lipids: guidelines & best treatment...

Lipids: Guidelines & Best Treatment Options

Michael Miller, MD, FACC, FAHA, FNLA

Professor of Cardiovascular Medicine

University of Maryland School of Medicine

www.drmichaelmiller.org

http://www.drmichaelmiller.org/

Michael Miller, MD, FACC, FAHA, FNLA

Professor of Cardiovascular Medicine, Epidemiology & Public Health

University of Maryland School of Medicine

Director, Center for Preventive Cardiology

University of Maryland Medical Center

Baltimore, MD

Disclosures• Advisory Board: Amarin: Steering Committee for the REDUCE-IT trial

• All adults should adhere to a healthy lifestyle.

• Statin therapy is recommended for adults in groups demonstrated to benefit.

• Engage in a clinician-patient discussion prior to initiating statin therapy, especially for primary preventionin patients with low ASCVD risk

• Current evidence is inadequate to support treatment to specific LDL-C and/or non-HDL-C goals.

• Initiate the appropriate intensity of statin therapy

General Principles of the 2013 ACC/AHA Cholesterol Guidelines

Stone NJ et al. Circulation. 2013

Nov 12 (Epub ahead of print).

Stable ASCVD with comorbidities on statin for 2o prevention

Consider ezetimibe

1st*

Monitor adherence

to meds & lifestyle,

& LDL-C response

Yes

Clinician-patient discussion factors to consider

1. Potential for additional ASCVD risk reduction from addition of non-statin

therapy.

2. Potential for adverse events or drug-drug interactions from addition of non-

statin therapy.

3. Patient preferences.

Consider adding or

replacing with PCSK9

inhibitor 2nd†

Patient has ≥50% LDL-C reduction (may consider LDL-C <70 mg/dL or

non-HDL-C <100 mg/dL) on maximally tolerated statin/other medications

1 2Optional non-statin

meds to consider

Decision for no

additional

medication

No

*May consider bile acid sequestrant (BAS) if ezetimibe intolerant and triglycerides <300 mg/dL. †Consider only if on maximally tolerated statin and either ezetimibe or BAS with persistent <50% LDL-C reduction or LDL-C 70 mg/dL.

Lloyd-Jones DM et al. J Am Coll Cardiol. 2016;68:92-125.

ACC Expert Consensus Pathway on Non-statin Therapies

Beyond Statins: Status of Add-on Therapies

• Ezetimibe

• PCSK9i

• OM3

• Apo C-III antisense antibodies

• Anti-inflammatory Compounds (Methotrexate, IL-1B)

Study drug is administered once daily in the evening.Cannon CP et al. Am Heart J. 2008;156:826-32.

100

90

80

70

60

50

40

R 1 4 8 12 16 24 36 48 60 72 84 96

Time since randomization (months)

EZ/Simvastatin 53.2 125.8 120.4 48.7 3.3M

ean

LD

L-C

(m

g/d

L)

Median Time avg

69.5 vs 53.7 mg/dL

Simvastatin 69.9 145.1 137.1 48.1 3.8

Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5

1 yr mean LDL-C TC TG HDL-C hsCRP

Simvastatin

EZ/Simvastatin

IMPROVE IT Trial: Effect on LDL-CEzetimibe (EZ) + Simvastatin vs Simvastatin Alone

FDA-Approved PCSK9 Inhibitors (fully human monoclonal antibodies)

Alirocumab:

• Indicated as adjunct to diet and 1) maximally tolerated statin therapy for the treatment of adults with

heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease

(ASCVD), who require additional lowering of LDL-C.

• Dose: Initiate 75 mg SC every 2 weeks (The majority of patients achieve sufficient LDL-C reduction with

this dosage.) If LDL-C response is inadequate, may be increased to 150 mg every 2 weeks.

Evolocumab:

• Indicated as an adjunct to diet and:

1) Maximally tolerated statin therapy for treatment of adults with heterozygous familial

hypercholesterolemia (HeFH) or clinical ASCVD, who require additional lowering of LDL-C

2) Other LDL-C-lowering therapies (eg, statins, ezetimibe, LDL apheresis) in patients with homozygous

familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C

• Dose: ASCVD or HeFH: 140 mg every 2 weeks or 420 mg once monthly. For HoFH: 420 mg once

monthly. Note: The 420 mg dose can be administered: 1) over 9 minutes by using the single-use on-body

infuser with prefilled cartridge, or 2) by SC.

Alirocumab Evolocumab Bococizumab

Sponsor Sanofi/Regeneron Amgen Pfizer

Trial ODYSSEY Outcomes FOURIER SPIRE I & 2

Sample Size 18,000 28,000 27,000

Patients 4-16 weeks post-ACS MI, stroke, or PAD High risk of CV event

Statin Evidence-based Rx Atorvastatin ≥20 mg or equivalent Lipid-lowering Rx

LDL-C ≥70 mg/dL ≥70 mg/dL 70-99, 100 mg/dL

Dosing (SC) Every 2 weeks Every 2 or Every 4 weeks Every 2 weeks

EndpointCHD death, MI, ischemic

stroke, or UA hospitalization

Primary: CV death, MI, stroke, UA

hospitalization or coronary revascularization

Key Secondary: CV death, MI, or stroke

CV death, MI, stroke, or

urgent revascularization

Completion February 2018 November 2016 Discontinued 11/2016

Available at: Clinicaltrials.gov.

PCSK9 Inhibitors Cardiovascular Outcomes Trials

Nicholls SJ, et al. JAMA. 2016;316:2373-2384.

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

0 8 16 24 32 40 48 56 64 72 80 88

LD

L-C

Perc

en

tag

e C

han

ge

fro

m B

ase

lin

e (

%)

Study Week

Mean LDL-C 93.0 mg/dL


Change from baseline 3.9%

Change from baseline -59.8%

29 mg/dL

90 mg/dL

GLAGOV: Percent Change in LDL-C During Treatment




Change from baseline 3.9%

Change from baseline -59.8%29 mg/dL

90 mg/dL

0.05

-0.95

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

Changein Percent Atheroma

Volume(%)

Statin

monotherapy

Statin-

evolocumab

P<0.0001

P = NS

P<0.001

GLAGOV Primary Endpoint: Percent Atheroma Volume


FOURIER

Further cardiovascular OUtcomes

Research with PCSK9 Inhibition

in subjects with Elevated Risk

MS Sabatine, RP Giugliano, AC Keech, N Honarpour,

SM Wasserman, PS Sever, and TR Pedersen,

for the FOURIER Steering Committee & Investigators

American College of Cardiology – 66th Annual Scientific Session

Late-Breaking Clinical Trial

March 17, 2017

Evolocumab SC 140 mg Q2W or 420 mg QM

Placebo SCQ2W or QM

LDL-C ≥70 mg/dL or

non-HDL-C ≥100 mg/dL

Follow-up Q 12 weeks

Screening, Lipid Stabilization, and Placebo Run-in

High or moderate intensity statin therapy (± ezetimibe)

27,564 high-risk, stable patients with established CV disease

(prior MI, prior stroke, or symptomatic PAD)

RANDOMIZED

DOUBLE BLIND

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

Trial Design

Characteristic Value

Age, years, mean (SD) 63 (9)

Male sex (%) 75

Type of cardiovascular disease (%)

Myocardial infarction 81

Stroke (non-hemorrhagic) 19

Symptomatic PAD 13

Cardiovascular risk factor (%)

Hypertension 80

Diabetes mellitus 37

Current cigarette use 28

Pooled data; no differences between treatment arms.

Median time

from most

recent event

~3 yrs

Baseline Characteristics


Characteristic Value

Statin use (%)*

High-intensity 69

Moderate-intensity 30

Ezetimibe use (%) 5

Median lipid measures (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.

Pooled data; no differences between treatment arms.

Lipid-lowering Therapy & Lipid Levels at Baseline


An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

0

10

20

30

40

50

60

70

80

90

100

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

LD

L C

ho

leste

rol

(mg

/dl)

Weeks

LDL Cholesterol

Evolocumab

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

Placebo

59% mean reduction (95%CI 58-60), P<0.00001

Absolute reduction: 56 mg/dl (95%CI 55-57)

LDL Cholesterol


An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

0%

2%

4%

6%

8%

10%

12%

14%

16%

Primary Endpoint

Evolocumab

Placebo

Months from Randomization

CV

Death

, M

I, S

tro

ke,

Ho

sp

fo

r U

A,

or

Co

rR

evasc

0 6 12 18 24 30 36

Hazard ratio 0.85

(95% CI, 0.79-0.92)

P<0.0001 12.6%

14.6%

Primary Endpoint


Anti-inflammatory Effects of Omega-3 through Mediator Balance

Modified from Endo J, Arita M. J Cardiol. 2016;67:22-7.

O

OH

6

Omega-6 PUFAs

Arachidonic acid (AA)

1

2

3

Prostaglandin E2 Leukotriene B4

Prostaglandin E3 Leukotriene B5

Less potent inflammatory mediators Anti-inflammatory mediators

Maresin

Resolvin E1 Protectin D1

OH

OH

OH

OH

O

O

O OO

Proinflammatory mediators

Omega-3 PUFAs

OH

OH

OHOH

OH

OH

OH

OH

O

O

OHOH

OHOH

OH

OH

3

3

O

OH

Docosahexaenoic acid

Eicosapentaenoic acid

OH

O

Omega-3:arachiadonic acid (AA) ratio can either enhance (↑ ω-3:AA ratio),

or inhibit (↓ ω-3:AA ratio) anti-inflammatory effects

Effect of EPA on Inflammatory Markers (Baseline to week 12, intent-to-treat population)

*P<0.01; †P<0.001; ‡P<0.0001 (vs placebo). P values for Lp-PLA2 were adjusted for multiple comparisons.

hsCRP=high-sensitivity C-reactive protein; ICAM-1=intercellular adhesion molecule-1; IL-6=interleukin-6; IPE=icosapent ethyl; Lp-PLA2=lipoprotein-associated

phospholipase A2; NS=not significant; Ox-LDL=oxidized low-density lipoprotein.

Bays HE et al. Am J Cardiovasc Drugs. 2013;13:37-46.

-2.5

-6.6

-13.6

11.0

-36.0

-2.4

-13.3

-19.0

-1.0

-22.0

-40

-30

-20

-10

0

10

20

MARINE 4 g/day

ANCHOR 4 g/day

ICAM-1 Ox-LDL Lp-PLA2 IL-6 hsCRPM

ed

ian

Pla

ce

bo

-ad

jus

ted

Ch

an

ge

(%

)

IPE

NS NS

NS

‡ †

‡

NS

*

†

NS

Effects of EPA on Atherosclerotic Plaques by Imaging Modality

Study Patient Population N Treatment Summary of Findings

Angiography

Domei et al, 2013

(J-EACH)Patients undergoing PCI 37

EPA (dose not specified) +

optimal LDL-C-lowering

statin therapy or statin alone

Significant in lumen diameter (P=0.020) & % stenosis

(P=0.026) in EPA+statin group vs statin-alone group

Nagahara et al, 2016Patients with ACS; all were

receiving statin treatment after

baseline CCTA measurement

82

EPA 1.8 g/day, EPA 0.93

g/day + DHA 0.75 g/day or

control

EPA significantly associated with prevention of plaque

progression (P=0.0061)

Multi-detector Row Computed Tomography

Shintani et al, 2012

(JELIS)Patients with suspected CAD and

LDL-C levels <160 mg/dL43 EPA or ezetimibe

Significant in soft-plaque volume in EPA group but not in

ezetimibe group; significant improvements in EPA group in

plaque area (P=0.017), lumen area (P=0.004), & plaque

volume vs ezetimibe group (P=0.036)

Carotid Ultrasound

Katoh et al, 2011 Patients with HTG 10 EPA 1.8 g/day

Significant in IMT with EPA treatment vs baseline

(P<0.05); IMT correlated with blood EPA concentration and

EPA/AA ratio (P<0.01)

Mita et al, 2007 Patients with T2DM 81 EPA 1.8 g/day or controlSignificant annual in mean IMT (P=0.029) &

maximal IMT (P=0.0008) in EPA group vs control group

Maeda et al, 2014Patients with risk factors for

arteriosclerosis46 EPA 1.8 g/day Significant in maximal IMT with EPA treatment (P<0.0001)

Takaki et al, 2011Patients with dyslipidemia and Hx

of CAD ≥3 months before study50

EPA 1.8 g/day + statin or

statin alone

No difference in change in baPWV observed between

groups (P=0.29); carotid β index was in EPA + statin

group vs statin-alone group (P=0.02)

Nelson JR et al. Vascul Pharmacol. 2017. In press.

EPA was associated with

significant reductions in

lumen diameter, plaque

volume, and intima-media

thickness

Alexander DD et al. Mayo Clin Proc. 2017;92:15-29. Circles represent the RR within the individual studies; 95% CIs are represented by

horizontal lines. Circle size is proportional to the weight of each study. Diamonds represent the summary relative risk estimate (SRRE).

Randomized Controlled Trials and Prospective Cohort

Studies of EPA+DHA and CHD Risk

Subjects with baseline TG levels >150 mg/dL

Subjects with baseline LDL-C >130 mg/dL Association between EPA+DHA intake and any CHD

event in prospective cohort studiesAuthor, year

Von Schacky et al, 1999

Marchioli et al, 2001

Yokoyama et al, 2007

Einvik et al, 2010

Roncaglioni et al, 2013

SRRE: 0.86 (95% CI: 0.76-0.98)

P-H: .30; I2: 18.7

Favors EPA+DHA Favors Control

1.00.2 0.5 2 5

RR (95% CI)

Author, year RR (95% CI)

1.00.2 0.5 2 5

Favors EPA+DHA Favors Control

Singh et al, 1997

Von Schacky et al, 1999

Marchioli et al, 2001

Yokoyama et al, 2007

Einvik et al, 2010

SRRE: 0.84 (95% CI: 0.72-0.98)

P-H: .21; I2: 30.20.2 0.5 1.0 2 5

Favors EPA+DHA

intake

Does not favor

EPA+DHA intake

Roncaglioni et al, 2013

Author, year RR (95% CI)

Pietinen et al, 1997

Albert et al, 1998

Yuan et al, 2001

Hu et al, 2002

Mozaffarian et al, 2005

Iso et al, 2006

Jarvinen et al, 2006

Jarvinen et al, 2006 (M)

Streppel et al, 2008

De Goede et al, 2010

Joensen et al, 2010 (F)

Joensen et al, 2010 (M)

Manger et al, 2010

Chiuve et al, 2012

Takata et al, 2013

Amiano et al, 2014 (F)

Amiano et al, 2014 (M)

Miyagawa et al, 2014

Bergkvist et al, 2015

Koh et al, 2015

SRRE: 0.82 (95% CI: 0.74-0.92)

P-H: .001; I2: 66.1

Ongoing EPA+DHA and EPA-only: CVD Outcome Studies

1,2. http://www.clinicaltrials.gov. RRR=relative risk reduction.

REDUCE-IT1 (Ongoing) STRENGTH2 (Ongoing)

Omega-3 type, Dose EPA, 4 g/day EPA+DHA (FFA), 4 g/day

Population International International

N ~8000 Estimated 13,000

GenderMen and non-pregnant or sterile women,

ages ≥45 yearsMen or women, ages ≥18 years

Risk ProfileTG >150 mg/dL

+CHD or ↑CHD riskHigh CV risk (50%), prior ASCVD (50%)

Follow-up 4–6 years (planned) 3-5 years (planned)

Statin Use100%

(at LDL-C goal)

100%

(at LDL-C goal)

Primary Endpoint Expanded major adverse cardiac event Expanded Major adverse cardiac event

Result Powered for 15% RRR Powered for 15% RRR

Baseline TG >200 mg/dL ≥200 mg/dL, <500 mg/dL

RR (CC)=Noncarriers of the 19X allele; RX (CT)=Carriers of the 19X allele. Pollin TI, et al. Science. 2008;322:1702-5 .

A Mutation in Human Apo C3 Causes Very Low TG Levels and Lower Coronary Calcium Scores

0

1000

2000

3000

4000

5000

6000

7000

8000

25 35 45 55 65 75 85 95

Age (years)

Co

ron

ary

Art

ery

Calc

ium

sco

re

RR (CC)

RX (CT)

RR (CC)

RX (CT)

90

90

70

60

50

40

30

20

10

00 0.2 0.4 0.6 0.8 1 1.2 1.4

Apo C-III (relative)

Fasti

ng

TG

(m

g/d

L)

Apo=apolipoprotein; TG=triglyceride(s); VLDL=very-low-density lipoprotein. Libby P. Eur Heart J. 2015;36:774-6.

Apo E

Hepatic uptakeLipolysis

Lipoprotein

Lipase

Inflammation

Apo C-III

Hepatic remnant

lipoprotein

receptors

Vascular cell

Adhesion

Molecule-1

Apo C3 Regulates Lipolysis, Inflammation, and Hepatic Remnant Lipoprotein Uptake

Liver

VLDL

TG-rich lipoprotein in plasma

Potentiation of Vascular Risk Induced by Apo C-III

Miller M. Arterioscler Thromb Vasc Biol. 2017; 37:1013-1014.

TRLs

CM/

VLDL

CMR/

VLDLR/

IDL

RemnantsVascular Wall

LDL,

sdLDL

LPL

HL LPL

Intestine

Apo B Apo B

Apo C-III

Lipoprotein

ReceptorsNF-ĸβ

VCAM1

Liver

Apo C-IIIApo C-III

Apo C-III Apo C-IIIApo C-III

Apo C-III

Apo C-III

Apo B

Apo C-III

Apo C-III

Apo C-III

Apo C-III

Apo C-III

Levels of Apo C-III (APOC3), TG & HDL-C following ISIS30481 Antisense Inhibitor of APOC3

Gaudet D et al. N Engl J Med. 2015;373:438-47.

Ridker PM. Circ Res. 2016;118:145-56.

Meta-analysis of hsCRP Levels in Healthy Individuals to Future Risks of CHD


Testing Anti-inflammatory Interventions for CVD Risk Reduction

Dose-dependent effects of canakinumab at 4 months for

CRP, interleukin-6, and fibrinogen among 556 diabetic

patients at high risk for vascular disease


Design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS)


Ridker PM et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1707914

Effects of Canakinumab, as Compared with Placebo, on Plasma Levels of High-Sensitivity C-Reactive Protein, Low-Density Lipoprotein (LDL)

Cholesterol, High-Density Lipoprotein (HDL) Cholesterol, and Triglycerides.


Cumulative Incidence of the Primary End Point and the Key Secondary Cardiovascular End Point.


Characteristics of the Trial Participants.


Incidence Rates and Hazard Ratios for Major Clinical Outcomes and All-Cause Mortality.


Incidence Rates and Numbers of Serious Adverse Events and Selected Safety Laboratory Data During Treatment, Stratified

According to Trial Group.

Cardiovascular Inflammation Reduction Trial (CIRT)

Primary Objective:

• To determine whether low dose methotrexate (target dose 15-20 mg/wk)

reduces MACE

Inclusion criteria (n=7000)

• Age ≥18 yrs at screening

• Documented MI (>60 days but <5 yrs)

• History of T2DM or MetS

Event Driven (530 events; MI, CVA, CV death)

• Average follow-up period: 3-4 years

Everett BM et al. Am Heart J. 2013;166:199-207.

Cardiovascular Inflammation Reduction Trial (CIRT)

Everett BM et al. Am Heart J. 2013;166:199-207.

CIRT: Titration Algorithm for Low-Dose Methotrexate

*New & persistent stomatitis, vomiting, diarrhea, unexplained cough with fever or shortness of breath. Everett BM et al. Am Heart J. 2013;166:199-207.

Lipids: Guidelines & Best Treatment Options: Conclusions

• Statins are the mainstay for treatment of hyperlipidemia

• Non-statin therapies (ezetimibe, PCSK9i) that lower LDL-C are

associated with improved outcomes, despite modest anti-

inflammatory effects

• Over the next 1-3 years, RCTs will examine effectiveness:

↓ TG (+/- inflammation) using OM3

↓ Inflammation (in the absence of lipid lowering)

lipids: guidelines & best treatment...

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