Non-Statin Approaches to Lower LDL Cholesterol

Ezetimibe is the most effective first-line non-statin medication for lowering LDL cholesterol, providing 18-25% reduction in LDL-C levels. 1, 2

Hierarchy of Non-Statin Therapies

Ezetimibe (10mg daily) should be used as the initial non-statin agent due to its demonstrated safety, tolerability, convenience, and single-tablet daily dosing 1, 3
Bile acid sequestrants (cholestyramine, colestipol, colesevelam) can reduce LDL-C by 18-25% and should be considered if patients have an inadequate response to ezetimibe or are ezetimibe-intolerant 1
PCSK9 inhibitors (evolocumab, alirocumab) provide 40-65% LDL-C reduction but are generally reserved for very high-risk patients due to cost considerations 1, 3
Dietary modifications can achieve LDL-C reductions of up to 25-30% when maximally implemented 1, 4

Blocks intestinal cholesterol absorption by interfering with Niemann Pick C1 like receptor 1 (NPC1L1) 1
Provides consistent 18-25% reduction in LDL-C when used as monotherapy 1, 2
Has a safety profile similar to placebo with no significant drug interactions 5, 6
Can be taken with or without food, but should be administered either ≥2 hours before or ≥4 hours after a bile acid sequestrant 2
Improves glucose metabolism and reduces inflammation markers (hsCRP) 7

Bind bile acids in the intestinal lumen, depleting the liver of bile and upregulating LDL receptor activity 1
Reduce LDL-C by 18-25% at daily doses of 24g cholestyramine, 20g colestipol, or 4.5g colesevelam 1
Demonstrated ~20% CVD risk reduction in primary prevention trials 1
May have modest hypoglycemic effects beneficial in diabetic patients 1
Limitations include gastrointestinal side effects and potential drug interactions 1
Should not be used in patients with triglycerides >300 mg/dL 3

Lowers LDL-C by 20-25% through incompletely defined mechanisms 1
Also raises HDL-C by up to 30% and lowers triglycerides by up to 50% 1
Has shown ~20% CVD risk reduction as monotherapy in earlier trials 1
Side effects include skin flushing, hepatotoxicity, hyperuricemia, and hyperglycemia 1
Recent trials showed no additional benefit when added to statin therapy 1

Provide modest LDL-C reduction (5-15%) but more significant effects on triglycerides 1
Have shown ~20% CVD risk reduction as monotherapy 1
Most beneficial in patients with high triglycerides and low HDL-C 1

Dietary modifications can achieve LDL-C reductions of up to 25-30% when maximally implemented 1
Plant sterols/stanols can reduce LDL-C by approximately 10% 4
Increased dietary fiber intake (particularly soluble fiber) can lower LDL-C by 5-10% 4
Nut consumption can reduce LDL-C by approximately 8% 4
Soy protein can lower LDL-C by 3-10% 4
Reduction in saturated and trans fats with increased polyunsaturated fat intake provides significant LDL-C lowering 1

Combining dietary modifications with a non-statin medication can provide additive LDL-C lowering effects 1
Adding ezetimibe to a low-dose statin produces LDL-C reduction similar to a three-fold increase in statin dose 5, 8
The combination of multiple non-statin approaches (diet + ezetimibe + bile acid sequestrant) can achieve substantial LDL-C reductions 1

Always assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ezetimibe 2
For every 1% reduction in LDL-C levels, relative risk for major CHD events is reduced by approximately 1% 1
Bile acid sequestrants should not be used in patients with triglycerides >300 mg/dL due to potential triglyceride elevation 3
Ezetimibe should be administered either ≥2 hours before or ≥4 hours after a bile acid sequestrant to avoid interference with absorption 2
The combination of dietary approaches can have a substantial impact on LDL-C levels and should not be underestimated 4