What are alternative low-density lipoprotein (LDL)-lowering medications for a patient with a history of allergy to statins (HMG-CoA reductase inhibitors)?

LDL-Lowering Medications for Statin-Allergic Patients

Start with ezetimibe 10 mg daily as first-line therapy, which reduces LDL-C by 15-20% with a placebo-like safety profile, then add bempedoic acid 180 mg daily if targets are not met, and reserve PCSK9 inhibitors for very high-risk patients with persistent LDL-C elevation. 1, 2, 3

Confirm True Statin Intolerance First

Before initiating alternative therapy, document that the patient has attempted at least 2 different statins, including at least one at the lowest approved daily dose, with adverse effects that resolved or improved upon dose reduction or discontinuation. 1, 2

First-Line Alternative: Ezetimibe

• Ezetimibe 10 mg daily should be the initial non-statin therapy for all statin-intolerant patients. 1, 2, 3
• Ezetimibe reduces LDL-C by 15-20% by inhibiting intestinal cholesterol absorption and has a side-effect profile similar to placebo. 2, 3, 4
• Unlike bile acid sequestrants, ezetimibe does not adversely affect triglyceride levels and has minimal drug interactions due to its minimal systemic absorption. 4
• Reassess lipid profile at 4-8 weeks after initiating ezetimibe to determine if additional therapy is needed. 1, 3

Second-Line Addition: Bempedoic Acid

• If LDL-C targets are not met with ezetimibe alone, add bempedoic acid 180 mg daily. 1, 3
• Bempedoic acid reduces LDL-C by 15-25% with low rates of muscle-related adverse effects because it works upstream from statins in the liver and is only activated in hepatocytes, not muscle cells. 1, 3
• The CLEAR Outcomes trial demonstrated a 13% reduction in major adverse cardiovascular events in statin-intolerant patients. 1
• The combination of ezetimibe plus bempedoic acid achieves approximately 35% LDL-C reduction. 1, 3
• Monitor liver function tests and uric acid levels when using bempedoic acid, as it can cause small increases in uric acid and slightly increased frequency of gout episodes in susceptible patients. 1, 5

Third-Line Option: PCSK9 Inhibitors

• Reserve PCSK9 inhibitors (evolocumab, alirocumab, or inclisiran) for very high-risk patients with LDL-C ≥70 mg/dL despite ezetimibe plus bempedoic acid. 1, 3
• PCSK9 inhibitors reduce LDL-C by approximately 50-60% and are well-tolerated in statin-intolerant patients with minimal muscle-related adverse effects. 1, 3, 6, 5
• Evolocumab (Repatha) is FDA-approved for statin-intolerant patients with primary hyperlipidemia, established ASCVD, or familial hypercholesterolemia at doses of 140 mg every 2 weeks or 420 mg once monthly. 6
• The main limitation is cost, so try ezetimibe and bempedoic acid first unless the patient has very high risk with markedly elevated LDL-C. 1
• Monitor LDL-C response every 3-6 months once on PCSK9 inhibitor therapy. 1

Alternative Options for Specific Scenarios

Bile Acid Sequestrants

• Consider bile acid sequestrants (colesevelam 3.8 g daily, cholestyramine) if triglycerides are <300 mg/dL and the patient cannot tolerate bempedoic acid. 1, 3
• These reduce LDL-C by 15-30% and provide a modest hypoglycemic effect beneficial in diabetic patients. 1, 3
• Major limitation: gastrointestinal side effects significantly limit tolerability. 2, 3

Niacin

• Niacin may be reasonable for LDL-C lowering in statin-intolerant patients, particularly those with low HDL cholesterol or elevated Lp(a). 1, 3
• However, clinical trials have failed to demonstrate added cardiovascular benefit when combined with statins. 7

Fibrates

• Reserve fibrates (fenofibrate preferred over gemfibrozil) for patients with triglycerides >500 mg/dL to prevent acute pancreatitis, not primarily for LDL-C lowering. 1, 3

Treatment Targets Based on Risk

Very High-Risk Patients (established ASCVD, recurrent events)

• Target LDL-C <55 mg/dL with ≥50% reduction from baseline. 1, 3
• Start ezetimibe, add bempedoic acid if needed, then add PCSK9 inhibitor if LDL-C remains ≥55 mg/dL. 1

High-Risk Patients (diabetes, multiple risk factors)

• Target LDL-C <70 mg/dL. 1, 3
• Start ezetimibe, add bempedoic acid if LDL-C remains ≥70 mg/dL, consider PCSK9 inhibitor only if LDL-C remains significantly elevated. 1

Moderate-Risk Patients

• Target LDL-C <100 mg/dL or at least 50% reduction from baseline. 1
• PCSK9 inhibitors do not have an established role for primary prevention in the absence of ASCVD or baseline LDL-C ≥190 mg/dL. 1

Critical Pitfalls to Avoid

• Do not use PCSK9 inhibitors as first-line therapy after ezetimibe in primary prevention without trying bempedoic acid first, as PCSK9 inhibitors lack an established role in this setting and are costly. 1
• Avoid bile acid sequestrants if triglycerides are ≥300 mg/dL, as they can worsen hypertriglyceridemia. 1, 3
• Do not assume muscle symptoms are statin-related without proper dechallenge and rechallenge, as many symptoms attributed to statins are not actually caused by them. 8
• Monitor for hyperuricemia and gout when using bempedoic acid, especially in patients with a history of gout. 1, 5

Essential Lifestyle Modifications

• Reduce saturated fat intake to <7% of total calories, trans fatty acids to <1% of total calories, and cholesterol to <200 mg/day. 1, 3
• Daily physical activity for at least 30 minutes, 5-7 days per week. 1
• Weight management targeting BMI 18.5-24.9 kg/m². 1