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BACK TO THE FUTURE:
CONTEMPORARY LIPID
LOWERING AGENTS
Dean A. Bramlet MD FACC FAHA FNLA
Asst. Consulting Professor of Medicine
Duke University, and
The Heart & Lipid Institute of Florida
ST. Petersburg, Florida
 Disclosures

• Speaker/Consultant- Aralez Pharmaceuticals, Inc.

• Speaker/Consultant- Amarin Pharmaceuticals, Inc.
• SpeakerConsultant/- Kowa Pharmaceuticals, Inc.
• Speaker/Consultant- Sanofi U.S. and Regeneron
Pharmaceuticals
• Consultant-Kastle
 BACK TO THE FUTURE
Marty McFly
“Hey Doc we better
back up. We don’t have
enough road to get up to 88
(mph).”

Dr. Emmett Brown

“Roads? Where
we’re going, we don’ need
roads.”
 PRESENTATION AGENDA
• Overview of new data on PCSK9 inhibitors
• Treating Populations with Hypertriglyceridemia
Omega-3 Fatty Acids
Fibrates and Niacin
• What to do when the Data is Lacking
 PRESENTATION AGENDA
• Overview of new data on PCSK9 inhibitors
• Treating Populations with Hypertriglyceridemia
Omega-3 Fatty Acids
Fibrates and Niacin
• What to do when the Data is Lacking
The Forgotten Majority: Residual Burden of CV
Events Remains High in the Statin “Megatrials”
80%
75% 75% 73%
69%
Residual Major Coronary Events (%)

62% 62%
60%

40%

20%

0%
Trial
4S LIPID CARE HPS WOS AFCAPS /
N 4,444 9,014 4,159 20,536 6,595 TexCAPS
6,605
LDL -36% -25% -28% -29% -26% -27%

Secondary High Risk Primary

Libby P. JACC 2005;46:1225.

WILL PCSK9-I ADDED TO HIGH INTENSITY
STATINS FURTHER REDUCE CV EVENTS?
WILL PCSK9-I ADDED TO HIGH INTENSITY
STATINS FURTHER REDUCE CV EVENTS?
 ODYSSEY LONG-TERM: Post-Hoc Analysis of Subgroup of
Adjudicated Major Adverse Cardiovascular Events*
1.0
0.06
Cumulative Probability of

0.8
0.04 Placebo

0.6
Event (%)

0.02 Alirocumab

0.4 0.00
0 12 24 36 52 64 78

0. 2 Cox model analysis Placebo + statin therapy at

HR = 0.52 (95% CI 0.31–0.90) maximum tolerated dose +/- LLT
Nominal P value ≤ 0.01
Alirocumab + statin therapy at
0.0 maximum tolerated dose +/- LLT

0 12 24 36 52 64 78
Time (weeks)
*same primary endpoint as ongoing ODYSSEY OUTCOMES trial
Robinson JG, et al. N Engl J Med. 2015;372(16):1489-1499.
 Clinical Outcomes Studies with
PCSK9 inhibitors
• META-ANALYSIS OF PCSK9-I CLINICAL DATA
• 24 studies-(n=10,159)
• Reduced risk of Myocardial Infarction-OR 0.49 (0.26-0.93)
• Reduced All Cause Mortality-OR 0.45 (0.23-0.86)
• PCSK9-I OUTCOME TRIALS
• FOURIER (NCT 01764633-25,000 patients)
• ODYSSEY OUTCOMES (NCT 01663402-18,000 patients)
• SPIRE I, II (NCT 01975376,89)-DISCONTINUED

Navarese EP et al. Ann Intern Med. 2015; 163:40-51.

 FOURIER
Further Cardiovascular Outcomes Research with
PCSK9 Inhibition in Patients with Elevated Risk
• OBJECTIVES:
• Test whether addition of evolocumab to statin Rx
further reduces incidence of MACE
• Examine long term safety/tolerability of evolocumab
• Investigate efficacy and safety of achieving
unprecented low levels of LDL-C
• Conducted in 1242 sites in 40 countries with
randomization 2/13-3/15
• Eligibility: 40-85 y/o (mean 63 y/o); median 2.2
years follow up
Sabatine, et al, Mar 17, 2017NEJMoa1615664
 FOURIER: Trial Design
27,564 high-risk, stable patients with established CV disease by virtue of
prior MI (81%), prior stroke (21%), or symptomatic PAD (13%)

Screening, Lipid Stabilization, and Placebo Run-in

High (69%) or moderate intensity statin therapy (± ezetimibe)

LDL-C ≥70 mg/dL or

non-HDL-C ≥100 mg/dL

RANDOMIZED
DOUBLE BLIND
Evolocumab SC Placebo SC
140 mg Q2W or 420 mg QM Q2W or QM

Follow-up Q 12 weeks

Sabatine MS et al. Am Heart J 2016;173:94-101

 FOURIER: Baseline Characteristics
Characteristic Value
Age, years, mean (SD) 63 (9)
Male sex (%) 75
Type of cardiovascular disease (%)
Myocardial infarction 81 Median time post
Stroke (non-hemorrhagic) 19 recent CVE ~3 yrs
Symptomatic PAD 13
Cardiovascular risk factor (%)
Hypertension 80
Diabetes mellitus 37
Current cigarette use 28

Sabatine, MS, et al; NEJM 2017 Pooled data; no differences between treatment arms
 FOURIER: Background Lipid Lowering
Therapy & Baseline Lipid Levels
Characteristic Value
STATIN USE (%)*
High-intensity 69
Moderate-intensity 30
Ezetimibe use (%) 5
MEDIAN LIPID LEVELS (IQR) – mg/dL
LDL-C 92 (80-109)
Total cholesterol 168 (151-189)
HDL-C 44 (37-53)
Triglycerides 133 (100-182)

*Per protocol, patients were to be on atorva ≥20 mg/d or equivalent.

1% were on low intensity or intensity data were missing.
Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines.
Sabatine, MS, et al; NEJM 2017 Pooled data; no differences between treatment arms
 LDL Cholesterol in FOURIER
100
Placebo
90

80
LDL Cholesterol (mg/dl)

70
59% mean reduction (95%CI 58-60), P<0.00001
60
Absolute reduction: 56 mg/dl (95%CI 55-57)
50

40

30
Evolocumab
20
(median 30 mg/dl, IQR 19-46 mg/dl)
10

0
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Weeks
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School Sabatine, MS, et al. NEJM 2017
 FOURIER
A. PRIMARY ENDPOINT
CV Death, MI CVA, Hosp. for
UA, Coronary Revasc.
B. SECONDARY ENDPOINT
CV Death, MI, CVA

Sabatine, MS, et al NEJM 2017

 Comparison to Cholesterol
Treatment Trialists Collaboration
Hazard Ratio (95% CI) per 1 mmol/L reduction in LDL-C

Major Coronary Events 0.78 (0.70-0.86)

0.80 (0.71-0.90)

Stroke 0.77 (0.66-0.91)

0.77 (0.63-0.94)
CTTC Meta-analysis Year 2
FOURIER Year 2
Coronary revascularization 0.75 (0.67-0.84)
Urgent 0.73 (0.62-0.86)
Elective 0.84 (0.73-0.98)

Major Vascular Events 0.77 (0.73-0.82)

0.83 (0.76-0.90)

0.5 1.0 2.0

Lipid-lowering therapy better Lipid-lowering therapy worse
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School CTTC data from Lancet 2010;376:1670-81
 CARDIOVASCULAR OUTCOMES
Evolocumab Placebo
Endpoint (N=13,784) (N=13,780) HR (95% CI)
3-yr Kaplan-Meier rate
CVD, MI, stroke, UA, or revasc 12.6 14.6 0.85 (0.79-0.92)
CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88)
Cardiovascular death 2.5 2.4 1.05 (0.88-1.25)
MI 4.4 6.3 0.73 (0.65-0.82)
Stroke 2.2 2.6 0.79 (0.66-0.95)
Hosp for unstable angina 2.2 2.3 0.99 (0.82-1.18)
Coronary revasc 7.0 9.2 0.78 (0.71-0.86)
Urgent 3.7 5.4 0.73 (0.64-0.83)
Elective 3.9 4.6 0.83 (0.73-0.95)
Death from any cause 4.8 4.3 1.04 (0.91-1.19)

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School FOURIER NEJM 2017
 Intensive LDL-C Lowering
& Cardiovascular Death
No clear benefit on CV mortality in multiple statin trials
# of CV Deaths
Trial Year More Less HR (95% CI)
Intensive Intensive
Rx Arm Rx Arm
PROVE-IT TIMI 22 2004 27 36 0.74 (0.45-1.22)
A2Z 2004 86 111 0.76 (0.57-1.01)
TNT 2005 101 127 0.80 (0.61-1.03)
IDEAL 2005 223 218 1.03 (0.85-1.24)
SEARCH 2010 565 572 0.99 (0.88-1.11)
IMPROVE-IT 2015 538 537 1.00 (0.89-1.13)
Summary 1540 1601 0.96 (0.90-1.03)

0.2 0.5 1 2 5
More intensive Less intensive
NEJM 2004;350:1495-504 AMA 2004;292:1307-16 NEJM 2005;352:1425-35 therapy better therapy better
JAMA 2005;294:2437-45 Lancet 2010;376:1658-69 NEJM 2015;372:2387-97
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
 In FOURIER
FOURIER

Sabatine, et al NEJM 2017

 FOURIER SAFETY ANALYSIS
Evolocumab Placebo
(N=13,769) (N=13,756)
ADVERSE EVENTS (%)
Any 77.4 77.4
Serious 24.8 24.7
Allergic reaction 3.1 2.9
Injection-site reaction 2.1 1.6
Treatment-related and led to d/c of study drug 1.6 1.5
Muscle-related 5.0 4.8
Cataract 1.7 1.8
Diabetes (new-onset) 8.1 7.7
Neurocognitive 1.6 1.5
LABORATORY RESULTS (%)
Binding Ab 0.3 n/a
Neutralizing Ab none n/a
New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School Sabatine, MS, et al: NEJM 2017
Swinger,KJ, 2015 Drug Safety.38(6);519
EBBINGHAUS TRIAL: A Neurocognitive
Non-inferiority Sub-study of Fourier

1850-1909

Wozniak, RH. 1999; Classics in Psychology

 EBBINGHAUS: CANTAB* ASSESSMENT
*Cambridge Neuropsychological Test Automated Battery-standardized tablet-based platform

1974 pts. w/o cognitive issues; age 63 y/o ave.; prior CVA in 20%

ACC Sciientific Sessions 2017; Giugliano,RP, et al. Clin Cardiol.2017 Feb;40(2):59-65

 IS ACHIEVING ULTRA-LOW LDL-C SAFE?
• Human LDL-C levels are ~ 30mg% in late gestation in utero
• FHBL patients generally healthy with low CVD risk
• Homozygous PCSK9 LOF Mutation: LDL-C 15mg/dl
• In Jupter, patients attaining LDL-C <50 mg% achieved 46%
reduction in ACM and 65% decrease in MACE
HOWEVER:
• TNT revealed a nonsignificant excess of non-CV deaths
(p=0.06) in patients receiving atorvastatin 80 vs 10 mg daily
• Meta-analysis indicates risk of incident DM was 12% (CI-4-
22%) greater with more intensive statin therapy than less
intensive statin therapy
LaRosa JC et al Am J Card 2012;1221-9
 ACHIEVING ULTRA-LOW LDL-C: Safety
• In ODYSSEY-LT: 575 (37.1%) patients achieved two
consecutive calculated LDL-C levels < 25 mg%, and 288
patients (8.6%) reached values <15mg%; no sig. increased
adverse effects observed
- No discontinuation/adjustments of Rx generally made
• In OSLER: AST and CK levels in patients on evolocumab with
LDL-C < 40mg% or < 25mg% (13.3%) were similar in adverse
effects to those with higher LDL-C
-No discontinuation/adjustment of Rx generally made

LaRosa JC et al Am J Card 2012;1221-9

 Alirocumab (ODYSSEY LONG TERM)
Safety Analysis In 575 (37.1%) Pts with LDL-C<25mg%*

*Among patients who received alirocumab, 575 (37.1%) had a calculated LDL-C level of < 25 mg/dL at 2
consecutive measurements. Rates of AEs were similar to those overall on RX.
Robinson JG, et al. N Engl J Med. 2015;372(16):1489-1499.
 PRESENTATION AGENDA
• Overview of new data on PCSK9 inhibitors
• Treating Populations with Hypertriglyceridemia
Omega-3 Fatty Acids
Fibrates and Niacin
• What to do when the Data is Lacking
Risk of Pancreatitis and Triglyceride Levels
Incidence of Acute Pancreatitis*
Observed rate (cases per 1000 patient–years)
1993-2007
Acute pancreatitis risk
2.5 is increased 4%
for each 100 mg/dL
2.0
increase in TG*
1.5

1.0 2010 Census US adults:

Trigs 200-499 mg/dl
0.5
36.4M
0.0
≤149 150-499 ≥500
Trigs >500 mg/dl
(n=31,740) (n=31,887) (n=3,642) 3.8M
TG Level (mg/dL)

*After adjustment for covariates and removal of patients hospitalized for gallstones, chronic pancreatitis, alcohol-related
morbidities, renal failure, and other biliary disease. Includes cases of Amylase >300 U/L
Murphy M, et al. JAMA Intern Med. 2013;173:162-164/Maki, K et al.J Clin Lipidol 2013(6) 413-426.
Triglyceride Level Is Significant CVD Risk Factor
Meta-Analysis of 29 Studies N = 262 525
Groups CHD Cases
CHD Risk Ratio* (95% CI)
Duration of follow-up
≥10 years 5902
<10 years 4256
Sex
Male 7728
Female 1994

Fasting status
Fasting 7484
Nonfasting 2674
Adjusted for HDL
Yes 4469
No 5689
Overall CHD Risk Ratio* 1.72 (1.56-1.90)
Decreased Increased
*Individuals in top versus bottom third of Risk 1 Risk 2
usual log-triglyceride values, adjusted for at
least age, sex, smoking status, lipid
concentrations, and blood pressure (most) Sarwar N, et al. Circulation. 2007;115:450-458.
 Statin Therapy Does Not Eliminate the CVD
Risk Associated With High Triglyceride Level
**High TG >354 (HPS); >207 (CARE/LIPID)
*Low TG <177 (HPS);<98 (CARE/LIPID) Low TG* + statin
High TG**+ statin
30
24.7
23.2
CVD Event Rate, %

20.3
20 18.3

10

0
HPS CARE/LIPID
HPS Collaborative Group. Lancet. 2002;360:7-22.
Sacks FM et al. Circulation. 2000;102:1893-1900.
Low HDL-C Increases CVD Risk Even if
LDL-C Levels are Well-Controlled
Treating to New Targets (TNT) Study
Patients With LDL-C ≤80 mg/dL on Atorvastatin 80 mg
12 P<.0001 for Inverse Relationship
Major CVD Events, %

10.1
10
8.1 7.7
8 7.2

0
≤40
<=40
41-50
41-50
51-60
51-60
>60
>60
n = 4874
HDL-C* (mg/dL)
*On-treatment level (3 months) Barter P, et al. Poster presented at 2006 ACC. Abstract 914-203.
TGRL METABOLISM IN HYPERTRIGLYCERIDEMIA

CETP Activated → TG
TG enrichment of LDL and HDL Cholesterol

Insulin Resistance Apo A-I

TG
Apo A-I
↑ FFA
HDL
HTGL HDL

TG CETP CE
Small,
TG TG TG dense
TG TG HDL
↑ TG TG
VLDL
TG VLDL Apo B-
Synthesis 100
CE

↑ VLDL TG CE
CETP
Synthesis Apo B-
Liver HTGL 100

Apo B- LDL
LDL
LD
TG
100 L
Small,
dense
LDL
CETP, cholesterol ester transfer protein; HTGL, hepatic TG lipase; CE, cholesteryl ester.
Miller M, et al. Circulation. 2011;123:2292-2333.
ONGOING OMEGA-3 TRIALS
REDUCE-IT
• 8000 patients > 44 y/o
• LDL-C<100 but >4Omg/dl
• CHD or High Risk
• Trigs >200 mg/dl
• Rx: Ethyl-EPA on Statins
• PRIMARY OUTCOME:
• MACE
Clin Trials.Gov .NCT01492361
STRENGTH
• 13,000 patients >18 y/o
• LDL-C <100 mg/dl
• High Risk on statins
• TG<500mg/dl & >180mg/dl
& HDL-C<42 men(<47wom)
• Rx: O-3-carboxylic acids
• PRIMARY OUTCOME:
• MACE
Clin Trials.Gov. NCT02104817
TREATING TRIGLYCERIDES:
WEIGHING THE DECISION

Potential
BENEFITS RISKS
TRIGLYERIDES: To Treat or Not To Treat:
TRIGLYERIDES: To Treat or Not To Treat:
“When you
arrive at a
fork in the
road, take
it.”
Lawrence Peter
“Yogi” Berra*

*18 time All-Star and winner of 10

World Series Championships
1925-2015
( greatest in MLB history)
BREAKING NEWS: Lifestyle Modifications are
The Cornerstones for Management of HTG

Diet Modification
(type and amount of carbohydrate and fat)
Control Diabetes Mellitus
BREAKING NEWS: Lifestyle Modifications are
The Cornerstones for Management of HTG
Diet Modification
Weight Loss (type and amount of
carbohydrate and fat)
Control Diabetes Mellitus

↓ Alcohol
↑ Physical Activity
Consumption

Miller et al. Circulation. 2011;123:2292-2333.

 PRESENTATION AGENDA
• Overview of new data on PCSK9 inhibitors
• Treating Populations with Hypertriglyceridemia
Omega-3 Fatty Acids
Fibrates and Niacin
• What to do when the Data is Lacking
 DIFFERENT TYPES OF MEDICAL
EVIDENCE MAY EXIST

Adapted from Evidence Based Medicine; Shetty, Suhasini,K.; 22,Jan 2015

FACTORS MAY MODIFY THE
SRENGTH OF RECOMMENDATIONS
• Treatment decisions involve trade-offs between
benefits, risks, disease burdon, and costs
• RCTs may have been is similar but not identical
populations to the subject of interest
• Many factors influence strength of recommendations
• Quality of evidence
• Baseline risks/relative importance of outcomes
• Relative and absolute magnitude of effect of Rx
• Precision of estimates of effects (confidence limits)
• Cost effectiveness of Rx
• Observation studies can provide moderate or high-
quality strength of evidence
UpToDate
AHA EVIDENCE CLASSIFICATION

American Heart Association

 WHAT TO DO WHEN DATA IS LACKING
• Avoid assumptions
• With something that is believed to be true without
proof, the tendency is to expect too much
• Be careful of preconceived ideas
• Formed in the mind in advance, especially if based on
little or no information or experience and may reflect
personal prejudices
• Try to recognize biases
• An unfair preference or dislike for something
• Use honesty in patient counseling
• Establish an informed alliance with the patient based on
the strength of data for treatment considerations
Modified from Hutchinson M et al sccgov.org/sites..The clinicians guide to writing treatment plans
and progress notes-accessed 1/9/2017
 2013 ACC/AHA Guidelines Preamble
“Guidelines attempt to define practices that meet the
needs of patients in most circumstances and are not
a replacement for clinical judgment.
The ultimate decision about care of a particular
patient must be made by the healthcare provider and
patient in light of the circumstances presented by
that patient.
As a result, situations might arise in which deviations
from these guidelines may be appropriate.”
Stone N et al. Circulation. 2014; 129(25 suppl 2):S1-45.
Conclusions:
In patients with known cardiovascular disease:

1. PCSK9 inhibition significantly & safely  major

cardiovascular events when added to statin therapy
-Benefit was achieved with lowering LDL-C well below current
highest risk target values
2. Niacin/Fibrate data in subgroup studies are supportive
for a role in addressing residual Lipid risk, but
confirmatory highest level of evidence is lacking
3. High doses Omega-3FAs safely reduce Triglycerides;
and in a Japanese outcomes study reduced CV events
4. Medicine is not an exact science , but a science of
probabilities;………………………………………………………..
………………………..and remember,
EVIDENCE MAY CHANGE OVER TIME !