NEW DEVELOPMENTS: T & CVD FDA & THE T TRIALS

2017 UPDATE FDUS Martin Miner MD Clinical Professor of Family Medicine and Urology Co-Director The Men’s Health Center The Miriam Hospital Warren Albert School of Medicine Brown University Providence, RI

NY TIMES EDITORIAL 2/5/14

¡   “substantial risks in prescribing testosterone to middle-age & older men for a variety of ailments.” “testosterone doubled the risk of CV disease in more than 7,000 men who were 65 years +” “testosterone tripled risk of heart attacks in a group of more than 48,000 middle-age men with previous histories of heart disease.”

¡   “the study provides the most compelling evidence yet that many American men have embarked on a perilous course of overtreatment “

¡   “testosterone is now being prescribed to men who are simply reluctant to accept the fact that they are getting older. “

A Firestorm!!!

¡   T levels decline with age = Normal Aging ¡   Secondary Hypogonadism = symptoms = Disease Mongering

§  “...loss of energy, libido and spontaneous erections, and ED” §  Is hormone repletion without long-term safety studies appropriate?

¡   T Trials: §  Included older men with declining levels for “no apparent reason other

than age” §  Obesity 62%; HTN 72%; h/o of MI 15%; DM 37% §  Target levels were the normal range for men age 19-40 years (280-873

ng/dL) a numerical endpoint, not consistent with clinical practice focused on symptom relief

§  Goal: to implement the IOM 2003 recommendation- coordinated set of clinical trials to determine efficacy of T therapy in older men with low levels for no other reason than age.

WHAT IS TESTOSTERONE DEFICIENCY?

FDA ADVISORY BOARD (SEP 17, 2014)

¡   Voted in favor for the FDA to impose stricter limitations on the T drug industry, particularly the language in product labels; this would clarify the appropriate therapeutic indications for TRT.

¡  With regards to the risk of CV events, the panelists confirmed that “evidence linking T therapy to an increased risk of heart attack, stroke & death is ‘inconclusive.”

¡   The panel further advised that the FDA should require drug manufacturers to conduct comprehensive studies to better assess the potential cardiovascular risks with TRT.

0 20 40 60 80

100

20-29 30-39 40-49 50-59 60-69 70-79 80+

Total Testosterone <11.3 nmol/L (325.6 ng/dL) Free Testosterone Index <0.153 Total T/SHBG

Prop

ortio

n of

Pat

ient

s (%

)

Age Harman SM et al. J Clin Endocrinol Metab. 2001;86:724-731.

Testosterone: Age Trends

12%-20%

28%

49%

Longitudinal Study: 890 healthy men with the comorbidities of aging

IS A LOW SERUM TESTOSTERONE LEVEL

ASSOCIATED WITH CARDIOVASCULAR RISK

FACTORS?

Query #1

PREVALENCE OF MAJOR RISK FACTORS FOR HYPOGONADISM

Risk Factor Hypogonadism*

Prevalence (95% CI)

Odds Ratio (95% CI)

Obesity 52.4 (47.9-56.9) 2.38 (1.93-2.93)

Type 2 diabetes 50.0 (45.5-54.5) 2.09 (1.70-2.58)

Hypertension 42.4 (39.6-45.2) 1.84 (1.53-2.22)

Hyperlipidemia 40.4 (37.6-43.3) 1.47 (1.23-1.76)

Asthma or COPD 43.5 (36.8-50.3) 1.40 (1.04-1.86)

Prostate disease 41.3 (36.4-46.2) 1.29 (1.03-1.62)

Overall Prevalence of Biochemical Hypogonadism in Clinical Practice: 38.9% HIM Study N = 2085 Presenting to the physician for any problem

Adapted from Mulligan T, et al. Int J Clin Pract. 2006;60:762-769. *Total Testosterone (TT) < 300 ng/dl] 

LOW SERUM TESTOSTERONE AND MORTALIT Y IN MALE VETERANS

¡   N=858 men > age of 40 ¡   Low T = total T < 250 ng/

mL §   < 8.7 nmol/L

¡   Mortal ity over 5 years §  20.1% with normal T

§  2 levels > 250 §  24.6% with equivocal T

§  N and low §  Odds Ratio 1.38

(P=0.06) §  34.9% with low T

§  2 levels < 250 §  Odds Ration 1.88

(P<0.001) Shores et al (Seattle) Arch Int Med 2006; 166: 1660-1665

Retrospective Study

LOW TESTOSTERONE AND INCREASED MORTALIT Y (N >500)

Studies HR (95% CI) Nature Men, n Follow-Up, yrs Mortality

Shores, 2006 1.88 (1.34–2.63) Retrospective 858 8 All-cause

Laughlin, 2008 1.38 (1.02–1.85) Prospective 794 20 CVD

Khaw, 2007 2.29 (1.60–3.26) Prospective 2314 of 11,606 10 All-cause/ CVD

Haring, 2010 2.32 (1.38–3.89) 2.56 (1.15-6.52) Prospective 1954 7.2

All-cause

CVD

Malkin, 2010 2.27 (1.45–3.60) Prospective 930 6.9 All-cause in men with CAD

Tivesten, 2009 1.65 (1.29–2.12) Prospective 3014 4.5 All-cause

Menke, 2010 1.43 (1.09–1.87) Prospective 1114 9 All-cause

Vikan, 2009 1.24 (1.01–1.54) Prospective 1568 11.2 All-cause

Pye 2014 2.3 (1.2-4.2) 3.0 if sex sx Prospective 2599 4.3 All Cause/CVD

Jones 2013 2.02 (1.2-3.4) Prospective 581 5.8 All cause

Corona, 2010 7.1 (1.8–28.6) Prospective 1687 4.3 CVD

Muraleedharan et al, 2013 2.02 (1.2-3.4) prospective 581 5.8 All-cause

Hyde et al, 2012 1.62 (1.20- 2.19)

prospective 4249 5.1 All-cause

1.71 (1.12-2.62) CVD

Lerchbaum et al, 2012

2.11 (1.60-2.79) prospective 2069 7.7

All-cause

1.77 (1.23-2.55) CVD

CAN TRT DECREASE CARDIOMETABOLIC RISKS

FOR HYPOGONADAL MALES ?

Query #2

SURVIVAL OF TREATED VERSUS UNTREATED TESTOSTERONE-DEFICIENT MEN IN VA POPULATION:

DOES TRT IMPROVE MORTALIT Y?

¡   1031 men aged >40 years, T <250 ng/dL ¡   Morta l i ty : 10.3% t reated, 20.7% untreated (P<.0001)

VA, US Department of Veterans Affairs. Shores MM et al. J Clin Endocrinol Metab. 2012 ;97(6):2050-8.

Surv

ival

by

Test

oste

rone

Tr

eatm

ent,

%

Log rank P=.029

1.00

0.

90

0.80

0 12 24 36 48 Time Since Testosterone Test Date, mo

1016 639 557 496 193 15 301 321 323 146

Untreated Treated

At risk, n

Untreated Treated

Observational Study of mortality testosterone-treated compared with untreated men

TRT IMPROVES SURVIVAL IN MEN WITH T2DM

Muraleedharan V, et al. Eur J Endocrinol. 2013.

Prospective Study 581 men with T2 DM over 5.8 y

“Testosterone Increases CVD Risk!”

The beginning: RPCT

• TOM Study:“Testosterone in Older Men with Mobility Limitation” •   N=209 men >65 years of age (of the 252 desired by power analysis) •   Baseline TT 100-350 ng/dL (free T <50 pg/mL or 170 pmol/L) •   1% testosterone gel 10 g QD, titrated to 5.0g-15.0g, 6 mo rx •   Target TT 500-1000 ng/dL •   Results of muscle performance and physical function were positive •   AE not dutifully recorded and minor in scope: i.e. dizziness, swelling,

etc •   Trial stopped at 9 mo by DSMB: 5 serious CVS events in T; 2 in P

groups

SO, HOW DID THE BELIEF OCCUR AND IT IS BASED ON WHAT?

TOM TRIAL: Basaria S. NEJM 2010

Vigen

Finkle

TRT Causes CVD

Finkle et al

PLoS One 2014 Xu et al

BMC 2013

Basaria et al NEJM 2010

Vigen et al JAMA 2013

•   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

•   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

•   No randomization or placebo •   No control group or clinical info •   Health insurance database •   90 days after start testosterone •   PDE5I Control” Group inherently healthier (no nitrates) •   Pre-prescription MI rate 3.48/1000 Post-prescription MI rate 4.75/1000

•   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

3 Cross-sectional Clinical Trials in Older Men & 1 Meta- Analysis Showing increase in CVS Events with T Use

Retrospective Analyses of EMR Also Show Conflicting Results (Inc CVS events)

EFFECTS OF TESTOSTERONE ON MUSCLE STRENGTH, PHYSICAL FUNCTION, BODY COMPOSITION, AND QUALIT Y OF LIFE IN

INTERMEDIATE-FRAIL AND FRAIL ELDERLY MEN: RPCT

¡   N=274 frail men, ages 65-90 ¡   Treated for 6 months

DBRPCT §  25-75 mg/d 1% T gel vs PBO

¡  Muscle function improved on T Rx (A)

¡   Lean mass increased and fat mass decreased (B)

¡   Somatic scales and sexual dysfunction scales decreased on Rx

¡   No Adverse CV events ¡   Almost identical study to

Basaria 2010 European Study Aging Male Srinivas_Shankar, Wu et al. (Australia) J.C.E.M. 2010

THE LARGEST META-ANALYSIS TO DATE, FOUND NO EVIDENCE OF INCREASED CV RISK

WITH T THERAPY AND CLEAR EVIDENCE OF IMPROVED METABOLIC PROFILES

CORONA G, MASEROLI E , RASTRELLI G , IS IDORI AM, SFORZA A ,

MANNUCCI E , MAGGI M.CARDIOVASCULAR RISK ASSOCIATED WITH TESTOSTERONE-BOOSTING MEDICATIONS:A SYSTEMATIC REVIEW AND META - ANALYSIS .EXPERT OPIN DRUG SAF. 2014;13:1327-51

A recently published meta-analysis of 75 placebo-controlled studies

CORONA META-ANALYSIS CONCLUSIONS

Available evidence “does not support a causal role between testosterone supplementation and adverse CV events when hypogonadism is properly diagnosed and replacement therapy correctly performed”.

Corona G, et al. Expert Opin Drug Saf. 2014;13: 1327-51.

RISK OF MYOCARDIAL INFARCTION IN OLDER MEN RECEIVING TESTOSTERONE THERAPY

•   6355 Medicare pts treated with at least one injection

of T between 1997 and 2005 Retrospective Cohort Study

•   Matched to 19,065 T non-users 1:3 ratio based on composite MI prognostic score

•   Results: •   TRT was not associated with increased risk of MI •   In men at high risk of MI, TRT was associated with a

reduced risk of MI •   No difference in risk for pts at lower CV risk

Baillargeon J, et al. Ann Pharmocother, 2014 Jul 2;48(9):1138-1144

CONCLUSIONS

¡  TRT has not been associated with significantly increased cardiovascular risk at least up to 36 months

¡  Low T levels are associated with poor cardiovascular health and known risk factors for cardiovascular disease, such as obesity, diabetes, and the metabolic syndrome.

¡  The body of evidence supports the need for long term placebo controlled randomized trials of T replacement in hypogonadal men with regard to morbidity and mortality

FDA CAUTIONS ABOUT USING TESTOSTERONE PRODUCTS FOR LOW TESTOSTERONE DUE TO AGING; REQUIRES LABELING

CHANGE TO INFORM OF POSSIBLE INCREASED RISK OF HEART ATTACK AND STROKE WITH USE

http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm

March 2015 FDA Drug Safety Communication

TRT DOES NOT INCREASE RATES OF ADVERSE

CARDIOVASCULAR EVENTS WHEN USED APPROPRIATELY

NEW EVIDENCE SINCE THE FDA’S 2015 COMMUNICATION

§  AIM: Study of hypogonadal men without MI or CVA after TRT evaluating for CV events and all cause morality.

§  METHODS: Retrospective 83, 010 vets with low TT (1999-2014) §   Gp1 TRT with normalization of TT §   Gp2 TRT without normalization of TT §   Gp3 no TRT

§  RESULTS: §   All-cause morality Gp1<Gp2<Gp3 §   MI and CVA Gp1<Gp2=Gp3 §   Treated men 56% Dec Mortality & 24% Dec MI (Gp1 vs Gp3)

§  CONCLUSIONS: §   Largest observational cohort with extended follow-up (15 yrs) §   Normalization of TT after TRT significantly reduced all-cause mortality

MI, and stroke

NORMALIZATION OF TESTOSTERONE LEVEL IS ASSOCIATED WITH REDUCED INCIDENCE OF MI AND

MORTALIT Y IN MEN

Sharma  R,  et  al.  European  Heart  J,  2015,  100(3):36;2706-­‐2715  

¡   AIM: To dete rmine the e f fec t o f tes tos te rone admin i s t ra t ion on subc l in i ca l a the rosc le ros i s p rog re s s ion in o lde r m e n w i t h l ow o r l ow -norm al te s tos te rone leve l s .

¡   MET HODS : §  N = 308 men > 60 yo with low or low normal T levels §  TT 100-400 ng/dL; FT < 50 pg/ml §  Mean Age: 67.6 yo; 42% HTN; 15% DM; 15% CVD; 27% Obese §  3-year DBPCT:

§  156 men 7.5 gm 1% T §  152 placebo gel daily x 3yrs

§  Dose adjusted to achieve levels 500-900 ng/dL §  Co Primary Outcomes: CIMT and CAC §  Secondary Outcomes: Sexual Function & HR QOL

¡   RES ULT S : §  Rate of change of CIMT Placebo 0.010mm/yr and in T 0.012 mm/yr p=0.89 §  Rate of change of CAC §  Placebo 41.4 Agatston units/year §  T 31.4 Agatston units/year p=0.54

¡   C ON C LU S ION S : §  No Changes in intima-media thickness or calcium scores associated with TRx §  Sexual desire, erectile function, overall sexual function scores, partner intimacy, health-related

quality of l ife did not dif fer significantly between groups §  Lack of CVD events is most significant & reassuring but again, §  not powered for safety §  When T given in appropriate dosages there is no serious morbidity/mortality

T EFFECTS ON ATHEROSCLEROSIS IN AGING MEN (TEAAM) 2015

Basaria S, Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. JAMA.2015; 314:570-581.

¡   AIM: Test hypothesis that basel ine TT, FT, E2 and SHBG are independently associated with sexual functions, v ital i ty, and physical functions in older hypogonadal men (Anemia; Bone Mass; Cognit ive Function also studied).

¡   METHODS: §   12 U.S. centers §   788 symptomatic men >65 yrs with TT<275 RDBPCT “Highest Quality”

¡   RESULTS: §   TT and FT had statistically significant associations with measures of sexual

desire, EF, and sexual activity, §   Not vitality and sexual function. §   Slightly better mood, less depression in T arm

¡   CONCLUSIONS: §   Statistically significant improvements in older men with T in some

parameters of sexual function and mood §   No increase in CVD events with T vs P (Study not powered for safety). §   Some improvement in strength utilized as walking distance though did not

reach target §  Sexual Function: 10 of 12 Domains increased PDQ, greatest in libido

Snyder  et  al.  T  Trials    JAMA  2016  Validated  by  Cunningham  et  al.  J  Clin  Endo  Metab  2016

EFFICACY OF T WITH SEXUAL FUNCTION, VITALIT Y, & PHYSICAL FUNCTION OF SYMPTOMATIC OLDER MEN

WITH LOW T AT BASELINE: T TRIALS

¡   AIM : Test the hypothesis that testosterone treatment of older men with low testosterone slows the progression of noncalcified coronary ar tery plaque volume in men with low testosterone

¡   METHODS: §  Men >65 y/o with only age related decline in T §  RDBPCT 9 centers §  170/788 men >65 years §  2 am levels <275 ng/dL (82P, 88T) §  Men allocated to treatment by minimization: computerized technique

provides best balance across groups on specific baseline characteristics ¡   RESULTS:

§  138 completed study (73T, 65P) §  Mean age 71.2 years §  Rx vs. Pbo showed increase in non-calcified plaque volume from baseline

to 12 months §  204mm3 to 232mm3 vs 317mm3 to 321mm3; (T vs Pbo) §  Est diff 41mm3; 95% CI 14-67mm3; p=.003 T group

TESTOSTERONE TREATMENT AND CORONARY ARTERY PLAQUE VOLUME: T TRIAL

Budoff MJ, Ellenberg SS, Lewis CE, Mohler ER 3rd, Wenger NK, Bhasin S, Barrett-Connor E, Swerdloff RS, Stephens-Shields A, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Gill TM, Matsumoto AM, Molitch ME, Nakanishi R, Nezarat N, Matsumoto S, Hou X, Basaria S, Diem SJ, Wang C, Cifelli D, Snyder PJ. JAMA. 2017 Feb 21;317(7):708-716. doi: 10.1001/jama.2016.21043.

¡   OUTCOMES: §  Primary outcome was Non-calcified Plaque Volume=sum of 4 types of

plaque: low attenuation, fibrous-fatty, fibrous and dense calcium §  Secondary outcomes: Total Plaque Volume = sum of all 4 types and

Coronary Artery Calcium Score (CAC) ¡   RESULTS:

§  Baseline: 61% BMI>30; 31% DM; 67% HTN; 63% Dyslipidemia; 66% Hx Cig abuse; 19% OSA

§  Mean ACC/AHA ASCVD Risk Score: 24% T; 27% P §  50.7% had CAC> 300 (severe atherosclerosis) §  Men in P group had “somewhat greater mean non-calcificed plaque

volume” by CCTA and “somewhat greater CAC score” §  T Treatment associated with a significant increase in fibrous plaque

volume (change 25 mm3) vs placebo (change 1 mm3) §  Fibrous Plaque “protective capping” of Vulnerable Plaque= More Stable

TESTOSTERONE TREATMENT AND CORONARY ARTERY PLAQUE VOLUME: T TRIAL

Budoff MJ, Ellenberg SS, Lewis CE, Mohler ER 3rd, Wenger NK, Bhasin S, Barrett-Connor E, Swerdloff RS, Stephens-Shields A, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Gill TM, Matsumoto AM, Molitch ME, Nakanishi R, Nezarat N, Matsumoto S, Hou X, Basaria S, Diem SJ, Wang C, Cifelli D, Snyder PJ. JAMA. 2017 Feb 21;317(7):708-716. doi: 10.1001/jama.2016.21043.

¡   COMMENTS: §  Among the 170 men in the CVS Trial in TRx group and in Pbo group

NONE reported MACE (NOT POWERED FOR SAFETY) §  Few studies have examined the effect of T on atherosclerosis in men:

TEEAM study in older men showed TRx did not affect the change from baseline CAC or CIMT over 3 years.1

§  Increase in non-calcified and total plaque volumes in men on TRx are concerning because any limitation of the vascular lumen could be considered deleterious2

§  Fibrous plaque is more stable & protective3 §  Single review suggests that total plaque burden may be more

important than ind plaque type2

1. Basaria S. JAMA 2015; 314(6)570-581 3. Samady H, Circulation 2011;124(7)779-788 2. Arbab-Zadeh A, et al. J Am Coll Cardiol 2015;65(8):846-855

TESTOSTERONE TREATMENT & CORONARY ARTERY PLAQUE VOLUME: T TRIAL

“The coronary luminal narrowing observed over 12 months in this study is an unprecedented drug effect and appears ominous in signifying accelerated atherosclerosis, and is perhaps a harbinger of increased cardiac ischemic events. Early plaque growth may explain previous reports suggesting an association between testosterone use and cardiovascular harm in older men as well as transient cardiovascular harms confined to the first 6 to 12 months after commencing testosterone treatment. These findings may provide a possible mechanistic basis of an adolescent “head start” in atherogenesis to explain the earlier onset and greater severity of atherosclerosis in men compared with age- matched women despite parallel age-specific risks of men and women.”

TESTOSTERONE TREATMENT AND CORONARY ARTERY PLAQUE VOLUME

Editorial Handelsman DJ. Testosterone and Male Aging Faltering Hope for Rejuvenation. JAMA 2017;317: 699-701

LIMITATIONS §  Non-randomization = Minimization of 170 men §  Dif ferent baseline groups due baseline plaque volume? §  Prognostic studies of non-calificied plaque volume non-existent §  Assumptions about composition of plaque components as detected

by CCTA not confirmed by direct radiologic-pathologic studies §  Plaque volume and radiologic characteristics of plaque: surrogate

outcomes; other factors that influence thrombosis and plaque rupture

§  Another interpretation: T increases fibrous component of plaque = stabil ity

Thus, testosterone therapy resulted in stabilization of coronary plaque? What is the meaning of this study? Stabilization is consistent with many retrospective/prospective reports of decreased major adverse cardiovascular events (MACE) after testosterone therapy.

TESTOSTERONE TREATMENT AND CORONARY ARTERY PLAQUE VOLUME

¡  39 RCTS and 10 Observational Studies Included ¡  Compared with Placebo Exogenous T Treatment did

not show any significant increase in risk of myocardial infarction, stroke or mortlity

¡  Observational studies showed marked clinical and methodological heterogeneity

¡  The evidence was rated as low quality; high risk of bias, imprecision, and inconsistency

¡  Low quality of evidence precludes definitive conclusion

SYSTEMATIC REVIEW & META-ANALYSIS CARDIOVASCULAR RISKS OF EXOGENOUS

TESTOSTERONE

Alexander GC, Iyer G, Lucas E et al. Am J Med 2017; 130: 293-305

TESTOSTERONE AND CARDIOVASCULAR DISEASE

Award likely to be appealed

and overturned due to US

Supreme Court ruling that such awards need be based on actual

damages.

Class Action Suit initiated

against T manufacture

rs in 2015

Purported that T manufactures

both conspired to limit knowledge

of T’s known thrombotic risks and participated in ad campaign

targeted to aging men with

diminished libido and fatigue

making most prescribing of T

“off label”

Abbvie found liable for

misleading plaintiff and his physician about

safety and Androgel’s

“propensity” for causing blood clots and fined $150 million in damages by jury

Both sides claim victory

First “bellwether trial” trial

decided July 24, 2017

found Abbvie guilty of

“misleading”

Abbvie found “not guilty” of its product not causing CVS

event and jurors awarded

no compensation

for injuries

T TODAY: A CLIMATE OF LITIGATION

§  Low T associated with increased atherosclerosis & MACE §  Meta-analyses show TRT has neutral (or possible beneficial)

effect on CV risk factors and cardiac events §  Current evidence about the safety of TRT is hampered by the

small n, brief study follow up and soft end points §  The TOM trial suggested possible increased CV risks of T

therapy in elderly and very frail individuals §  Caution is warranted in interpreting & extrapolating findings to other doses

and formulations of T or to other populations, particularly men with hypogonadism w/o CVD or mobility limitations.

§  Serious limitations of recent JAMA (Vigen), Plos One(Finkel), and BMC (Xu) Retrospective and Meta-analysis studies as pointed out by many investigators and FDA

§  No black box warning regarding MI, stroke or death; FDA says weak signal may exist. No association or causal basis.

§  T Trials: soft support for T improving sexual function and mood §  No improvement in cognitive function and frailty §  Increase in non-calcified plaque of unknown significance

CONCLUSIONS