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Update on the Treatment of
Hyperlipidemia

Wafaa Abou-Zeineddine, PharmDMedstar Washington Hospital CenterWashington Metropolitan Society of Health Systems PharmacistsMay 30, 2015 Please MUTE phones and do not put call on HOLD


• Nothing to disclose


• Name the 4 Statin Benefit Groups for risk reduction of atherosclerotic cardiovascular disease (ASCVD) • Discuss primary and secondary ASCVD risk • List risk factors that estimate the 10 year ASCVD • Discuss the role of statins and other drug classes in ASCVD risk reduction Terms and Definitions
• Atherosclerotic Cardiovascular Disease (ASCVD): - Coronary Heart Disease (CHD) or revascularization - Stroke or Transient Ischemic Attack (TIA) - Peripheral Arterial Disease or revascularization • ASCVD events: -Fatal or non-fatal Stroke


Terms and Definitions
• Low density lipoprotein cholesterol (LDL-C) • Very low density lipoprotein cholesterol (VLDL)• Triglyceride (TG) • Total Cholesterol (TC)• High density lipoprotein cholesterol (HDL-C)• Non-HDL Cholesterol = VLDL+LDL = TC–HDL-C -Non-HDL-C includes atherogenic lipoproteins


Collaboration of Professional Organizations
in Development of New Guidelines

• In 2013 The National Heart, Lung, and Blood Institute (NHLBI) collaborated with the American College of Cardiology and the American Heart Association (ACC/AHA) to develop clinical practice guidelines: -Assessment of Cardiovascular (CV) Risk-Lifestyle Modifications to Reduce CV Risk-Overweight and Obesity in Adults-Management of Blood Cholesterol • Focus on highest quality evidence to develop recommendations for these 4 guidelines


Strategies to Reduce ASCVD Risk
Past Guidelines:
• Treat to Cholesterol Target
• Lower Cholesterol is better
• Risk based treatment approaches
Present Guideline (2013):
• Lifestyle modification remains a critical
component in ASCVD risk reduction prior to and in conjunction with cholesterol-lowering therapy • Focus on Statin RCTs (overwhelming evidence)• Risk Factors (RFs) for ASCVD


What's New in the 2013 Blood
Cholesterol Guideline?

1. Focus on Atherosclerotic Cardiovascular Disease (ASCVD) Risk Reduction: 4 Statin Benefit Groups 2. New Perspective on LDL-C and Non-HDL 3. Global Risk Assessment for Primary Prevention: Use of the New Pooled Cohort Equations to estimate 10-Year ASCVD Risk 4. Safety Recommendations What's New in the 2013 Blood
Cholesterol Guideline? (cont.)

5. Role of biomarkers and noninvasive tests 6. Future Updates to the Blood Cholesterol Guideline: RCTs comparing alternative treatment strategies (non-statins) are needed for future evidence based guidelines for optimum ASCVD risk reduction and for the management of complex lipid disorders Features of 2013 ACC/AHA Guideline on
the Treatment of Blood Cholesterol to
Reduce ASCVD in Adults

• Treatment of Blood Cholesterol with Statin to reduce ASCVD events in adults based on RCTs • Limited number of expert opinion recommendations only when RCT evidence is not present • Not a comprehensive approach to the detection,
evaluation, and treatment of lipid disorders as had
been done in the ATPIII Report
• Not a source for questions regarding complex lipid disorders. This is beyond the scope of the systemic evidence review Overview of the Guidelines
• Extensive and consistent evidence was found
supporting use of statins for the prevention of
ASCVD in many higher risk Primary and ALL
Secondary Prevention individuals without NYHA
class II-IV Heart Failure and who were not
receiving Hemodialysis
• The trials were not designed to evaluate the effect of titrated statin treatment to achieve pre-specified LDL-C or Non-HDL-C goals • Hence the Expert Panel was unable to find RCT evidence to support titrating cholesterol-lowering drug therapy to achieve target LDL-C and Non-HDL-C levels as recommended by ATPIII RCT Results found by Expert Panel
• Initiation of -Moderate Intensity Statin therapy: LDL-C reduction of approx. 30- <50% -High Intensity Statin therapy: LDL-C reduction ≥ 50% is a critical factor in reducing ASCVD • Remains an important component of ASCVD risk • Prospective cohort studies and RCTs suggest that healthier dietary patterns are associated with lower chronic disease risk, including CVD and risk factors such as type 2 Diabetes Mellitis (DMII) and Hypertension (HTN) 2013 ACC/AHA Lifestyle Management
Guideline: Diet – Lowering LDL-C and BP

• Recommendations for lowering LDL-C & BP(A: strong):• Consume a dietary pattern that emphasizes -intake of vegetables, fruits and whole grain-includes low-fat dairy products-Poultry, fish, legumes-Non-tropical vegetable oils and nuts-Limits intake of sweets, sugary beverages & red meat • Adapt dietary pattern based on appropriate calorie requirements, food preferences and nutrition therapy for other medical conditions e.g. DM.
• Achieve this pattern by following plans such as DASH, USDA food pattern, or the AHA diet.
Diet – Lowering LDL-C (A)
• Aim for a dietary pattern that achieves - 5% to 6% of Calories from saturated fat - 26-27% of Calories from fat • Reduce % Calories from trans fat Diet: Lowering Blood Pressure
• Lower Sodium intake (A: strong)• Consume no more than 2,400 mg sodium/day• Further reduction of sodium intake to 1,500 mg/day is associated with even greater reduction in BP (B: moderate) • Combine DASH diet with lower sodium intake Lifestyle Modification: Physical Activity
• Reduce LDL-C, Non-HDL-C and BP: -Advise moderate to vigorous intensity aerobic physical activity 3-4 times weekly for an average of 40 minutes Metabolic Syndrome (NCEP/ATPIII)
Risk Factor
Abdominal Obesity Waist Circumference >102 cm (> 40 inches) > 88 cm (> 35 inches) Blood Pressure (BP) Fasting Glucose (Glc) Classification of Overweight and Obesity
• Disease risk for DMII, HTN and CVD
Disease Risk
Disease Risk
♂ ≤ 102cm
♂ ≥ 102cm
♀≤ 88 cm
♀ ≥88 cm
25.0-29.9 Increased 35.0-39.9 Very high Major Risk Factors for CVD
(NCEP/ATPIII guideline)
• Age (♂>45, ♀>55 yrs)
• FH of premature CHD: MI or sudden death in ♂
relatives <55, ♀ relatives<45 yr • Cigarette smoking
• HTN or on drugs for HTN
• Low HDL-C (< 40 mg/dl) and high LDL-C
• DM: CHD risk equivalent (in ATP III)
Also referred to in the 2013 Guidelines along
with DM as Traditional Risk Factors
Emerging Risk Factors for CVD
(NCEP/ATPIII guideline)
• Triglycerides/non-HDL-C
• Subclinical atherosclerotic disease
• High VLDL
• Lipoprotein a
• Homocysteine
• Thrombogenic/ Hemostatic factors
• Inflammatory markers/ CRP
• Impaired Fasting Glc
Additional Risk Factors
• Primary LDL ≥ 160 mg/dl or other evidence of genetic hyperlipidemia • CAC score ≥ 300 Agatston or > 75th % for age, • Ankle-Brachial Index (ABI) < 0.9
• Carotid Intima-media thickness (CIMT)
• Other Traditional RFs: HDL, SBP, tobacco
• Elevated lifetime risk of ASCVD
Risk Assessment Tools in Primary Prevention
Framingham Risk Score
Pooled Cohort Equations
ACC/AHA 2013
Race: AA, White,
• Total Cholesterol (TC) • Smoker/non-smoker • If Risk-based treatment decision still unsure, ≥ 1 of the following may be • Systolic Blood Pressure considered: FH, CRP, (SBP) un-treated/treated • Total number of points • Reasonable to assess were added to calculate Traditional RFs (left) the 10-yr risk of a CHD including DM every 4-6 yr Intensity of Risk Reduction Therapy
• Risk Assessment is a prerequisite to risk reduction
• Intensity of risk reduction therapy is based on Absolute Risk (both Guidelines) • NCEP/ATPIII: risk assessment based on Framingham Scoring System. Outcome of interest was CHD • ACC/AHA 2013 guideline uses Pooled Cohort Equations from the community • Outcome of interest is focused on estimation of first hard ASCVD events--- first occurrence of non-fatal MI or CHD death, or fatal or non-fatal stroke Focus of 2013 Guideline ASCVD Risk
Reduction: 4 Statin Benefit Groups

• Clinical ASCVD• Primary Elevations of LDL-C ≥ 190 mg/dl• 40-75 yrs of age with DM & LDL-C 70-189 mg/dl• Without clinical ASCVD or DM who are 40-70 yrs of age with LDL-C 70-189 mg/dl Statins for ASCVD Prevention
• Statin Treatment is recommended for primary and secondary prevention of ASCVD based on evidence from RCTs, reviews and meta-analyses of RCTs.
• If Age ≥ 21 yrs and LDL ≥ 190 mg/dl after Maximum Intensity Statin achieved, consider
addition of a NON-STATIN to further reduce LDL
• Treatment Targets: No recommendation for or against specific LDL or Non-HDL targets for the primary or secondary prevention of ASCVD High- Moderate- and Low-Intensity Statin
Therapy Reviewed by the Expert Panel in RCTs

High-Intensity Statin Moderate-Intensity
Low-Intensity Statin
Daily dose lowers Daily dose lowers LDL Daily dose lowers LDL on average by on average by approx. LDL on average by Atorvastatin (40mg-1 Atorvastatin 10 (20)mg Simvastatin 10 mgtrial: if unable to Rosuvastatin (5) 10 mg Pravastatin 10-20mg tolerate 80mg) 80mg Simvastatin 20-40 mg Pravastatin 40 (80) mg Fluvastatin 20- Fluvastatin XL 80 mg Pitavastatin 1 mg Fluvastatin 40 mg BID Pitavastatin 2-4 mg Secondary Prevention
Recommendations for Secondary Prevention

1. High-Intensity Statin Therapy should be initiated or continued as First-line therapy in ♀ and ♂ Age ≤ 75 yrs who have Clinical ASCVD 2. In individuals with Clinical ASCVD in whom High- Intensity Statin therapy is contraindicated or adverse effects are present, Moderate-Intensity Statin can be used if tolerated.
3. In individuals with Clinical ASCVD > 75 yrs of Age. Evaluate potential for ASCVD Risk Reduction and adverse effects, drug-drug interactions, and consider opin.
patient preference when initiating a Moderate- or High-Intensity Statin. It is reasonable to continue statin therapy when tolerated.
Primary Prevention: ≥ 21 Yrs with LDL ≥190
≥ 21 Yrs, LDL ≥190 mg/dl
1. LDL ≥190 mg/dl or Triglyderides (TG) ≥ 500 mg/dl, evaluate for Secondary causes of Hyperlipidemia 2. Age ≥ 21 Yrs with Primary LDL ≥190 mg/dl: treat with a BStatin --10-Yr ASCVD Risk Estimate not requiredHigh-Intensity Statin if tolerated. If not, use maximum tolerated statin.
3. ≥ 21 Yrs and Untreated LDL ≥190 mg/dl, reasonable to Euse High-Intensity Statin to achieve at least 50% LDL reduction 4. ≥ 21 Yrs and Untreated LDL ≥190 mg/dl, after Maximum Intensity Statin achieved, consider addition of
a NON-STATIN to further reduce LDL
Primary Prevention: Adults ≥ 21yrs,
LDL ≥190 mg/dl

• Adults ≥ 21yrs with Primary LDL ≥190 mg/dl have a high lifetime risk for ASCVD events due to lifetime exposure to elevated LDL (genetics) • Extensive evidence shows a ↓ LDL of 39mg/dl by Statin therapy → ↓ ASCVD Risk by 20% • High-Intensity Statin therapy recommended to achieve at least a 50% ↓ in LDL.
• In addition to maximally tolerated Statin Dose, Non-Statin Cholesterol-lowering drug is needed Primary Prevention: DM and LDL 70-189 mg/dl
Primary Prevention in DM and LDL 70-189 mg/dl
1. Moderate-Intensity Statin therapy should be initiated Aor continued for adults 40-75 Yrs of Age with DM 2. High-Intensity Statin Therapy is reasonable for adults 40-75 Yrs of Age with DM with a ≥ 7.5% estimated 10-Yr ASCVD risk unless contraindicated3. Adults with DM and Age <40 or > 75, it is reasonable to evaluate the potential for ASCVD benefits, and for adverse effects, drug-drug interactions, and patient preference when deciding to initiate, continue or intensify Statin therapy Primary Prevention in Diabetes
• High level of evidence supports use of Moderate-Intensity Statin in DM, Ages 40-75yr • High-Intensity Statins recommended in Ages 40- 75 yr with or without DM + ≥ 7.5% 10-Yr ASCVD Risk • Individuals with Diabetes, Age 40-75 yr are at an ↑ lifetime risk ASCVD events and death aid in Risk
Primary Preven Ass
tion: No DM; With LDL 70-189 mg/dl
1. Use Pooled Cohort Equations to Estimate 10-Yr ASCVD ERisk for LDL 70-189 mg/dl without Clinical ASCVD to guide initiation of Statin therapy for the Primary Prevention of ASCVD2. Adults 40-75 Yrs and LDL 70-189 mg/dl without Clinical AASCVD or DM & estim. 10-Yr ASCVD Risk ≥ 7.5% should be treated with Moderate- to High-Intensity Statin 3. Reasonable to offer Treatment with Moderate-Intensity CStatin to Adults Ages 40-75 Yrs, with LDL 70-189 mg/dl without Clinical ASCVD or DM and an estimated 10-Yr ASCVD Risk of 5% to <7% 4. Statin for Primary Prevention with LDL 70-189 mg/dl, without Clinical ASCVD or DM discuss benefits, ADR, pref.
5. Adults with LDL < 190 mg/dl not in a Statin Benefit Gp, Emay consider additional RFs to decide on Statin therapy Primary Prevention: Selected Individuals
• Additional factors may be considered for treatment
decisions in adults with LDL-C< 190 mg/dl not identified in a Statin Benefit Group: • -Primary LDL≥ 160mg/dl or other evidence of genetic hyperlipidemia • - FH of premature ASCVD• -hs-CRP• -CAC score• -ABI• -Elevated lifetime risk of ASCVD• Consideration of Traditional RFs• Additional factors may be identified in the future Heart Failure and Hemodialysis
• The Expert Panel makes no recommendations regarding initiation or continuation of statins in patients with NYHA Classes II-IV ischemic systolic heart failure or in patients on maintenance hemodialysis. • The potential for ASCVD risk reduction benefit, adverse effects, drug-drug interactions using Statin therapy and choice of Statin must be considered by the treating clinician Age in Global risk Assessment for
Primary Prevention

• Most ASCVD events occur after age 70 yrs• Age represents cumulative RF exposure• Individuals ≥ 70 yrs with no other RFs still have an estimated 10-yr risk ≥ 7.5% • This age group hence has the greatest potential for Absolute Risk Reduction Secondary Causes of Hyperlipidemia
Most Commonly Seen in Clinical Practice
Secondary Elevated LDL-C

Saturated or trans Wt gain, very low-fat diets, fats, weight gain, high intake of refined CHO, excessive Alcohol intake PO estrogens, GCs, BA seq, glucocorticoids (GC), PIs, sirolimus, tamoxifen, amiodarone bbs(not Coreg), thiazides Biliary obstruction, Lipodystrophies, CRF, nephrotic syndrome nephrotic syndrome Disorders & Hypothyroidism DM (poorly controlled), ∆ States of Obesity Hypothyroidism, Obesity, Statin Safety Recommendations
Parameter Recommendation

Not routinely measured.
Obtain a Hx of current/previous muscle Sxs baseline Measure if at ↑ risk for adverse muscle event Measure baseline ALT before initiating statin Evaluate for new-onset DM. Continue statin, recommend lifestyle changes Age > 75yr, If High-intensity statin not tolerated, use Moderate Hepatic or intensity statinRenal Dis.
Caution in organ transplant , HIV, elderly drug reg.
Pregnancy Category X, also avoid during lactation PHARMACOTHERAPY: Drug Classes
• Statins• Non-Statins: -Bile Acid sequestrants -Cholesterol absorption inhibitor -Omega 3 Fatty Acids Drug Classes in Hyperlipidemia Treatment
Drug Class
Lipid/ Lipoprotein Effects
HMG-CoA reductase ↓63% (rosuvastatin) ↑HDL: 5-15%↓TG: 7-30% Bile Acid Sequestrants ↓LDL: 15-30%↑HDL: 3-5% ↑HDL: 15-35%↓TG: 20-50% ↓LDL: 5-20%↑HDL: 15-35%↓TG: 20-50% HMG-CoA Reductase Inhibitors (Statins)
Dose (mg)
Initial: 2 Maximum: 4 Monitoring Statin Therapy
• Initial fasting lipid panel: TC, TG, HDL-C and
• 4-12 weeks later: second lipid panel to determine adherence • Every 3-12 months thereafter• Adherence to both medication and lifestyle regimens are required to reduce ASCVD risk • High-Intensity Statin therapy reduces ASCVD risk more than Moderate-Intensity Statin therapy • If patient requiring High-Intensity Statin is intolerant to it, start Moderate-Intensity Statin Selected Drug Interactions with Statins
• Amiodarone ↑risk of myopathy with lovast & simvast
• Azoles ↑lovastatin levels by 20%; pravastatin and
rosuvastatin are least altered • Macrolides ↑risk of severe myopathy with Statins with a 40% ↑with atorvastatin. ↓ pitavastatin dose • Protease Inhibitors ↑risk of myopathy • Protease Inhibitors ↓pravastatin levels• Rifampin ↓ simvastatin and fluvastatin levels• Verapamil ↑risk of myopathy with atorvastatin, simvastatin, lovastatin • Digoxin levels may ↑ by 20% with atorvastatin• Warfarin causes ↑INR with lova, simva, rosuv, fluva• Oral Contraceptives: atorvast. & rosuv. can ↑AUC Dose (gm/day) ↓ LDL
Niacin Safety Recommendations
• Before initiation, up-titration, then q6 months: obtain baseline hepatic transaminases, HgbA1c or fasting Glc, uric acid • Avoid if LFTs > 2-3 X ULN, persistent severe cutaneous Sxs, persistent hyperglycemia, acute gout, unexplained GI Sxs • Flushing: start low and titrate slowly over weeks, take with food or Aspirin 325 mg ½ hr before dose Bile Acid Sequestrants (Resins)
9 gm packets (4 gm drug)378 gm bulkLight: 210 gm bulk 5 gm packets (5 gm drug)450 gm bulk1 gm tablets Bile Acid Sequestrants (BSA)
• MOA: bind to cholesterol and bile acids in GI tract inhibiting re-absorption and enterohepaticcycling • ADRs: bloating, gas, constipation• Avoid if baseline TG ≥ 300 mg/dl • Decreases absorption of Vitamins A,D,E,K• Monitoring: Fasting Lipid Panel before BSA initiated, 3 months after, then every 6-12 months Cholesterol absorption Inhibitor:
Ezetimibe (Zetia)

• MOA: Inhibits absorption of dietary and biliary • Dose: 10 mg po daily• Drug-Drug Interaction: can ↑ cyclosporine level Fibric acids
Fibric Acid
ClCr 30-80 ml/min: start 145 mg tabat 48 mg/dClCr <15ml/min: contraindicated Fibrates Safety Recommendations
Gemfibrozil should not be initiated in patients
on Statins because of increased risk of myopathy and rhabdomyelosis • Fenofibrate may be given with a low- or
moderate-intensity Statin if the benefits from ASCVD risk reduction or Triglyceride lowering (TG> 500 mg/dl) outweighs risk • Fenofibrate is renally dosed: • -eGFR 30-59 ml/min/1.73m2: Max.= 54mg/d• -eGFR< 15 ml/min: Avoid Evidence Gaps and Need for Future
Research: High Priority Research Areas
• Outcomes of RCTs to evaluate statins for primary
prevention of ASCVD in adults > 75 yrs • Outcomes of RCTs to evaluate alternative treatment strategies for ASCVD risk reduction– titration to specific cholesterol goals versus fixed-dose statin therapy in high risk pt • RCTs to determine whether submaximal statin doses, combined with non-statins, reduce ASCVD risk in statin-intolerant patients • Evaluation of new-onset diabetes associated with • Outcomes of RCTs of new lipid-modifying agents to determine ASCVD event reduction benefits when added to evidence-based statin therapy • New ACC/AHA blood cholesterol guideline arose from a review of RCTs, reviews and meta-analyses of RCT.
• Lifestyle modification remains a critical component in ASCVD risk reduction prior to and in conjunction with cholesterol-lowering therapy • Overwhelming evidence from RCTs demonstrated that statins provide a reduction in ASCVD events • Focus on Atherosclerotic Cardiovascular Disease (ASCVD) Risk Reduction: 4 Statin Benefit Groups • Focus on Percentage Reduction in LDL of ≥ 50% in High-Intensity Statin therapy and 30-< 50% in Moderate-Intensity Statin therapy required to achieve ASCVD risk reduction in Primary and Secondary Prevention • After Maximum Intensity Statin achieved, may consider addition of a Non-Statin to further reduce LDL • Not a comprehensive approach to the detection, evaluation and treatment of lipid disorders References
• Stone, NJ., Robinson J., Lichtenstein AH et al. 2013
ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report by the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 1-84 • Online version for blood cholesterol guidelines:• • Eckel RH, Jacicic J, Ard J et al. 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Disease Risk. J Am Coll Cardiol. 2013:1-45.
• Lifestyle management guideline: • Goff DC et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013.
• Taylor F, Huffman MD, Macedo AR et al. Statins for the primary prevention of cardiovascular disease. Cochrane database of systemic reviews 2013:CD004816.
• Cholesterol Treatment Trialist Collaboration, Mihaylova B, Emberson J et al. The effects of lowering LDL-cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
• The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of high Blood Cholesterol in Adults (Adult Treatment Panell III) Manuscript version.
• Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of high Blood Cholesterol in Adults. JAMA 2001; 285(No.19):2486-97.
• Drug Facts and Comparisons. 2009: 809-838.
• AHFS Drug Information. American Society of Health Systems Pharmacy. 2014:1748-1829.

Source: http://wmshp.org/sg_current_event_content_new/Hyperlipidemia2_2015.pdf

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COMPENDIUM OF PRIMERS Evaluating Statistics Probability and Odds and Interpreting Their Ratios 1Type I and Type II Errors 3Absolute vs. Relative Differences 5Correlation Coefficients 695% CIs for the Number Needed to Treat 8Statistical Significance and P values 995% Confidence Intervals 11 Evaluating Study Designs Before–After Studies: Evaluating a Report of a "Successful" Intervention 14Group Randomized Trials 16Cost-Effectiveness Analysis 18Interpreting Surveys 21Utilities 23Scores: What Counts? 24 Special Topics Lead-Time, Length, and Overdiagnosis Biases 25Dissecting a Medical Imperative 26HEDIS 28Geographic Variation in Health Care 30