Mechanistic Plaque Reduction and Stabilization at LDL 70 mg/dL
For patients with chronic coronary disease already at an LDL-C of 70 mg/dL on statin therapy, adding ezetimibe provides mechanistic plaque stabilization benefits and further reduces cardiovascular events, even when LDL-C is already at this threshold. 1
Evidence for Further LDL Lowering Below 70 mg/dL
The relationship between LDL-C reduction and cardiovascular benefit is continuous without a lower threshold—"lower is better for longer"—meaning that achieving LDL-C levels below 70 mg/dL provides additional event reduction. 1
The 2025 AHA/ACC guidelines explicitly state that rates of adverse cardiovascular events are inversely proportional to LDL-C levels achieved, with no apparent floor effect. 1
For very high-risk patients with chronic coronary disease, an LDL-C target below 55 mg/dL can be considered, representing approximately a 15 mg/dL further reduction from the 70 mg/dL threshold. 1
The IMPROVE-IT trial demonstrated that adding ezetimibe to statin therapy in post-acute coronary syndrome patients consistently reduced cardiovascular events regardless of baseline LDL-C, including in patients starting with LDL-C between 50-70 mg/dL (HR 0.92,95% CI 0.80-1.05). 2
Guideline-Directed Approach for Patients at LDL 70 mg/dL
Step 1: Risk Stratification
Determine if the patient meets "very high-risk" criteria, which includes: 1
- History of multiple major ASCVD events (recent ACS within 12 months, history of MI, ischemic stroke, or symptomatic peripheral artery disease), OR
- One major ASCVD event plus multiple high-risk conditions (age ≥65 years, diabetes, hypertension, CKD, current smoking, persistently elevated LDL-C ≥100 mg/dL despite therapy, or history of heart failure) 1
Step 2: Add Ezetimibe for Very High-Risk Patients
For very high-risk patients with LDL-C ≥70 mg/dL on maximally tolerated statin therapy, adding ezetimibe is reasonable (Class 2a, Level B-R). 1
Ezetimibe provides an additional 15-20% LDL-C reduction through complementary cholesterol absorption inhibition, which would lower a 70 mg/dL level to approximately 55-60 mg/dL. 3, 4
The IMPROVE-IT trial showed that adding ezetimibe to simvastatin reduced the primary composite endpoint by 6.4% relative risk (absolute risk difference 2.0 percentage points, HR 0.936, P=0.016) over 7 years. 5
Step 3: Consider PCSK9 Inhibitors for Persistent Elevation
If LDL-C remains ≥70 mg/dL (or ≥55 mg/dL in very high-risk patients) on maximally tolerated statin plus ezetimibe, adding a PCSK9 inhibitor is reasonable (Class 2a, Level A). 1
PCSK9 inhibitors reduce LDL-C by approximately 50-60% from baseline and have demonstrated cardiovascular event reduction in patients with established ASCVD. 6
The sequential approach (statin → add ezetimibe → add PCSK9i) is recommended because most patients achieve LDL-C <70 mg/dL with statin plus ezetimibe, making PCSK9 inhibitors unnecessary in many cases. 1
Mechanistic Benefits Beyond LDL Lowering
Ezetimibe demonstrates pleiotropic anti-inflammatory and antioxidative effects beyond its LDL-lowering properties, contributing to plaque stabilization. 4
These effects include reduced oxidative stress, decreased inflammatory markers, and improved endothelial function, which mechanistically contribute to atherosclerotic plaque stabilization independent of the degree of LDL reduction. 4
Even in patients with extremely low baseline LDL levels (<40 mg/dL), continued statin therapy is associated with improved survival (HR 0.51,95% CI 0.33-0.79), suggesting benefits beyond simple LDL reduction. 7
Safety Considerations at Lower LDL Targets
Intensive lipid lowering to LDL-C levels below 70 mg/dL or even below 55 mg/dL is safe, with no increase in adverse events including malignancy, transaminase elevation, or rhabdomyolysis. 5, 7
The IMPROVE-IT trial showed similar rates of prespecified muscle, gallbladder, hepatic adverse effects, and cancer between ezetimibe/simvastatin and simvastatin monotherapy groups. 5
Monitor ALT and CK before intensifying therapy and recheck 8±4 weeks after adding ezetimibe, particularly watching for muscle symptoms. 8
Common Pitfalls to Avoid
Do not increase statin dose to achieve lower LDL targets once on maximally tolerated high-intensity statin therapy—add non-statin therapy instead. 3
There is no RCT evidence supporting titration to specific LDL-C numerical goals through statin dose escalation; guidelines recommend fixed-dose intensity strategies. 3
High-dose statin escalation increases rates of transaminase elevations without proportional additional benefit compared to adding ezetimibe. 3
Do not delay adding ezetimibe in very high-risk patients simply because LDL-C is "at goal" of 70 mg/dL—the evidence supports further reduction to <55 mg/dL in this population. 1, 2