the deficiency is severe to hypospadias when it is mild. If testosterone deficiency occurs during the third trimester, cryptorchidism and/or micropenis may result. Failure to undergo or complete puberty indicates deficient testosterone secrejon. Symptoms that could indicate hypogonadism in an adult male are decreases in energy, libido, muscle mass, and body hair, as well as hot flashes, gynecomasja, and inferjlity.

7

8

9 Hypogonadism And disease And as a risk marker..

10

11

12 Update: Hypogonadotropic Hypogonadism in Type 2 Diabetes and Obesity 25% of men with type 2 diabetes have subnormal free testosterone concentrajons in associajon with inappropriately low LH and FSH concentrajons. Another 4% have subnormal testosterone concentrajons with elevated LH and FSH concentrajons. The Endocrine Society, therefore, now recommends the measurement of testosterone in pajents with type 2 diabetes on a roujne basis. The subnormal testosterone concentrajons are not related to glycosylated hemoglobin or durajon of diabetes, but are associated with obesity, very high C- reacjve protein concentrajons, and mild anemia. In addijon, subnormal testosterone concentrajons in these men are associated with a two to three Jmes elevated risk of cardiovascular events and death in two early studies. Short- term studies of testosterone therapy in hypogonadal men with type 2 diabetes have demonstrated an increase in insulin sensijvity and a decrease in waist circumference. However, the data on the effect of testosterone replacement on glycemic control and cardiovascular risk factors such as cholesterol are inconsistent. As far as sexual funcjon is concerned, testosterone treatment increases libido but does not improve erecjle dysfuncjon and thus, phosphodiesterase inhibitors may be required. Trials of a longer durajon are clearly required to definijvely establish the benefits and risks of testosterone replacement in pajents with type 2 diabetes and low testosterone. (J Clin Endocrinol Metab 96: , 2011)

13 Hypogonadism CVD and other morbidity a therapeujc agenda? MulJple studies show relajonship of low Te and CVD and cancer mortality (with or without adjustment) RaJonale for androgen replacement has been suggested (e.g. improved lean mass reduced fat mass, improved funcjonal status)

14

15 Hypogonadism CVD and other morbidity a therapeujc agenda? MulJple studies show relajonship of low Te and CVD and cancer mortality (with or without adjustment) RaJonale for androgen replacement has been suggested (e.g. improved lean mass reduced fat mass, improved funcjonal status)

16 CVD Safety No Large dbpc RCT (like WHI) Other benefits in truly hypogonadal men, and risks (eg erythrocytosis, OSA, prostajc hypertrophy) Meta- analysis of 51 trials Mixed criteria, age, including younger HIV posijve men No increased CVD events, including subgroup aged >65 years

17 CVD Safety In older men 2 RCTS both very short durajon: Testosterone in Older Men with Sarcopenia (mean age 74 years) Stopped early because of self- reported CVD events (unspecified outcome) NEJM :109 intermediate frail and frail elderly men Physical funcjon, body composijon etc No excess CVD events JCEM :639

18 CVD Safety 209 Community- dwelling men, 65 years of age or older, with limitajons in mobility and a total serum testosterone level of 3.5 to 12.1 nmol per liter or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular- related adverse events. As compared with the placebo group, the testosterone group had significantly greater improvements in leg- press and chest- press strength and in stair climbing while carrying a load The data and safety monitoring board recommended that the trial be disconjnued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. NEJM :109

19 CVD Safety ParJcipants: community- dwelling intermediate- frail and frail elderly men at least 65 yr of age with a total T at or below 12 nmol/liter or free T at or below 250 pmol/liter. Two hundred seventy- four parjcipants were randomized to transdermal T (50 mg/d) or placebo gel for 6 months. Results: Isometric knee extension peak torque improved in the T group (vs. placebo at 6 months), adjusted difference was 8.6 (95% confidence interval, ; P = 0.02) Newton- meters. Lean body mass increased and fat mass decreased significantly in the T group by /- 1.8 and 0.9 +/- 1.6 kg, respecjvely. Physical funcjon improved among older and frailer men. SomaJc and sexual symptom scores decreased with T treatment; adjusted difference was (- 2.4 to ) and (- 2.5 to - 0.2), respecjvely. JCEM :639

20 2 Recent RetrospecJve cohort studies 1. Veterans Affairs 2. Truven Health Calims database

21 1. Veterans Affairs Men undergoing coronary angiography Subsequent Te measurement Te <10.41nmol/l 8709 of who, 1223 started treatment Untreated 681 deaths, 420 MI,486 CVA Treated 67 deaths, 23 MI, 33 CVA Kaplan- Meier esjmates at 3 years 19.9% vs 25.7% event, hazards model adjusjng for baseline CAD Te was associated with increased risk HR 1.29 (95% CI ) Effect size unrelated to baseline CAD presence

22 1. Veterans Affairs 1/3 on injectable Te Mean age 63 years, 13 % normal coronaries, 58% obstructed FU 27.5 months LiCle informajon about whether Te prescribing was appropriate or not (per guidelines) JAMA (17)

23 2. Truven Health N=55,000 men first prescripjon for Te F/U 90 days Compared with rate of MI in year before precripjon, and with N=167,00 filling first script for PDE5 inhibitor (eg Cialis) Increased RR MI of 1.36 ( ) compared with preprecripjon RR 1.90 ( ) cf PDE5inh

24 2. Truven Health Mean age 55, 10% prevalent IHD Overall event rate 1.25 cases per 1000 pajent years Increased risk in those <65 only with history of IHD (RR 2.07, absolute event excess 10 cases per 1000 pajent years)

25 We await Testosterone Trial in Older Men (n=800 >65 years, 1 year)

26 Case Mr B a 55 year old office worker approaches you with his wife and idenjfies diminished libido as an issue. He is on no treatment, slightly overweight and has no personal or past relevant personal history. Exam is NAD

27 Case Mr B a 55 year old office worker approaches you with his wife and idenjfies diminished libido as an issue. He is on no treatment, slightly overweight and has no personal or past relevant personal history. Exam is NAD He wonders if testosterone could be a problem You agree to measure it Te = 12

28

29 Case Mr B a 55 year old office worker approaches you with his wife and idenjfies diminished libido as an issue. He is on no treatment, slightly overweight and has no personal or past relevant personal history. Exam is NAD He wonders if testosterone could be a problem You agree to measure it Te = 7

30 n.b 200 ng/dl = 6.94

31 How to do it? Make a diagnosis. IdenJfy rajonale to treat Only treat hypogonadal man with signs/ symptoms Establish safety to inijate Choice of agent therapeujc trial Review therapeujc trial Choice of long term agent Monitoring, conjnuing treatment.

32

33

34

35

36 Measuring testosterone Measurement of the serum total testosterone concentrajon is usually an accurate reflecjon of testosterone secrejon. The normal range in most laboratories is about 300 to 800 ng/dl (10-28 mmol/l). Measurement of the serum free testosterone concentrajon is worthwhile only when it is suspected that an abnormality in testosterone binding to sex hormone- binding globulin coexists with hypogonadism. The two most common situajons of abnormal testosterone binding are obesity, which reduces binding in proporjon to the degree of obesity, and male senescence, which increases binding slightly Serum free testosterone should be performed by equilibrium dialysis and only in those few laboratories that specialize in endocrine tesjng. The free testosterone concentrajon, as calculated from the total testosterone, SHBG, and albumin concentrajons, may also be reliable, but there are many different equajons for this calculajon and they give vastly different results, some of which reflect the results obtained by equilibrium dialysis becer than others Bioavailable testosterone, i.e., the total of free testosterone and that bound weakly to albumin, which is not precipitated by ammonium sulfate, also appears to accurately reflect androgen status. While most commercially available total testosterone assays are able to disjnguish eugonadal from hypogonadal states in males, they are oten not sufficiently sensijve or accurate for measurement of serum testosterone concentrajons in females or prepubertal children InterpretaJon of serum testosterone measurements in young men should take into considerajon its diurnal fluctuajon, which reaches a maximum at about 8 AM and a minimum, approximately 70 percent of the maximum, at about 8 PM