Secondary Prevention of ASCVD: Novel Therapies to Improve Outcomes in Patients with

Hypercholesterolemia

Joyce L. Ross, MSN, CRNP, CLS, FNLA, FPCNAPresident, National Lipid Association

Past President, Preventive Cardiovascular Nurses Association

Consultative Education Specialist, Cardiovascular Risk Intervention

University of Pennsylvania Health System - RetiredPhiladelphia, PA

Lynne T. Braun, PhD, CNP, FAHA, FAANP, FPCNA, FAAN, FNLA

Professor of Nursing and Medicine Nurse Practitioner,

Department of Adult Health and Gerontological NursingRush University College of Nursing

Department of Internal MedicineRush Heart Center for Women

Chicago, IL

Learning ObjectivesUpon completion of this educational activity, the participant should be able to:• Outline the mechanisms of action for PCSK9

inhibitors.• Identify potential advantages, disadvantages,

and clinical uses for PCSK9 inhibitors.• Discuss guideline controversies with regard to

statin use for the treatment of patients with ASCVD and hypercholesterolemia.

• Develop a plan to increase patient adherence to treatment regimens for hypercholesterolemia.

Heart Disease Is the Leading Cause of Death in the US

020406080

100120140160180

20142015

Dea

thspe

r100

,000

stan

dardpop

ulation

Heartdiseasedeathsincreased in2015forthefirsttimesince1993.

Adapted by Lillian McVey from Xu J, et al. NCHS Data Brief No. 267. December 2016. Used with permission.

LDL: Lower is Better

Raymond C, et al. Cleve Clin J Med. 2014;81(1):11-19.

IMPROVE-ITSimva40/EZ10

Benefits of Decreased LDL-C

Efficacy and Safety of LDL-Lowering Therapy

• Meta-analysis of outcomes from 174,000 participants in 27 randomized trials

• Overall, a 20% to 25% RRR of major vascular events with statin therapy or more intensive statin therapy

• This translated to an approximate 1% reduction in CHD deaths for every 2 mg/dLlowering in LDL-C

Cholesterol Treatment Trialists’ (CTT) Collaboration. Lancet. 2015;385(9976):1397-1405.

Evolution of Guidelines and Landmark Trials

NCEPATP I

1988

FraminghamMRFIT

LRC-CPPTCoronary Drug

ProjectHelsinkiHeartCLAS

NCEPATP II

1993

Angiographic Trials (FATS,

POSCH, SCORE, STARTS,

Ornish, MARS)Meta-analyses

(Holmes Rossouw)

NCEPATP III

2001

4SWOSCOPS

CARELIPID

AFCAPS/TexCAPS

NCEPATP IIIUpdate2004

HPSPROVE-IT

ASCOT-LLAPROSPER

ALLHAT-LLT

ACC/AHA, IAS, NLA

2013/2014

TNTIDEAL

ACCORDJUPITER

CTT Meta-analyses

ENHANCESHARP

AURORACORONAAIM HIGH

HPS2-Thrive

ACCECDP

2016

IMPROVE-IT

NCEP ATP = National Cholesterol Education Panel Adult Treatment Panel; ACC = American College of Cardiology; AHA = American Heart Association; IAS = International Atherosclerosis Society; NLA = National Lipid Association; ECDP = Expert Consensus Decision Pathway

Expanded/Modified Treatment Recommendations

Trends in Cardiovascular Disease:Mortality in Men and Women

Reprinted with permission. Mozaffarian F, et al. Circulation. 2015;131:e29-e322. ©2015 American Heart Association, Inc.

Males FemalesYear

1979 1980 1985 1990 1995 2000 2005 2013350

370

390

410

430

450

470

490

510

Dea

ths

in T

hous

ands

530

550

Statins

WHI

HRT Stopped

Awareness campaigns for

women and heart disease

ACC/AHA 2013 Guideline: Paradigm Shift

• New goal is ASCVD risk reduction rather than targeting specific LDL-C levels

• Statin intensity matched to ASCVD risk level, with less dependence on LDL-C levelsGroups most likely to benefit from

statin therapyRecommended statin intensity

Patients with clinical ASCVD High intensity

LDL-C ≥190 mg/dL High intensity

Diabetics age 40-75 years with LDL-C 70-189 mg/dL and without clinical ASCVD

≥7.5% 10-year ASCVD risk = high intensity<7.5% 10-year ASCVD risk = moderate

intensity

Non-diabetics age 40-75 years with an estimated 10-year ASCVD risk of ≥7.5%

Moderate to high intensity if appropriate after clinician-patient discussion

Finkel JB, Duffy D. Trends Cardiovasc Med. 2015;25(4):340-347. Stone NJ, et al. Circulation. 2014;129(25 Suppl 2):S1-45.

ACC/AHA 2013 Guideline: Paradigm Shift

• Evidence-based fixed dose of statins recommended as first-line treatment in all patients with elevated ASCVD risk– Non-statins reserved for when statins are

contraindicated or not tolerated• Pooled Cohort Risk Assessment Equation

– Replaces the Framingham Risk Score (FRS)– Estimates ASCVD risk based on gender, age, race,

HDL-C, total cholesterol, systolic blood pressure, presence of diabetes and/or hypertension, smoking status

• 10-year risk threshold for consideration of initiation of statin therapy lowered from ≥10% to ≥7.5%

Stone NJ, et al. Circulation. 2014;129(25 Suppl 2):S1-45.

ACC/AHA 2013 Paradigm Shift:Pros and Cons

Updated recommendation Pro Con

Targeting ASCVD risk vs LDL-C levels

-Will avoid undertreatment of high-risk patients with already low levels of LDL- Simple to implement

- May undertreat residual risk in patients with elevated LDL-C despite recommended statin intensity

Emphasis on statin therapy and avoidance of non-statin agents in most patients

-Avoids adverse events (AEs) associated with polypharmacy

- May undertreat residual risk in patients with elevated LDL-C despite recommended statin intensity

Use of new risk calculator -More current and applicable to African-American and Caucasian populations- Includes stroke in risk estimation

- May overestimate risk in some groups

Lower risk calculator cut point for statin therapy initiation

- Identifies a subset of patients not previously identified that may benefit from statin therapy

- The number of patients on statin therapy, especially based on age alone, may be excessive

Finkel JB, Duffy D. Trends Cardiovasc Med. 2015;25(4):340-347.

Statin Safety Recommendations• Use moderate-intensity statin therapy in patients who

are predisposed to statin-associated AEs– Multiple or serious comorbidities, including impaired renal or

hepatic function– History of previous statin intolerance or muscle disorders– Unexplained ALT elevations >3 times ULN– Concomitant use of drugs affecting statin metabolism– >75 years of age– History of hemorrhagic stroke– Asian ancestry

• CK should not be routinely measured, although it is reasonable to measure baseline CK in individuals at increased risk for adverse muscle events

CK = creatinine kinaseStone NJ, et al. Circulation. 2014;129(25 Suppl 2):S1-45. Rosenson RS, et al. J Clin Lipidol. 2014;8(3 Suppl):S58-S71.

Statins and Muscle Symptoms• Frequency of statin-associated muscle symptoms

– 1% to 5% in randomized controlled trials– 11% to 29% in observational cohorts

• Spectrum of statin-associated muscle AEs– Myalgia: unexplained muscle discomfort often described

as “flu-like” symptoms with normal CK level– Myopathy: muscle weakness (not attributed to pain or

elevated CK)– Myositis: muscle inflammation– Myonecrosis: muscle enzyme elevations or elevated CK– Myonecrosis with myoglobinuria or acute renal failure

(clinical rhabdomyolysis)

Rosenson RS, et al. J Clin Lipidol. 2014;8(3 Suppl):S58-S71.

Statins and Adherence• The most common non-genetic factor

contributing to reduced statin response is poor medication adherence

• 40% to 70% of patients discontinue statin therapy within one year of initiation

• The most common patient-reported reason for statin discontinuation or noncompliance is AEs– >90% of statin-associated AEs are muscle related

• Fear of symptoms and AEs also contributes to non-adherence

Banach M, et al. Int J Cardiol. 2016;225:184-196.

Provider-Related Factors That May Impact Adherence

• Failure to provide adequate explanations of benefits/AEs of medications

• Ineffective communication with the patient• Perceived lack of efficacy in medication

regimen• Prescribing complex drug regimens• Neglecting to consider cost issues• Neglecting to communicate among patient’s

various providers• Lack of time, lack of time, lack of time!

Improving Adherence: NLA Recommendations

• Simplify the regimen• Provide clear education using visual aids and simple,

low-literacy educational materials• Engage patients in decision making, addressing their

specific needs, values, and concerns• Address perceived barriers of taking medications• Identify suboptimal health literacy and use “teach-

back” techniques to increase patient understanding of those behaviors needed to be successful

• Screen and eliminate drug-drug and drug-disease interactions leading to low adherence or drug discontinuation

• Praise and reward successful behaviorsJacobson TA, et al. J Clin Lipidol. 2015;9(6):S1-S122.

Statin Intolerance• Definition:

– A clinical syndrome characterized by the inability to tolerate at least 2 statins

– Manifests as either objectionable symptoms (real or perceived) or abnormal lab determinations, which are temporally related to statin treatment

• Reversible upon discontinuation• Reproducible by re-challenge

• Approximately 1 in 10 patients taking statins will report intolerance

• Novel non-statin agents may be appropriate in intolerant individuals

Guyton JR, et al. J Clin Lipidol. 2014;8(3 Suppl):S72-S81.Rosenson RS, et al. J Clin Lipidol. 2014;8(3 Suppl):S58-S71.

Managing Muscle Symptoms• Switch to an alternate statin

– 92% of patients are able to tolerate a second statin after discontinuing their initial statin due to AEs

– 72.5% of patients who are intolerant to 2 statins due to myalgia can successfully tolerate a third statin

• Use an alternate dosing strategy– Lower dose of the same statin– Less-than-daily dosing

• Once-weekly dosing of a long-acting statin

• Switch to non-statin lipid-lowering therapy in truly intolerant patients

Rosenson RS, et al. J Clin Lipidol. 2014;8(3 Suppl):S58-S71.

Statin Intolerance RecommendationsFor providers:• Statin intolerance is a real and valid

phenomenon• Statin use may increase hepatic transaminase

levels, the risk for diabetes mellitus, and cognitive difficulties

• Decisions on statin intolerance should be made in conjunction with the patient– Providers should help patients distinguish statin

intolerance from “drug allergy”– Statin treatment should be maintained whenever

possible in patients with statin intoleranceGuyton JR, et al. J Clin Lipidol. 2014;8(3 Suppl):S72-S81.

Statin Intolerance RecommendationsFor patients:• Statin therapy is one of the most effective ways to lower

the risk of atherosclerosis• The prevention of death and disability from improved

atherosclerosis is far greater than the risk of taking a statin

• There is little evidence that statins damage the liver or block essential functions of the liver

• Before stopping a statin due to side effects, counsel with a health care professional is advised

• Most people who experience intolerance to a statin will be able to tolerate a second statin

• Lifestyle changes are still an important aspect of reducing heart attack and stroke risk

Guyton JR, et al. J Clin Lipidol. 2014;8(3 Suppl):S72-S81.

“Penicillin” for Cholesterol

• The first statin, mevastatin (compactin), was isolated from penicillium citrinum in the 1970s.

• “The millions of people whose lives will be extended through statin therapy owe it all to Akira Endo...” from: “A tribute to Akira Endo, discoverer of a ‘Penicillin’ for cholesterol.” Atherosclerosis Supplements. 5(3):13-16 · October 2004.

Infection Cholesterol lowering

Intolerance and Adherence: Clinical Tips

• Work with patients to establish pharmacologic and non-pharmacologic goals

• Patient-provider communication– Discuss importance of statin treatment

• Continuing treatment with statins prevents acute CV events• Review how statins work to prevent CV events

– Review potential for AEs• Potential for AE is present with any new medication• Contact the provider if any changes in health or condition are

observed– Stress the importance of adherence

• Non-adherence is a major cause of inadequate LDL-C lowering and related negative health outcomes

Banach M, et al. Int J Cardiol. 2016;225:184-196.

Monitoring and Optimizing Statins• Monitoring statin therapy

– Regularly assess adherence to medication, lifestyle, and therapeutic response

– Perform fasting lipid panel within 4-12 weeks after initiation or dose adjustment

• Every 3-12 months thereafter

• Optimizing statin therapy– Maximum tolerated intensity of statin should be

used in individuals for whom a high- or moderate-intensity statin is recommended, but not tolerated

Stone NJ, et al. Circulation. 2014;129(25 Suppl 2):S1-45.

Managing Insufficient ResponseIntensity of Statin Therapy Reasonable Expectation for

Treatment ResponseHigh-intensity statin therapy Average LDL-C reduction of ≥50%

from the untreated baselineModerate-intensity statin therapy Average LDL-C reduction of 30% to

<50% from the untreated baseline

• Non-statin cholesterol-lowering drug(s) may be considered if the ASCVD risk-reduction benefits outweigh the potential for AEs. High-risk individuals include:• Clinical ASCVD in those <75 years of age• Baseline LDL ≥190 mg/dL• Age 40 to 70 years with diabetes mellitus

• Preference should be given to agents shown to reduce ASCVD events in RCTs

RCTs = randomized controlled trialsStone NJ, et al. Circulation. 2014;129(25 Suppl 2):S1-45.

PCSK9• A secreted enzymatic protein of the subtilisin family of

serine proteases• Primarily synthesized in the liver; also found in the

intestines and kidneys• Interferes with removal of LDL particles from circulation • Binds with the LDL-R/LDL complex

– Complex is degraded by the lysosome → degradation of the LDL-R

– LDL-R can’t recycle to the cell membrane– LDL clearance is decreased

• Gain of function mutations are associated with FH and premature CVD

FH = familial hypercholesterolemia; CVD = cardiovascular disease. Joseph L, Robinson JG. Prog Cardiovasc Dis. 2015;58(1):19-31.

PCSK9 (cont’d)

• Individuals with loss-of-function PCSK9gene mutations…– Have LDL-C levels that are 28% lower than

those without the mutation– Have an 88% relative decrease in risk for

atherosclerotic CV events• Gain-of-function PCSK9 gene mutations

lead to increased levels of LDL-C

Cohen JC, et al. N Engl J Med. 2006;354(12):1264-1272.

PCSK9 Inhibitors: Mechanism of Action

PCSK9 self-processing, secretion, and export

PCSK9

PCSK9

LDL Particle

LDL-R

Endocytosis of LDL-R/PCSK9

complex

Plasma

LDL, LDL-R, and PCSK9 degradation

Lysosome

Endosome

LDL-R = LDL receptors

Adapted by Lilian McVey from Shimada YJ, Cannon CP.

Eur Heart J. 2015;36(36):2415-2424. Used with permission.

Rationale Behind PSCK9 as a Therapeutic Target

PCSK9 # of LDL Receptors

LDL-C

PCSK9 # of LDL Receptors LDL-C

PCSK9: Rapid Deployment from Discovery to Clinic

2003• PCSK9 mutation

linked to autosomal dominant hyper-cholesterolemia

2005• Expanded role of

PCSK9 in cholesterol regulation

• Begin epidemiological studies on loss of function PCSK9 mutation and cardiovascular protection

2012• Alirocumab

phase 1 and 2 trials

• Evolocumab phase 1 and 2 trials

• Antisense oligonucleotide preclinical data

2014• Alirocumab

phase 3 trials• Evolocumab

phase 3 trials • Bococizumab

phase 2 trial• ALN-PCS02

phase 1 trial (siRNA)

• BMS-962476 phase 1 trial (mimetic peptide)

2015• Alirocumab

approved• Evolocumab

approved

Adapted by Lillian McVey from: 1) Joseph L, Robinson JG. Prog Cardiovasc Dis. 2015;58(1):19-31. 2) Stein EA, et al. N Engl J Med. 2012;366(12):1108-1118. 3) Dias CS, et al. J Am Coll Cardiol. 2012;60(19):1888-1898. Alirocumab [injection] Prescribing Information, 2015. Evolocumab Prescribing Information, 2015.

Available PCSK9 InhibitorsAlirocumab• Fully human IgG1 mAB• Indicated for:

– HeFH– Clinical ASCVD

• Dose:– 75-150 mg SQ q 2 weeks

• LDL reduction:– 50% to 60%

Evolocumab• Fully human IgG2 mAB• Indicated for:

– HeFH– Clinical ASCVD– HoFH

• Dose: – 140 mg SQ q 2 weeks or – 420 mg SQ (3 injections) q

month• LDL reduction:

– 50% to 60%

HeFH = heterozygous familial hypercholesterolemia, HoFH = homozygous familial hypercholesterolemia.

Alirocumab [injection] Prescribing Information, 2015; Evolocumab Prescribing Information, 2015; Dadu RT, Ballantyne CM. Nat Rev Cardiol. 2014;11(10):563-575; Gumbiner B, et al. Circulation. 2012;126:a13322; www.clinicaltrials.gov; www.pharmacist.com/express-scripts-cover-both-new-cholesterol-drugs.

PSCK9 PharmacologyAlirocumab• Half life:

– 17-20 days• Tmax to max serum

concentration:– 3-7 days

• Vd:– 0.05 L/kg

• Metabolism:– Low doses: by binding to PCSK9 – Higher doses: nonsaturable

proteolytic pathway• Dose adjustment:

– If LDL not optimally lowered, increase to 150 mg

– No adjustment for liver or kidney dysfunction or P450 drugs

• Drug interactions:– Statins (by ↑ing SREBP2)

Evolocumab• Half life:

– 11-17 days• Tmax to max serum

concentration:– 3-4 days

• Vd:– 0.05 L/kg

• Metabolism:– Low doses: by binding to PCSK9 – Higher doses: nonsaturable

proteolytic pathway• Dose adjustment:

– No adjustment for liver or kidney dysfunction or P450 drugs

• Drug interactions:– Statins (by ↑ing SREBP2)

Alirocumab [injection] Prescribing Information, 2015; Evolocumab Prescribing Information, 2015; Rallidis LS, Lekakis J. Hellenic J Cardiol. 2016;57(2):86-91.

LDL-C Lowering Efficacy of PCSK9 mAbs: Monotherapy

ODYSSEY-MONODrug Decrease in

LDL-C Ezetimibe 20%Alirocumab 75/150 mg

53%

MENDEL-2Drug Decrease in

LDL-C Ezetimibe 18%Evolocumab140 mg q 2 weeks

57%

Evolocumab420 mg q 4 weeks

56%

Roth EM, et al. Int J Cardiol. 2014;176(1):55-61.Koren MJ, et al. J Am Coll Cardiol. 2014;63(23):2531-2540.

LDL-C Lowering Efficacy of PCSK9 mAbs: Background of Statin Therapy

Drug Decrease in LDL-C

HeFH Clinical ASCVD

Alirocumab 75 mg q 2 weeks 48% 46%

Alirocumab 75/150 mg q 2 weeks 54% 43%

Alirocumab 150 mg q 2 weeks 63% 62%

Evolocumab 140 mg q 2 weeks 61% 71%

Evolocumab 420 mg q 4 weeks 60% 63%

Robinson JG, et al. N Engl J Med. 2015;372(16):1489-1499.Alirocumab [injection] Prescribing Information, 2015; Evolocumab Prescribing Information, 2015.

Alirocumab – Adverse EventsAlirocumab Placebo

Nasopharyngitis 11% 11%Influenza 6% 5%

UTI 5% 5%Injection site reaction 7% 5%

LFT >3x ULN 1.7% 1.4%Myalgias 4% 3%

Drug discontinuation 0.4% 0.2%Neurocognitive 0.8% 0.7%

Antidrug antibodies (ADAs) 5% 0.6%

Neutralizing antibody(Nab)

1.2% (of which, in 0.3%led to decreased

efficacy)0

Alirocumab [injection] Prescribing Information, 2015.

Evolocumab – Adverse EventsEvolocumab Placebo

Nasopharyngitis 11% 10%

Influenza 8% 6%

UTI 5% 4%

Injection site reaction 6% 5%

Myalgias 4% 3%

Drug discontinuation 2% 1%

Neurocognitive ≤0.2% ≤0.2%Antidrug

antibodies (ADAs) 0.1% 0

Neutralizing antibody (Nab) 0 0

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125522s000lbl.pdf.

Alirocumab: ODYSSEY Long-Term Trial Results

Robinson JG, et al. N Engl J Med. 2015;372(16):1489-1499. Used with permission.

Evolocumab: OSLER-1 and -2 Long-Term Trial Results

Sabatine MS, et al. N Engl J Med. 2015;372(16):1500-1509. Used with permission.

2016 ACC Consensus Statement on Non-Statin Therapy

• For high-risk patients with clinical ASCVD or LDL-C ≥190 mg/dL and failure to achieve at least a 50% reduction in LDL-C on maximally tolerated statin, non-statins may be considered in this order:1. Ezetimibe – first additional medication added2. Bile acid sequenstrants – inefficacy of/intolerance to ezetimibe3. PCSK9 inhibitors if therapy goals are not met on maximally

tolerated statin/ezetimibe therapy• PCSK9 inhibitors not recommended for use in primary

prevention patients in the absence of FH due to lack of long-term data

Lloyd-Jones DM, et al. J Am Coll Cardiol. 2016;68(1):92-125.

Clinical Tips for Therapeutic Management of PCSK9 Inhibitors

• First patient-administered injection should be performed in office after education– Offer to have second injection performed in office as well if the

patient has ongoing reservations

• Common mistakes during injection:– Expediting the warming phase– Improper storage– Failing to discard the pen– Rubbing the site after injection is complete– Pulling the pen away prior to the full injection (15-20 seconds)– Not pushing the pen down firmly such that yellow tip is still visible

Alirocumab [injection] Prescribing Information, 2015; Evolocumab Prescribing Information, 2015.

LDL Apheresis

• Indicated when patients have failed diet and maximum drug therapy from at least 2 separate classes of hypolipidemic drugs for ≥6 months …Plus– HeFH with LDL-C ≥500 mg/dL– HeFH with LDL-C ≥300 mg/dL– Functional HeFH with LDL-C ≥200 mg/dL in

patients with CAD• May be considered upon failure of PCSK9

inhibitors

CAD = coronary artery diseaseJacobson TA, et al. J Clin Lipidol. 2014;8(5):473-488.

Investigational Agent: Anacetrapib• Cholesteryl ester transfer protein (CEPT) inhibitor1

• Phase 3 DEFINE trial (2-year extension of 76-week base study):1– Anacetrapib reduced LDL-C by 39.9% and increased

HDL-C by 153.3% vs placebo– Study is still ongoing2

• Phase 3 REVEAL trial ongoing2

– Goal is to determine whether lipid modification with anacetrapib 100 mg daily reduces the risk of major coronary events in patients with circulatory problems receiving statin therapy for LDL-C levels

1. Gotto AM Jr, et al. J Cardiovasc Pharmacol Ther. 2014;19(6):543-549.2. REVEAL trial. ClinicalTrials.gov Identifier: NCT01252953. https://clinicaltrials.gov/ct2/show/NCT01252953.

Investigational Agents: TA-8995CEPT inhibitor evaluated in patients with mild dyslipidemia

in the phase 2 TULIP trial

010203040506070

ReductioninLDL-C,%27.4

32.745.3 45.3

68.263.3

020406080

100120140160180

IncreaseinHDL-C,%

75.8

124.3

157.1179.0

152.1 157.5

Adapted by Lillian McVey from Hovingh GK, et al. Lancet. 2015;386(9992):452-460.Used with permission.

Investigational Agents: ETC-1002• Dual adenosine triphosphate citrate lyase

inhibitor/adenosine monophosphate-activated protein kinase activator

• Oral, once-daily small molecule in phase 2 development

• May have a modest beneficial effect on LDL-C as well as other cardiometabolicrisk factors

Banach M, et al. Int J Cardiol. 2016;225:184-196.Nikolic D, et al. Atherosclerosis. 2014;237(2):705-710.

Case 1• 54-year-old female with CAD• History includes hyperlipidemia, obesity, former smoker• Family history of premature CAD (mother MI at age 55)• Medications:

− Nebivolol 5 mg daily− Furosemide 20 mg daily− NTG 0.4 mg SL− Rosuvastatin 2.5 mg twice a week

• Statin intolerance: pravastatin (mental cloudiness), atorvastatin(muscle aches), pitavastatin (muscle aches), rosuvastatin (muscle/joint pain)

• Lipid panel: − Total cholesterol 187 mg/dL− Triglycerides 87 mg/dL− HDL-C 49 mg/dL− LDL-C 121 mg/dL

Case 1 (cont’d)• Evolocumab 140 mg subcutaneously

every 2 weeks• 6-week lipid panel: − Total cholesterol 140 mg/dL− Triglycerides 85 mg/dL− HDL-C 53 mg/dL− LDL-C 70 mg/dL

• Mild nasopharyngitis; fatigue for 2 days after injection

Case 2• 30-year-old female with hypercholesterolemia

and family history of premature CAD• On simvastatin 20 mg:

– Total cholesterol 334 mg/dL– Triglycerides 124 mg/dL– HDL-C 43 mg/dL– LDL-C 266 mg/dL

• Uses effective birth control and doesn’t plan on becoming pregnant in the near future

Case 2 (cont’d)• Statin changed to atorvastatin 80 mg daily• Counseled on heart-healthy diet and

regular exercise• 8-week lipid panel

– LDL-C decreased to 172 mg/dL (from 266 mg/dL)• Plan to intensify healthy lifestyle changes

and consider additional therapies• Subsequent LDL-C 142 mg/dL• Is this LDL low enough?

Conclusion• Abnormal LDL-C levels are a major predictor of

CV outcomes in patients with ASCVD• Recent guidelines have been the impetus for a

paradigm shift in ASCVD management– Focus on ASCVD risk reduction rather than specific

LDL-C targets– Emphasis on statin therapy

• Optimal benefit from statins diminished by:– AEs, particularly muscle symptoms– Adherence– Intolerance

Conclusion (cont’d)• New PCSK9 inhibitors provide an alternative method of

reducing LDL-C and associated ASCVD risk– Effectively reduces LDL-C as monotherapy and in combination

with statins– Well tolerated with a low rate of side effects and AEs– Some long-term data available (78 weeks for alirocumab)

• Several promising agents currently in development– CEPT inhibitors– Dual adenosine triphosphate citrate lyase inhibitor/adenosine

monophosphate-activated protein kinase activator• Advances in LDL-C pharmacotherapy will likely translate into

further reductions in LDL-C and associated gains in cardiovascular outcomes

Secondary Prevention of ASCVD:

Novel Therapies to Improve Outcomes in Patients with Hypercholesterolemia

References

Alirocumab [injection] Prescribing Information. sanofi-aventis U.S. LLC, Bridgewater, NJ. 2015.

Banach M, Stulc T, Dent R, Toth PP. Statin non-adherence and residual cardiovascular risk: There is need for

substantial improvement. Int J Cardiol. 2016;225:184-196.

Brown MS, Goldstein JL. A tribute to Akira Endo, discoverer of a “penicillin” for cholesterol. Atherosclerosis

Supplements. 2004;5:13-16.

Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of LDL-lowering therapy among men and

women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet.

2015;385(9976):1397-1405.

Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against

coronary heart disease. N Engl J Med. 2006;354(12):1264-1272.

Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol. 2014;11(10):563-575.

Dias CS, Shaywitz AJ, Wasserman SM, et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels:

results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers

and hypercholesterolemic subjects on statins. J Am Coll Cardiol. 2012;60(19):1888-1898.

Evolocumab Prescribing Information. Amgen Inc. Thousand Oaks, CA. 2015.

Finkel JB, Duffy D. 2013 ACC/AHA cholesterol treatment guideline: Paradigm shifts in managing atherosclerotic

cardiovascular disease risk. Trends Cardiovasc Med. 2015;25(4):340-347.

Gotto AM Jr, Ker U, Chatterjee MS, et al. Lipids, safety parameters, and drug concentrations after an additional 2

years of treatment with anacetrapib in the DEFINE study. J Cardiovasc Pharmacol Ther. 2014;19(6):543-549.

Gumbiner B, Udata T. The effects of single dose administration of RN316 (PF-04950615), a humanized IgG2a

monoclonal antibody binding proprotein convertase subtilisin kexin type 9, in hypercholesterolemic subjects

treated with and without atorvastatin. Circulation 2012;126:A13322, abstract.

Guyton JR, Bays HE, Grundy SM, et al. An assessment by the Statin Intolerance Panel: 2014 update. J Clin Lipidol.

2014;8(3 Suppl):S72-S81.

Hovingh GK, Kastelein JJ, van Deventer SJ, et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients

with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet.

2015;386(9992):452-460.

Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered

management of dyslipidemia: part 1 – executive summary. J Clin Lipidol. 2014;8(5):473-488.

Jacobson TA, Maki CK, Orringer CE, et al. National Lipid Association recommendations for patient-centered

management of dyslipidemia: part 2. J Clin Lipidol. 2015;9(6):S1-S122.

Joseph L, Robinson JG. Proprotein Convertase Subtilisin/kexin type 9 (PCSK9) inhibition and the future of lipid

lowering therapy. Prog Cardiovasc Dis. 2015;58(1):19-31.

Koren MJ, Lundgvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2

randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2531-2540.

Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC expert consensus decision pathway on the role of non-

statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a

report of the American College of Cardiology Task Force on clinical expert consensus documents. J Am Coll Cardiol.

2016;68(1):92-125.

Mozaffarian F, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics--2015 update: a report from the

American Heart Association. Circulation. 2015;131(4):e29-e322.

Nikolic D, Mikhailidis DP, Davidson MH, Rizzo M, Banach M. ETC-1002: a future option for lipid disorders?

Atherosclerosis. 2014;237(2):705-710.

Pharmacist.com. Express Scripts to cover both new cholesterol drugs. October 7, 2015.

www.pharmacist.com/express-scripts-cover-both-new-cholesterol-drugs

Rallidis LS, Lekakis J. PCSK9 inhibition as an emerging lipid lowering therapy: unanswered questions. Hellenic J

Cardiol. 2016;57(2):86-91.

Raymond C, Cho L, Rocco M, Hazen SL. New cholesterol guidelines: worth the wait? Cleve Clin J Med.

2014;81(1):11-19.

REVEAL trial. ClinicalTrials.gov Identifier: NCT01252953, anacetrapib; ([REVEAL]Randomized EValuation of the

Effects of Anacetrapib Through Lipid-modification, 2016. Accessed December 9,

2016.https://clinicaltrials.gov/ct2/show/NCT01252953.

Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular

events. N Engl J Med. 2015;372(16):1489-1499.

Rosenson RS, Baker SK, Jacobson TA, et al. An assessment by the Statin Muscle Safety Task Force: 2014 update. J

Clin Lipidol. 2014;8(3 Suppl):S58-S71.

Roth EM, Taskinen MR, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in

patients with hypercholesterolemia: results of a 24-week, double-blind, randomized phase 3 trial. Int J Cardiol.

2014;176(1):55-61.

Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and

cardiovascular events. N Engl J Med. 2015;372(16):1500-1509.

Shimada YJ, Cannon CP. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: past, present, and the

future. Eur Heart J. 2015;36(36):2415-2424.

Stein EA, Mellis S, Yancopouulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J

Med. 2012;366(12):1108-1118.

Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to

reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart

Association Task Force on practice guidelines. Circulation. 2014;129(25 Suppl 2):S1-45.

Xu J, Murphy SL, Kochanek KD, Arias E. Mortality in the United States, 2015. NCHS Data Brief No. 267. December

2016.