Lipid Guidelines Who, What, and How Low Anita Ralstin, MS, CNP Next Step Health Consultant, LLC New Mexico Heart Institute

Disclosures ! None

Objectives

! List factors used in screening for dyslipidemia in children, adolescents and adults

! Discuss rational for pharmacological treatment as it relates to treatment goals.

! Identify the role of statin and non-statin therapy in dyslipidemia management.

! Name the significant differences between the ACA/AHA and the AACE lipid guidelines.

Rationale of Guidelines

! 2016 approximately 660,000 US residents had a new coronary event

! 305,000 had recurrent events ! Dyslipidemia is a primary, major risk factor ! 30 year trends show improvement in LDL numbers

but 69% have an LDL < 100 ! Doubling of obesity and elevated triglycerides levels

Whose Guidelines? ! AHA/ACC 2013 guidelines with update 2017 for

non-statin therapy. ! http://www.onlinejacc.org/content/accj/

63/25_Part_B/2889.full.pdf ! http://www.onlinejacc.org/content/accj/

70/14/1785.full.pdf ! New guidelines expected this year.

! American Association of Clinical Endocrinologists (AACE) 2017 guidelines ! https://www.aace.com/files/lipid-guidelines.pdf

Choices, choices

AHA/ACC 2013 ! Shared decision making ! Lifestyle ! Follow lab work to determine adherence ! Approaches to statin intolerance ! ACC Statin Intolerance app

! Broad recommendations for non-statin therapy ! Risk evaluation with…

ACC ASCVD Risk App

10 year CV Risk Score Example

AHA/ACC 2013 Four Statin Groups Benefit Groups

Patient Group Major Recommendations Adults > 21 years with clinical ASCVD

!  < 75 years, high-intensity statin (or moderate with safety concerns)

!  > 75 moderate-intensity Adults > 21 years with LDL > 190 !  High-intensity to achieve > 50%

LDL reduction !  May consider combination

therapy Adults 40-75 without ASCVD with DM and LDL 70-189

!  Moderate-intensity statin !  10 year risk > 7.5% consider

high-intensity Adults 40-75 without ASCVD, DM with LDL 70-189 and 10 year risk >7.5

!  High-intensity !  10 year risk 5-7.5% moderate

intensity

Intensity of Statin Therapy ACC/AHA 2013 Guidelines

High Moderate Low Lowers LDL > 50% Lowers LDL 30-50% Lowers LDL <30%

Atorvastatin 40-80 mg Rosuvastatin 20-40 mg

Atorvastatin 10-20 mg Fluvastatin 40 mg BID Fluvastatin XL 80 mg Lovastatin 40 mg Pravastatin 40-80 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg

Fluvastatin 20-40 mg Lovastatin 20 mg Pitavastatin 1 mg Pravastatin 10-20 mg Simvastatin 10 mg

ACC Statin Apps

AHA/ACC 2017 Update

! IMPROVE-IT trial (2015): Patients with ACS statin + ezetimibe lowered LDL with clinically modest reduction in CV events over 7 years.

! FDA approval: monoclonal antibodies to PCSK9 with favorable (18 month) outcome data, long term trials underway.

AHA/ACC 2013 Four Statin Benefit Groups 2017 Update

Patient Group Major Recommendations Update

Adults > 21 years with clinical ASCVD

!  < 75 years, high-intensity statin (or moderate with safety concerns)

!  > 75 moderate-intensity

!  LDL reduction of >50% and may consider LDL <70 or non HDL < 100

!  Add non-statin therapy

Adults > 21 years with LDL > 190

!  High-intensity to achieve > 50% LDL reduction

!  May consider combination therapy

Adults 40-75 without ASCVD with DM and LDL 70-189

!  Moderate-intensity statin !  10 year risk > 7.5%

consider high-intensity

Adults40-75 without ASCVD, DM with LDL 70-189 and 10 year risk >7.5

!  High-intensity !  10 year risk 5-7.5%

moderate intensity

ACC/AHA 2013 Guideline 2017 Update

High Moderate Low Lowers LDL > 50% Lowers LDL 30-50% Lowers LDL <30%

Atorvastatin 40-80 mg Rosuvastatin 20-40 mg

Atorvastatin 10-20 mg Fluvastatin 40 mg BID Fluvastatin XL 80 mg Lovastatin 40 mg Pravastatin 40-80 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg

Fluvastatin 20-40 mg Lovastatin 20 mg Pitavastatin 1 mg Pravastatin 10-20 mg Simvastatin 10 mg

Optional Interventions to Consider !  Referral to lipid specialist and registered dietitian !  Ezetimibe !  Bile acid sequestrants !  PCSK9 inhibitors !  Mipomersen, loimtapide, LDL apheresis for familial

hypercholesteremia

AACE Atherosclerotic CV Risk Factors

Major Risk Factors Additional Risk Factors Nontraditional RF

!  Advancing age !  High total cholesterol

level !  High Non HDL !  High LDL !  DM !  HTN !  CKD 3,4 !  Cigarette smoking !  Family Hx

!  Obesity, abdominal obesity

!  Family Hx , hyperlipidemia

!  High small dense LDL !  High Apo B !  High LDL

concentration !  PCOS !  Dyslipidemia triad

!  High lipoprotein (a) !  High Clotting factors !  High inflammatory

markers (hsCRP, Lp-PLA2)

!  High Homocysteine !  Apo E4 isoform !  High uric acid !  High TG-rich

remnants

AACE Screening Tools

! Framingham Risk Assessment (https:// www.framinghamheartstudy.org/risk-functions/ coronary-heart-disease/hard-10-year-risk.php)

! Multi-Ethnic Study of Atherosclerosis (https://www.mesa-nhlbi. org/MESACHDRisk/MesaRiskScore/RiskScore. aspx)

! Reynolds Risk Score (http://www.reynoldsriskscore.org) ! United Kingdom Prospective Diabetes Study (UKPDS) (https://www.dtu.ox.ac. uk/riskengine)

AACE Screening Considerations

! Women’s ASCVD risk is frequently under assessed. ! Use Reynolds or Framingham

! Childhood and adolescence should be diagnosed early to reduce CV events in adulthood.

! HDL > 60, subtract 1 risk factor ! Elevated TG should be incorporated in risk

assessment

Screening: Who and When ! Familial hypercholesterolemia with family history of

! Premature ASCVD (MI, SCD <55 yo father; < 65 yo mother (or first degree relative)

! Adults with DM ! Annual

! Young adults ! Every 5 years, age 20 or higher

! Middle age adults (men 45-65; women 55-65) ! 1-2 years

! Older Adults (over 65) ! Screen annually; both men and women

! Children at risk (family Hx of premature ASCVD or high cholesterol !  Initial screening at age 3, repeat 9-11 and age 18

Lab Tests

! Lipid profile ! Can be done non-fasting if fasting is impractical

! Apolipoproteins ! ApoB reflects the particle concentration of LDL and all

other atherogenic lipoproteins. ! hsCRP ! Indicated inflammation in the body ! Used to further assess risk when labs borderline.

! Lipoprotein-associated phospholipase A2 (Lp-PLA2) ! Further assess risk when hsCRP elevated.

AACE Risk Categories

Risk Category Risk factors/10 year risk Extreme !  Progressive ASCVD including unstable

angina with LDL < 70 !  Established CV disease with DM, CKD 3-4

or HeFH !  History of premature ASCVD

Very High !  Established re recent hospitalization for ACS, 10 year risk > 20%

!  DM or CKD 3-4 !  HeFH

High !  > 2 risk factors and 10 yr risk 10-20% !  DM or CKD 3-4 with no other risk

Moderate !  < 2 risk factors and 10 year risk < 10% Low !  No risk factors

Treatment Goals Adults

Risk LDL Non-HDL ApoB Extreme <55 <80 <70 Very High <70 <100 <80 High <100 < 130 < 90 Moderate < 100 < 130 < 90 Low < 130 < 160 NR

Triglyceride Level Classification

TG Category TG Concentration mg/dL

Goal

Normal < 150 Borderline 150-199 < 150 High 200-499 < 150 Very High >500 < 150

Children and Adolescent LDL Levels

Category LDL, mg/dl Acceptable < 100 Borderline 100-129

High > 130

Screening in Children and Adolescents

! USPSTF December 2016 recommendations ! Asymptomatic children and adolescents 20 years

or younger there is insufficient evidence of benefit ! Risk assessment to include obesity, familial

hypercholesterolemia ! When needed screen with lipid panel ! Intervention: lifestyle

Screening in Children and Adolescents Cont’d

! National Heart Lung and Blood Institute endorsed by the American Academy of Pediatrics 2017 ! Universal screening 9-11 year olds with non-fasting

lipid panel ! Children with DM, HTN, over 95th BMI or smoke ! Screen between 2-8 and 12-16 with fasting lipid.

! AACE ! Children at risk (family Hx of premature ASCVD or high cholesterol) !  Initial screening at age 3, repeat 9-11 and age 18

! Ongoing debate

The Over 75 Patient

! Fewer older patients involved in trials. ! Consider the 10 year ASCVD risk ! Consider moderate vs high intensity statin therapy ! Drug-drug interactions ! Patient preference

Treatment ! Lifestyle ! Physical activity ! 4-6 times weekly 30 minutes

! Nutrition ! Reduced calorie, reduce saturated, trans fats,

increase fiber and plant stanols/sterols ! Nutrition counseling

! Smoking cessation ! Co-decision with patient

Pharmacologic Therapy

! HMG-CoA reductase inhibitors (statins) ! Reduce LDL 21-55%, up regulation of hepatic

LDL receptors ! Cholesterol absorption inhibitors (ezetimibe) ! LDL reduction 10-18% alone ! With statin LDL reduction 34-61%

! PCSK9 (alirocumab/Praluent , evolocumab/Repatha) ! LDL reduction 48-71%,

Pharmacologic Therapy cont’d

! Fibric acid derivatives: (gemfibrozil, fenofibrate, fenofibric acid) ! TG reduction 20-35%, fenofibrate reduces LDL

and TC 20-25% ! Niacin currently out of favor ! Bile acid sequestrants (cholestyramine, colestipol,

colesevelam ! LDL reduction 15-25%

Statin Therapy ! Refer to ACC/AHA statin intensity chart ! Check LFTs prior to starting and as clinically indicated ! Evaluate for myalgias and muscle weakness ! Drug-drug interaction with some ! CYP450 3A4, warfarin, cyclosporine protease inhibitors

! Simvastatin 80 mg no longer recommended ! Simvastatin 20 with amlodipine or ranolazine ! Rosuvastatin plasma levels may be higher in Asian ! New onset DM risk; monitor patients with metabolic

syndrome

Statin Therapy ! 1 year of statin use can see a 20-25% reduction in global CV

risk. Those at higher risk have more benefit. ! Safety

! Myalgia: rhabdomyolysis extremely rare ! Hemorrhagic stroke: odds ratio of 1:1.2 ! Diabetes: overweight, glucose intolerance, metabolic

syndrome ! Cost

! Generic statin $48-120/year. !  If followed 2013 AHA/ACC guidelines 12.3 million

additional statin eligible would have a gain of 183,000 quality adjusted life years and save the US $3.8 billion in healthcare dollars.

Ezetimibe (Zetia)

! Inhibits intestinal absorption of cholesterol ! Dose: 10 mg daily ! Rare myopathies ! Most effective when co-administered with statin.

(LDL reduction of 34-61%)

PCSK9 ! Monoclonal antibodies that target and inactivate

proprotein convertase subtilisin kesin 9, a liver protein. This results in reducing LDL receptor degradation and increased LDL clearance.

! alirocumab/Praluent and evolocumab/Repatha ! Similar benefits and minimal SE ! Both SQ administration ! Costly $14000.00/year ! Consider referral to lipid expert to evaluate and

initiate.

alirocumab/Praluent ! 75 mg SQ every 2 weeks; max dose 150 mg every 2

weeks ! Alternative 300 mg every 4 weeks

! Check LDL 4-8 weeks ! Missed dose ! Within 7 days take, longer than 7 days wait till next

scheduled dose. ! Refrigerate ! No data on pregnancy/lactation ! No renal or hepatic dosing adjustments ! No change in statin dose

Odyssey 1 Trial alirocumab

From Highlights of Prescribing Information sanofi-adventis

evolocumab/Repatha ! 140 mg SQ every 2 weeks or 420 mg once a

month ! Indicated for ASHD, HoFH and HeFH ! Check LDL 4-8 weeks post initiation ! Missed dose ! Within 7 days take, longer than 7 days wait till

next scheduled dose. ! Refrigerate ! No pregnancy/lactation data ! Small study with 10 youth 13-17 years with HoFH ! No renal or hepatic dose adjustments

LAPLACE-2 Trial

From Highlights of prescribing Information: Repatha Amgen

Non-Statin Cost Effectiveness !  Ezetimibe brand name $2600/ year. ! To be cost effective would need an 80%

reduction in cost of brand ($575/ year) ! Generic has not been researched and costs

$550-$2550/year ! PCSK9 ! Not cost effective at current $14,000 per year. ! Would need to be in the $4000-$6000 to be

cost effective. ! Consider for the extremely high risk individual.

Fibric Acid Derivatives ! gemfibrozil may increase LDL 10-15%, increase

risk of myalgias ! fenofibrate or fenofibric acid: ! Several dosing amounts ! Indicated for hypertriglyceridemia,

hypercholesterolemia, mixed dyslipidemia ! Usually well tolerated ! Reduce dose for mild to moderate GFR

impairment. ! Contraindicated for GFR <30

nicotinic acid/Niacin

! Side effect of flushing, itching, abd pain, hepatotoxicity

! Elevated serum glucose ! Increases uric acid levels

Bile Acid Sequestrants

! cholestyramine, colestipol, colesevelam ! Action: bind cholesterol rich bile acids and eliminate

in stool. ! Side effects of GI complaints ! Bind other drugs and reduce absorption ! Reduce absorption of fat soluble nutrients ! Use as an alternative to ezetimibe.

MTP inhibitor

! lomitapide (Juxtapid) indicated only for adults with homozygous familial hypercholesterolemia (HoFH) ! Prescriber certification required ! Prior authorization required ! Dose capsules 5mg to 60 mg ! CYP3A4 drug-drug interaction ! Hepatotoxicity ! High number of GI side effects reported ! High cost ! Single arm, uncontrolled study of 29 patients LDL

reduction of 45%

Follow up and Monitoring

!  AACE: Reassess lipid status 6 weeks after initiation and at 6 week intervals until treatment goal reached. ! Check LFTs before starting and at 3 months post

initiation. Repeat periodically. ! AHA/ACC: follow up in 4-12 weeks with lipid panel

until goal reached. ! Complex patients: consider referral to lipid

specialist.

Thank You ! Questions?