What injectable medications are available for treating high cholesterol, specifically hypercholesterolemia?

Injectable Medications for Hypercholesterolemia

PCSK9 inhibitors are the primary injectable medications available for treating hypercholesterolemia, and should be added to maximally tolerated statin therapy and ezetimibe in patients with high or very high cardiovascular risk whose LDL-C remains ≥100 mg/dL despite optimal oral therapy. 1

Available PCSK9 Inhibitors

Monoclonal Antibodies

1. Evolocumab (Repatha)

   • Dosing: 140 mg every 2 weeks or 420 mg once monthly, subcutaneous injection 2
   • Efficacy: 50-65% LDL-C reduction when added to statins 3
   • Additional benefits: Reduces Lp(a) by up to 25%, increases HDL-C by 4.5-6.8% 3

2. Alirocumab (Praluent)

   • Dosing: 75-150 mg every 2 weeks, subcutaneous injection 4
   • Efficacy: 8-67% LDL-C reduction at 12-24 weeks 4
   • Additional benefits: Increases HDL-C by 6-12% 4

3. Inclisiran (siRNA-based PCSK9 inhibitor)

   • Newer agent mentioned in guidelines but with less extensive clinical experience 1

Patient Selection Algorithm

Step 1: Identify High-Risk Patients

Patients who should be considered for PCSK9 inhibitor therapy include:

• Those with heterozygous familial hypercholesterolemia (HeFH) 1
• Those with established atherosclerotic cardiovascular disease (ASCVD) 1
• Those with very high cardiovascular risk 1

Step 2: Verify Inadequate Response to Oral Therapy

PCSK9 inhibitors should be considered when:

• LDL-C remains ≥100 mg/dL despite maximally tolerated statin and ezetimibe therapy in patients with HeFH or ASCVD 1
• LDL-C remains ≥70 mg/dL in patients with very high cardiovascular risk despite maximally tolerated statin and ezetimibe therapy 1

Step 3: Select Appropriate PCSK9 Inhibitor

• Both evolocumab and alirocumab have similar efficacy profiles 4
• Evolocumab has stronger evidence for patients with HeFH 4
• Alirocumab has stronger evidence for patients with high CV risk not at LDL-C goals 4

Clinical Evidence for Efficacy

Cardiovascular Outcomes

• The FOURIER trial demonstrated that evolocumab reduced major cardiovascular events by 15% and the composite of cardiovascular death, MI, or stroke by 20% over 2.2 years in patients with ASCVD 1, 3
• The ODYSSEY OUTCOMES trial showed that alirocumab reduced the composite primary endpoint (death from CHD, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) by 15% over 2.8 years 1
• Patients with diabetes showed greater absolute risk reduction (2.3%) with alirocumab compared to those with prediabetes (1.2%) or normoglycemia (1.2%) 1

Lipid-Lowering Efficacy

• In the LAPLACE-2 trial, evolocumab reduced LDL-C by 63-71% compared to placebo when added to statins 2
• In the DESCARTES trial, evolocumab 420 mg monthly reduced LDL-C by 55% compared to placebo at 52 weeks 2

Important Considerations and Caveats

1. Cost Implications

   • PCSK9 inhibitors are significantly more expensive than oral therapies (~$14,300/year) 5
   • Cost-effectiveness varies by country; generally borderline cost-effective in European countries 6

2. Patient Selection

   • Strong recommendations exist for adding PCSK9 inhibitors in high and very high-risk patients 1
   • Strong recommendations against adding another drug in low cardiovascular risk patients 1

3. Shared Decision Making

   • Given the variability in patient values and preferences, shared decision making is warranted when considering PCSK9 inhibitors 1
   • Consider discussing the balance between cardiovascular risk reduction and medication burden/cost

4. Monitoring

   • Regular lipid panel monitoring is needed to assess response
   • Injection site reactions may occur but are generally mild 4

5. Insurance Coverage

   • Insurance approval often requires documentation of:
     • Diagnosis of HeFH and/or ASCVD
     • LDL-C >100 mg/dL despite maximally tolerated statin and ezetimibe therapy
     • Statin intolerance documentation if applicable 5

PCSK9 inhibitors represent a significant advancement in lipid management, particularly for high-risk patients unable to achieve target LDL-C levels with oral therapies. Their use should be targeted to those most likely to benefit, given their cost and the need for injectable administration.