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DYSLIPIDEMIANareeta Sharma, PharmD, MS
Pharmacy Practice Fellow
University of the Pacific, Thomas J. Long School of Pharmacy
August 26, 2021
Disclosure
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Objectives
• Identify risk factors for dyslipidemia and atherosclerotic cardiovascular disease (ASCVD)
• Classify patients based on their risk for future ASCVD events
• Describe statin and non-statin pharmacologic options for managing dyslipidemia
• Create a treatment plan for patients with dyslipidemia
Introduction• Cholesterol
• Vital structural component of cell membranes
• Necessary for hormone synthesis and bile acid production
• Lipoproteins• Transport cholesterol, triglycerides (TG), and fat-
soluble vitamins throughout the body
• Very-low-density-lipoproteins (VLDL)
•Carries TG
• High-density-lipoproteins (HDL)
•Carries more proteins, less cholesterol
• Low-density-lipoproteins (LDL)
•Carries cholesterol
•Friedewald equation: LDL = TC – HDL - (TG/5)
• TC = total cholesterol
• Not applicable if TG > 400 mg/dL
• Dyslipidemia
• Abnormal level of cholesterol and other lipids in the blood
• High low-density lipoproteins (LDL) and/or total cholesterol (TC)
• High triglycerides (TG)
• Low high-density lipoproteins (HDL)
• Risk factor of atherosclerotic cardiovascular disease (ASCVD)
• Atherosclerosis
• Plaque build-up that affects coronary, cerebral, and peripheral arteries
https://ndnr.com/cardiopulmonary-medicine/dietary-management-of-dyslipidemia-a-review-of-evidence-based-strategies/
Primary vs. Secondary Dyslipidemias
Primary or Familial Dyslipidemia
• Genetic or familial defects can contribute
• Severe cholesterol elevations, putting patient at risk for premature ASCVD
• Homozygous familial hypercholesterolemia (HoFH) • LDL ≥ 500 mg/dL
• Heterozygous familial hypercholesterolemia (HeFH) • LDL 250-450 mg/dL
Secondary or Acquired Dyslipidemia
• Diet –excessive alcohol, carbohydrate or fat intake, anorexia, weight gain,
• Drugs –atypical antipsychotics, diuretics, beta blockers, glucocorticoids, oral estrogen and progestin, tacrolimus
• Disorders –nephrotic syndrome, hypothyroidism, pregnancy
• Diseases or comorbid conditions –obesity, liver disease, uncontrolled diabetes, chronic kidney disease (CKD)
Dyslipidemia Risk Factors
Poor diet Obesity Lack of exercise Smoking
Pregnancy Hypertension Diabetes Drugs
Genetics and family
historyAge
Screening
Begin at age 20
Fasting or non-fasting labs
Assess risk factors and ASCVD risk score
Fasting Lipid Profile (FLP)
TC (mg/dL)<200 Desirable
200-239 Borderline High≥240 High
LDL (mg/dL)<100 Desirable
100-129 Above Desirable130-159 Borderline High160-189 High
≥190 Very HighHDL (mg/dL)
<40 (men) Low<50 (women) Low
TG (mg/dL)<150 Desirable
150-199 Borderline High200-499 High
≥500 Very High
ASCVD Risk Assessment
• Evaluates a patient's risk of having a cardiovascular event during the next 10 years
• Nonfatal myocardial infarction (MI), coronary heart disease death, nonfatal and fatal stroke, and transient ischemic attack (TIA), or peripheral arterial disease (PAD) presumed to be of atherosclerotic origin
• Do not calculate for a patient who has already had a cardiovascular event
• Considered to have clinical ASCVD
https://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate/
Lifestyle Modifications• Diet
• Increased intake of vegetables, fruits, whole grains, legumes, and healthy protein sources (low-fat dairy products, low-fat poultry, fish/seafood, nuts)
• Increased intake of soluble fiber
• Limit intake of sweets, sugar-sweetened beverages, and red meats
• Exercise
• Aerobic moderate-to-vigorous intensity physical activity 3-4 sessions/week, lasting ~40min/session
• Smoking cessation
Therapeutic Recommendations
2018 AHA/ACC Guideline on the Management of Blood Cholesterol
Statin Benefit Groups
Clinical ASCVDSevere
hypercholesterolemia (LDL ≥ 190 mg/dL)
40-75 years old with LDL 70-189 mg/dL and diabetes (no ASCVD)
40-75 years old with LDL 70-189 mg/dL and
estimated 10-year ASCVD risk ≥ 7.5% (no ASCVD, no diabetes)
Clinical ASCVD
• Initiate high intensity statin (HIS)• If HIS is contraindicated or statin-related ADRs emerge, then initiate
moderate intensity statin (MIS) or maximally-tolerated statin• Initiate ezetimibe if additional therapy is required• If on maximally-tolerated statin + ezetimibe but LDL ≥ 70 mg/dL or
non-HDL ≥ 100 mg/dL, then consider PCSK9 inhibitor
≤ 75 years old
• MIS or maximally-tolerated statin, after evaluation of potential for ASCVD risk reduction, adverse effects, DDIs, patient frailty, and patient preferences
> 75 years old
Severe Hypercholesterolemia (LDL ≥ 190 mg/dL)
• Initiate maximally-tolerated statin therapy
21 to 75 years old
• Add nonstatin therapy to maximally-tolerated statin
21 to 75 years old on statin therapy, but LDL reduction is < 50%
40-75 years old with LDL 70-189 mg/dL and diabetes (no ASCVD)
• Initiate (at least) a MIS
40 to 75 years old, regardless of 10-year ASCVD risk
• Initiate a HIS
40 to 75 years old with diabetes and multiple ASCVD risk factors
• Maximally-tolerated statin + ezetimibe
40 to 75 years old with diabetes and ASCVD risk score ≥ 20%
• Initiate maximally-tolerated statin after a clinician-patient discussion• Or continue statin therapy, if patient was already on a statin
> 75 years old with diabetes
40-75 years old with LDL 70-189 mg/dL and estimated 10-year ASCVD risk ≥ 7.5% (no ASCVD, no diabetes)
• Intermediate Risk• Can initiate a MIS
40 to 75 years old without diabetes, with LDL 70-189 mg/dL, and with ASCVD risk score ≥ 7.5% - < 20%
• High Risk• Can initiate a HIS
40 to 75 years old without diabetes, with LDL 70-189 mg/dL, and with ASCVD risk score ≥ 20%
Case Question
JP is a 68 year old male.PMH: HTN, atrial fibrillation, stroke, anxiety, DMT2Medication list: lisinopril 40mg daily, metoprolol succinate 100mg daily, Eliquis 5mg BID, sertraline 50mg daily, metformin 500mg BIDFLP: TC 274 mg/dL, LDL 183 mg/dL, HDL 48 mg/dL, TG 215 mg/dL
Which is the most appropriate therapeutic recommendation for this patient?
a) HIS if estimated 10-year ASCVD risk ≥ 7.5%
b) Statin therapy is contraindicated in this patient
c) It is not appropriate to estimate the 10-year ASCVD risk in this patient
d) MIS if estimated 10-year ASCVD risk ≥ 7.5%
Case Question
JP is a 68 year old male.PMH: HTN, atrial fibrillation, stroke, anxiety, DMT2Medication list: lisinopril 40mg daily, metoprolol succinate 100mg daily, Eliquis 5mg BID, sertraline 50mg daily, metformin 500mg BIDFLP: TC 274 mg/dL, LDL 183 mg/dL, HDL 48 mg/dL, TG 215 mg/dL
Which is the most appropriate therapeutic recommendation for this patient?
a) HIS if estimated 10-year ASCVD risk ≥ 7.5%
b) Statin therapy is contraindicated in this patient
c) It is not appropriate to estimate the 10-year ASCVD risk in this patient
d) MIS if estimated 10-year ASCVD risk ≥ 7.5%
Pharmacologic ManagementStatins
Ezetimibe
Bila Acid Sequestrants
Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) Inhibitors
Bempedoic Acid
Fibrates
Omega-3 Fatty Acids
Statins
• Drug of choice for managing dyslipidemia
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Statin Intensity Options
HIGH INTENSITY (HIS)
MODERATE INTENSITY (MIS)
LOW INTENSITY(LIS)
Daily dose ↓ LDL ≥ 50% Daily dose ↓ LDL 30-40% Daily dose ↓ LDL < 30%
Atorvastatin 40-80 mg dailyRosuvastatin 20-40 mg daily
Atorvastatin 10-20 mg dailyRosuvastatin 5-10 mg dailySimvastatin 20-40 mg dailyPravastatin 40-80 mg dailyLovastatin 40 mg dailyFluvastatin XL 80 mg dailyFluvastatin 40 mg BIDPitavastatin 2-4 mg daily
Simvastatin 10 mg dailyPravastatin 10 –20 mg dailyLovastatin 20 mg dailyFluvastatin 20-40 mg dailyPitavastatin 1 mg daily
Statin Clinical Pearls
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• Simvastatin Lovastatin
• 10 mg/day -verapamil, diltiazem, dronedarone• 20 mg/day -amiodarone, amlodipine, ranolazine
• 20 mg/day -diltiazem, dronedarone, verapamil, amlodipine• 40 mg/day -amiodarone, ticagrelor
Statin-associated Muscle Symptoms (SAMS)
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Risk Factors for SAMS
Advanced age (>65yo) Female Low BMI Frequent heavy
exercise
Increased serum statin
concentrations, due to increased dose or
DDIs
Hypothyroidism Renal impairment
Management of SAMSPatient with suspected
SAMS
Utilize Statin-Associated Muscle Symptoms Clinical
Index (SAMS-CI)
Low SAMS-CI Score
Evaluate for: other causes affecting musculoskeletal
system
Statin discontinuation
After symptoms resolution initiate: same dose of same statin OR alternative statin
of similar intensity
High SAMS-CI Score
Before diagnosing statin intolerance: review DDIs
and co-morbidities to assess for nonstatin causes
Statin discontinuation
After symptom resolution, initiate: lower dose of same statin OR alternative statin
of similar intensity OR statin with a different
pharmacokinetic profile
• Symptoms typically improve within 1-2 weeks of statin discontinuation
• Patient's symptoms should be reassessed 2-3 weeks after statin discontinuation
• Statins with longer half-lives can be dosed every other day or less often, which reduces exposure to therapy
• Addition of coenzyme Q10 (CoQ10) is reported to provide relief, but is not supported by randomized clinical trials
• If patient cannot tolerate therapy despite trials of multiple statins, initiate nonstatin therapy
Case Question
Which of the following are appropriate therapeutic recommendations for a patient with a history of type 2 diabetes who requires a moderate intensity statin, but experienced muscle pain while on lovastatin 40mg daily? The patient has a high SAMS-CI score and a nonstatin cause of muscle pain cannot be identified.
a) Atorvastatin 10mg daily
b) Simvastatin 10mg daily
c) Atorvastatin 40mg daily
d) Simvastatin 40mg daily
Case Question
Which of the following are appropriate therapeutic recommendations for a patient with a history of type 2 diabetes who requires a moderate intensity statin, but experienced muscle pain while on lovastatin 40mg daily? The patient has a high SAMS-CI score and a nonstatin cause of muscle pain cannot be identified.
a) Atorvastatin 10mg daily
b) Simvastatin 10mg daily
c) Atorvastatin 40mg daily
d) Simvastatin 40mg daily
Ezetimibe (Zetia)
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Clinical Trial: IMPROVE-IT • Double blind, randomized trial
• Involved patients who had been hospitalized for ACS within preceding 10 days
• Randomized into two groups:• simvastatin 40mg + ezetimibe 10mg
• simvastatin 40mg + placebo
• Primary end point was a composite of cardiovascular death, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke
• When added to statin therapy, ezetimibe resulted in incremental lowering of LDL levels and improved cardiovascular outcomes
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. New England Journal of Medicine. 2015;372(25):2387-2397. https://doi.org/10.1056/NEJMoa1410489. Accessed Jul 1, 2021. doi: 10.1056/NEJMoa1410489.
Bile Acid Sequestrants –cholestyramine (Questran), colesevelam (Welchol)
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https://www.webmd.com/drugs/2/drug-4803/cholestyramine-light-oral/details
PCSK9 Inhibitors –alirocumab (Praluent), evolocumab (Repatha)
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•https://www.repatha.com/how-to-start-repatha-injection
Clinical Trial: FOURIER
• Double blind, randomized trial• Involved patients with ASCVD and LDL ≥ 70 mg/dL who
were receiving statin therapy• Randomized into groups:
• Evolocumab (140mg SC q2 weeks or 420 mg monthly)• Placebo injections
• Primary end point was a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization
• Absolute risk reduction: 1.5%, Number needed to treat: 67• When added to statin therapy, evolocumab resulted in
additional LDL lowering and improved cardiovascular outcomes
• Evolocumab indications• Secondary prevention for patients on maximally-
tolerated statin +/- ezetimibe, with LDL ≥ 70 mg/dL• Very high risk patients who are intolerant to statins and
are not at goal, despite use of other lipid-lowering agents
• Patients with FH and LDL ≥ 190 mg/dL, depending on treatment cholesterol levels and other risk factors
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. New England Journal of Medicine. 2017;376(18):1713-1722. https://doi.org/10.1056/NEJMoa1615664. Accessed Jul 1, 2021. doi: 10.1056/NEJMoa1615664.
Clinical Trial:ODYSSEY OUTCOMES
• Double blind, randomized trial• Involved patients with hx of ACS 1-12 months earlier, LDL ≥
70 mg/dL, non-HDL cholesterol ≥ 100 mg/dL, receiving HIS (or at the max-tolerated dose)
• Randomized into groups:• Alirocumab (75 mg q2 weeks)• Placebo injections
• Primary end point was a composite of death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization
• Absolute risk reduction: 1.6%, Number needed to treat: 63• When added to maximally-tolerated statin therapy,
alirocumab resulted in a lower risk of recurrent ischemic cardiovascular events among patients who had a previous ACS event
• Alirocumab indications• Secondary prevention for patients on maximally-tolerated statin
+/- ezetimibe, with LDL ≥ 70 mg/dL• Patients with FH and on maximally-tolerated statin
Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. New England Journal of Medicine. 2018;379(22):2097-2107. https://doi.org/10.1056/NEJMoa1801174. Accessed Jul 1, 2021. doi: 10.1056/NEJMoa1801174.
Bempedoic Acid (Nexletol)
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Clinical Trial:CLEAR Harmony
• Double blind, randomized trial
• Involved patients with ASCVD, HeFH, or both with LDL ≥ 70mg/dL while receiving maximally-tolerated statin +/- additional lipid-lowering therapy
• Randomized into two groups:• Bempedoic acid
• Placebo
• Primary end point was safety and secondary end point was the percentage change in LDL level at week 12 of 52 weeks
• Bempedoic acid added to maximally-tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo and led to significantly lower LDL levels
Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. New England Journal of Medicine. 2019;380(11):1022-1032. https://doi.org/10.1056/NEJMoa1803917. Accessed Jul 16, 2021. doi: 10.1056/NEJMoa1803917.
Fibrates -fenofibrate (Antara, Tricor, Trilipix), gemfibrozil (Lopid)
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Omega-3 Fatty Acids -Omega-3 Acid Ethyl Esters (Lovaza), icosapent ethyl (Vascepa), omega-3-carboxylic acids (Epanova)
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Clinical Trial:REDUCE-IT • Double blind, randomized trial
• Involved patients with established CVD or with diabetes and other risk factors, who had been receiving statin therapy and who had a fasting TG 135-499 mg/dL and LDL 41-100 mg/dL
• Randomized into two groups:• icosapent ethyl 2 g BID
• placebo
• Primary end point was a composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina
• Among patients with elevated TG levels on maximally-tolerated statins, icosapent ethyl significantly lowered the risk of ischemic events compared to patients who received placebo
• Expanded FDA indication for Vascepa: adjunct to maximally-tolerated statin therapy to reduce the risk of MI, stroke, coronary revascularization and unstable angina requiring hospitalization in adults with TG levels ≥150 mg/dl and established CVD or diabetes mellitus and two or more additional risk factors for CVD
Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. New England Journal of Medicine. 2019;380(1):11-22. https://doi.org/10.1056/NEJMoa1812792. Accessed Jul 1, 2021. doi: 10.1056/NEJMoa1812792.
Case Question
LM is a 57 year old female
PMH: HTN, DMT2, GERD, PAD, and hypothyroidism
Medication list: metformin 500mg daily, linagliptin 5mg daily, losartan 50mg daily, amlodipine 10mg daily, ASA 81mg daily, levothyroxine 88 mcg daily
FLP: TC 214 mg/dL, LDL 136 mg/dL, HDL 41 mg/dL, TG 186 mg/dL
What statin benefit group does LM belong to?
a) Clinical ASCVD
b) Severe hypercholesterolemia
c) 40-75 years old with LDL 70-189 mg/dL and diabetes
d) 40-75 years old with LDL 70-189 mg/dL and estimated 10-year ASCVD risk ≥ 7.5%
Case Question
LM is a 57 year old female
PMH: HTN, DMT2, GERD, PAD, and hypothyroidism
Medication list: metformin 500mg daily, linagliptin 5mg daily, losartan 50mg daily, amlodipine 10mg daily, ASA 81mg daily, levothyroxine 88 mcg daily
FLP: TC 214 mg/dL, LDL 136 mg/dL, HDL 41 mg/dL, TG 186 mg/dL
What statin benefit group does LM belong to?
a) Clinical ASCVD
b) Severe hypercholesterolemia
c) 40-75 years old with LDL 70-189 mg/dL and diabetes
d) 40-75 years old with LDL 70-189 mg/dL and estimated 10-year ASCVD risk ≥ 7.5%
Case Question
LM is a 57 year old female
PMH: HTN, DMT2, GERD, PAD, and hypothyroidism
Medication list: metformin 500mg daily, linagliptin 5mg daily, losartan 50mg daily, amlodipine 10mg daily, ASA 81mg daily, levothyroxine 88 mcg daily
FLP: TC 214 mg/dL, LDL 136 mg/dL, HDL 41 mg/dL, TG 186 mg/dL
Which is the most appropriate statin to initiate for LM?
a) Simvastatin 20mg daily
b) Lovastatin 40mg daily
c) Atorvastatin 20mg daily
d) Rosuvastatin 20mg daily
Case Question
LM is a 57 year old female
PMH: HTN, DMT2, GERD, PAD, and hypothyroidism
Medication list: metformin 500mg daily, linagliptin 5mg daily, losartan 50mg daily, amlodipine 10mg daily, ASA 81mg daily, levothyroxine 88 mcg daily
FLP: TC 214 mg/dL, LDL 136 mg/dL, HDL 41 mg/dL, TG 186 mg/dL
Which is the most appropriate statin to initiate for LM?
a) Simvastatin 20mg daily
b) Lovastatin 40mg daily
c) Atorvastatin 20mg daily
d) Rosuvastatin 20mg daily
Case QuestionTJ is a 67 year old Hispanic male presenting for a routine follow-up.
PMH: DMT2, COPD, HTN
SH: smokes 1 PPD, drinks 1-2 beers/day
Medication list: metformin 1000mg PO BID, Januvia 100mg PO daily, ASA 81mg PO daily, lisinopril 20mg PO daily, Symbicort 160/4.5 mcg 2 puffs BID, albuterol 90mcg 1 puff q4h prn SOB/wheezing
VS: HR 79, BP 146/85
Ht 72in, Wt 210lbs
Fasting Labs: TC 250 mg/dL, HDL 54 mg/dL, TG 872 mg/dL, LDL 142mg/dL, SCr 0.7 mg/dL
How would you manage this patient’s dyslipidemia?
Case QuestionTJ is a 67 year old Hispanic male presenting for a routine follow-up.
PMH: DMT2, COPD, HTN
SH: smokes 1 PPD, drinks 1-2 beers/day
Medication list: metformin 1000mg PO BID, Januvia 100mg PO daily, ASA 81mg PO daily, lisinopril 20mg PO daily, Symbicort 160/4.5 mcg 2 puffs BID, albuterol 90mcg 1 puff q4h prn SOB/wheezing
VS: HR 79, BP 146/85
Ht 72in, Wt 210lbs
Fasting Labs: TC 250 mg/dL, HDL 54 mg/dL, TG 872 mg/dL, LDL 142mg/dL, SCr 0.7 mg/dL
How would you manage this patient’s dyslipidemia?
• Lifestyle modifications
• 67 years old + diabetes• Statin –determine intensity based on ASCVD
risk score
• TG > 500 • Fibrate or omega-3 fatty acid to prevent
acute pancreatitis• Avoid gemfibrozil
References• Dixon DL, Riche DM. Dyslipidemia. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A
Pathophysiologic Approach, 11e. McGraw Hill; Accessed June 26, 2021. https://accesspharmacy-mhmedical-com.tjlsophs.idm.oclc.org/content.aspx?bookid=2577§ionid=231921082
• Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. New England Journal of Medicine. 2019;380(11):1022-1032. https://doi.org/10.1056/NEJMoa1803917. Accessed Jul 13, 2021. doi: 10.1056/NEJMoa1803917.
• Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: A report of the american college of cardiology/american heart association task force on clinical practice guidelines. Circulation. 2019;139(25):e1082-e1143. https://www.ahajournals.org/doi/10.1161/CIR.0000000000000625. Accessed Jul 1, 2021. doi: 10.1161/CIR.0000000000000625.
• Backes JM, Ruisinger JF, Gibson CA, Moriarty PM. Statin-associated muscle symptoms –Managing the highly intolerant. Journal of Clinical Lipidology. 2017;11(1):24-33. https://doi.org/10.1016/j.jacl.2017.01.006. Accessed July 6, 2021. doi:10.1016/j.jacl.2017.01.006
• Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. New England Journal of Medicine. 2019;380(1):11-22. https://doi.org/10.1056/NEJMoa1812792. Accessed Jul 1, 2021. doi: 10.1056/NEJMoa1812792.
• Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. New England Journal of Medicine. 2018;379(22):2097-2107. https://doi.org/10.1056/NEJMoa1801174. Accessed Jul 1, 2021. doi: 10.1056/NEJMoa1801174.
• Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. New England Journal of Medicine. 2015;372(25):2387-2397. https://doi.org/10.1056/NEJMoa1410489. Accessed Jul 1, 2021. doi: 10.1056/NEJMoa1410489.
• Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. New England Journal of Medicine. 2017;376(18):1713-1722. https://doi.org/10.1056/NEJMoa1615664. Accessed Jul 1, 2021. doi: 10.1056/NEJMoa1615664.
