• Recent ACS (within the past 12 mo.)
• History of MI (other than recent ACS event listed above)
• History of ischemic stroke
• Symptomatic PAD (history of claudication with ABI <0.85, or previous revascularization or amputation)

• Age ≥ 65 y
• Heterozygous familial hypercholesterolemia
• History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD event(s)
• Diabetes
• Hypertension
• CKD (eGFR 15-59 mL/min/1.73 m2)
• Current smoking
• Persistently elevated LDL-C (LDL-C ≥100 mg/dL [≥2.6 mmol/L]) despite maximally tolerated statin therapy and ezetimibe
• History of congestive HF

• Family history of premature ASCVD (males, age <55 y; females age <65 y)
• Primary hypercholesterolemia (LDL-C 160–189 mg/dL [4.1–4.8 mmol/L); non–HDL-C 190–219 mg/dL [4.9–5.6 mmol/L] *
• Metabolic syndrome (increased waist circumference, elevated triglycerides [≥150 mg/dL], elevated blood pressure, elevated glucose, and low HDL-C [ <40 mg/dL in men; <50 mg/dL in women] are factors; tally of 3 makes the diagnosis
• Chronic kidney disease (eGFR 15–59 mL/min/1.73 m2 with or without albuminuria; not treated with dialysis or kidney transplantation)
• Chronic inflammatory conditions such as psoriasis, RA, or HIV/AIDS
• History of premature menopause (before age 40 y) and history of pregnancy-associated conditions that increase later ASCVD risk such as preeclampsia
• High-risk race/ethnicities (e.g., South Asian ancestry)
• Lipid/biomarkers: Associated with increased ASCVD risk
  o Persistently* elevated, primary hypertriglyceridemia (≥175 mg/dL)
  o If measured:
  1. Elevated high-sensitivity C-reactive protein (≥2.0 mg/L)
  2. Elevated Lp(a): A relative indication for its measurement is family history of premature ASCVD. An Lp(a) ≥50 mg/dL or ≥125 nmol/L constitutes a risk-enhancing factor especially at higher levels of Lp(a).
  3. Elevated apoB ≥130 mg/dL: A relative indication for its measurement would be triglyceride ≥200 mg/dL. A level ≥130 mg/dL corresponds to an LDL-C≥160 mg/dL and constitutes a risk-enhancing factor
  4. ABI <0.9

• Percentage LDL-C reduction achieved with evidence-based statin therapy (if < 50% and not on maximally tolerated statin, should increase statin therapy first and reinforce lifestyle modifications) and whether patient is above LDL-C threshold for consideration of nonstatin therapies
• For patients with ASCVD, patient’s status as very high risk or not very high risk on evidence-based statin therapy (See Criteria for Defining Patients at Very High-Risk of future ASCVD Events)*
• For patients without ASCVD or baseline LDL-C ≥190 mg/dL, patient’s baseline predicted 10-year ASCVD risk pre-statin and presence of risk enhancing factors (See Risk-Enhancing Factors for Clinician–Patient Risk Discussion)†
• Available scientific evidence of ASCVD risk reduction (and magnitude of benefit) when nonstatin therapy is added to evidence-based statin therapy‡
• Additional desired % LDL-C lowering beyond that achieved on evidence-based statin therapy§
• Mean percentage LDL-C lowering expected with proposed nonstatin therapy when added to evidence-based statin therapy

• See Strategies and Nonstatin Agents Considered for Management of LDL-Related ASCVD Risk.

• Potential out-of-pocket cost of therapy to the patient (e.g., insurance plan coverage, pharmacy or medical benefit, copayment, availability of assistance programs).

• Patient’s perception of benefit from addition of nonstatin therapy.
• Convenience of nonstatin therapy (e.g., route, setting [home or medical office], and frequency of administration, pill burden, storage).
• Potential of nonstatin therapy to jeopardize adherence to other evidence-based therapies.
• Cost of nonstatin therapy.
• Anticipated life expectancy, comorbidities, and impact of therapy on quality of life.

• Consider referring any patient with ASCVD and/or baseline LDL-C ≥190 mg/dL, baseline LDL-C ≥190 mg/dL, or intolerance to at least 2 (preferably 3) statin therapies with 1 attempt at the lowest FDA-approved dose and a trial of an alternative statin therapy regimen (eg, every-other-day dosing)
• Referral is recommended for patients with ASCVD and baseline LDL-C ≥190 mg/dL who did not achieve ↓ LDL-C ≥50% and LDL-C <70 mg/dL (or non–HDL-C <100 mg/dL) on maximally tolerated statin therapy in combination with nonstatin therapy
• May also consider referring other patients unable to achieve adequate LDL-C reduction
• Considerations in referring: Lipid specialists may be available for virtual visits for patients in some rural or remote locations

• Consider referring any patient with ASCVD and/or baseline LDL-C ≥190 mg/dL, or baseline LDL-C ≥190 mg/dL
• Referral is recommended for patients with ASCVD and baseline LDL-C ≥190 mg/dL who did not achieve ↓ LDL-C ≥50% and LDL-C <70 mg/dL (or non–HDL-C <100 mg/dL) on maximally tolerated statin therapy in combination with nonstatin therapy
• May also consider referring other patients unable to achieve adequate LDL-C reduction

• Mechanism of action: Inhibits NPC1L1 protein; reduces cholesterol absorption in small intestine.
• FDA-approved indication(s): As adjunct to diet to:
  1. ↓ TC, LDL-C, ApoB, non–HDL-C in patients with primary hyperlipidemia, either alone or in combination with statin therapy;
  2. ↓ TC, LDL-C, ApoB, non–HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate;
  3. ↓ TC, LDL-C with HoFH, in combination with atorvastatin or simvastatin;
  4. ↓ sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia)
• Dose: 10 mg orally daily, with or without food. Take either ≥2 h before or ≥4 h after BAS, if used in combination
• Mean % reduction in LDL-C (per PI): Monotherapy—18%; combination therapy with statin therapy (incremental reduction)—25%
• Contraindication: History of hypersensitivity to this medication.
• Warnings/precautions:
  1. Not recommended in patients with moderate/severe hepatic impairment.
  2. Persistent elevations in hepatic transaminases may occur with concomitant statin therapy. Monitor hepatic transaminases before and during treatment based on monitoring recommendations for statin therapy.
  3. Cases of myopathy and rhabdomyolysis have been reported when ezetimibe was used alone or in combination with statin therapy.
• Adverse effects: Monotherapy—upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremities. In combination with statin—nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, diarrhea
• Use during pregnancy/lactation: No safety data in humans; avoid use
• Drug–drug interactions: Cyclosporine, fibrates, BAS
• CV outcomes trials: IMPROVE-IT (The addition of ezetimibe to moderate-intensity statin therapy in patients with recent ACS resulted in incremental lowering of LDL-C and reduced the primary composite endpoint of CV death, nonfatal MI, UA requiring rehospitalization, coronary revascularization [≥30 days after randomization], or nonfatal stroke. The median follow-up was 6 years); SHARP (Simvastatin plus ezetimibe reduced LDL-C and reduced the primary endpoint of first major ASCVD event [nonfatal MI or CHD death, nonhemorrhagic stroke, or any arterial revascularization procedure] compared with placebo in patients with CKD over a median follow-up of 4.9 years)
• Other prescribing considerations: Generally well tolerated. Generic available

• Mechanism of action: Human mAb to PCSK9. Binds to PCSK9 and increases the number of LDL receptors available to clear circulating LDL-C
• FDA-approved indication(s):
• Alirocumab and evolocumab:
  1. ↓ LDL-C in adults with primary hyperlipidemia (including HeFH) as adjunct to diet, either alone or in combination with other lipid-lowering therapies
• Alirocumab:
  1. ↓ risk of MI, stroke, and unstable angina requiring hospitalization in adults with ASCVD;
  2. ↓ LDL-C in adults with HoFH as adjunct to other LDL-C–lowering therapies
• Evolocumab:
  1. ↓ risk of MI, stroke, and coronary revascularization in adults with ASCVD;
  2. ↓ LDL-C in pediatric patients (aged ≥10 years) with HeFH as adjunct to diet and other LDL-C–lowering therapies;
  3. ↓ LDL-C in adults and pediatric patients (aged ≥10 years) with HoFH as adjunct to diet and other LDL-C–lowering therapies
• Dose and route of administration:
• Alirocumab: Administer SC in the thigh, abdomen, or upper arm. In adults with ASCVD or primary hyperlipidemia: initiate 75 mg SC every 2 weeks. If more LDL-C reduction needed, may ↑ dose to 150 mg every 2 weeks. Alternative starting dose is 300 mg SC every 4 weeks. For the 300-mg dose, administer 2 (150-mg) injections consecutively at 2 different injection sites. In adults with HeFH undergoing LDL apheresis or adults with HoFH, administer 150 mg SC every 2 weeks
• Evolocumab: Administer SC in the thigh, abdomen, or upper arm. In adults with ASCVD, adults with primary hypercholesterolemia, including with established clinical ASCVD or HeFH, or in pediatric patients (aged ≥10 years) with HeFH, administer 140 mg SC every 2 weeks or 420 mg SC once monthly in abdomen, thigh, or upper arm. In adults or pediatric patients (aged ≥10 years) with HoFH, administer 420 mg SC once monthly; if more LDL-C reduction is needed after 12 weeks, may ↑ dose to 420 mg every 2 weeks. In adults or pediatric patients (age ≥10 years) with HoFH on LDL apheresis, may initiate 420 mg SC every 2 weeks to correspond with apheresis schedule; evolocumab should be given after apheresis is complete. To administer 420-mg dose, either use the prefilled single-dose on-body infuser or give 3 (140-mg) injections consecutively within 30 min.
• Mean % LDL-C reduction (per PI):
• Alirocumab: when added to maximally tolerated statin therapy, alirocumab 75 mg and 150 mg SC every 2 weeks ↓ LDL-C by an additional 45% and 58%, respectively, when added to maximally tolerated statin therapy.
• Evolocumab: 140 mg every 2 weeks and 420 mg SC every 4 weeks, ↓ LDL-C by an additional 64% and 58%, respectively.
• Contraindication: History of hypersensitivity to the medication.
• Warnings/precautions: Hypersensitivity reactions occurred during clinical trials. If a serious hypersensitivity reaction occurs, discontinue therapy; treat according to standard of care; monitor until signs and symptoms resolve.
• Adverse effects:
• Alirocumab: In patients with primary hyperlipidemia: nasopharyngitis, injection site reactions, influenza; in patients with ASCVD: noncardiac chest pain, nasopharyngitis, myalgia. No evidence of increase in cognitive adverse effects observed in ODYSSEY Outcomes or CANTAB.
• Evolocumab: In patients with primary hyperlipidemia: nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions; in patients with ASCVD: diabetes, nasopharyngitis, upper respiratory tract infection.
• No evidence of an increase in cognitive adverse effects observed in FOURIER or EBBINGHAUS.
• Use during pregnancy/lactation: No safety data in humans; avoid use.
• Drug-drug interactions: No clinically significant drug-drug interactions identified for alirocumab or evolocumab
• CV outcomes trials:
• Alirocumab: ODYSSEY Outcomes in 18,600 post-ACS (4-52 weeks) patients on evidence-based statin therapy; Demonstrated that addition of alirocumab reduced the primary endpoint of CHD death, MI, ischemic stroke, or hospitalization for UA.
• Evolocumab: FOURIER in 27,564 patients with prior MI, stroke, or PAD on atorvastatin ≥20 mg or equivalent; Demonstrated that addition of evolocumab reduced the primary endpoint of CV death, MI, stroke, revascularization, or hospitalization for unstable angina.
• Other prescribing considerations: Robust LDL-C reduction, cost, SC administration at home, may require prior authorization.
• Evolocumab: Advise latex-sensitive patients that the needle covers on the products contain latex.

• Mechanism of action: ACL inhibitor; inhibits cholesterol synthesis in the liver; increases LDL receptor density. Bempedoic acid and its active metabolite require coenzyme A activation by ACSVL1, which is expressed primarily in the liver.
• FDA-approved indication(s): ↓ LDL-C in adults with ASCVD or HeFH as adjunct to diet and maximally tolerated statin therapy.
• Dose: 180 mg orally once daily, with or without food.
• Mean % reduction in LDL-C (per PI): Combination therapy with statin therapy (placebo-corrected incremental reduction)—17%-18%.
• Contraindication: none
• Warnings/precautions:
  1. May ↑ serum uric acid. Advise patients to contact their clinician if symptoms of hyperuricemia occur. Assess serum uric acid when clinically indicated. Monitor patients for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs, as appropriate. Assess uric acid level before initiation and if signs and symptoms of hyperuricemia occur.
  2. Discontinue immediately if the patient experiences rupture of a tendon. Consider discontinuing if the patient experiences joint pain, swelling, or inflammation. Advise patients to rest at the first sign of tendinitis or tendon rupture and to contact their health care provider if tendinitis or tendon rupture symptoms occur. Consider alternative therapy in patients with a history of tendon disorders or tendon rupture.
• Adverse effects: Upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, elevated liver enzymes.
• Use during pregnancy/lactation: Discontinue when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. There are no available data on use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
• Drug–drug interactions: Avoid concomitant simvastatin >20 mg daily or pravastatin >40 mg daily.
• CV outcomes trials: CV outcomes trials not completed. CLEAR Outcomes trial completion expected later in 2022.
• Other prescribing considerations: cost; pill burden; requires prior authorization

• Refer to section on ezetimibe for information specific to this agent.
• Mechanism of action: See the mechanisms of action for bempedoic acid and ezetimibe included in this table.
• FDA-approved indication(s): ↓ LDL-C in adults with ASCVD or HeFH as adjunct to diet and maximally tolerated statin therapy.
• Dose: 1 tablet (180 mg bempedoic acid/10 mg ezetimibe) orally, once daily, with or without food. Swallow whole. Take either ≥2 hours before or ≥4 hours after BAS, if used in combination.
• Mean % reduction in LDL-C (per PI): Combination therapy with statin therapy (placebo-corrected incremental reduction)—38%.
• Contraindication: History of hypersensitivity to ezetimibe.
• Warnings/precautions:
  1. May ↑ serum uric acid. Advise patients to contact their clinician if symptoms of hyperuricemia occur. Assess serum uric acid when clinically indicated. Monitor patients for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs as appropriate. Assess uric acid level before initiation and if signs and symptoms of hyperuricemia occur.
  2. Discontinue immediately if the patient experiences tendon rupture. Consider discontinuing if the patient experiences joint pain, swelling, or inflammation. Advise patients to rest at the first sign of tendinitis or tendon rupture and to contact their health care provider if tendinitis or tendon rupture symptoms occur. Consider alternative therapy in patients with a history of tendon disorders or tendon rupture.
• Adverse effects: Upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremities, anemia, elevated liver enzymes, diarrhea, arthralgia, sinusitis, fatigue, influenza. Consider alternative therapy if history of tendon disorder or rupture; discontinue immediately if tendon rupture occurs.
• Use during pregnancy/lactation: Discontinue when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. There are no available data on use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
• Drug–drug interactions: Cyclosporine; fibrates. Avoid concomitant simvastatin >20 mg daily or pravastatin >40 mg daily.
• CV outcomes trials: CV outcomes trials for bempedoic acid not completed. Completion of CLEAR Outcomes trial expected later in 2022. CV outcomes trial will not be required for fixed-dose combination of ezetimibe and bempedoic acid.
• Prescribing considerations: ↓ LDL-C within the range of moderate-intensity statin therapy; cost; requires prior authorization

• Mechanism of action: siRNA targeting PCSK9; inhibits PCSK9 production in liver, thereby prolonging activity of LDL receptors.
• FDA-approved indication(s): ↓ LDL-C in adults with ASCVD or HeFH as adjunct to diet and maximally tolerated statin therapy.
• Dose: Administer 284 mg SC on day 1, day 90, and then every 6 months by a clinician.
• Mean % reduction in LDL-C (per PI): 48%-52%
• Contraindications (per PI): None
• Warnings/precautions (per PI): None
• Adverse effects: Injection site reaction, arthralgia, urinary tract infection, diarrhea, bronchitis, pain in extremities, dyspnea
• Use during pregnancy/lactation: No safety data in humans; avoid use.
• Drug–drug interactions (per PI): None
• CV outcomes trials: CV outcomes trials not yet completed. ORION-4 currently in progress with estimated completion in 2026. VICTORION-2P currently in progress with estimated completion in 2027.
• Other prescribing considerations: robust LDL-C reduction, cost, requires SC administration by a clinician, requires prior authorization.

• Mechanism of action: Nonabsorbed, lipid-lowering polymer that binds bile acids in the intestine and impedes their reabsorption. As the bile acid pool ↓, the hepatic enzyme cholesterol 7-a-hydroxylase is up-regulated, which ↑ conversion of cholesterol to bile acids. This causes ↑ demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme HMG-CoA reductase and ↑ numbers of hepatic LDL receptors. These compensatory effects result in ↑ clearance of LDL particles from the blood, in turn resulting in ↓ serum LDL-C levels. Serum TG levels may ↑ or remain unchanged.
• FDA-approved indication(s):
• Colesevelam: As an adjunct to diet and exercise
  1. ↓ LDL-C in adults with primary hyperlipidemia;
  2. ↑ glycemic control in adults with type 2 diabetes;
  3. ↓ LDL-C in boys and post-menarchal girls (aged 10-17 years) with HeFH who are unable to reach LDL-C targets after an adequate trial of diet therapy and lifestyle modifications. Cholestyramine, colestipol: ↓ LDL-C with primary hyperlipidemia, as adjunct to diet
• Dose and route of administration:
• Colesevelam: Tablets: 6 tablets orally once daily or 3 tablets orally twice daily; take tablets with a meal and liquid.
  Suspension: one 3.75-g packet orally daily, or one 1.875-g packet orally twice daily; mix powder with 8 ounces of water, fruit juice, or soft drink; take with meal.
• 3.75 g is equivalent to 6 tablets. 1.875 g is equivalent to 3 tablets;
• Cholestyramine: 8-16 g/day orally, divided into 2 doses;
• Colestipol: 2-16 g/day orally, given once or in divided doses
• Mean % LDL reduction (per PI):
• Colesevelam: Monotherapy—15% (6 tablets daily); in combination with low- to moderate-intensity statin therapy—additional 10%-16% reduction in LDL-C (data from simvastatin 10 mg, atorvastatin 10 mg). Cholestyramine: Monotherapy—10.4% vs placebo.
• Colestipol: not provided in PI. In dose-ranging RCT with monotherapy, doses of 5, 10, and 15 g resulted in 16.3%, 22.8%, and 27.2% reductions in LDL-C, respectively
• Contraindications (per PI):
• Colesevelam: TG >500 mg/dL; history of hypertriglyceridemia-induced pancreatitis; bowel obstruction.
• Cholestyramine: History of serious hypersensitivity to this medication.
• Use during pregnancy/lactation: Considered safe to use
• Colestipol: Complete biliary obstruction, history of serious hypersensitivity to this medication.
• Warnings/precautions: May ↑ TG and cause acute pancreatitis, monitor TG, discontinue if signs and symptoms of acute pancreatitis occur; may cause GI obstruction, avoid with gastroparesis, other GI motility disorders, and history of major GI tract surgery with risk for bowel obstruction; may cause vitamin K or fat-soluble vitamin deficiencies, oral vitamins should be given ≥4 hours before this medication; may decrease absorption of other medications, other medications should be given ≥4 hours before this medication. Some products contain phenylalanine, which may be harmful to patients with phenylketonuria.
• Adverse effects: Constipation, dyspepsia, and nausea.
• Use during pregnancy/lactation: Considered safe to use
• Drug-drug interactions: In general, BAS may decrease absorption of other medications; it is a good practice for all other medications to be given ≥4 hours before BAS. Concomitant use of BAS is known to decrease absorption of cyclosporin, oral contraceptives containing ethinyl estradiol and norethindrone, olmesartan, phenytoin, sulfonylureas, thyroid replacement therapy, warfarin; give these medications ≥4 hours before BAS. For patients on warfarin, monitor INR frequently during BAS initiation and then periodically. Cholestyramine may increase exposure to metformin; monitor glycemic control.
• CV outcomes trials: In LRC-CPPT, 3,806 asymptomatic middle-aged men with primary hypercholesterolemia were randomized to cholestyramine resin vs placebo for an average of 7.4 years. The cholestyramine group experienced a 19% reduction in risk (P < 0.05) of the primary endpoint—definite CHD death and/or definite nonfatal MI. The effects of colesevelam and colestipol on cardiovascular morbidity and mortality have not been determined
• Considerations in prescribing: Pill burden; inconvenience in preparation of oral suspension preparations; drug interactions, GI side effects; exacerbation of hypertriglyceridemia; orally administered, colesevelam lowers HbA1c 0.5% in diabetes; CV outcomes data not available for all products

• Mechanism of action: Human monoclonal antibody that binds to and inhibits ANGPTL3. Promotes VLDL processing and clearance upstream of LDL formation
• FDA-approved indication(s): ↓ LDL-C in adults and pediatric patients (aged ≥12 years) with HoFH as adjunct to other LDL-C–lowering therapies
• Dose and route of administration: 15 mg/kg administered by healthcare professional as IV infusion once monthly (every 4 weeks). See PI for preparation and administration instructions.
• Mean % reduction in LDL-C (per PI): Combination therapy with other lipid-lowering therapies (incremental reduction)—49%.
• Contraindication: History of serious hypersensitivity to this medication.
• Warnings/precautions:
  1. Hypersensitivity reactions occurred during clinical trials. If a serious hypersensitivity reaction occurs, discontinue therapy; treat according to standard of care; monitor until signs and symptoms resolve.
  2. May cause fetal toxicity; inform patients who may become pregnant of risk to fetus; obtain a pregnancy test before initiating therapy in patients who may become pregnant; advise patients who may become pregnant to use contraception during treatment and for ≥5 months following the last dose. Discontinue this medication if patient becomes pregnant. Clinicians should report pregnancies that occur while taking this medication (1-833-385-3392).
• Adverse effects: nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, nausea.
• Use during pregnancy/lactation: Avoid use.
• Drug–drug interactions: No clinically significant drug-drug interactions have been identified
• CV outcomes trials: The effect of evinacumab on CV morbidity and mortality has not been determined
• Other prescribing considerations: See prescribing information for complete preparation and administration instructions. Robust LDL-C reduction; cost, IV administration, requires prior authorization

• Mechanism of action: Directly binds and inhibits microsomal triglyceride transfer protein, which resides in the lumen of the endoplasmic reticulum, thereby preventing the assembly of apoB-containing lipoproteins in enterocytes and hepatocytes. This inhibits synthesis of chylomicrons and VLDL and leads to ↓ LDL-C
• FDA-approved indications: ↓ LDL-C, TC, apoB, and non–HDL-C in patients with HoFH, as adjunct to a low-fat diet and other lipid-lowering treatments (including LDL apheresis, where available)
• Dose and route of administration: Initiate 5 mg orally once daily. Titrate dose based on acceptable safety/tolerability: increase to 10 mg daily after at least 2 weeks and then, at a minimum of 4-week intervals, to 20 mg, 40 mg, up to the maximum recommended dose of 60 mg daily
• Mean % LDL reduction (per PI): Mean and median percent changes in LDL-C from baseline when added to baseline lipid-lowering therapy were -40% and -50%, respectively
• Black box warnings:
  1. May cause elevations in liver transaminases; measure ALT, AST, alkaline phosphatase, total bilirubin before initiating this medication; during treatment, adjust dose if ALT or AST ≥3 times the upper limit of normal; discontinue this medication for clinically significant liver toxicity.
  2. Increases hepatic fat (hepatic steatosis) with or without concomitant increases in transaminases. Hepatic steatosis associated with lomitapide may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. Because of the risk of hepatotoxicity, lomitapide is only available through the REMS program
• Contraindications:
  1. Pregnancy.
  2. concomitant use with strong/moderate CYP3A4 inhibitors;
  3. moderate/severe hepatic impairment or active liver disease including unexplained persistent abnormal liver function tests.
• Warnings/precautions:
  1. May cause fetal toxicity; inform patients who may become pregnant of risk to fetus; obtain a pregnancy test before initiating therapy in patients who may become pregnant; advise patients who may become pregnant to use contraception during treatment and for ≥2 weeks following the last dose. Discontinue this medication if patient becomes pregnant. Clinicians should report pregnancies that occur while taking this medication (1-877-902-4099).
• Adverse effects: Diarrhea, nausea, vomiting, dyspepsia, and abdominal pain.
• Use during pregnancy/lactation: Avoid use.
• Drug–drug interactions:
  1. CYP3A4 inhibitors increase exposure to lomitapide. Strong/moderate CYP3A4 inhibitors are contraindicated with lomitapide. Avoid grapefruit juice.
  2. Do not exceed 30 mg daily of lomitapide when used concomitantly with weak CYP3A4 inhibitors, including atorvastatin and oral contraceptives.
  3. Increases plasma concentration of warfarin; monitor INR regularly, especially with lomitapide dose adjustment.
  4. Increased systemic exposure to simvastatin and lovastatin exposure with lomitapide. Limit statin dose when coadministered due to myopathy risk.
  5. Consider dose reduction of P-glycoprotein substrates because of possible increased absorption with lomitapide.
  6. Separate lomitapide dosing with BAS by at least 4 hours.
• CV outcomes trials: The effect of lomitapide on CV morbidity and mortality has not been determined
• Considerations in prescribing: Cost, oral administration, requires strict adherence to low-fat diet and gradual dose escalation to reduce GI side effects, requires daily doses of specific vitamins (Vitamin E 400 IU, linoleic acid ≥200 mg, alpha-linolenic acid ≥210 mg, eicosapentaenoic acid ≥110 mg, docosahexaenoic acid ≥80 mg); requires monitoring of transaminase levels, long-term consequences of hepatic steatosis unknown, prescriber training, REMS program

• Mechanism of action: Selectively removes apo B-containing lipoproteins, producing an acute reduction in LDL-C.
• FDA approved indication: Patients with FH unresponsive to pharmacologic and dietary management who are either functional homozygotes with an LDL-C >500mg/dL, functional heterozygotes with no known CV disease but an LDL-C >300mg/dL, or functional heterozygotes with known cardiovascular disease and LDL-C >200mg/dL
• Dose and route of administration: Extracorporeal technique performed weekly or biweekly
• Mean % LDL-C reduction: With weekly or biweekly treatment, average LDL-C can ↓ to ~50–60% of the original levels. LDL-C increases after each apheresis session but does not return to the original level
• Adverse effects: Problems with venous access; transient hypotension, fatigue; bleeding; hypocalcemia; iron deficiency due to regular phlebotomy for diagnostic purposes; heparin allergy; and bradykinin syndrome (especially with ACEi)
• Drug–drug interactions: ACEi should not be used with dextran sulfate method owing to risk of bradykinin syndrome
• CV outcomes trials: Limited due to ethical considerations in RCTs of very high-risk patients with HoFH, but it is reasonable to assume reductions in CV disease events are proportional to the degree of LDL-C lowering
• Considerations in prescribing: Cost, extracorporeal technique, inconvenient, locations not readily available in some regions, time-consuming, robust reduction in LDL-C

• Recent ACS (within the past 12 mo.)
• History of MI (other than recent ACS event listed above)
• History of ischemic stroke
• Symptomatic PAD (history of claudication with ABI <0.85, or previous revascularization or amputation)

• Age ≥ 65 y
• Heterozygous familial hypercholesterolemia
• History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD event(s)
• Diabetes
• Hypertension
• CKD (eGFR 15-59 mL/min/1.73 m2)
• Current smoking
• Persistently elevated LDL-C (LDL-C ≥100 mg/dL [≥2.6 mmol/L]) despite maximally tolerated statin therapy and ezetimibe
• History of congestive HF

• Family history of premature ASCVD (males, age <55 y; females age <65 y)
• Primary hypercholesterolemia (LDL-C 160–189 mg/dL [4.1–4.8 mmol/L); non–HDL-C 190–219 mg/dL [4.9–5.6 mmol/L] *
• Metabolic syndrome (increased waist circumference, elevated triglycerides [≥150 mg/dL], elevated blood pressure, elevated glucose, and low HDL-C [ <40 mg/dL in men; <50 mg/dL in women] are factors; tally of 3 makes the diagnosis
• Chronic kidney disease (eGFR 15–59 mL/min/1.73 m2 with or without albuminuria; not treated with dialysis or kidney transplantation)
• Chronic inflammatory conditions such as psoriasis, RA, or HIV/AIDS
• History of premature menopause (before age 40 y) and history of pregnancy-associated conditions that increase later ASCVD risk such as preeclampsia
• High-risk race/ethnicities (e.g., South Asian ancestry)
• Lipid/biomarkers: Associated with increased ASCVD risk
  o Persistently* elevated, primary hypertriglyceridemia (≥175 mg/dL)
  o If measured:
  1. Elevated high-sensitivity C-reactive protein (≥2.0 mg/L)
  2. Elevated Lp(a): A relative indication for its measurement is family history of premature ASCVD. An Lp(a) ≥50 mg/dL or ≥125 nmol/L constitutes a risk-enhancing factor especially at higher levels of Lp(a).
  3. Elevated apoB ≥130 mg/dL: A relative indication for its measurement would be triglyceride ≥200 mg/dL. A level ≥130 mg/dL corresponds to an LDL-C≥160 mg/dL and constitutes a risk-enhancing factor
  4. ABI <0.9

• Percentage LDL-C reduction achieved with evidence-based statin therapy (if < 50% and not on maximally tolerated statin, should increase statin therapy first and reinforce lifestyle modifications) and whether patient is above LDL-C threshold for consideration of nonstatin therapies
• For patients with ASCVD, patient’s status as very high risk or not very high risk on evidence-based statin therapy (See Criteria for Defining Patients at Very High-Risk of future ASCVD Events)*
• For patients without ASCVD or baseline LDL-C ≥190 mg/dL, patient’s baseline predicted 10-year ASCVD risk pre-statin and presence of risk enhancing factors (See Risk-Enhancing Factors for Clinician–Patient Risk Discussion)†
• Available scientific evidence of ASCVD risk reduction (and magnitude of benefit) when nonstatin therapy is added to evidence-based statin therapy‡
• Additional desired % LDL-C lowering beyond that achieved on evidence-based statin therapy§
• Mean percentage LDL-C lowering expected with proposed nonstatin therapy when added to evidence-based statin therapy

• See Strategies and Nonstatin Agents Considered for Management of LDL-Related ASCVD Risk.

• Potential out-of-pocket cost of therapy to the patient (e.g., insurance plan coverage, pharmacy or medical benefit, copayment, availability of assistance programs).

• Patient’s perception of benefit from addition of nonstatin therapy.
• Convenience of nonstatin therapy (e.g., route, setting [home or medical office], and frequency of administration, pill burden, storage).
• Potential of nonstatin therapy to jeopardize adherence to other evidence-based therapies.
• Cost of nonstatin therapy.
• Anticipated life expectancy, comorbidities, and impact of therapy on quality of life.

• Consider referring any patient with ASCVD and/or baseline LDL-C ≥190 mg/dL, baseline LDL-C ≥190 mg/dL, or intolerance to at least 2 (preferably 3) statin therapies with 1 attempt at the lowest FDA-approved dose and a trial of an alternative statin therapy regimen (eg, every-other-day dosing)
• Referral is recommended for patients with ASCVD and baseline LDL-C ≥190 mg/dL who did not achieve ↓ LDL-C ≥50% and LDL-C <70 mg/dL (or non–HDL-C <100 mg/dL) on maximally tolerated statin therapy in combination with nonstatin therapy
• May also consider referring other patients unable to achieve adequate LDL-C reduction
• Considerations in referring: Lipid specialists may be available for virtual visits for patients in some rural or remote locations

• Consider referring any patient with ASCVD and/or baseline LDL-C ≥190 mg/dL, or baseline LDL-C ≥190 mg/dL
• Referral is recommended for patients with ASCVD and baseline LDL-C ≥190 mg/dL who did not achieve ↓ LDL-C ≥50% and LDL-C <70 mg/dL (or non–HDL-C <100 mg/dL) on maximally tolerated statin therapy in combination with nonstatin therapy
• May also consider referring other patients unable to achieve adequate LDL-C reduction

• Mechanism of action: Inhibits NPC1L1 protein; reduces cholesterol absorption in small intestine.
• FDA-approved indication(s): As adjunct to diet to:
  1. ↓ TC, LDL-C, ApoB, non–HDL-C in patients with primary hyperlipidemia, either alone or in combination with statin therapy;
  2. ↓ TC, LDL-C, ApoB, non–HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate;
  3. ↓ TC, LDL-C with HoFH, in combination with atorvastatin or simvastatin;
  4. ↓ sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia)
• Dose: 10 mg orally daily, with or without food. Take either ≥2 h before or ≥4 h after BAS, if used in combination
• Mean % reduction in LDL-C (per PI): Monotherapy—18%; combination therapy with statin therapy (incremental reduction)—25%
• Contraindication: History of hypersensitivity to this medication.
• Warnings/precautions:
  1. Not recommended in patients with moderate/severe hepatic impairment.
  2. Persistent elevations in hepatic transaminases may occur with concomitant statin therapy. Monitor hepatic transaminases before and during treatment based on monitoring recommendations for statin therapy.
  3. Cases of myopathy and rhabdomyolysis have been reported when ezetimibe was used alone or in combination with statin therapy.
• Adverse effects: Monotherapy—upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremities. In combination with statin—nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, diarrhea
• Use during pregnancy/lactation: No safety data in humans; avoid use
• Drug–drug interactions: Cyclosporine, fibrates, BAS
• CV outcomes trials: IMPROVE-IT (The addition of ezetimibe to moderate-intensity statin therapy in patients with recent ACS resulted in incremental lowering of LDL-C and reduced the primary composite endpoint of CV death, nonfatal MI, UA requiring rehospitalization, coronary revascularization [≥30 days after randomization], or nonfatal stroke. The median follow-up was 6 years); SHARP (Simvastatin plus ezetimibe reduced LDL-C and reduced the primary endpoint of first major ASCVD event [nonfatal MI or CHD death, nonhemorrhagic stroke, or any arterial revascularization procedure] compared with placebo in patients with CKD over a median follow-up of 4.9 years)
• Other prescribing considerations: Generally well tolerated. Generic available

• Mechanism of action: Human mAb to PCSK9. Binds to PCSK9 and increases the number of LDL receptors available to clear circulating LDL-C
• FDA-approved indication(s):
• Alirocumab and evolocumab:
  1. ↓ LDL-C in adults with primary hyperlipidemia (including HeFH) as adjunct to diet, either alone or in combination with other lipid-lowering therapies
• Alirocumab:
  1. ↓ risk of MI, stroke, and unstable angina requiring hospitalization in adults with ASCVD;
  2. ↓ LDL-C in adults with HoFH as adjunct to other LDL-C–lowering therapies
• Evolocumab:
  1. ↓ risk of MI, stroke, and coronary revascularization in adults with ASCVD;
  2. ↓ LDL-C in pediatric patients (aged ≥10 years) with HeFH as adjunct to diet and other LDL-C–lowering therapies;
  3. ↓ LDL-C in adults and pediatric patients (aged ≥10 years) with HoFH as adjunct to diet and other LDL-C–lowering therapies
• Dose and route of administration:
• Alirocumab: Administer SC in the thigh, abdomen, or upper arm. In adults with ASCVD or primary hyperlipidemia: initiate 75 mg SC every 2 weeks. If more LDL-C reduction needed, may ↑ dose to 150 mg every 2 weeks. Alternative starting dose is 300 mg SC every 4 weeks. For the 300-mg dose, administer 2 (150-mg) injections consecutively at 2 different injection sites. In adults with HeFH undergoing LDL apheresis or adults with HoFH, administer 150 mg SC every 2 weeks
• Evolocumab: Administer SC in the thigh, abdomen, or upper arm. In adults with ASCVD, adults with primary hypercholesterolemia, including with established clinical ASCVD or HeFH, or in pediatric patients (aged ≥10 years) with HeFH, administer 140 mg SC every 2 weeks or 420 mg SC once monthly in abdomen, thigh, or upper arm. In adults or pediatric patients (aged ≥10 years) with HoFH, administer 420 mg SC once monthly; if more LDL-C reduction is needed after 12 weeks, may ↑ dose to 420 mg every 2 weeks. In adults or pediatric patients (age ≥10 years) with HoFH on LDL apheresis, may initiate 420 mg SC every 2 weeks to correspond with apheresis schedule; evolocumab should be given after apheresis is complete. To administer 420-mg dose, either use the prefilled single-dose on-body infuser or give 3 (140-mg) injections consecutively within 30 min.
• Mean % LDL-C reduction (per PI):
• Alirocumab: when added to maximally tolerated statin therapy, alirocumab 75 mg and 150 mg SC every 2 weeks ↓ LDL-C by an additional 45% and 58%, respectively, when added to maximally tolerated statin therapy.
• Evolocumab: 140 mg every 2 weeks and 420 mg SC every 4 weeks, ↓ LDL-C by an additional 64% and 58%, respectively.
• Contraindication: History of hypersensitivity to the medication.
• Warnings/precautions: Hypersensitivity reactions occurred during clinical trials. If a serious hypersensitivity reaction occurs, discontinue therapy; treat according to standard of care; monitor until signs and symptoms resolve.
• Adverse effects:
• Alirocumab: In patients with primary hyperlipidemia: nasopharyngitis, injection site reactions, influenza; in patients with ASCVD: noncardiac chest pain, nasopharyngitis, myalgia. No evidence of increase in cognitive adverse effects observed in ODYSSEY Outcomes or CANTAB.
• Evolocumab: In patients with primary hyperlipidemia: nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions; in patients with ASCVD: diabetes, nasopharyngitis, upper respiratory tract infection.
• No evidence of an increase in cognitive adverse effects observed in FOURIER or EBBINGHAUS.
• Use during pregnancy/lactation: No safety data in humans; avoid use.
• Drug-drug interactions: No clinically significant drug-drug interactions identified for alirocumab or evolocumab
• CV outcomes trials:
• Alirocumab: ODYSSEY Outcomes in 18,600 post-ACS (4-52 weeks) patients on evidence-based statin therapy; Demonstrated that addition of alirocumab reduced the primary endpoint of CHD death, MI, ischemic stroke, or hospitalization for UA.
• Evolocumab: FOURIER in 27,564 patients with prior MI, stroke, or PAD on atorvastatin ≥20 mg or equivalent; Demonstrated that addition of evolocumab reduced the primary endpoint of CV death, MI, stroke, revascularization, or hospitalization for unstable angina.
• Other prescribing considerations: Robust LDL-C reduction, cost, SC administration at home, may require prior authorization.
• Evolocumab: Advise latex-sensitive patients that the needle covers on the products contain latex.

• Mechanism of action: ACL inhibitor; inhibits cholesterol synthesis in the liver; increases LDL receptor density. Bempedoic acid and its active metabolite require coenzyme A activation by ACSVL1, which is expressed primarily in the liver.
• FDA-approved indication(s): ↓ LDL-C in adults with ASCVD or HeFH as adjunct to diet and maximally tolerated statin therapy.
• Dose: 180 mg orally once daily, with or without food.
• Mean % reduction in LDL-C (per PI): Combination therapy with statin therapy (placebo-corrected incremental reduction)—17%-18%.
• Contraindication: none
• Warnings/precautions:
  1. May ↑ serum uric acid. Advise patients to contact their clinician if symptoms of hyperuricemia occur. Assess serum uric acid when clinically indicated. Monitor patients for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs, as appropriate. Assess uric acid level before initiation and if signs and symptoms of hyperuricemia occur.
  2. Discontinue immediately if the patient experiences rupture of a tendon. Consider discontinuing if the patient experiences joint pain, swelling, or inflammation. Advise patients to rest at the first sign of tendinitis or tendon rupture and to contact their health care provider if tendinitis or tendon rupture symptoms occur. Consider alternative therapy in patients with a history of tendon disorders or tendon rupture.
• Adverse effects: Upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, elevated liver enzymes.
• Use during pregnancy/lactation: Discontinue when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. There are no available data on use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
• Drug–drug interactions: Avoid concomitant simvastatin >20 mg daily or pravastatin >40 mg daily.
• CV outcomes trials: CV outcomes trials not completed. CLEAR Outcomes trial completion expected later in 2022.
• Other prescribing considerations: cost; pill burden; requires prior authorization

• Refer to section on ezetimibe for information specific to this agent.
• Mechanism of action: See the mechanisms of action for bempedoic acid and ezetimibe included in this table.
• FDA-approved indication(s): ↓ LDL-C in adults with ASCVD or HeFH as adjunct to diet and maximally tolerated statin therapy.
• Dose: 1 tablet (180 mg bempedoic acid/10 mg ezetimibe) orally, once daily, with or without food. Swallow whole. Take either ≥2 hours before or ≥4 hours after BAS, if used in combination.
• Mean % reduction in LDL-C (per PI): Combination therapy with statin therapy (placebo-corrected incremental reduction)—38%.
• Contraindication: History of hypersensitivity to ezetimibe.
• Warnings/precautions:
  1. May ↑ serum uric acid. Advise patients to contact their clinician if symptoms of hyperuricemia occur. Assess serum uric acid when clinically indicated. Monitor patients for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs as appropriate. Assess uric acid level before initiation and if signs and symptoms of hyperuricemia occur.
  2. Discontinue immediately if the patient experiences tendon rupture. Consider discontinuing if the patient experiences joint pain, swelling, or inflammation. Advise patients to rest at the first sign of tendinitis or tendon rupture and to contact their health care provider if tendinitis or tendon rupture symptoms occur. Consider alternative therapy in patients with a history of tendon disorders or tendon rupture.
• Adverse effects: Upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremities, anemia, elevated liver enzymes, diarrhea, arthralgia, sinusitis, fatigue, influenza. Consider alternative therapy if history of tendon disorder or rupture; discontinue immediately if tendon rupture occurs.
• Use during pregnancy/lactation: Discontinue when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. There are no available data on use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
• Drug–drug interactions: Cyclosporine; fibrates. Avoid concomitant simvastatin >20 mg daily or pravastatin >40 mg daily.
• CV outcomes trials: CV outcomes trials for bempedoic acid not completed. Completion of CLEAR Outcomes trial expected later in 2022. CV outcomes trial will not be required for fixed-dose combination of ezetimibe and bempedoic acid.
• Prescribing considerations: ↓ LDL-C within the range of moderate-intensity statin therapy; cost; requires prior authorization

• Mechanism of action: siRNA targeting PCSK9; inhibits PCSK9 production in liver, thereby prolonging activity of LDL receptors.
• FDA-approved indication(s): ↓ LDL-C in adults with ASCVD or HeFH as adjunct to diet and maximally tolerated statin therapy.
• Dose: Administer 284 mg SC on day 1, day 90, and then every 6 months by a clinician.
• Mean % reduction in LDL-C (per PI): 48%-52%
• Contraindications (per PI): None
• Warnings/precautions (per PI): None
• Adverse effects: Injection site reaction, arthralgia, urinary tract infection, diarrhea, bronchitis, pain in extremities, dyspnea
• Use during pregnancy/lactation: No safety data in humans; avoid use.
• Drug–drug interactions (per PI): None
• CV outcomes trials: CV outcomes trials not yet completed. ORION-4 currently in progress with estimated completion in 2026. VICTORION-2P currently in progress with estimated completion in 2027.
• Other prescribing considerations: robust LDL-C reduction, cost, requires SC administration by a clinician, requires prior authorization.

• Mechanism of action: Nonabsorbed, lipid-lowering polymer that binds bile acids in the intestine and impedes their reabsorption. As the bile acid pool ↓, the hepatic enzyme cholesterol 7-a-hydroxylase is up-regulated, which ↑ conversion of cholesterol to bile acids. This causes ↑ demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme HMG-CoA reductase and ↑ numbers of hepatic LDL receptors. These compensatory effects result in ↑ clearance of LDL particles from the blood, in turn resulting in ↓ serum LDL-C levels. Serum TG levels may ↑ or remain unchanged.
• FDA-approved indication(s):
• Colesevelam: As an adjunct to diet and exercise
  1. ↓ LDL-C in adults with primary hyperlipidemia;
  2. ↑ glycemic control in adults with type 2 diabetes;
  3. ↓ LDL-C in boys and post-menarchal girls (aged 10-17 years) with HeFH who are unable to reach LDL-C targets after an adequate trial of diet therapy and lifestyle modifications. Cholestyramine, colestipol: ↓ LDL-C with primary hyperlipidemia, as adjunct to diet
• Dose and route of administration:
• Colesevelam: Tablets: 6 tablets orally once daily or 3 tablets orally twice daily; take tablets with a meal and liquid.
  Suspension: one 3.75-g packet orally daily, or one 1.875-g packet orally twice daily; mix powder with 8 ounces of water, fruit juice, or soft drink; take with meal.
• 3.75 g is equivalent to 6 tablets. 1.875 g is equivalent to 3 tablets;
• Cholestyramine: 8-16 g/day orally, divided into 2 doses;
• Colestipol: 2-16 g/day orally, given once or in divided doses
• Mean % LDL reduction (per PI):
• Colesevelam: Monotherapy—15% (6 tablets daily); in combination with low- to moderate-intensity statin therapy—additional 10%-16% reduction in LDL-C (data from simvastatin 10 mg, atorvastatin 10 mg). Cholestyramine: Monotherapy—10.4% vs placebo.
• Colestipol: not provided in PI. In dose-ranging RCT with monotherapy, doses of 5, 10, and 15 g resulted in 16.3%, 22.8%, and 27.2% reductions in LDL-C, respectively
• Contraindications (per PI):
• Colesevelam: TG >500 mg/dL; history of hypertriglyceridemia-induced pancreatitis; bowel obstruction.
• Cholestyramine: History of serious hypersensitivity to this medication.
• Use during pregnancy/lactation: Considered safe to use
• Colestipol: Complete biliary obstruction, history of serious hypersensitivity to this medication.
• Warnings/precautions: May ↑ TG and cause acute pancreatitis, monitor TG, discontinue if signs and symptoms of acute pancreatitis occur; may cause GI obstruction, avoid with gastroparesis, other GI motility disorders, and history of major GI tract surgery with risk for bowel obstruction; may cause vitamin K or fat-soluble vitamin deficiencies, oral vitamins should be given ≥4 hours before this medication; may decrease absorption of other medications, other medications should be given ≥4 hours before this medication. Some products contain phenylalanine, which may be harmful to patients with phenylketonuria.
• Adverse effects: Constipation, dyspepsia, and nausea.
• Use during pregnancy/lactation: Considered safe to use
• Drug-drug interactions: In general, BAS may decrease absorption of other medications; it is a good practice for all other medications to be given ≥4 hours before BAS. Concomitant use of BAS is known to decrease absorption of cyclosporin, oral contraceptives containing ethinyl estradiol and norethindrone, olmesartan, phenytoin, sulfonylureas, thyroid replacement therapy, warfarin; give these medications ≥4 hours before BAS. For patients on warfarin, monitor INR frequently during BAS initiation and then periodically. Cholestyramine may increase exposure to metformin; monitor glycemic control.
• CV outcomes trials: In LRC-CPPT, 3,806 asymptomatic middle-aged men with primary hypercholesterolemia were randomized to cholestyramine resin vs placebo for an average of 7.4 years. The cholestyramine group experienced a 19% reduction in risk (P < 0.05) of the primary endpoint—definite CHD death and/or definite nonfatal MI. The effects of colesevelam and colestipol on cardiovascular morbidity and mortality have not been determined
• Considerations in prescribing: Pill burden; inconvenience in preparation of oral suspension preparations; drug interactions, GI side effects; exacerbation of hypertriglyceridemia; orally administered, colesevelam lowers HbA1c 0.5% in diabetes; CV outcomes data not available for all products

• Mechanism of action: Human monoclonal antibody that binds to and inhibits ANGPTL3. Promotes VLDL processing and clearance upstream of LDL formation
• FDA-approved indication(s): ↓ LDL-C in adults and pediatric patients (aged ≥12 years) with HoFH as adjunct to other LDL-C–lowering therapies
• Dose and route of administration: 15 mg/kg administered by healthcare professional as IV infusion once monthly (every 4 weeks). See PI for preparation and administration instructions.
• Mean % reduction in LDL-C (per PI): Combination therapy with other lipid-lowering therapies (incremental reduction)—49%.
• Contraindication: History of serious hypersensitivity to this medication.
• Warnings/precautions:
  1. Hypersensitivity reactions occurred during clinical trials. If a serious hypersensitivity reaction occurs, discontinue therapy; treat according to standard of care; monitor until signs and symptoms resolve.
  2. May cause fetal toxicity; inform patients who may become pregnant of risk to fetus; obtain a pregnancy test before initiating therapy in patients who may become pregnant; advise patients who may become pregnant to use contraception during treatment and for ≥5 months following the last dose. Discontinue this medication if patient becomes pregnant. Clinicians should report pregnancies that occur while taking this medication (1-833-385-3392).
• Adverse effects: nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, nausea.
• Use during pregnancy/lactation: Avoid use.
• Drug–drug interactions: No clinically significant drug-drug interactions have been identified
• CV outcomes trials: The effect of evinacumab on CV morbidity and mortality has not been determined
• Other prescribing considerations: See prescribing information for complete preparation and administration instructions. Robust LDL-C reduction; cost, IV administration, requires prior authorization

• Mechanism of action: Directly binds and inhibits microsomal triglyceride transfer protein, which resides in the lumen of the endoplasmic reticulum, thereby preventing the assembly of apoB-containing lipoproteins in enterocytes and hepatocytes. This inhibits synthesis of chylomicrons and VLDL and leads to ↓ LDL-C
• FDA-approved indications: ↓ LDL-C, TC, apoB, and non–HDL-C in patients with HoFH, as adjunct to a low-fat diet and other lipid-lowering treatments (including LDL apheresis, where available)
• Dose and route of administration: Initiate 5 mg orally once daily. Titrate dose based on acceptable safety/tolerability: increase to 10 mg daily after at least 2 weeks and then, at a minimum of 4-week intervals, to 20 mg, 40 mg, up to the maximum recommended dose of 60 mg daily
• Mean % LDL reduction (per PI): Mean and median percent changes in LDL-C from baseline when added to baseline lipid-lowering therapy were -40% and -50%, respectively
• Black box warnings:
  1. May cause elevations in liver transaminases; measure ALT, AST, alkaline phosphatase, total bilirubin before initiating this medication; during treatment, adjust dose if ALT or AST ≥3 times the upper limit of normal; discontinue this medication for clinically significant liver toxicity.
  2. Increases hepatic fat (hepatic steatosis) with or without concomitant increases in transaminases. Hepatic steatosis associated with lomitapide may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. Because of the risk of hepatotoxicity, lomitapide is only available through the REMS program
• Contraindications:
  1. Pregnancy.
  2. concomitant use with strong/moderate CYP3A4 inhibitors;
  3. moderate/severe hepatic impairment or active liver disease including unexplained persistent abnormal liver function tests.
• Warnings/precautions:
  1. May cause fetal toxicity; inform patients who may become pregnant of risk to fetus; obtain a pregnancy test before initiating therapy in patients who may become pregnant; advise patients who may become pregnant to use contraception during treatment and for ≥2 weeks following the last dose. Discontinue this medication if patient becomes pregnant. Clinicians should report pregnancies that occur while taking this medication (1-877-902-4099).
• Adverse effects: Diarrhea, nausea, vomiting, dyspepsia, and abdominal pain.
• Use during pregnancy/lactation: Avoid use.
• Drug–drug interactions:
  1. CYP3A4 inhibitors increase exposure to lomitapide. Strong/moderate CYP3A4 inhibitors are contraindicated with lomitapide. Avoid grapefruit juice.
  2. Do not exceed 30 mg daily of lomitapide when used concomitantly with weak CYP3A4 inhibitors, including atorvastatin and oral contraceptives.
  3. Increases plasma concentration of warfarin; monitor INR regularly, especially with lomitapide dose adjustment.
  4. Increased systemic exposure to simvastatin and lovastatin exposure with lomitapide. Limit statin dose when coadministered due to myopathy risk.
  5. Consider dose reduction of P-glycoprotein substrates because of possible increased absorption with lomitapide.
  6. Separate lomitapide dosing with BAS by at least 4 hours.
• CV outcomes trials: The effect of lomitapide on CV morbidity and mortality has not been determined
• Considerations in prescribing: Cost, oral administration, requires strict adherence to low-fat diet and gradual dose escalation to reduce GI side effects, requires daily doses of specific vitamins (Vitamin E 400 IU, linoleic acid ≥200 mg, alpha-linolenic acid ≥210 mg, eicosapentaenoic acid ≥110 mg, docosahexaenoic acid ≥80 mg); requires monitoring of transaminase levels, long-term consequences of hepatic steatosis unknown, prescriber training, REMS program

• Mechanism of action: Selectively removes apo B-containing lipoproteins, producing an acute reduction in LDL-C.
• FDA approved indication: Patients with FH unresponsive to pharmacologic and dietary management who are either functional homozygotes with an LDL-C >500mg/dL, functional heterozygotes with no known CV disease but an LDL-C >300mg/dL, or functional heterozygotes with known cardiovascular disease and LDL-C >200mg/dL
• Dose and route of administration: Extracorporeal technique performed weekly or biweekly
• Mean % LDL-C reduction: With weekly or biweekly treatment, average LDL-C can ↓ to ~50–60% of the original levels. LDL-C increases after each apheresis session but does not return to the original level
• Adverse effects: Problems with venous access; transient hypotension, fatigue; bleeding; hypocalcemia; iron deficiency due to regular phlebotomy for diagnostic purposes; heparin allergy; and bradykinin syndrome (especially with ACEi)
• Drug–drug interactions: ACEi should not be used with dextran sulfate method owing to risk of bradykinin syndrome
• CV outcomes trials: Limited due to ethical considerations in RCTs of very high-risk patients with HoFH, but it is reasonable to assume reductions in CV disease events are proportional to the degree of LDL-C lowering
• Considerations in prescribing: Cost, extracorporeal technique, inconvenient, locations not readily available in some regions, time-consuming, robust reduction in LDL-C

• The 10-year calculated ASCVD risk is a quantitative estimation of absolute risk based upon data from representative population samples.
• The 10-year risk estimate for "optimal risk factors" is represented by the following specific risk factor numbers for an individual of the same age, sex and race: Total cholesterol of ≤ 170 mg/dL, HDL-cholesterol of ≥ 50 mg/dL, untreated systolic blood pressure of ≤ 110 mm Hg, no diabetes history, and not a current smoker.
• While the risk estimate is applied to individuals, it is based on group averages.
• Just because two individuals have the same estimated risk does not mean that they will or will not have the same event of interest.
• Example: If the 10-year ASCVD risk estimate is 10%, this indicates that among 100 patients with the entered risk factor profile, 10 would be expected to have a heart attack or stroke in the next 10 years.

• The lifetime calculated ASCVD risk represents a quantitative estimation of absolute risk for a 50 year old man or woman with the same risk profile.
• This estimation of risk is based on the grouping of risk factor levels into 5 strata.
  • All risk factors are optimal*
  • ≥1 risk factors are not optimal†
  • ≥1 risk factors are elevated‡
  • 1 major risk factor§
  • ≥2 major risk factors§
• The division of lifetime risk by these 5 strata leads to thresholds in the data with large apparent changes in lifetime risk estimates.
• Example: An individual that has all optimal risk factors except for a systolic blood pressure of 119 mm Hg has a lifetime ASCVD risk of 5%. In contrast, a similar individual that has all optimal risk factors except for a systolic blood pressure of 120 mm Hg has a lifetime ASCVD risk of 36%. This substantial difference in lifetime risk is due to the fact that they are in different stratum.

*Optimal risk levels for lifetime risk are represented by the simultaneous presence of all of the following: Untreated total cholesterol <180 mg/dL, untreated blood pressure <120/<80 mm Hg, no diabetes history, and not a current smoker

†Nonoptimal risk levels for lifetime risk are represented by 1 or more of the following: Untreated total cholesterol of 180 to 199 mg/dL, untreated systolic blood pressure of 120 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg, and no diabetes history and not a current smoker

‡Elevated risk levels for lifetime risk are represented by 1 or more of the following: Untreated total cholesterol of 200 to 239 mg/dL, untreated systolic blood pressure of 140 to 159 mm Hg or diastolic blood pressure of 90 to 99 mm Hg, and no diabetes history and not a current smoker

§Major risk levels for lifetime risk are represented by any of the following: Total cholesterol ≥240 mg/dL or treated, systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg or treated, or diabetes, or current smoker

Diet recommendations for LDL-C lowering

1. Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains; includes low-fat dairy products, poultry, fish, legumes, non-tropical vegetable oils and nuts; and limits intake of sweets, sugar-sweetened beverages, and red meats. (I A)
   • Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions (including diabetes mellitus).
   • Achieve this pattern by following plans such as the DASH dietary pattern, the USDA Food Pattern, or the AHA Diet.
2. Aim for a dietary pattern that achieves 5-6% of calories from saturated fat.
3. Reduce percent of calories from saturated fat.
4. Reduce percent of calories from trans fat. (I A)

Diet recommendations for blood pressure lowering

1. Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains; includes low-fat dairy products, poultry, fish, legumes, non-tropical vegetable oils and nuts; and limits intake of sweets, sugar-sweetened beverages, and red meats. (I A)
   • Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions (including diabetes mellitus).
   • Achieve this pattern by following plans such as the DASH dietary pattern, the USDA Food Pattern, or the AHA Diet.
2. Lower sodium intake.
3. Consume no more than 2400 mg of sodium per day. (I B)

Diets for weight loss

1. Prescribe a diet to achieve reduced calorie intake for obese or overweight individuals who would benefit from weight loss, as part of a comprehensive lifestyle intervention with 1 of the following:
   • 1200-1500 kcal/day for women and 1500-1800 kcal/day for men.
   • 500-750 kcal/day energy deficit.
   • Use one of the evidence-based diets that restricts certain food types (e.g., high-carbohydrate foods, low-fiber foods, or high-fat foods) in order to create an energy deficit by reduced food intake.
2. Prescribe a calorie-restricted diet for obese or overweight individuals who would benefit from weight loss, based on the patient's preferences and health status, and preferably refer to a nutrition professional for counseling.

Lifestyle interventions and counseling for weight loss

1. Advise participation in a comprehensive lifestyle program that assists participants in adhering to a lower calorie diet and increasing physical activity through the use of behavioral strategies.
2. Prescribe on site, high-intensity (i.e., >14 sessions in 6 months) comprehensive weight loss interventions provided in individual or group sessions by a trained interventionist.
3. Consider prescription of electronically delivered weight loss programs (including by telephone) that includes personalized feedback from a trained interventionist, recognizing that it may result in smaller weight loss than face-to-face interventions. (IIa A)
4. Consider some commercial-based programs that provide comprehensive lifestyle interventions, provided there is peer-reviewed published evidence of their safety and efficacy. (IIa A)
5. Consider a very low calorie diet (<800 kcal/day) only in limited circumstances and only when provided by trained practitioners in a medical care setting where medical monitoring and high intensity lifestyle intervention can be provided. (IIa A)
6. Advise individuals who have lost weight to participate long term (>1 year) in a comprehensive weight loss maintenance program.
7. Prescribe face-to-face or telephone-delivered weight loss maintenance programs that provide regular contact (> monthly) with a trained interventionist who helps participants engage in high levels of physical activity (i.e., 200-300 minutes/week), monitor body weight regularly (> weekly), and consume a reduced-calorie diet (need to lower body weight).

Selection criteria for bariatric surgical treatment of obesity

1. Advise adults with a BMI ≥40 kg/m2 or BMI ≥35 kg/m2 with obesity-related co-morbid conditions who are motivated to lose weight and who have not responded to behavioral treatment with or without pharmacotherapy with sufficient weight loss to achieve targeted health outcome goals that bariatric surgery may be an appropriate option to improve health and offer referral to an experienced bariatric surgeon for consultation and evaluation. (IIa A)

Physical activity recommendations for modifying lipids and blood pressure lowering

1. Advise adults to engage in aerobic physical activity to reduce LDL-cholesterol, non-HDL-cholesterol, and blood pressure. (IIa A)
   • Frequency: 3-4 sessions a week
   • Intensity: Moderate to vigorous
   • Duration: 40 minutes on average

Physical activity recommendations for secondary prevention*

1. Aerobic exercise
   • Frequency: 3-5 days/week
   • Intensity: 50-80% of exercise capacity
   • Duration: 20-60 minutes
   • Modalities: Examples include walking, treadmill, cycling, rowing, stair climbing, and arm/leg ergometry
2. Resistance exercise
   • Frequency: 2-3 days/week
   • Intensity: 10-15 repetitions/set to moderate fatigue
   • Duration: 1-3 sets of 8-10 upper and lower body exercises
   • Modalities: Examples include calisthenics, elastic bands, cuff/hand weights, dumbbells, free weights, wall pulleys, and weight machines

5 R's for patients not ready to quit

1. Relevance—Encourage the patient to indicate why quitting is personally relevant.
2. Risks—Ask the patient to identify potential negative consequences of tobacco use.
3. Rewards—Ask the patient to identify potential benefits of stopping tobacco use.
4. Roadblocks—Ask the patient to identify barriers or impediments to quitting.
5. Repetition—The motivational intervention should be repeated every time an unmotivated patient has an interaction with a clinician. Tobacco users who have failed in previous quit attempts should be told that most people make repeated quit attempts before they are successful.

5 A's for patients that are ready to quit

1. Ask—Systematically identify all tobacco users at every visit.
2. Advise—Strongly urge all smokers to quit.
3. Assess—Identify smokers willing to make a quit attempt.
4. Assist—Aid the patient in quitting.
5. Arrange—Schedule follow-up contact.

Clinical ASCVD includes acute coronary syndromes, history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin.

High-intensity statin therapy should be initiated or continued as first-line therapy in women and men ≤75 years of age who have clinical ASCVD, unless contraindicated.

In individuals with clinical ASCVD in whom high-intensity statin therapy would otherwise be used, when high-intensity statin therapy is contraindicated or when characteristics predisposing to statin-associated adverse effects are present, moderate-intensity statin should be used as the second option if tolerated.

In individuals with clinical ASCVD >75 years of age, it is reasonable to evaluate the potential for ASCVD risk-reduction benefits and for adverse effects, drug-drug interactions and to consider patient preferences, when initiating a moderate- or high-intensity statin. It is reasonable to continue statin therapy in those who are tolerating it. (IIa B)

Individuals with LDL-C ≥190 mg/dL or triglycerides ≥500 mg/dL should be evaluated for secondary causes of hyperlipidemia. (I B)

Adults ≥21 years of age with primary LDL-C ≥190 mg/dL should be treated with high-intensity statin therapy unless contraindicated. For individuals unable to tolerate high-intensity statin therapy, use the maximum tolerated statin intensity. (I B)

For individuals ≥21 years of age with an untreated primary LDL-C ≥190 mg/dL, it is reasonable to intensify statin therapy to achieve at least a 50% LDL-C reduction. (IIa B)

For individuals ≥21 years of age with an untreated primary LDL-C ≥190 mg/dL, after the maximum intensity of statin therapy has been achieved, addition of a nonstatin drug may be considered to further lower LDL-C. Evaluate the potential for ASCVD risk reduction benefits, adverse effects, drug-drug interactions, and consider patient preferences. (IIb C)

Moderate-intensity statin therapy should be initiated or continued for adults 40 to 75 years of age with diabetes mellitus.

High-intensity statin therapy is reasonable for adults 40 to 75 years of age with diabetes mellitus with a ≥7.5% estimated 10-year ASCVD risk unless contraindicated. (IIa B)

In adults with diabetes mellitus, who are <40 or >75 years of age, it is reasonable to evaluate the potential for ASCVD benefits and for adverse effects, for drug-drug interactions, and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy. (IIa C)

The Pooled Cohort Equations should be used to estimate 10-year ASCVD risk for individuals with LDL-C 70 to 189 mg/dL without clinical ASCVD to guide initiation of statin therapy for the primary prevention of ASCVD. (I B)

Before initiating statin therapy for the primary prevention of ASCVD in adults with LDL-C 70 - 189 mg/dL without clinical ASCVD or diabetes it is reasonable for clinicians and patients to engage in a discussion which considers the potential for ASCVD risk reduction benefits and for adverse effects, for drug-drug interactions, and patient preferences for treatment. (IIa C)

Adults 40 to 75 years of age with LDL-C 70 to 189 mg/dL, without clinical ASCVD or diabetes and an estimated 10-year ASCVD risk ≥7.5% should be treated with moderate- to high-intensity statin therapy.

It is reasonable to offer treatment with a moderate-intensity statin to adults 40 to 75 years of age, with LDL-C 70 to 189 mg/dL, without clinical ASCVD or diabetes and an estimated 10-year ASCVD risk of 5% to <7.5%. (IIa B)

In adults with LDL-C <190 mg/dL who are not otherwise identified in a statin benefit group, or for whom after quantitative risk assessment a risk-based treatment decision is uncertain, additional factors may be considered to inform treatment decision making. In these individuals, statin therapy for primary prevention may be considered after evaluating the potential for ASCVD risk reduction benefits, adverse effects, drug-drug interactions, and discussion of patient preferences. (IIb C)

These factors may include:

Statin benefit may be less clear in other groups; additional factors may be considered to inform treatment decision making.

1. 5 to <7.5% 10-year ASCVD risk
2. Primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias
3. Family history of premature ASCVD
4. High sensitivity C-reactive protein ≥2 mg/L
5. Coronary artery calcium score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity
6. Ankle-brachial index <0.9
7. Lifetime risk of ASCVD

To maximize the safety of statins, selection of the appropriate statin and dose in men and nonpregnant/nonnursing women should be based on patient characteristics, level of ASCVD risk, and potential for adverse effects.

Moderate-intensity statin therapy should be used in individuals in whom high-intensity statin therapy would otherwise be recommended when characteristics predisposing them to statin associated adverse effects are present.

Characteristics predisposing individuals to statin adverse effects include, but are not limited to: (I B)

• Multiple or serious comorbidities, including impaired renal or hepatic function.
• History of previous statin intolerance or muscle disorders.
• Unexplained ALT elevations >3 times ULN.
• Patient characteristics or concomitant use of drugs affecting statin metabolism.
• >75 years of age.

Additional characteristics that may modify the decision to use higher statin intensities may include, but are not limited to:

• History of hemorrhagic stroke.
• Asian ancestry.

• Decreasing the statin dose may be considered when 2 consecutive values of LDL-C levels are <40 mg/dL. (IIb C)
• It may be harmful to initiate simvastatin at 80 mg daily or increase the dose of simvastatin to 80 mg daily. (III A)

• CK should not be routinely measured in individuals receiving statin therapy. (III A)
• Baseline measurement of CK is reasonable for individuals believed to be at increased risk for adverse muscle events based on a personal or family history of statin intolerance or muscle disease, clinical presentation, or concomitant drug therapy that might increase the risk for myopathy. (IIa C)
• During statin therapy, it is reasonable to measure CK in individuals with muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or generalized fatigue. (II C)

It is reasonable to evaluate and treat muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or fatigue, in statin-treated patients according to the following management algorithm: (IIa B)

• To avoid unnecessary discontinuation of statins, obtain a history of prior or current muscle symptoms to establish a baseline before initiating statin therapy.
• If unexplained severe muscle symptoms or fatigue develop during statin therapy, promptly discontinue the statin and address the possibility of rhabdomyolysis by evaluating CK, creatinine, and a urinalysis for myoglobinuria.
• If mild to moderate muscle symptoms develop during statin therapy:
  • Discontinue the statin until the symptoms can be evaluated.
  • Evaluate the patient for other conditions that might increase the risk for muscle symptoms (e.g., hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases).
  • If muscle symptoms resolve, and if no contraindication exists, give the patient the original or a lower dose of the same statin to establish a causal relationship between the muscle symptoms and statin therapy.
  • If a causal relationship exists, discontinue the original statin. Once muscle symptoms resolve, use a low dose of a different statin.
  • Once a low dose of a statin is tolerated, gradually increase the dose as tolerated.
  • If, after 2 months without statin treatment, muscle symptoms or elevated CK levels do not resolve completely, consider other causes of muscle symptoms listed above.
  • If persistent muscle symptoms are determined to arise from a condition unrelated to statin therapy, or if the predisposing condition has been treated, resume statin therapy at the original dose.

• Baseline measurement of hepatic transaminase levels (ALT) should be performed before initiating statin therapy. (I B)
• During statin therapy, it is reasonable to measure hepatic function if symptoms suggesting hepatotoxicity arise (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine or yellowing of the skin or sclera). (IIa C)

Individuals receiving statin therapy should be evaluated for new-onset diabetes mellitus according to the current diabetes screening guidelines. Those who develop diabetes mellitus during statin therapy should be encouraged to adhere to a heart healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce their risk of ASCVD events. (I B)

For individuals taking any dose of statins, it is reasonable to use caution in individuals >75 years of age, as well as in individuals that are taking concomitant medications that alter drug metabolism, taking multiple drugs, or taking drugs for conditions that require complex medication regimens (e.g., those who have undergone solid organ transplantation or are receiving treatment for HIV). A review of the manufacturer's prescribing information may be useful before initiating any cholesterol-lowering drug. (IIa C)

For individuals presenting with a confusional state or memory impairment while on statin therapy, it may be reasonable to evaluate the patient for nonstatin causes, such as exposure to other drugs, as well as for systemic and neuropsychiatric causes, in addition to the possibility of adverse effects associated with statin drug therapy. (IIb C)