Hyperlipidemia Update

Alabama ACC Meeting, June 2016

Vera Bittner, MD, MSPH, FACC

Professor of Medicine

Section Head, General Cardiology, Prevention, and Imaging

Medical Director, Cardiac Rehabilitation and CCU

University of Alabama at Birmingham

Disclosures: Vera Bittner, MD, MSPH

UAB Contracts

Sanofi/Regeneron Steering Committee ODYSSEY

Amgen Investigator Pharmacoepidemiology

DalCor National Coordinator DalGene

Astra-Zeneca National Coordinator

Site PI

STRENGTH

ARTEMIS

Bayer Site PI COMPASS

Other

Eli Lilly 2 Advisory Boards

Amgen 1 Advisory Board

Pfizer TNT related manuscripts

PackHealth Review of grant proposal

ABIM CVD Question Writing

Committee

Outline

2013 ACC/AHA Cholesterol Guideline Recap

2016 ACC Consensus Decision Pathway on

Non-Statin Therapy

PCSK9 Inhibitors: The Holy Grail of Lipid Rx?

2013 ACC/AHA Cholesterol Guideline Principles

Treatment strategy based on net benefit

Risk assessment by pooled cohort risk equation– Individualized use of additional risk indicators

Benefit estimate largely based on RCT’s and their patient-level meta-analyses

Four Statin Benefit Groups– ASCVD

– Primary LDL-C≥190 mg/dL (suggesting FH)

– DM, Age 40-75 yo, LDL-C 70-189 mg/dL

– Age 40-75, LDL-C 70-189 mg/dL,10y ASCVD risk ≥7.5%

Intensity of Statin Therapy:

Matched to Risk, Age, Co-morbidity

Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice.

There might be a biologic basis for a less-than-average response.

lnitiation of simva 80 mg or titration to 80 mg not recommended by FDA (↑ risk of myopathy and rhabdomyolysis)

Clinician/Patient Discussion is Central

Clinician-Patient DiscussionPrior to initiating statin therapy discuss:

1.Potential for ASCVD risk reduction benefit

2.If decision is unclear, consider primary LDL-C ≥160 mg/dL,

family hx of premature ASCVD, lifetime ASCVD risk,

abnormal CAC or ABI, or hs-CRP≥2 mg /dL

3.Potential for adverse effects and drug-drug interactions

4.Healthy lifestyle

5.Management of other risk factors

6.Patient preferences

Monitoring

Rx and

Adherence

Guidance for non-

statin therapy

Tables 9 and 10 in the 2013 ACC/AHA Guideline

Regular LDL-C

monitoring

recommended;

F/U every 3-12

months

Heterogeneity

of Statin

Response in

RCT’s

JUPITER

High Intensity Statin

LIPID

Moderate Intensity Statin

TNT

Dose Increase 10 to 80 mgAFCAPS/TexCAPS

Placebo Arm

Boekholdt M et al. JACC 2014;64:485–94

Waterfall plots:

Distribution of % in LDL-C

(LDL-C) ([1 y – BL]/BL)

Achieved LDL-C: Does It Matter?

Boekholdt M et al. JACC 2014;64:485–94

Pooled data from

TNT

IDEAL

SPARCL

JUPITER

“Lower LDL-C Is Better”

Alternate Explanations

Lower LDL-C achieved with statins is better

Statin-responsive individuals have better

prognosis

– Differences in lipid metabolism

– Environmental factors

Adherent individuals have better prognosis

– Adherence as a personality trait

– Ability to tolerate high intensity statin

Individuals with lower baseline LDL-C have

better prognosis

Does It Matter How We Get There?

Trial Intervention LDL-C Effect Outcomes

HERS Premarin/Provera 15% No benefit on CHD; ↑

VTE

AIM High Niacin 12% No change; ?↑ stroke

HPS 2 Thrive Niacin/laropiprant 16% No change in MCV; ↑

DM and other AE

ILLUMINATE Torcetrapib 28% Stopped for harm

CVE ↑25%, Death ↑58%

ACCELERATE Evacetrapib 37% Stopped for futility

JELIS EPA No change MCE 19%

IMPROVE-IT Ezetimibe 24% 1o EP 6.4%

Does It Matter How We Get There?

Trial Intervention LDL-C Effect Outcomes

HERS Premarin/Provera 15% No benefit on CHD; ↑

VTE

AIM High Niacin 12% No change; ?↑ stroke

HPS 2 Thrive Niacin/laropiprant 16% No change in MCV; ↑

DM and other AE

ILLUMINATE Torcetrapib 28% Stopped for harm

CVE ↑25%, Death ↑58%

ACCELERATE Evacetrapib 37% Stopped for futility

JELIS EPA No change MCE 19%

IMPROVE-IT Ezetimibe 24% 1o EP 6.4%

Does It Matter How We Get There?

Trial Intervention LDL-C Effect Outcomes

HERS Premarin/Provera 15% No benefit on CHD; ↑

VTE

AIM High Niacin 12% No change; ?↑ stroke

HPS 2 Thrive Niacin/laropiprant 16% No change in MCV; ↑

DM and other AE

ILLUMINATE Torcetrapib 28% Stopped for harm

CVE ↑25%, Death ↑58%

ACCELERATE Evacetrapib 37% Stopped for futility

JELIS EPA No change MCE 19%

IMPROVE-IT Ezetimibe 24% 1o EP 6.4%

JACC Online April 2016

“Expert Consensus Documents are intended to provide guidance for clinicians

in areas where evidence may be limited, new and evolving, or lack sufficient

data to fully inform clinical decision making.” James L. Januzzi, MD, FACC

Questions for the Consensus Panel

In what patient populations should non-statin therapies be considered?

In what situations should non-statin therapies be considered?– When is the amount of LDL-C lowering (% LDL-C reduction

or LDL-C achieved on Rx) less than anticipated, less than desired, or inadequate?

– Which treatment options should be considered in patients who are truly statin intolerant?

If non-statin therapies are to be added, which agents or therapies should be considered and in what order?

Note: Severe hypertriglyceridemia not addressed!

Patient Groups Under Consideration

ASCVD

Uncomplicated ASCVD on maximally tolerated statin with less than anticipated response

ASCVD with co-morbidities– Diabetes

– ASCVD event within < 3 months

– ASCVD event on statin

– Poorly controlled major ASCVD risk factors

– Elevated Lp(a)

– CKD

ASCVD and 1o LDL-C elevation ≥190 mg/dL

Primary Prevention

Age ≥21, primary LDL-C ≥190

mg/dL

Age 40-75, DM, LDL-C 70-189

mg/dL

Age 40-75, LDL-C 70-189

mg/dL, 10 year risk ≥7.5%

What To Do When Therapeutic Response

Is Less Than Anticipated / Desired?

Re-assessment of lifestyle– Consider referral to registered dietitian

Maximize statin intensity, if not on high intensity therapy

Treat other risk factors

Assessment of statin adherence– Misunderstanding

– Statin related AE

– Drug-drug interactions

– Cost

Manage statin intolerance, if present

ODYSSEY ALTERNATIVE

Unable to tolerate ≥2 statins, including one at the lowest approved starting dose, due to muscle symptoms.

Excluded patients with muscle sx during 4-wk placebo run-in – 47 of 361 patients did not complete placebo run-in

– 23 of 47 failed because of muscle AE

Moriarty et al. JCL 2015;9:758-769

Don’t Underestimate The Impact of The Media …

Danish population

N=674,900 initiated statins

1995-2010

Statin use increased from <1% to 10%

Discontinuation rate increased from 6 to 18%

Nielsen and Nordestgaard. European Heart Journal (2016) 37, 908–916

… And The

Consequences

Nielsen and Nordestgaard.

European Heart Journal (2016) 37, 908–916

Statin Intolerance App

What Non-Statins Are Recommended?

Soluble fiber / stanols / sterols

Ezetimibe

Bile acid sequestrants– Use only if TG <300 mg/dL

PCSK9 inhibitors

FH only: Mipomersin / Lomitapide / Apheresis

Niacin NOT RECOMMENDED– “On the basis of currently available evidence of non-efficacy

and potential harms, the Committee judged that there are no clear indications for the routine use of niacin preparations as additional non-statin therapies, and niacin is therefore not recommended for use in any of the clinical situations addressed below.”

Stable

ASCVD

ASCVD with

Comorbidities

Take Home

Statins first, at appropriate intensity

Consider non-statins, if

– Less than desired response to statins

– Statin intolerance

Non-statins under consideration:

– Soluble fiber / stanols / sterols

– Ezetimibe

– Bile acid sequestrants

– PCSK9 inhibitors

PCSK9 Inhibition

Proprotein Convertase Subtilisin-Kexin Type 9

Secreted serine protease

Targets the LDL-receptor

for degradation

– May also influence Apo B

synthesis and TG secretion

Gain of function mutation

higher LDL-C

Loss of function mutation

lower LDL-CLambert et al. Atherosclerosis 2009;203:1–7

Soutar AK. Curr Op Lipidol 2011;22:192–196

What Happens with PCSK9

Inhibition?

CLINICAL PHARMACOLOGY & THERAPEUTICS 2016;99:597-71

LDL-C Effects on Statin Background Therapy

OSLER

Odyssey Longterm

Sabatine et al. NEJM 2015;372:1500-9

Robinson et al. NEJM 2015;372:1489-99

Alirocumab

Evolocumab

Post-hoc Data on

CV Outcomes

Robinson et al. NEJM 2015;372:1489-99

Sabatine et al. NEJM 2015;372:1500-9

Odyssey Longterm

(Alirocumab)

OSLER

(Evolocumab)

Safety

Alirocumab

– Nasopharyngitis, injection site reactions, influenza

Evolocumab

– Nasopharyngitis, URI, influenza, back pain, and

injection site reactions

Self-reported cognitive AE*

– Alirocumab vs placebo: 1.2% vs 0.5%

– Evolocumab vs placebo: 0.9% vs 0.3%

*Deliria, confusion; cognitive and attention disorders and disturbances; dementia and amnestic conditions; disturbances in thinking and

perception; mental impairment disorders

Percentages quoted in ACC Non-statin Consensus document 2016

FDA Approval

Alirocumab (Praluent)

Adjunct to diet and maximally

tolerated statin to treat adults with

HeFH or clinical ASCVD who need

more LDL-C reduction.

Initiate 75 mg SQ every 2 weeks

May ↑ dose to 150 mg every 2

weeks

Evolocumab (Repatha)

Adjunct to diet and maximally tolerated statin to treat adults with HeFH or clinical ASCVD who need more LDL-C reduction

Adjunct to diet and other LDL-lowering Rx (e.g., statins, ezetimibe, LDL apheresis) in patients with HoFH who need more LDL-C reduction

ClinicL ASCVD or HeFH: 140 mg SQ every 2 weeks or 420 mg SQ monthly

HoFH: give 420 mg SQ monthly (three 140 mg injections within 30 min)

Cost

US

– Evolocumab: about $14,100/year

– Alirocumab: about $14,600/year

– Manufacturer coupons

– Formulary varies by insurance plan

» e.g. CVS Caremark carries only Evolocumab

UK

– Evolocumab: agreed upon list price $5,780/year

– Alirocumab: agreed upon list price $5,780/year

http://www.fiercepharma.com/pharma/nice-gives-tentative-broad-approval-to-both-repatha-praluent; dated 5/6/2016; accessed 5/26/2016

PCSK9 mAb Outcomes Trials in Progress

Alirocumab: ODYSSEY Outcomes; N=18.6K– Post ACS patients on max tolerated statin

– 1o EP: CHD Death, MI, ischemic stroke and hospitalization for UA

– Estimated completion in early 2018

Evolocumab: FOURIER; N=27.5K– Prior MI, stroke or PAD on atorva >20 mg or equivalent

– 1o EP: CV death, MI, stroke, revascularization or hospitalization for UA

– May present at ACC 2017

Bococizumab: SPIRE I; Estimated enrollment 17K– Pts at high risk of CV event with LDL-C 70-99 mg/dL on lipid-lowering therapy

– 1o EP: CV death, MI, stroke, urgent revascularization

– Estimated study completion 6/2018

Bococizumab: SPIRE II; Estimated enrollment 9K– Pts at high risk of CV event with LDL-C >100 mg/dL on lipid-lowering therapy

– 1o EP: CV death, MI, stroke, urgent revascularization

– Estimated study completion 3/2018

Thank You