In 2010, in the Battle with Our #1 Killer:

We Were at the Goal Line…

Sidney S. & Rana J. JAMA Card. 2017

did we fumble the ball?

“Turns back the clock on cardiovascular disease prevention"

Stanley Hazen MD, Northwestern

“A massive paradigm shift that dramatically changes the approach to

disease."

James de Lemos MD, U Texas

Controversy: As Many Experts Predicted,

Our Guidelines Did Not Reverse the Trend

“The nihilism…may harm many patients, …and confuse many doctors.”

Dr. Fernando Civiera, Press. Spanish Atherosclerosis Soc

Why does the trend continue in the wrong direction?

Our guidelines fail to provide a primary prevention strategy

Four Stunning Statistics Tell Us the Need for

Earlier, More Aggressive Primary Prevention

• In 45-55 yo, the leading cause of death is CAD

• ¾ of MIs are 1st heart attack

• ½ of MIs occur without prior Sx [caused by <50% stenosis]

• Statin primary prevention trials: 40% reduction events/5 yrs

Our Guidelines need an effective:

Detection strategy for CAD before Sx

Treatment philosophy for these patients

Wiegman A. Bogalusa Heart Study. JAMA 2004 a

0

2

4

6

8% surface with plaque at autopsy

Risk factor in youth: autopsy if death in 20’s, follow living into 40-50’s

0 1 >2 2

Number of risk factors

In Youth, Traditional Risk Factors Identify

High Risk That Tracks into Middle Age

Since risk in kids tracks into middle age,

begin profiling in youth [e.g. 1st lipid profile in 20’s]

In Early Middle Age, Calcium Identifies

The Presence of CAD & High Risk for Events

Daga N. JCCT 2013

Calcium score>0

Diabetics 43%

Non-diabetics 24%

Ca++ Scan, 3723 a-sx pts, aged <40 [mean 35y], 4% diabetic, 56% men

We have the tool for detection but not the strategy:

Even though you can detect early CAD before a catastrophe,

4 Ca scans to detect 1 at-risk person is just not cost-effective

•309 positive scan (10.2%) at mean age 40 y, mean Ca score 22

•Any Ca++ : 5x increase cardiovascular events

•Ca score 1-19: 2.6x

20-99: 5.8x

>100: 9.8x and 22 deaths/100 participants

“Adults < 50y with any Ca++ are at elevated risk of CV events & death”

3043 a-Sx age 18-30, RF’s, Ca Scan 15 y later, 108 events at 12 y f/u

Carr JJ, JAMA 2017

The Crucial Insight: What Happens If You Combine

Risk Factor Analysis with Ca++ Scanning?

The Critical Insight for Detection of pre-Sx CAD

If you stratify by risk factor score > median before scanning:

you need to screen only two 35-45 year olds to get 1 positive!!

We have detected high risk. pre-Sx CAD, now what?

Coronary Disease is a Dietary Disease:

The Mediterranean Diet

30% cardiac events at 4.8 yrs

Good: fruits, veggies, nuts, olive oil, fish, wine

Very bad: transfats, simple sugars

Not good: animal fat, red meat

Estruch R. The PrediMed Trial. NEJM 2013

7447 A-sx people, randomized, Mediterranean vs low fat diet, 4.8y f/u

What if You Followed the Diet for a Lifetime?

The Lowest Rate of Coronary Ca++ Ever Measured

Diet is catfish, piranhas, wild pig, wild fruits, nuts, rice, plantains & corn

Life is 10% daily sedentary vs 54% in USA

The Tsimane of the Bolivian Jungle

Courtesy, Greg Thomas MD Lancet. March 2017

Coronary Calcium Score

But diet and exercise is insufficient when CAD is present,

so then what?

Aggressive Rx: If Ca++ is Detected,

Treat with a Generic Statin, Aiming for <70mg/dl

Q3

Q1

Q2

Placebo

Evolocumab

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

27,564 CAD, PCSK9 mab, on-Rx LDL 30, 26 mo f/up, 25% risk

Sabatine M. NEJM 2016

Lower Is Better

No safety issues

Challenging Conventional Wisdom:

Four Maverick-y Shah-Forrester “Guidelines”

• Ca scanafter 35, but only for above average risk- by-age

• Statins: if Ca score is >0, no if Ca score=0

• Lower is better: so use higher dose statins, aim for <70 mg/dl

• Once you choose statin Rx, same dose with or without Sx

Our Hypothesis

These 4 changes in practice would dislodge CAD as the #1

killer of 45-55 year olds.

What changes are on the near horizon?

0 3 6 9 120 150 180

Days from first injection

P-<0.0001

% LDL change

60

0

30

300 mg sq at day 1 and 9, then Q6 month

B

If LDL is Not at “Target” with Statin: PCSK-9 mab?*

We Need a Cost/Convenience Alternative

No safety issues

Reduced injection burden

Inclisiran: a long-acting RNA inhibitor of PCSK-9 synthesis

*88 of prescriptions are not filled

The Critical Insight for Detection

If you stratify by risk factor score > median before scanning:

you need to screen only two 35-45 year olds to get 1 positive!!

Placebo SC q 3 months

Canakinumab 150/300 SC q 3 months

39% reduction in hsCRP

No change in LDLC

15% reduction in MACE

Ridker P. ESC 2017

Suppression of Inflammation in CAD

Reduces Cardiac Events

10,061 MI, CRP>2, canakinumab q3mo, MACE, 5 yr f/u

The anti-inflammatory effect is an independent mechanism

Antonopoulos A. Science Translational Medicine. July 2017

•Distinguished vulnerable plaque [156 CAD, 117 no CAD]

•Identified plaque rupture site in MI with high sensitivity/specificity

•Applicable to existing CT angiograms without additional equipment

Perivascular Fat Reveals Local Coronary Inflammation

Histologically inflamed fat attenuates xray much less than does normal fat

The “fat attenuation index”

New Ideas for a New Era in Prevention:

How We Will Win the Battle With CAD

•We finally have a viable strategy to detect/Rx CAD prior to Sx

•LDL-C can fall to 25 with no apparent short term risk

•PCSK-9 mab: too costly/inconvenient; alternatives will appear

•Inhibiting inflammation independently reduces events

•We will soon be identifying vulnerable plaques

In the past year

In the beginning, God created the Heavens &

the Earth & populated the Earth with

broccoli, cauliflower & spinach, green &

yellow & red vegetables of all kinds, so Man

& Woman would live long & healthy lives.

But Nature’s Greatest Battle…

Then using God's great gifts, Satan created

Ben & Jerry's Ice Cream & Krispy Creme

Donuts. And Satan said, "You want

chocolate with that?" And Man said,

"Yes!" & Woman said, " as long as you're

at it, add some sprinkles." And they gained

10 pounds. And Satan smiled.

God then brought forth running shoes so

that His children might lose those extra

pounds. And Satan gave cable TV with a

remote control so Man would not have to

toil changing the channels. And Man &

Woman laughed & cried before the

flickering light & gained pounds.

God then brought forth running shoes so

that His children might lose those extra

pounds. And Satan gave cable TV with a

remote control so Man would not have to

toil changing the channels. And Man &

Woman laughed & cried before the

flickering blue light & gained pounds.

God then gave lean beef so that Man might

consume fewer calories & still satisfy his

appetite. And Satan created McDonald's &

its 99-cent double cheeseburger. Then said,

"You want fries with that?" & Man replied,

"Yes! & super size them!" & Satan said, "It

is good." And Man went into cardiac arrest.

God sighed & created quadruple

bypass surgery.

Then Satan created HMOs

Intro: Set theme of Controversy

4 stunning st: man and his dog

Combine RF and Ca: St Paul on road to Damascus

PCSK9: If you don’t know where you’re going…

Frequency distrib: a man and his dog

Video: no caveat about age. Pimple

PCSK9: If you don’t know where you’re going…

Concl manage: Some people see things that are…

Carlin: some pple hv to go to work & don’t hv time for all that

The widely held hypothesis

•CAD is a dietary disease, driven predominantly by LDL

•The 35% ↓ mortality was driven by dietary change + statins

Why Did CAD Mortality Fall So Rapidly?

#1: Base risk assessment on age

#2: Treat CAD when you know it exists

Two Principles of Early Prevention That Will

Reverse the Trend & Win the Battle with CAD

Early and Aggressive

Base Your Risk Assessment On Age

Age (years) Risk evaluation

Youth 10-20 Physical exam, BP, BMI

20-40 Physical exam, BP, BMI

Lipid panel every 5 years

If >35yr: diabetic or high risk, Ca++ scan

>40 Physical exam

Lipid panel

Ca++ scan if > average risk for age

Carotid scan if Ca++ negative, but high risk

Age

(years)

Management

10-20 School exercise program

Diet for overweight

Consider statin if upper 5% of LDL for age after lifestyle

20-40 Lifestyle modification

Treat risk factors

Statin if Ca++ scan>0

>40 Lifestyle modification

Treat risk factors

Statin if Ca++ scan>0

Consider 2nd drug: LDL >100 after statin if other risk factors

Preventive Management of a Lifetime Disease

LDL initiation criteria vs level of risk

160 mg/dL if low-risk

130 mg/dL if moderate-risk

100 mg/dL if moderately high-risk

Reduces annual healthcare cost by $430 million

Maximum impact LDL initiation criteria was:

130 mg/dL if 0 risk factors

100 mg/dL for persons with ≥ 1 risk factor

Rx all with moderate and moderately high-risk regardless of LDL

Benefit: $9900 per quality-adjusted life-year

Primary prevention, modeled US population ≥35 years of age

“Low-cost statins are cost-effective for even modestly ↑ LDL.

Adverse effects do not outweigh benefits in any subgroup.”

Concerned About Statin Overuse?

“It’s Not About the Money”

Lazar L. Circ 2011 Schwartz S. Circ 2011

Tuzcu EM. JACC 2005; 45:1538

19 y.o man

33 y.o.woman

262 transplanted hearts, IVUS, 0.5 m threshold

0

20

40

60

80

100

13-19 20-29 30-39 40-49 >50

What Do We Know About CAD Before Symptoms?

What is the Best Strategy to Prevent MI?

Are Our Current Guideline Right or Wrong?

The human cost

CAD is cause of death in 30% of US population

Leading cause of death in people 45-55 years old

50% of MI & sudden death occur with no prior Sx

The $ cost

Cardiovascular disease costs $317 billion/year

720,000 heart attacks/year: 515,000 are 1st MI

Cost of MI over a lifetime: $750,000

What we know

CAD begins in youth

Complications begin to occur without warning in middle age

Risk for catastrophe for an individual is identifiable at any age

In youth substantial risk factors confers marked increased risk

In early middle age coronary Ca++ identifies CAD & risk

How We Will Win Cardiology’s Greatest Battle:

Cost Effective Early Dx and Rx

•Support school programs

•Lipid panel if >20 years old

•Use Ca scan driven by > average risk in a-sx middle age

Treat CAD when present •Discuss prudent diet and lifestyle with every patient

•Coronary Ca++ means CAD & elevated risk for catastrophe

•When using statins, aim for <70mg/dl regardless of symptoms

•Use secondary drugs in high risk patients who are not near LDL target*

•Don’t fret about low LDL on Rx: <50mg/dl is probably ideal

*US guidelines have no recommended target

Assess risk in at every age

PCSK-9 is a protease that down-regulates the LDL receptor:

•Degrades the LDL receptor

•Prevents intracellular LDL receptor recycling to cell surface

•Reduces clearance of LDL from the circulation. Thereby…

PCSK-9 increases the blood level of LDL cholesterol.

So, blocking PCSK-9 ↓↓ LDL, even in patients on statin Rx

What Have We Learned in the Past Year?

The LDL Treshold For Atherosclerosis

•Familial hyperlipidemia: age 15

•Age 40 for high risk

•Age 60 for “normal”

Baum SJ. J Clin Lipidology 2014

Preventive Management of Atherosclerosis

•Diet: what’s good, what’s bad

•Risk factors [LDL, smoking, exercise, BP, weight]

•Statins

•Secondary drugs

Statin Intolerance

• 86% are myalgia or myositis

• Withdrawal and rechallenge is useful strategy

• Rx:

Alternate day dosing [most tolerate rosuva 5mg/1wk]

Ezetimibe

PCSK9 inhibitor

Other: niacin, BAS, fibrates, aphersis

Gordon T. J Clin Lipidology 2015

Dilemmas In Prevention of Coronary Disease

•When to initiate LDL lowering therapy

•The use of an LDL target

•Use of the recent ATP guidelines

•Use of secondary therapies after statins

•Treatment of low HDL

Your Guidelines for LDL Management

Are Dead Wrong

PK Sweden data

The First Step in Primary Prevention: Diet

•Epidemiologic data [5% less events at 3-5 years]*

•5yr randomized trial vs low fat [30% less at 4.8 years]

Good: fruits, veggies, nuts, olive oil, fish, wine

Very bad: transfats, simple sugars

Not good: animal fat, red meat

*“Adherence to the Mediterranean diet may contribute to

primary prevention of CVD in the UK”

Tong T. BMC Med 9-16

The Mediterranean Diet

PCSK-9 Inhibition Has Major

Advantages and Disadvanages

Advantages

•Effect on LDL is comparable to a high dose potent statin

•Effect is additive to statin

•Toxicity appears to be quite low

Disadvantages

•Cost: about $14K/year

•Patient acceptance: 3 subcutaneous 1 ml injections each month

Your Guidelines for LDL Management

Are Dead Wrong

What our guidelines should say

CAD is a dietary disease, but diet alone rarely reduces LDL to normal

Identify risk in youth, again before 40 as well as after 40

A pill a day is not so bad if it’s cheap, non-toxic & prevents early death

Use LDL targets to guide your Rx

Remain alert to use of PCSK9s when become cost effective

Dilemmas In Prevention of Coronary Disease

•When to initiate preventive management

•The use of an LDL target

•Use of the recent ATP guidelines

•Use of secondary therapies after statins

•Treatment of low HDL, and high triglycerides

19 y.o man

33 y.o.woman

What if We Started Management

Earlier in te Course of Disease?

When should prevention begin?

It must begin in youth & young adults

“Turns back the clock on cardiovascular disease prevention"

Stanley Hazen MD, Northwestern

“A massive paradigm shift that dramatically changes the approach to

disease."

James de Lemos MD, U Texas

“The guidelines will revert back once we get a positive study showing

that adding another agent to a statin reduces risk,“

Roger Blumenthal MD, Johns Hopkins

Why Was the Criticism of Our US Guidelines

So Passionate and Widespread?

“The nihilism…may harm many patients, …and confuse many doctors.”

Dr. Fernando Civiera, Press. Spanish Atherosclerosis Soc

The guidelines expand statin use which is good,

but abandon the LDL target, & is fuzzy on asymptomatic pts.

Cardiovascular Outcomes At One Year

Favor Evolocumab

Evolocumab plus standard of care

0

0 30 60 90 120 150 180 210 240 270 300 330 365

Days since Randomization

1

2 Standard of care alone

0.95%

2.18%

Sabatine M. ACC 2015

4465 pts, 20% CAD, 80% RFs, 70% statins, Evolo vs SOC

Mean LDL fell from 130 to 52 mg/dl

Cardiac events , %

GLAGOV trial shows plaque regression at 1.5y by intravascular

ultrasound in 968 pts [at annual Am Heart Assn meeting next month].

No Increase in Adverse Events

When Stratified by On-Treatment LDL-C

All

EvoloMab

Stnd of

Care LDL <25

n=773

25 to <40

759

<40

1532

≥40

1426

Adverse Events (%) 70.0 68.1 69.1 70.1 69.2 64.8

Serious 7.6 6.9 7.2 7.8 7.5 7.5

Muscle-related 4.9 7.1 6.0 6.9 6.4 6.0

Neurocognitive 0.5 1.2 0.8 1.0 0.9 0.3

ALT/AST/>3×ULN

0.9 0.8 0.8 1.3 1.0 1.2

CK >5×ULN 0.4 0.9 0.7 0.5 0.6 1.2

How Statins Make Some People Crazy July 30, 2017 by Larry Husten 10 Comments

Intelligent discussion about statins is threatened by zealous partisans

Outline What we know/think know: atherogen, youth, hi risk identifble, lower better

How statins make some people crazy

Pro: in CAD, in Asx, diet not enuf

Con: drug co, short$/SAE-long bene, mag benef, disutility

New information: pcsk,

Best mgmnt approach:

CAD Prevalence Rises Monotonically with Age,

And Risk of an Event Falls with LDL

0

40

80

120

Wild animals & primates

Humans Age 1-12

Hunter- gatherers

US Adults

30

70

The normal range?

What is the Future Significance of

PCSK9 Inhibition?

Forrester, J. Redefining normal cholesterol. JACC 2010

LDL mg/dL Why?

“Normal” Human LDL isn’t 100 mg or even 70 mg/dl

P<0.0001

Patients grouped by quartile of baseline LDL-C and by treatment arm

Q

4

Q

3

Q

2 Q3 Q1

Q1

Q2

Placebo

Evolocumab

Q

4

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Tuzcu EM. JACC 2005; 45:1538

19 y.o man

33 y.o.woman

262 transplanted hearts, IVUS, 0.5 mm threshold

0

20

40

60

80

100

13-19 20-29 30-39 40-49 >50

Calcium scan is positive in 40-60% by age 45

CAD Becomes Apparent in Middle Age,

But it Begin in Youth

We know the normal range of LDL, can detecting CAD early,

and we can prevent it before symptoms

…but what do you do when you know the right answer but

the teacher won’t call on you ?

0

40

80

44 65

20% vs 36% reduction

in overall mortality

Same relative ↓risk in pts with baseline LDL-C 130, 100 and 70 mg/dl

Ridker P. JACC 2011

17,802 “healthy” pts, 20mg rosuva vs placebo, 1.9 yr f/u

% Reduction in CV events

Overall population <50 mg/dl subgroup

Is Treating Asymptomatic Patients to <70mg/dl Safe?

Major Cardiac Events in:

40 of 250 patients randomized to placebo (16%)

15 of 232 patients randomized to colchicine (5::%).

Relative risk reduction: 67%.

Number needed to treat to prevent one event: 11

LoDoCo trial. Nidorf S. JACC 2013

Does Inhibition of Inflammation in Patients with CAD

Reduce Cardiac Events?

532 stable CAD, on statin, 0.5mg colchicine v placebo, 3y f/u

PCSK-9 Inhibition Has Major

Advantages and Disadvanages

Advantages

•Effect on LDL is comparable to a high dose potent statin

•Effect is additive to statin

•Toxicity appears to be quite low

Disadvantages

•Cost: about $14K/year

•Patient acceptance: 3 subcutaneous 1 ml injections each month

Forrester J, JACC 2011

0

4

8

50 70 90 110 130 150 170 190

LDL mg/dl

Cardiac Events %

The LDL Level That Prevents Cardiac Events in Patients Without Symptoms

57 mg/dl

Randomized trials of statins, 5 years duration

In patients with established CAD, the intersection point for

zero events is <30 mg/dl.

Agency for Healthcare Research and Quality 2016

500K 1st MI’s x $20K = $10B

Reduce 1st MI by half: save $5B

Why More Aggressive?

Cardiovascular Disease Costs $317 Billion/Year

720,000 heart attacks/year: 515,000 are 1st heart attack

Heart attack hospitalization costs $21,500 per stay [5.3 days]

What is the Best Management Strategy?

Are Our Current Guideline Right or Wrong?

The human cost

CAD is cause of death in 30% of US population

Leading cause of death in people 45-55 years old

50% of MI & sudden death occur with no prior Sx

The $ cost

Cardiovascular disease costs $317 billion/year

720,000 heart attacks/year: 515,000 are preventable 1st MI

With the diagnostic and therapeutic tools we have,

I do not think we are doing enough

What we know

CAD begins in youth

Complications begin to occur without warning in middle age

Risk for catastrophe for an individual is identifiable at any age

In youth substantial risk factors confers marked increased risk

In early middle age coronary Ca++ identifies CAD & risk

Cohen J. NEJM 3/2006

-60

-40

-20

0

-57%

LDL

-19%

Cardiac Events

What About Lowering LDL-C?

When Nature Lowers LDL-C Prior to Symptoms

12787 subjects, 3% PCSK-9 mutation, 15 year f/u

People with mutation vs rest of population

The Implication

If we could identify high risk long before symptoms,

we could have a huge impact on CAD.

0

40

80

120

Wild animals & primates

Humans Age 4-12

Hunter- gatherers

US Adults

30

70 This is probably the normal range

What Nature Tells Us About

The Ideal Level of LDL-C

O’Keefe J. JACC 2004

LDL mg/dL

But until recently neither dietary management nor statins

could consistently get us to this range.

New Information and New Thinking in

the Detection and Management of CAD

•The central ideas in an effective management strategy

•The critical new facts we have learned about CAD

•How new data creates a new management strategy

Let’s Start With Atherogenesis

CAD is as simple as a pimple:

2 distinct processes: fat accumulation followed by inflammatory reaction

Plaques that rupture cause MI and sudden death

Plaques that rupture are not necessarily stenotic

That’s why:

50% of MI & sudden death occur with no prior angina

CAD is the leading cause of death for 45-55 year olds

The Subtle Difference Between Bypassing or

Opening Stenoses vs Preventing Plaque Rupture

Can we detect & treat coronary disease

cost effectively prior to a catastrophe?

Number of Risk Factors 0 1 2 3 4

30 year risk

10 year risk

%

Risk

25 year old man

Low risk

Intermediate risk

High risk

5x higher risk,

42% risk by age 55

A Fundamental Flaw in Thinking About Pre-Sx CAD:

10 Year Risk is Very Different From Lifetime Risk

The long lag time between disease onset & catastrophe

CAD begins in youth, but

unexpected MI and death only begins in middle age

New Thinking and New Information in

the Detection and Management of CAD

•The central ideas in an effective management strategy

•The critical new facts we have learned about CAD

•How new data creates a new management strategy

The Man Least Likely to Have a Coronary…

An effete vegetarian of Bolivian descent,

Who has never met a deadline in his life,

Is scrawny & unathletic but is constantly flexing his puny muscles,

Washes down his leafy greens with a glass of Zinfandel,

And has been taking omega-3’s, Vit E, ASA, Lipitor and Repatha,

Ever since his prophylactic castration

Following the death of his 102 year old father

50

56 mg/dl

100 LDL Cholesterol (mg/dl)

Evolocumab

Placebo

0

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Weeks

27,564 stable CAD, 99% on statin, LDL 92, evolo vs SofC, 26 mo f/up

What Have We Learned About LDL in the Past Year? A new drug class: PCSK-9 inhibitors increase LDL receptor expression

Median LDL: 30 mg/dl

No difference in adverse events, diabetes or cognitive function

Sabatine M. NEJM 2017

2%

4%

6%

2%

4%

6%

Placebo

Evolocumab

0% 0%

0 3 6 9 12 12 18 24 30 36

Months from Randomization

16% RRR

HR 0.84 P=0.008

25% RRR

HR 0.75 P<0.00001

Placebo

Evolocumab

CV Death, MI, Stroke, Hosp for unstable angina, or coronary revasc

12.6%

14.6%

LDL Lowering To 30mg/dl Reduces Events &

Benefit Increases With Time

“An incredible set of data…

a new era in cardiovascular medicine.

Clyde Yancy MD

79% of prescriptions initially were rejected

53% ultimately were rejected

35% were abandoned at the pharmacy

Navar A. ACC 2017

PCSK-9 Inhibitors: A Monumental Conceptual Advance

With [As Yet] Limited Public Health Importance

45,029 patients, 1st PCSK9 prescription, Amgen data base

88%

0 3 6 9 120 150 180

Days from first injection

P-<0.0001

% LDL change

60

0

30

300 mg sq at day 1 and 9, then Q6 month

B

A PCSK-9 Alternative: Inclisiran A synthetic long-acting RNA inhibitor of PCSK-9 synthesis

Potential Advantages

• All patients responded with markled fall in LDL-C

• No safety signal

• Sustained effect between infrequent injections

• Reduced injection burden may improve adherence

What’s New In the Detection and Management of CAD

•The barriers to an effective management a strategy

•The critical new facts we have learned about CAD

•How new data creates a new management strategy

Age

(years)

Management

10-20 School exercise program

Diet for overweight

Consider statin if upper 5% of LDL for age after lifestyle

20-40 Lifestyle modification

Treat risk factors

Statin if Ca++ scan>0

>40 Lifestyle modification

Treat risk factors

Statin if Ca++ scan>0

Consider 2nd drug: LDL >100 after statin if other risk factors

Preventive Management of a Lifetime Disease

What About HDL ?

HDL Raising No Longer Works Like It’s Supposed To

•Gene variants that increase HDL do not decrease CAD risk

•Three CETP inhibitor trials failed despite raising HDL

•Two niacin trials were stopped for futility

•Two fibrate trials [which ↓TG/↑HDL] did not alter events

“HDL is related to risk, but that doesn't mean raising HDL is beneficial.

We do know lower LDL has a big impact on risk, so message remains,

Get those LDL numbers down.”

Robert Eckel MD

The best treatment of low HDL… is low LDL.

What About Triglycerides?

Use of Fibrates Has Become Uncertain

•Gemfibrozil & omega-3 FA’s reduce risk in low HDL/high TG subgroup

•Fibrates remain good for people with very high TG [>500mg/dl]

•Fibrates have secondary benefits in diabetes, like ↓retinopathy

•Lifestyle modification [diet, exercise, less alcohol, etc] also does ↓TG

•For routine CAD patients the best treatment of ↑TG is optimal statin Rx

“There is no evidence that fibrates should be routinely added to a statin in

patients with diabetes. When TG is >200 mg/dL & HDL is <35 mg/dL

after statins, however, fibrates can be considered.”

Henry Ginsberg MD

2 trials show no MI/CVA benefit of fibrate added to statin Rx

20% vs 36% reduction

in overall mortality

Cannon C. Improve-It Trial. NEJM 2015

18,144 ACS pts, LDL 50-125, simva 40 v simva 40+ezet 10, 8 yr f/u

On Rx LDL: 70 vs 54 mg/dl

What About Secondary Drugs After Statins?

Simva† EZ/Simva†

Male 34.9 33.3

Female 34.0 31.0

Age < 65 years 30.8 29.9

Age ≥ 65 years 39.9 36.4

No diabetes 30.8 30.2

Diabetes 45.5 40.0

Prior LLT 43.4 40.7

No prior LLT 30.0 28.6

LDL-C > 95 mg/dl 31.2 29.6

LDL-C ≤ 95 mg/dl

38.4 36.0

Ezetimibe is the most widely used secondary drug

in patients not at target.

Guidance for Use of PCSK-9 Inhibitors

Until Better Choices Become Available

In patients on maximally tolerated statin Rx:

1. CAD: LDL>100

2. Familial hypercholesterolemia: LDL >130

3. High risk & statin intolerant

Gordon T. J Clin Lipidology 2015

CAD

Cancer

CVA

New Zealand

“In this decade we will win

The Battle with the Nation’s Leading Killer”

USA data for the skeptics

In past decade, heart disease deaths fell 30%.

CAD now causes 24% of all deaths, whereas cancer causes 23%.

Forrester, J. Redefining normal cholesterol. JACC 2010

Choosing Between Two Strategies

Cost of 1st MI =$50,000

Statin reduces MI in a-sx CAD by about 40%

Cost of aggressive Dx & Rx

lipid panel + scan =$225

Statin/yr = $1,800/yr

Cost is roughly 2000/yr

Cost of watchful waiting

500K 1st MI’s x $50K/MI = $25B/yr

Prevent 40% of 1st MI’s, save $4B.

130 M betw 40-60

Cost of 130M x 2000= 260B

Agency for Healthcare Research and Quality 2016

Why More Aggressive?

Cardiovascular Disease Costs $317 Billion/Year

720,000 heart attacks/year: 515,000 are 1st heart attack

Heart attack hospitalization costs $21,500 per stay [5.3 days]

Wiegman A. JAMA 2004

0

2

4

6

8% surface with plaque

93 youth with prior risk factor data studied at autopsy

0 1 >2 2 Number of risk factors

In Youth, Traditional Risk Factors Identify

High Risk That Tracks into Middle Age

Bogalusa Heart Study

Age Risk evaluation Management

Youth

Physical exam, BMI

Lipid panel at age 20

Lifestyle modification

Manage risk factors

LDL upper 5%: statin

Early

middle

age

Diabetic/high risk: Ca++ scan

Statin if Ca++ scan>0

Middle

age

Ca++ scan if > average risk

US if no Ca++ but high risk

Statin if Ca++ scan>0

Target LDL-C <70 mg/dl

if LDL>100 consider 2nd drug

In 2010, in the Battle with Our #1 Killer:

We Were at the Goal Line…

Sidney S. & Rana J. JAMA Card. 2017

Our Guidelines didn’t provide an effective:

Detection strategy for CAD before Sx

Treatment strategy for these patients