What are the alternative treatments to statin therapy for lowering Low-Density Lipoprotein (LDL) cholesterol levels?

Alternative Treatments to Statin Therapy for Lowering LDL Cholesterol

For patients who cannot tolerate statins or need additional LDL-cholesterol lowering beyond statins, several effective alternative therapies are available, including ezetimibe, PCSK9 inhibitors, bempedoic acid, bile acid sequestrants, and various combination approaches. 1

First-Line Alternatives to Statins

Ezetimibe

• Reduces LDL cholesterol by 15-20% when used as monotherapy 2
• Can be used alone or in combination with low-dose statins in statin-intolerant patients 1
• FDA-approved as an adjunct to diet to reduce elevated LDL-C in adults with primary hyperlipidemia 2
• Has an excellent safety profile with no association with muscle symptoms 3

PCSK9 Inhibitors

• Three options available:
  • Monoclonal antibodies (mAbs): Evolocumab and alirocumab
    • Reduce LDL cholesterol by 50-60% 1
    • Demonstrated cardiovascular outcomes benefits in the FOURIER and ODYSSEY OUTCOMES trials 1
    • Administered by subcutaneous injection every 2-4 weeks 1
  • Small interfering RNA (siRNA): Inclisiran
    • Reduces LDL cholesterol by 49-52% 1
    • Less frequent dosing (day 1, day 90, then every 6 months) 1
    • Cardiovascular outcome trials are ongoing 1

Bempedoic Acid

• Novel LDL-lowering agent that works in the same pathway as statins but without activity in skeletal muscle 1
• Lowers LDL cholesterol by 15-24% (24% when used without statins) 1
• Demonstrated 13% reduction in major adverse cardiovascular events in statin-intolerant patients in the CLEAR Outcomes trial 1
• Associated with fewer muscle-related adverse effects than statins 3

Bile Acid Sequestrants (e.g., Cholestyramine)

• Can be considered as an alternative therapy for statin-intolerant patients 1, 4
• Typically administered in 1-6 doses per day, mixed with water or other fluids 4
• Less effective than other options but has established safety profile 5

Approach to Statin Intolerance

Step-by-Step Management Algorithm

1. First attempt: Try different statins or modified dosing regimens

   • Switch to a different high-intensity statin if indicated 1
   • Try pravastatin or fluvastatin which may cause fewer muscle symptoms 6
   • Consider alternate-day or twice-weekly dosing 1, 7

2. If still intolerant after trying at least 3 statins: Add or switch to non-statin therapies

   • Ezetimibe monotherapy as first non-statin option 1
   • Bile acid sequestrants as an alternative 1, 6

3. If LDL goals not achieved with above measures:

   • For very high-risk patients with ASCVD: Consider PCSK9 inhibitors 1
   • For statin-intolerant patients: Consider bempedoic acid 1

4. For patients with persistent severe hypercholesterolemia despite therapy:

   • Consider combination therapy with multiple non-statin agents 1
   • In extreme cases with multiple cardiovascular events, lipoprotein apheresis may be considered 6

Efficacy Considerations

• Intermittent statin dosing provides less LDL reduction than daily dosing (21.3% vs 27.7%) but significantly better than no statin (21.3% vs 8.3%) 7
• Alternative LDL-lowering strategies (moderate-intensity statin plus ezetimibe) have shown comparable efficacy to high-intensity statins for cardiovascular outcomes with fewer side effects 8
• Combination of ezetimibe with bempedoic acid can achieve additional 19% reduction in LDL cholesterol 1

Special Considerations

For Patients with ASCVD

• PCSK9 mAbs are preferred as initial PCSK9 inhibitors due to demonstrated cardiovascular outcomes benefits 1
• Inclisiran may be considered in patients with poor adherence to PCSK9 mAbs or those unable to self-inject 1

For Patients with Diabetes

• Alternative LDL-lowering strategies may reduce risk of new-onset diabetes compared to high-intensity statins (10.2% vs 11.9%) 8
• PCSK9 inhibitors showed greater absolute risk reduction in patients with diabetes (2.3%) compared to those with prediabetes (1.2%) or normoglycemia (1.2%) 1

Common Pitfalls to Avoid

• Failing to try multiple statins before declaring complete statin intolerance - at least 3 different statins should be tested 6
• Not considering alternative dosing regimens (every other day, twice weekly) before abandoning statins 1, 7
• Using combination statin/fibrate or statin/niacin therapy, which has not shown improved outcomes and may increase side effects 1
• Overlooking the potential of moderate-intensity statin plus ezetimibe, which can achieve similar outcomes to high-intensity statins with better tolerability 8