Click the Terms tab at the bottom of the app before using the LDL-C Lowering Therapy, Hypertriglyceridemia, Statin Intolerance, or ASCVD Risk Estimator tools in the Lipid Manager (“the Product”) to read the full Terms of Service and License Agreement (the “Agreement”) which governs the use of the Product. The Agreement includes, among other detailed terms and conditions, certain disclaimers of warranties by the American College of Cardiology Foundation (“ACCF”) and requires the user to agree to release ACCF from any and all liability arising in connection with your use of the Product. By using the Product, you accept and agree to be bound by all of the terms and conditions set forth in the Agreement, including such disclaimers and releases. If you do not accept the terms and conditions of the Agreement, you may not proceed to use the Product. The Agreement is subject to change from time to time, and your continued use of the Product constitutes your acceptance of and agreement to be bound by any revised terms of the Agreement.
This app assumes that the patient is currently taking the maximally tolerated dose of statin therapy or has attempted to take statin therapy
LDL-C has increased from baselineValue must be entered in format xxx.xxx
Value must be entered in format xxx.xxxValue must be between 1.036 - 25.874 (mmol/L)Value must be entered in format xxx.xxx
Data message
Value must be entered in format xxx.xxx Value must be entered in format xxx.xxxValue must be between 1.036 - 25.874 (mmol/L)Value must be entered in format xxx.xxx
Data message
mg
mg/dL
Value must be entered in format xxx.xxxValue must be entered in format xxx.xxxValue must be between 1.036 - 4.920 (mmol/L)Value must be between 40 - 189 (mg/dL)Value must be between 1.813 - 4.920 (mmol/L)Value must be between 70 - 189 (mg/dL)
Value must be greater than or equal to 4.921 (mmol/L)
Value must be greater than or equal to 190 (mg/dL)
Data message
Note:
These estimates may underestimate the 10-year and
lifetime risk for persons from some race/ethnic groups,
especially American Indians, some Asian Americans (e.g., of
south Asian ancestry), and some Hispanics (e.g., Puerto Ricans),
and may overestimate the risk for others, including some
Asian Americans (e.g., of east Asian ancestry) and some
Hispanics (e.g., Mexican Americans). Because the primary use of
these risk estimates is to facilitate the very important
discussion regarding risk reduction through lifestyle change,
the imprecision introduced is small enough to justify proceeding
with lifestyle change counseling informed by these results.
Value must be between 1.036 - 25.874 (mmol/L) Value must be between 40 - 999 (mg/dL)Value must be between 1.036 - 25.874 (mmol/L)Value must be between 40 - 999 (mg/dL)
Data message
mg/dL
LDL-C has increased from baselineValue must be between 1.036 - 25.874 (mmol/L)
Value must be between 40 - 999 (mg/dL)Value must be between 1.036 - 25.874 (mmol/L)Value must be between 40 - 999 (mg/dL)
Data message
mg/dL
Value must be between 1.036 - 25.874 (mmol/L)Value must be between 40 - 999 (mg/dL)Value must be between 1.036 - 25.874 (mmol/L)Value must be between 40 - 999 (mg/dL)
Data message
mg/dL
Value must be between 1.036 - 25.874 (mmol/L)Value must be between 40 - 999 (mg/dL)Value must be between 1.036 - 25.874 (mmol/L)Value must be between 40 - 999 (mg/dL)
Data message
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
Considerations for Lowering LDL-C
It is recommended that for adults aged 20-39 years with long duration of diabetes, albuminuria, eGFR <60 ml/min/1.73 m2, retinopathy, neuropathy, or ABI <0.9, it may be reasonable to initiate statin therapy.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
Considerations for Lowering LDL-C
It is reasonable to continue moderate- or high-intensity statin therapy in patients with diabetes after age 75 years if therapy is well-tolerated.
It may be reasonable to have a clinician patient discussion in which the potential benefits and risks of initiating statin therapy in this age group are reviewed. The decision to initiate nonstatin therapy in individuals >75 years of age should be individualized based on considerations of expected longevity, frailty, polypharmacy, susceptibility to adverse effects of treatment, and goals of care.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
Considerations for Lowering LDL-C
Patients aged <40 years without ASCVD but with ASCVD risk factors should not be considered for 10-year risk assessment
Adults <40 years of age with LDL-C values ≥160 mg/dL and/or a family history of premature cardiovascular disease may benefit from statin consideration.
In patients with a family history of premature ASCVD, measurement of lipoprotein a (Lp(a)) may help identify patients who may benefit from early statin initiation due to the high heritability of Lp(a) and its well-known association with higher ASCVD risk. For patients >32 years of age, CAC scoring has been shown to help identify those patients with traditional risk factor burden or a family history of premature cardiovascular disease. These patients may be at higher long-term absolute risks for cardiovascular disease and therefore may be more likely to experience potential benefit from statin initiation in early adult life.
Continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
If lipid-lowering response is still less-than-anticipated
, it may be reasonable to consider PCSK9 mAb. Please refer to the 2018 Guideline information on PCSK9 mAb.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
Considerations for Lowering LDL-C
Increase to a high intensity statin if not already taking.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
Considerations for Lowering LDL-C
Increase to a high intensity statin if not already taking.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
Considerations for Lowering LDL-C
Increase to a high intensity statin if not already taking.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
If lipid-lowering response is still less-than-anticipated
, it may be reasonable to consider PCSK9 mAb. Please refer to the 2018 Guideline information on PCSK9 mAb.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
If lipid-lowering response is still less-than-anticipated
, it may be reasonable to consider PCSK9 mAb. Please refer to the 2018 Guideline information on PCSK9 mAb.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
Considerations for Lowering LDL-C
In primary prevention patients >75 years of age, the patient clinician discussion should consider the limited adequate RCT data to inform these decisions. The writing committee recommends consideration of ASCVD risk in the context of patient goals, competing risks for non-cardiovascular disease death, patient frailty, susceptibility to adverse effects, and polypharmacy to derive individual-level recommendations for statin initiation in this highly heterogenous groups.
When the goals of therapy in the clinician patient discussion have been achieved, it is reasonable to continue to monitor adherence to lifestyle modifications, medication, and LDL-C response to therapy. If there is persistent hypertriglyceridemia , clinicians should refer to the ACC Hypertriglyceridemia application.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
If lipid-lowering response is still less-than-anticipated
, it may be reasonable to consider adding or replacing with PCSK9 mAb. Please refer to the 2018 Guideline information on PCSK9 mAb.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
If lipid-lowering response is still less-than-anticipated
, it may be reasonable to consider LDL apheresis under care of lipid specialist. Please refer to the 2018 Guideline information on LDL apheresis.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia
, refer to the ACC Hypertriglyceridemia application.
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia , refer to the ACC Hypertriglyceridemia application.
Additional Considerations for Lowering LDL-C
Optimizing Lifestyle and Medication Therapy
Addressing adherence
Assess the number of missed statin doses per month.
Evaluate barriers to adherence. See patient tools in the Reference Section of this app for help.
Addressing lifestyle
Diet
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.
Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions (including diabetes).
Achieve this pattern by following plans such as the DASH dietary pattern, the USDA Food Pattern, or the AHA Diet.
Aim for a dietary pattern that achieves 5%–6% of calories from saturated fat.
Reduce percent of calories from saturated fat.
Reduce percent of calories from trans fat.
Exercise
In general, advise adults to engage in aerobic physical activity to reduce LDL-C and non–HDL-C: 3–4 sessions per week, lasting on average 40 min per session, and involving moderate- to vigorous-intensity physical activity.
See Resource section of this app for more information.
Evaluating for statin intolerance
Evaluate for statin intolerance if unable to tolerate a moderate intensity statin . See ACC's Statin Intolerance App for help.
If intolerant of at least 2 statin therapies with 1 attempt at lowest approved FDA daily dose and trial of alternative statin therapy dosing regimens,
consider PCSK9 mAb and/or ezetimibe first line; bempedoic acid or inclisiran second line; consider evinacumab third line for HofH.
Routine clinical assessment and interventions
Major ASCVD risk factors, including tobacco use, diabetes, elevated blood pressure, and obesity should be addressed as needed and controlled.
Consider specialists
Consider referral to lipid specialist and registered dietician nutritionist for all patients.
Assess the number of missed statin doses per month.
Evaluate barriers to adherence. See patient tools in the Reference Section of this app for help.
Addressing lifestyle
Diet
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.
Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions (including diabetes).
Achieve this pattern by following plans such as the DASH dietary pattern, the USDA Food Pattern, or the AHA Diet.
Aim for a dietary pattern that achieves 5%–6% of calories from saturated fat.
Reduce percent of calories from saturated fat.
Reduce percent of calories from trans fat.
Exercise
In general, advise adults to engage in aerobic physical activity to reduce LDL-C and non–HDL-C: 3–4 sessions per week, lasting on average 40 min per session, and involving moderate- to vigorous-intensity physical activity.
See Resource section of this app for more information.
Evaluating for statin intolerance
Evaluate for statin intolerance if unable to tolerate a moderate intensity statin . See ACC's Statin Intolerance App for help.
If intolerant of at least 2 statin therapies with 1 attempt at lowest approved FDA daily dose and trial of alternative statin therapy dosing regimens, consider first-line therapy with ezetimibe and/or PCSK9 mAb, second-line therapy with bempedoic acid or inclisiran, and third-line therapy with evinacumab for HoFH.
Routine clinical assessment and interventions
Major ASCVD risk factors, including tobacco use, diabetes, elevated blood pressure, and obesity should be addressed as needed and controlled.
Consider specialists
Consider referral to lipid specialist and registered dietician nutritionist for all patients.
Assess the number of missed statin doses per month.
Evaluate barriers to adherence. See patient tools in the Reference Section of this app for help.
Addressing lifestyle
Diet
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.
Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions (including diabetes).
Achieve this pattern by following plans such as the DASH dietary pattern, the USDA Food Pattern, or the AHA Diet.
Aim for a dietary pattern that achieves 5%–6% of calories from saturated fat.
Reduce percent of calories from saturated fat.
Reduce percent of calories from trans fat.
Exercise
In general, advise adults to engage in aerobic physical activity to reduce LDL-C and non–HDL-C: 3–4 sessions per week, lasting on average 40 min per session, and involving moderate- to vigorous-intensity physical activity.
See Resource section of this app for more information.
Evaluating for statin intolerance
Evaluate for statin intolerance if unable to tolerate a moderate intensity statin . See ACC's Statin Intolerance App for help.
If intolerant of at least 2 statin therapies with 1 attempt at lowest approved FDA daily dose and trial of alternative statin therapy dosing regimens, consider ezetimibe first line; BAS second line; consider bempedoic acid as third line.
Routine clinical assessment and interventions
Major ASCVD risk factors, including tobacco use, diabetes, elevated blood pressure, and obesity should be addressed as needed and controlled.
Consider specialists
Consider referral to lipid specialist and registered dietician nutritionist for all patients.
Patient-Clinician Discussion Points for Adding Non-Statin Therapy
Potential for additional ASCVD risk reduction from addition of nonstatin therapy to evidence-based statin therapy to lower LDL-C
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
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
Potential for clinically significant adverse events or drug-drug interactions from addition of nonstatin therapy to evidence-based statin therapy for lowering LDL-C
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], frequency of administration, pill burden, storage)
Potential of nonstatin therapy to jeopardize adherence to other evidence-based therapies
Anticipated life expectancy, comorbidities, and impact of therapy on quality of life
Once acceptable response is achieved with lipid-lowering therapy, continue to monitor LDL-C level and
adherence to medications and lifestyle. If persistent hypertriglyceridemia see ACC’s Hypertriglyceridemia App
for help.
Potential for non-statin therapy to help lower LDL-C and reduce ASCVD risk
Discuss w/ patients w/o ASCVD, or with LDL-C ≥ 190:
"Your Baseline 10-year ASCVD Risk before starting statin treatment was …"
Clinician Note: 10-year risk > 20% and/or baseline LDL > 160 mg/dL are considered high risk markers for ASCVD.
(If unsure of patient’s baseline risk, use ASCVD Risk Estimator tool in this app to calculate)
Discuss w/ patients w/ ASCVD:
"Evidence shows that being on an appropriate statin has an effect on your risk of recurrent events."
Example: In the Treating New Targets trial, patients with CHD who received Atorvastatin 10 mg daily had a 5-year event rate of 10.9%, and those who received 80 mg of atorvastatin daily had a 5-year event rate of 8.7%.
Discuss with all patients:
"You also have the following high risk markers for ASCVD and comorbidities that could contribute to your risk..."
Clinician Note: Indicate which of the following risk markers and comorbidities the patient has.
10-year ASCVD risk > 20%
LDL-C > 160 mg/dL at baseline
family history of premature ASCVD with or without elevated Lp(a), or ASCVD event ( recent (<3 months) or while taking a statin
other poorly controlled major ASCVD risk factor(s) (e.g. smoking, hypertension)
elevated lipoprotein(a)
elevated hs-CRP
evidence of accelerated subclinical atherosclerosis (e.g., coronary artery calcification)
diabetes
symptomatic heart failure
CKD with or without maintenance hemodialysis
other risk-modifying conditions (e.g. HIV, chronic inflammatory disorders)
"You may help lower your ASCVD risk by addressing these risk factors."
"Evidence shows that a potentially effective way to reduce your ASCVD risk is by lowering your LDL-C."
Example: For each 40 mg/dL reduction in LDL-C using evidence based therapies, there appears to be an approximate 20% relative reduction in ASCVD risk.
"So far on your statin, we’ve been able to reduce your LDL-C by ~%
I would like to reduce it even further."
Clinician Note: If reduction is < 50% and patient not on maximally tolerated statin, should increase statin first and reinforce lifestyle modifications.
Discuss with patient if on maximally tolerated statin, and response had been inadequate:
"Adding non-statin therapy to statins had been shown to potentially help lower LDL-C and reduce ASCVD risk."
Medication-specific examples:
Ezetimibe: May lower LDL-C an additional 25% on average. IMPROVE-IT study showed 6% relative/2% absolute risk reduction in a composite ASCVD endpoint over 7 years when added to a moderate intensity statin.
PCSK9 Inhibitors: May lower LDL-C an additional 60% on average.
Bile Acid sequesterants: Data on ASCVD risk reduction are lacking for addition of BAS to statins.
Niacin preparations: Associated with no benefit and potential for significant harms when added to statin therapy.
"I would like to try one of these additional therapies to help bring your LDL-C down the recommended amount and reduce your ASCVD risk."
Potential adverse events and drug-drug interactions from non-statin therapy
1) Colesevelam: Tablets: 6 tablets PO once daily or 3 tablets PO twice daily; take tablets with a meal and liquid. Suspension: one 3.75-gram packet PO daily, or one 1.875-gram packet PO twice daily; mixed powder with 4–8 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
2) Cholestyramine: 8–16 g/day orally divided into 2 doses
3) Colestipol: 2 to 16 g/day orally given once or in divided doses
Mean % LDL reduction
Colesevelam: Monotherapy-15% (6 tablets daily); combination with low- to moderate intensity statin-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 g, 10 g, and 15 g resulted in 16.3%, 22.8%, and 27.2% reduction in LDL-C, respectively. (Superko HR, Greenland P, Manchester RA, et al. Am J Cardiol. 1992;70:135-40.)
Adverse effects
Constipation, dyspepsia, and nausea. Post-marketing reports with colesevelam include ↑ seizure activity or ↓ phenytoin levels in patients receiving phenytoin, ↓ INR in patients receiving warfarin, ↑ TSH in patients receiving thyroid hormone replacement therapy, bowel obstruction, dysphagia, esophageal obstruction, fecal impaction, hypertriglyceridemia, pancreatitis, and increased transaminases.
Drug-drug interactions
cyclosporine, glimepiride, glipizide, levothyroxine, olmesartan coadministered with medoxomil, oral contraceptives containing ethinyl estradiol and norethindrone, phenytoin, warfarin. Drugs with potential interaction should be taken at least 4 hours after BAS to avoid impeding their absorption.
Prescribing considerations
Pill burden; inconvenience in preparation of oral suspension preparations; GI side effects; exacerbation of hypertriglyceridemia; orally administered, colesevelam lowers HbA1c 0.5% in diabetes; CV outcomes data not available.
Food source must be low in saturated fat and cholesterol, and include one or more of the following whole oat or barley foods: 1) oat bran. 2) rolled oats. 3) whole oat flour. 4) whole grain barley or dry milled barley.
Mean % LDL reduction
With intake of 3.0-12.4 g/day, mean TC and LDL-C levels were ↓ relative to control by 9.7 and 11.6 mg/dL, respectively.
Adverse effects
Few safety concerns. If viscous fiber supplements such as fiber laxatives are used, it is critical to consume adequate fluid as directed on the product label to avoid intestinal blockage (a rare occurrence).
Drug-drug interactions
Reduced carotenoid absorption. Regular consumption of fruits and vegetables should help to counteract this potential effect.
Prescribing considerations
GI tolerability
Less than anticipated
If lipid-lowering response is still less than anticipated
Ezetimibe
Variables suggesting ezetimibe initiation:
- Goal is to lower LDL-C by up to an additional 25%
- Recent ACS <3 months
- Cost considerations with recent availability of generic ezetimibe and future cost savings
- Ease of use as oral agent with low pill burden
- Consistent with patient preferences
Variables indicating greatest likelihood of benefit from adding ezetimibe following ACS are:
- Congestive heart failure
- Hypertension
- Age >75 years
- Diabetes
- Stroke
- CABG
- PAD
- eGFR <60 mL/min per 1.73m2
- Smoking
May consider a bile acid sequesterant (BAS) as optional alternative agent if ezetimibe intolerant and triglycerides <300 mg/dL (EC). Patients who achieve <50% LDL-C reduction and triglycerides <300 mg/dL while taking maximally tolerated statin and ezetimibe, addition of BAS may be considered (IIB, B).
PCSK9 Inhibitors
Recommendations from recent 2018 ACC/AHA Cholesterol Guideline:
- In patients 30 to 75 years of age with heterozygous FH and with an LDL-C level of 100 mg/dL (≥2.6 mmol/L) or higher while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered. (IIb, B)
- In patients 40 to 75 years of age with a baseline LDL-C level of 220 mg/dL (≥5.7 mmol/L) or higher and who achieve an on-treatment LDL-C level of 130 mg/dL (≥3.4 mmol/L) or higher while receiving maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered. (IIb, C)
- In patients with clinical ASCVD, who are judged to be very high-risk and considered for PCSK9 therapy, maximally tolerated LDL-C lowering therapy should include maximally tolerated statin therapy and ezetimibe. (I,B)
- In patients with clinical ASCVD, who are judged to be very high-risk and who are on maximally tolerated LDL-C lowering therapy with LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL, it is reasonable to add a PCSK9 inhibitor following a clinician-patient discussion about the net benefit, safety, and cost. (IIa, A)
- Patients with clinical ASCVD who are judged to be very high risk include those with a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions
Additional suggestions:
- Please see section 7 of the 2018 ACC/AHA Cholesterol Guideline for a full discussion of cost and value considerations for PCSK9 inhibitors.
- May be preferred in addition to ezetimibe if patient requires >25% additional LDL-C lowering.
- Strongly consider if fully statin intolerant and attempts to lower LDL-C with ezetimibe or BAS result in persistent <50% LDL-C reduction (or may consider LDL-C ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL).
- It is reasonable to engage in a clinician-patient discussion with consideration of
Net risk reduction benefit of a PCSK9 inhibitor
Cost
Administration by subcutaneous injection
Every 14-day or monthly dosing schedule
Storage requirements (refrigeration)
Clinicians should preferentially prescribe drugs that have been shown in RCT's to provide ASCVD risk-reduction benefits that outweigh the potential for adverse effects and drug-drug interactions, and consider patient preferences.
If lipid-lowering response is still less than anticipated after non-statin agent(s)
Referral to a lipid specialist and registered dietician nutritionist recommended.
Hypertriglyceridemia
Having fasting triglycerides ≥ 150 mg/dL
FH Diagnostic Categories
ICD-10 Category
Clinical Criteria
With Genetic Testing Performed
Heterozygous FH
LDL-C ≥160 mg/dL (4 mmol/L) for children and ≥190 mg/dL (5 mmol/L) for adults and with 1 first-degree relative similarly affected or with premature CAD or with positive genetic testing for a LDL-C–raising gene defect (LDL receptor, apoB, or PCSK9)
Presence of 1 abnormal LDL-C–raising gene defect (LDL receptor, apoB, or PCSK9). Diagnosed as heterozygous FH if LDL-C–raising defect positive and LDL-C <160 mg/dL (4 mmol/L). Occasionally, heterozygotes will have LDL-C >400 mg/dL (10 mmol/L); they should be treated similarly to homozygotes. Presence of both abnormal LDL-C–raising gene defects (LDL receptor, apoB, or PCSK9) and LDL-C–lowering gene variant(s) with LDL-C <160 mg/dL (4 mmol/L).
Homozygous FH
LDL-C ≥400 mg/dL (10 mmol/L) and 1 or both parents having clinically diagnosed FH, positive genetic testing for a LDL-C–raising gene defect (LDL receptor, apoB, or PCSK9) or autosomal-recessive FH. If LDL-C >560 mg/dL (14 mmol/L) or LDL-C >400 mg/dL (10 mmol/L) with aortic valve disease or xanthomata at <20 y of age, homozygous FH highly likely.
Presence of 2 identical (true homozygous FH) or nonidentical (compound heterozygous FH) abnormal LDL–raising gene defects (LDL receptor, apoB, or PCSK9); includes the rare autosomal-recessive type. Occasionally, homozygotes will have LDL-C <400 mg/dL (10 mmol/L).
Family history of FH
LDL-C level not a criterion; presence of a first-degree relative with confirmed FH
Genetic testing not performed
Abbrevations:
apoB = apolipoprotein B
CAD = coronary artery disease
FH = familial hypercholesterolemia
ICD-10 = International Classification of Disease, 10th Revision
LDL = low-3 density lipoprotein
LDL-C = low-density lipoprotein cholesterol
PCSK9 = proprotein convertase subtilisin/kexin type 9
*Gidding SS, Champagne MA, de Ferranti SD, et al. The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. Circulation. 2015;132:2167–2192.
Phytosterols
Doses and administration
1-3 g PO per day consumed with meals either once daily or in divided doses
Mean % LDL reduction
Consumption of 2 g/day of phytosterols ↓ LDL-C by 5-15%. LDL-C ↓ plateaus at doses above ~3 g/day.
Adverse effects
Phytosterol esters have "generally recognized as safe" (GRAS) status in the US. Potential safety concern regarding phytosterol consumption in patients with phytosterolemia. Side effects may include mild bloating, diarrhea, or constipation.
Drug-drug interactions
BAS administration should be separated from phytosterol use by 2-4 hours to avoid binding of the latter in the gut.
Prescribing considerations
Generally well tolerated; modest ↓ in LDL-C; CV outcomes data not available.
PCSK9 inhibitors
Doses and administration
Alirocumab—initiate 75 mg subcutaneously (SQ) every 2 weeks. If more LDL reduction needed, may ↑ dose to 150 mg every 2 weeks. Alternative starting dose is 300 mg SQ every 4 weeks.
Evolocumab—in primary hypercholesterolemia with established clinical ASCVD or HeFH, give 140 mg SQ every 2 weeks or 420 mg SQ once monthly in abdomen, thigh, or upper arm. In HoFH, give 420 mg SQ once monthly. To administer 420 mg, give 3 (140 mg) injections consecutively within 30 minutes.
Mean % LDL reduction
Alirocumab—when added to maximally tolerated statin therapy, alirocumab 75 mg and 150 SQ every 2 weeks ↓ LDL-C by an additional 43% and 47%, respectively. When added to maximally tolerated statin therapy evolocumab 140 mg every 2 weeks and 420 mg SQ every 4 weeks, ↓ LDL-C by an additional 64% and 58%, respectively.
Adverse effects
Alirocumab—nasopharyngitis, injection site reactions, influenza.
Evolocumab—nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions. No evidence of increase in cognitive adverse effects observed in FOURIER or EBBINGHAUS.
Drug-drug interactions
No clinically significant drug-drug interactions identified for alirocumab or evolocumab.
Prescribing considerations
Cost, SQ administration, robust LDL-C reduction, CV outcomes trials not completed for alirocumab, burdensome prior authorization process.
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.
PCSK9 mAb
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 this 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 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.
Bempedoic acid
Mechanism of action:
ACL inhibitor; inhibits cholesterol synthesis in the liver; increases LDL receptor density. Bempedoic acid and its active metabolite require activation by 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 PO 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 expected to completion later in 2022.
Other prescribing considerations:
cost; pill burden; requires prior authorization
Bempedoic acid and ezetimibe
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.
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
Inclisiran
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%
Contraindication (per PI):
None
Warnings/precautions (per PI):
None
Adverse effects:
Injection site reaction, arthralgia, urinary tract infection, diarrhea, bronchitis, pain in extremity, 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 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.
Evinacumab
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).
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
Lomitapide
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.
Contraindication:
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.
LDL Apheresis
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.
Moderate Intensity Statin
Evaluate for statin intolerance
Evaluate for statin intolerance if unable to tolerate a moderate intensity statin . See ACC's Statin Intolerance App for help.
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-α-hydroxylase, is upregulated, 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 ↑ the number 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 to
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 (10 to 17 years of age) 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: Complete biliary obstruction, history of serious hypersensitivity to this medication.
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.
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.
Lipid Specialist
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
Registered Dietician Nutritionist
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
Criteria for Defining Patients at Very High-Risk of future ASCVD Events
Major ASCVD Events
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)
High-risk Conditions
Age ≥ 65 y
Heterozygous familial hypercholesterolemia
History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD event(s)
Reprinted with permission from 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. J Am Coll Cardiol. 2019;73:e285-350.
*Very high-risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions.
Abbreviations:
ABI = ankle-brachial index
ACS = acute coronary syndrome
ASCVD = atherosclerotic cardiovascular disease
CKD = chronic kidney disease
eGFR = estimated glomerular filtration rate
HF = heart failure
LDL-C = low-density lipoprotein cholesterol
MI = myocardial infarction
PAD = peripheral artery disease
Risk-Enhancing Factors for Clinician–Patient Risk Discussion
Family history of premature ASCVD (males, age < 55 y; females age <65 y)
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
Elevated high-sensitivity C-reactive protein (≥2.0 mg/L)
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).
Administration by subcutaneous injection
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
ABI <0.9
Lipid Specialist
Approach
Consider referring patients with baseline LDL-C ≥190 mg/dL, very high risk for ASCVD, complex lipid disorders, statin intolerance or multiple lipid medication intolerances, or familial hypercholesterolemia for consultation with a lipid specialist for advanced management.
Considerations
Lipid specialists may not be easily available in some rural or remote locations.
Lomitapide
Doses and administration
Initiate 5 mg PO 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, and up to maximum recommended dose of 60 mg daily.
Mean % LDL reduction
Mean and median percent changes in LDL-C from baseline when added to baseline lipid-lowering therapy were -40% and -50%, respectively.
Adverse effects
Diarrhea, nausea, vomiting, dyspepsia, and abdominal pain. 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.
Drug-drug interactions
CYP3A4 inhibitors increase exposure to lomitapide. Strong and moderate CYP3A4 inhibitors are contraindicated with lomitapide. Avoid grapefruit juice. Do not exceed 30 mg daily of lomitapide when used concomitantly with weak CYP3A4 inhibitors, including atorvastatin and oral contraceptives. Increases plasma concentrations of warfarin; monitor INR regularly, especially with lomitapide dose adjustment. Increased systemic exposure to simvastatin and lovastatin exposure with lomitapide. Limit statin dose when co-administered due to myopathy risk. Consider dose reduction of P-gp substrate because of possible increased absorption with lomitapide. Separate lomitapide dosing with BAS by at least 4 hours. Because of the risk of hepatotoxicity, lomitapide available only through REMS program.
Prescribing considerations
Cost, oral administration, requires strict adherence to low-fat diet and gradual dose escalation to reduce GI side effects, requires monitoring of transaminase levels, long-term consequences of hepatic steatosis unknown, prescriber training, REMS program
Response to addition of mipomersen to maximally tolerated lipid-lowering medication in patients with HoFH—25%.
Adverse effects
Injection site reactions, flu-like symptoms, nausea, headache and elevations in serum transaminases, specifically ALT. Increases hepatic fat (hepatic steatosis) with or without concomitant increases in transaminases. May be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. Because of the risk of hepatotoxicity, mipomersen is available only through REMS program
Drug-drug interactions
No clinically relevant pharmacokinetic interactions were reported between mipomersen and warfarin, simvastatin, or ezetimibe.
Prescribing considerations
Cost, SQ administration, requires monitoring of transaminase levels, long-term consequences of hepatic steatosis unknown, prescriber training, REMS program
Extracorporeal technique performed weekly or biweekly.
Mean % LDL 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.
Prescribing considerations
Cost, extracorporeal technique, inconvenient, locations not readily available in some regions, time-consuming, robust reduction in LDL-C.
Homozygous FH*
Clinical Criteria
LDL-C ≥400 mg/dL (10 mmol/L) and 1 or both parents having clinically diagnosed FH, positive genetic testing for a LDL-C raising gene defect (LDL receptor, apoB, or PCSK9) or autosomal-recessive FH
If LDL-C >560 mg/dL (14 mmol/L) or LDL-C >400 mg/dL (10 mmol/L) with aortic valve disease or xanthomata at <20 years of age, homozygous FH highly likely
With Genetic Testing Performed
Presence of 2 identical (true homozygous FH) or nonidentical (compound heterozygous FH) abnormal LDL raising gene defects (LDL receptor, apoB, or PCSK9); includes the rare autosomal-recessive type
Occasionally, homozygotes will have LDL-C <400 mg/dL (10 mmol/L)
*Gidding SS, Champagne MA, de Ferranti SD, et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation. 2015;132:2167–92.
The option to calculate risk will appear in this part of the app for patients 40 – 75 years old. This age range is determined by the studies upon which the 10-year risk score is based, as well as the Hypertriglyceridemia expert consensus content.
Diabetes-specific high-risk features include long duration (≥10 years for type 2 diabetes or ≥20 years for type 1 diabetes, albuminuria ≥30 mcg of albumin/mg creatinine, eGFR <60 mL/min/1.73 m², retinopathy, neuropathy, ankle-brachial index <0.9.
Significant atherosclerotic plaque observed in an asymptomatic patient on any of the following diagnostic studies: coronary artery calcification noted on computed tomography (CT) studies, including calcium scoring, cardiac CT coronary angiography, chest CT for ruling out pulmonary embolism, chest CT for lung cancer screening, or diagnostic chest CT; carotid plaque noted on carotid ultrasound or angiography; or abnormal ankle-brachial index or plaque noted on peripheral arterial angiography.
These are factors that may be considered within the context of individual patients, not firm triggers for adding medication.
Use clinical judgement. In general, patients should be treated first with maximally-tolerated statin intensity (in addition to lifestyle) before considering additional medications. Patients unable to tolerate even a moderate-intensity statin should be evaluated for statin intolerance.
Having fasting triglycerides ≥ 150 mg/dL
Patient with ASCVD may have any one of the following: ACS or history of myocardial infarction (MI) stable or unstable angina coronary revascularization stroke transient ischemic attack presumed to be of atherosclerotic origin peripheral arterial disease or revascularization
Defined as cigarette smoker based on patient population studied in relevant clinical trials. Use clinical discretion in regards to patients who use e-cigarettes and other tobacco products.
Smokes every day or on some days.
Does not currently smoke and has been abstinent for at least 7 days in a row.
<50% reduction in LDL-C or LDL-C ≥100 mg/dL or non-HDL-C ≥130 mg/dL
<50% reduction in LDL-C or LDL-C ≥2.590 mmol/L or non-HDL-C ≥3.367 mmol/L
<50% reduction in LDL-C or LDL-C ≥100 mg/dL or non-HDL-C ≥130 mg/dL
<50% reduction in LDL-C or LDL-C ≥2.590 mmol/L or non-HDL-C ≥3.367 mmol/L
Having fasting triglycerides ≥ 150 mg/dL
Having fasting triglycerides ≥ 150 mg/dL
Having fasting triglycerides ≥ 150 mg/dL
Having fasting triglycerides ≥ 150 mg/dL
Having fasting triglycerides ≥ 150 mg/dL
<50% reduction in LDL-C or LDL-C ≥70 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.813 mmol/L
Having fasting triglycerides ≥ 150 mg/dL
Having fasting triglycerides ≥ 150 mg/dL
Having fasting triglycerides ≥ 150 mg/dL
Having fasting triglycerides ≥ 150 mg/dL
Having fasting triglycerides ≥ 150 mg/dL
Having fasting triglycerides ≥ 150 mg/dL
Having fasting triglycerides ≥ 150 mg/dL
<50% reduction in LDL-C or LDL-C ≥70 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.813 mmol/L
Having fasting triglycerides ≥ 150 mg/dL
<50% reduction in LDL-C or LDL-C ≥70 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.813 mmol/L
Having fasting triglycerides ≥ 150 mg/dL
Having fasting triglycerides ≥ 150 mg/dL
<50% reduction in LDL-C or LDL-C ≥55 mg/dL or non-HDL-C ≥85 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.424 mmol/L or non-HDL-C ≥2.201 mmol/L
<50% reduction in LDL-C or LDL-C ≥55 mg/dL or non-HDL-C ≥85 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.424 mmol/L or non-HDL-C ≥2.201 mmol/L
Having fasting triglycerides ≥ 150 mg/dL
<50% reduction in LDL-C or LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.813 mmol/L or non-HDL-C ≥2.590 mmol/L
<50% reduction in LDL-C or LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.813 mmol/L or non-HDL-C ≥2.590 mmol/L
<50% reduction in LDL-C or LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.813 mmol/L or non-HDL-C ≥2.590 mmol/L
Having fasting triglycerides ≥ 150 mg/dL
<50% reduction in LDL-C or LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.813 mmol/L or non-HDL-C ≥2.590 mmol/L
<50% reduction in LDL-C or LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.813 mmol/L or non-HDL-C ≥2.590 mmol/L
<50% reduction in LDL-C or LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.813 mmol/L or non-HDL-C ≥2.590 mmol/L
<50% reduction in LDL-C or LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.813 mmol/L or non-HDL-C ≥2.590 mmol/L
<50% reduction in LDL-C or LDL-C ≥55 mg/dL or non-HDL-C ≥85 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.424 mmol/L or non-HDL-C ≥2.201 mmol/L
<50% reduction in LDL-C or LDL-C ≥55 mg/dL or non-HDL-C ≥85 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.424 mmol/L or non-HDL-C ≥2.201 mmol/L
<50% reduction in LDL-C or LDL-C ≥55 mg/dL or non-HDL-C ≥85 mg/dL
<50% reduction in LDL-C or LDL-C ≥1.424 mmol/L or non-HDL-C ≥2.201 mmol/L
Having fasting triglycerides ≥ 150 mg/dL
Daily dose lowers LDL-C, on average by approximately 30% to <50%
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20–40 mg
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg BID
Pitavastatin 2–4 mg
Daily dose lowers LDL-C, on average by approximately 30% to <50%
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20–40 mg
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg BID
Pitavastatin 2–4 mg
Daily dose lowers LDL-C, on average by approximately 30% to <50%
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20–40 mg
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg BID
Pitavastatin 2–4 mg
e.g., route and frequency of administration, pill burden, storage
Daily dose lowers LDL-C, on average by approximately 30% to <50%
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20–40 mg
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg BID
Pitavastatin 2–4 mg
