What are alternative treatments to olpasiran for lowering Low-Density Lipoprotein (LDL) cholesterol?

Alternative Treatments to Olpasiran for LDL Cholesterol Lowering

For patients requiring LDL cholesterol reduction, the first-line alternatives to olpasiran are high-intensity statins (rosuvastatin 20-40 mg or atorvastatin 40-80 mg) combined with ezetimibe 10 mg daily, which together can reduce LDL-C by approximately 50-60% and have proven cardiovascular outcomes benefits. 1

Primary Alternative Strategy: Statin-Based Therapy

High-Intensity Statins

• Rosuvastatin 20-40 mg daily or atorvastatin 40-80 mg daily are the cornerstone of LDL-lowering therapy, with rosuvastatin providing slightly greater LDL-C reduction per dose 2
• These agents reduce LDL-C by 50-63% at maximum doses and have extensive cardiovascular outcomes data demonstrating reduction in CV death, MI, and stroke 1, 2
• For Asian patients, initiate rosuvastatin at 5 mg daily due to increased plasma concentrations, with careful dose titration 2

Adding Ezetimibe

• Ezetimibe 10 mg daily should be added to maximally tolerated statin therapy when LDL-C goals are not achieved with statin monotherapy 1
• Ezetimibe provides an additional 18-25% LDL-C reduction when combined with statins by inhibiting intestinal cholesterol absorption 1
• The IMPROVE-IT trial demonstrated that ezetimibe added to moderate-intensity statin therapy reduced cardiovascular events (CV death, MI, stroke, revascularization) over 6 years in patients with recent acute coronary syndrome 1
• This combination is generally well-tolerated with common side effects including nasopharyngitis, myalgia, upper respiratory tract infection, and arthralgia 1

Secondary Alternative: PCSK9 Inhibitors

When to Consider PCSK9 Inhibitors

• PCSK9 inhibitors (alirocumab or evolocumab) should be considered when patients fail to achieve LDL-C <70 mg/dL (or non-HDL-C <100 mg/dL) on maximally tolerated statin plus ezetimibe 1
• These agents are particularly appropriate for patients with established ASCVD at very high risk or those with baseline LDL-C ≥190 mg/dL 1

Alirocumab (Praluent)

• Alirocumab is the direct alternative PCSK9 inhibitor to evolocumab (Repatha) with similar mechanism of action, efficacy, and safety profile 3, 4
• Dosing: Start with 75 mg subcutaneously every 2 weeks or 300 mg every 4 weeks; may increase to 150 mg every 2 weeks if LDL-C response is inadequate 4
• Provides 45-58% additional LDL-C reduction when added to maximally tolerated statin therapy 3
• The ODYSSEY Outcomes trial demonstrated reduction in CV death, MI, stroke, and unstable angina requiring hospitalization in patients with established cardiovascular disease 3, 4
• Common adverse effects include nasopharyngitis, injection site reactions, influenza, and myalgia 3, 4

Evolocumab (Repatha)

• Reduces LDL-C by 59-64% when added to maximally tolerated statin therapy, achieving median LDL-C levels as low as 30 mg/dL 5
• The FOURIER trial showed 15% reduction in composite CV endpoints (CV death, MI, stroke, revascularization, or hospitalization for unstable angina) and 20% reduction in CV death, MI, or stroke 5

Alternative Strategy for Statin-Intolerant Patients

Moderate-Intensity Statin Plus Ezetimibe

• For patients who cannot tolerate high-intensity statins, a moderate-intensity statin combined with ezetimibe 10 mg daily provides comparable cardiovascular outcomes 6
• This alternative strategy demonstrated equivalent 3-year rates of death or cardiovascular events compared to high-intensity statin monotherapy (7.5% vs 7.7%) 6
• This approach achieved mean LDL-C of 64.8 mg/dL and was associated with lower rates of new-onset diabetes (10.2% vs 11.9%) and drug intolerance requiring discontinuation (4.0% vs 6.7%) 6

Additional Non-Statin Options

Bile Acid Sequestrants

• Reduce LDL-C by 15-30% by binding bile acids in the intestine and promoting hepatic conversion of cholesterol to bile acids 3
• Can be added for additional LDL-C lowering but have significant gastrointestinal side effects and drug-drug interactions 1, 3
• Must be taken either ≥2 hours before or ≥4 hours after other medications 1

Bempedoic Acid

• A newer non-statin agent that inhibits ATP citrate lyase, reducing cholesterol synthesis 3
• Particularly useful in statin-intolerant patients or as add-on therapy 3

Clinical Decision Algorithm

1. Start with maximally tolerated statin therapy (rosuvastatin 20-40 mg or atorvastatin 40-80 mg daily) 1, 2
2. Add ezetimibe 10 mg daily if LDL-C goals not achieved (target <70 mg/dL for ASCVD patients) 1
3. Consider PCSK9 inhibitor (alirocumab or evolocumab) if still not at goal on statin plus ezetimibe 1, 3
4. For statin-intolerant patients, use moderate-intensity statin plus ezetimibe or consider bempedoic acid 3, 6
5. Refer to lipid specialist for patients with baseline LDL-C ≥190 mg/dL who fail to achieve ≥50% LDL-C reduction and LDL-C <70 mg/dL on maximally tolerated combination therapy 1

Important Considerations

Key Differences from Olpasiran

• Olpasiran is an investigational siRNA targeting lipoprotein(a), not primarily an LDL-lowering agent 7, 8, 9
• While olpasiran reduces LDL-C modestly, its primary mechanism is reducing Lp(a) synthesis by 70-101% 7, 9
• The alternatives listed above are FDA-approved therapies with proven cardiovascular outcomes data, whereas olpasiran is still in clinical trials 7, 8

Monitoring and Safety

• Assess LDL-C as early as 4 weeks after initiating or adjusting therapy 2, 4
• Monitor hepatic transaminases when using statins, particularly in combination with ezetimibe 1
• Watch for myopathy, rhabdomyolysis, and new-onset diabetes with statin therapy 1, 2, 6
• PCSK9 inhibitors require assessment for hypersensitivity reactions including vasculitis and angioedema 4

Cost-Effectiveness Considerations

• Generic statins and ezetimibe are available and cost-effective 1, 10
• PCSK9 inhibitors are significantly more expensive and should be reserved for patients who fail first-line therapies 3
• Atorvastatin 80 mg may be more cost-effective than rosuvastatin 40 mg with similar efficacy 10