Primary Prevention- LDL-C ≥190 mg/dL

Introduction

The 2018 multi-society (including the American College of Cardiology and American Heart Association (ACC/AHA)) cholesterol guideline considers adults with a primary elevation in low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL (severe hypercholesterolemia) aged ≥20 years or older who are without clinical atherosclerotic cardiovascular disease (ASCVD) one of the four statin benefit groups. Although not all adult patients with LDL-C ≥190 mg/dL have familial hypercholesterolemia (FH), all do have a genetic lipid disorder and require LDL-C lowering drug therapy to reduce their high risk of premature ASCVD. Children and adolescents aged 10 years and older with LDL-C levels persistently ≥190 mg/dL or ≥160 mg/dL with a clinical presentation consistent with FH can also benefit from statin therapy (see Familial Hyperlipidemias).

Secondary causes of hyperlipidemia should be ruled out at the time of first identification of an LDL-C level ≥190 mg/dL, or if LDL-C or triglycerides increase during therapy despite continued adherence to lifestyle and drug therapy.

Do not estimate risk when LDL-C is ≥190 mg/dL. There is no reason to estimate 10-year ASCVD or lifetime risk since all patients with LDL-C ≥190 mg/dL require drug therapy. Moreover, risk estimation is not accurate when LDL-C exceeds 190 mg/dL and the Pooled Cohort Equations (PCE) markedly underestimate ASCVD risk in this patient group.

Clinical Highlight I

• LDL-C ≥190 mg/dL is too high at any age and requires cholesterol-lowering drug therapy to reduce ASCVD risk.
• In adults ≥20 y, start a high-intensity statin unless there is a contraindication.
• In adult patients 20-75 y who do not achieve at least a 50% LDL-C reduction and/or whose LDL-C levels are ≥100 mg/dL on a maximally tolerated statin therapy, consider adding ezetimibe and/or a PCSK9 monoclonal antibody.
• In children and adolescents 10 y and older with an LDL-C level of ≥190 mg/dL or ≥160 mg/dL with a clinical profile consistent with FH who do not achieve an adequate response with lifestyle therapy, consider initiating statin therapy.
• Aggressively manage other risk factors, including immediate smoking cessation.
• Cascade screen relatives for FH.

Initiating Statin Therapy: LDL-C ≥190 mg/dL Adults

The 2018 multi-society cholesterol guideline recommends (Class of Recommendation [COR] I) initiating a maximally tolerated (ideally high-intensity) statin therapy in all patients with a primary elevation in LDL-C ≥190 mg/dL unless there are contraindications. This recommendation is based on an extensive body of randomized trial evidence that shows each 39 mg/dL reduction in LDL-C with statins reduces CV events by about 21%, with consistent relative risk reductions across the range of LDL-C levels.

Several primary and secondary prevention statin trials performed in hypercholesterolemic patient populations included patients with LDL-C ≥190 mg/dL (WOSCOPS, 4S, MEGA). These trials demonstrated substantial relative and absolute reductions in ASCVD risk. High-intensity statins reduce cardiovascular (CV) risk more than moderate-intensity statins (TNT, IDEAL, PROVE-IT). Moreover, statins reduce ASCVD events in lower risk primary prevention patients with LDL-C <130 mg/dL (JUPITER), providing further support that intensification of statin therapy will further reduce ASCVD risk in patients with higher LDL-C levels.

Initial Evaluation

A fasting or nonfasting lipid panel should be performed and liver transaminases checked at baseline prior to initiating statin therapy. Evaluation for secondary causes of hyperlipidemia should be undertaken in a patient with newly identified LDL-C ≥190 mg/dL or triglycerides ≥500 mg/dL (see Secondary Hyperlipidemia). Liver transaminases should be measured again only if there are signs or symptoms of hepatotoxicity. Patients with unexplained liver transaminases >3 times the upper limit of normal should undergo additional evaluation (see Managing Adverse Effects During Statin Therapy). A creatine kinase (CK) test is only recommended for patients with a history of previous statin-associated side effects, muscle diseases, or elevated CK levels.

Maximally Tolerated Statin Therapy

A maximally tolerated statin regimen, ideally high-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) is recommended (COR I) for all patients with LDL-C ≥190 mg/dL unless contraindications are present (Table 11-1).

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Children

Atherosclerosis begins early in life, with the burden of atherosclerosis accelerated in individuals with heterozygous HF (HeFH). Although CV outcomes trials have not been performed in individuals <40 years, there is compelling evidence that starting statins in late childhood or adolescence in patients with FH has a substantial impact on atherosclerosis development and progression. Statins have been shown to regress carotid intimal medial thickening in children with HeFH to the level of their nonaffected siblings. Longitudinal studies of young adults with FH have shown statin therapy initiated in adolescence was associated with a reduction in ASCVD events in young adulthood.

The National Heart, Lung, and Blood Institute (NHLBI) CV prevention guideline for children and adolescents recommends initiating a statin around age 8-10 years of age in children with HeFH. Moderate-intensity statins appear efficacious and safe in this age group as well as in adolescents. Optimal treatment includes achieving a 50% LDL-C reduction or an LDL-C <130 mg/dL. The 2018 multi-society cholesterol guideline states that initiation of statin therapy is reasonable (COR IIa) in children 10 years of age and older whose LDL-C levels are ≥190 mg/dL or ≥160 mg/dL with a clinical presentation consistent with FH, if after 3-6 months of lifestyle therapy (which is recommended; COR I) they do not show an adequate response. The intensity of statin therapy and the potential addition of ezetimibe should be decided taking the patient’s and/or the patient’s family’s preferences into consideration. If LDL-C levels remain at or above 190 mg/dL by age 20, a maximally tolerated statin therapy is indicated (COR I).

See Familial Hyperlipidemias regarding screening of children and adolescents and cascade screening once a patient with severe hyperlipidemia has been identified; also refer to the NHLBI pediatric CV prevention guideline.

Treatment of adults or children with homozygous FH (HoFH) is briefly discussed in Familial Hyperlipidemias; patients with HoFH should be referred to a lipid specialist with expertise in lipid disorders.

Adding Nonstatin Therapy Nonstatin Therapy Usually Needed in Patients With LDL-C ≥190 mg/dL

Many of patients with baseline LDL-C ≥190 mg/dL will also need the addition of a nonstatin to achieve a ≥50% reduction in LDL-C or to further lower LDL-C to reduce ASCVD risk. LDL-C treatment thresholds are discussed below.

Ezetimibe is the preferred nonstatin choice in these patients since it has been shown to reduce ASCVD events when added to background statin therapy in the IMPROVE-IT study. Often, patients with LDL-C ≥190 mg/dL can achieve LDL-C levels close to 100 mg/dL with the combination of a high-intensity statin and ezetimibe. For example, the average LDL-C in patients with HeFH is about 240 mg/dL. A 50% LDL-C reduction from a high-intensity statin (such as atorvastatin 80 mg or rosuvastatin 20-40 mg) would on average result in LDL-C of 120 mg/dL, and the additional 20% average reduction in LDL-C from ezetimibe would then further reduce LDL-C to 96 mg/dL on average. The 2018 multi-society cholesterol guideline considers ezetimibe therapy reasonable (COR IIa) in patients 20-75 years of age and a baseline LDL-C level of ≥190 mg/dL who do not achieve at least a 50% reduction in LDL-C on maximally tolerated statin therapy or whose LDL-C level remains ≥100 mg/dL.The 2022 ACC Expert Consensus Decision Pathway (ECDP) on nonstatins also considers ezetimibe (with or without a PCSK9 monoclonal antibody [mAb]) the preferred option in these patients.

Other nonstatins may be needed to further lower LDL-C to desired levels. PCSK9 inhibitors are the most effective nonstatins, as they decrease LDL-C by 45% to 65% when added to background lipid-lowering therapy (see Treatment Approaches). Often, HeHF patients on statin with or without ezetimibe therapy can achieve LDL-C levels <70 mg/dL with PCSK9 inhibitors. However, these drugs require subcutaneous injection and are very expensive the 2018 multi-society cholesterol guideline considers PCSK9 inhibitors to be of uncertain value in patients with FH but no evidence of clinical ASCVD. The guideline defines two scenarios in which the use of a PCSK9 inhibitor may be considered (COR IIb): 1) for patients 30-75 years of age with HeFH whose LDL-C level remains ≥100 mg/dL despite maximally tolerated statin and ezetimibe therapy; and 2) for patients 40-75 years of age with a baseline LDL-C level of ≥220 mg/dL and an LDL-C level of ≥130 mg/dL on maximally tolerated statin and ezetimibe therapy.

Since the 2018 multi-society cholesterol guideline was published, the ASCVD risk reduction efficacy of PCSK9 mAbs has been demonstrated. Therefore, the 2022 ACC ECDP uses less stringent criteria than the 2018 multi-society cholesterol guideline for considering PCSK9 mAbs for primary prevention in patients with primary hypercholesterolemia. It recommends considering a PCSK9 mAb (with or without ezetimibe) as a first-line nonstatin option for patients who do not achieve ≥50% reduction in LDL-C and whose LDL-C level remains ≥100 mg/dL on maximally tolerated statin therapy. The siRNA PCSK9 inhibitor inclisiran and the cholesterol synthesis inhibitor bempedoic acid are suggested as second-line options. In the case of HoFH, the 2022 ACC ECDP suggests considering evinacumab, lomitapide and/or LDL apheresis under the case of a lipid specialist.

Less effective LDL-C lowering agents include niacin and bile acid sequestrants which lower LDL-C about 15%-30% but have adverse effect profiles that may limit their use. Both have been shown as monotherapy to reduce CAD (coronary artery disease) events in men with hypercholesterolemia with and without CAD (Coronary Drug Project, LRC-CPPT). The 2018 multi-society cholesterol guideline states that bile acid sequestrants may be considered (COR IIb) in patients 20-75 years of age with baseline LDL-C levels ≥190 mg/dL who achieve a <50% reduction in LDL-C levels and whose triglyceride levels are ≤300 mg/dL on a maximally tolerated statin and ezetimibe combination regimen.

Fibrates may be useful in patients with combined hyperlipidemia who have both LDL-C and triglyceride elevations.

Gemfibrozil has been shown to reduce CAD events in primary prevention men with hypercholesterolemia (Helsinki Heart Study) but gemfibrozil is contraindicated in statin-treated patients. Fenofibrate has a reasonable safety profile when used with a moderate-intensity statin (ACCORD) but no data are available when used concomitantly with a high-intensity statin.

Healthy Lifestyle Habits and Risk Factor Control

All patients should be counseled to adhere to healthy lifestyle habits and control weight. Participants in randomized trials were counseled on healthy lifestyle habits and the ASCVD risk reduction benefit of statins added to healthy lifestyle habits.

ASCVD risk factors should be treated aggressively in individuals with genetic hypercholesterolemias because they markedly increase CVD risk. Smoking is particularly detrimental when combined with hypercholesterolemia, akin to “pouring gasoline on a fire.” Aggressively work with patients to encourage immediate smoking cessation.

LDL-C Treatment Thresholds: Patients With Untreated LDL-C ≥190 mg/dL

Since the 2013 ACC/AHA cholesterol guideline was based on evidence from CV outcomes trials, it moved away from treat to goal approaches due to a lack of evidence for titration strategies. The focus shifted to intensification of statin therapy, with a ≥50% reduction in LDL-C considered an indicator of adequacy of therapy for high-risk patients. This approach is largely maintained in the 2018 multi-society cholesterol guideline, although absolute LDL-C thresholds were reintroduced to guide decisions of adding select nonstatins to the treatment.

Patients with severe elevations in (LDL-C ≥190 mg/dL) were largely excluded from the CV outcomes trials due to ethical considerations that these patients required active LDL-C–lowering drug therapy. It should be noted that in the high-intensity statin trials TNT, IDEAL and PROVE-IT, which excluded patients with LDL-C ≥190 mg/dL, an LDL-C level of <100 mg/dL was achieved in the high-intensity statin group. The high-intensity statin groups consistently had greater CV risk reduction than the moderate-intensity statin groups. IMPROVE-IT demonstrated further CV event reduction when ezetimibe was added to statin therapy in patients with LDL-C 50-100 mg/dL. These results served as the basis for the COR IIa recommendation from the 2018 cholesterol guidelines to add ezetimibe to the regimen if LDL-C remains ≥100 mg/dL despite maximally tolerated statin therapy. The same consideration threshold is recommended in the 2022 ACC ECDP.

Considering the epidemiologic evidence, it is reasonable to try to achieve an LDL-C level 90-100 mg/dL long-term in patients with FH, since this is the level at which little atherosclerosis develops in younger to middle-aged adults. Achieving this level of LDL-C may require multiple drugs, and the potential benefits need to be weighed against the potential for adverse effects, costs to the patient that may impact adherence and patient preferences.

Evidence from meta-analyses of statin trials suggests that there is no lower LDL-C limit to the reduction in ASCVD events or regression of atherosclerosis. Therefore, it might be reasonable to intensify LDL-C lowering therapy to achieve LDL-C levels of 50-70 mg/dL in selected patients with genetic hypercholesterolemia who:

• Have clinically manifest ASCVD
• Are older than 35 years with diabetes, smoking, hypertension, a very premature family history of ASCVD, long-term exposure to untreated LDL-C >250 mg/dL, or Lp(a) >50 mg/dL
• Have a large burden of subclinical atherosclerosis.

Achieving an LDL-C level of <70 mg/dL in patients with familial or other genetic hypercholesterolemias will require multiple drugs and likely a PCSK9 inhibitor which can lower LDL-C by 45% to 65% when added to maximal lipid-lowering therapy in patients with and without HeFH. The potential benefits need to be weighed against the potential for adverse effects, costs to the patient that may impact adherence and patient preferences. The duration of therapy needed to stabilize plaque cannot be determined with currently available methods, but consideration could be given to reducing the drug treatment intensity after 5 to 10 years to maintain LDL-C levels of 90-100 mg/dL since a legacy effect of statin therapy has been observed after 10 to 20 years of follow-up in statin trials. Such a decision should be based on patient preferences, cost considerations and adverse effects.

Contraindications to Treatment: Pregnancy and Nursing Mothers

Statin and most nonstatin therapies, including PCSK9 monoclonal antibodies, should not be used in women of childbearing age who contemplate becoming pregnant or are unwilling to practice effective contraception. Statins should not be used by nursing mothers. However, women with familial hypercholesterolemia should start statin therapy by age 20 at the latest, with emphatic advice to the patient and partner to practice effective contraception.

Refer to Familial Hyperlipidemias and the specific drug sections for additional information on contraindications and safety.

Cascade Screening

Cascade screening should be considered in all patients with LDL-C ≥190 mg/dL, regardless of the age at which hypercholesterolemia is first detected. The 2018 multi-society cholesterol guideline considers reverse-cascade screening of family members (first-, second- and third-degree biological relatives) of children and adolescents with moderate or severe hypercholesterolemia reasonable (COR IIa).

For additional identification and treatment recommendations for children and adolescents, refer to the NHLBI pediatric guidelines for identification and treatment recommendations for patients <21 years of age.