What is the optimal management strategy for a patient with a history of cardiovascular disease and an LDL (low-density lipoprotein) level of 70 mg/dL on statin therapy, given the absence of a clear minimum LDL goal for reversing all heart disease?

Optimal LDL-C Management for Patients with Cardiovascular Disease at 70 mg/dL on Statin Therapy

For a patient with established cardiovascular disease and LDL-C of 70 mg/dL on statin therapy, add ezetimibe to achieve an LDL-C goal below 70 mg/dL, and consider targeting below 55 mg/dL if the patient meets very high-risk criteria. 1, 2

Risk Stratification Determines Target LDL-C

Your first step is determining whether this patient qualifies as "very high-risk" versus standard ASCVD risk:

Very high-risk characteristics include: 1, 2

• History of multiple major ASCVD events (e.g., prior MI plus prior stroke)
• Recent acute coronary syndrome within the past 2 years
• Baseline LDL-C ≥190 mg/dL with clinical ASCVD
• Multiple high-risk conditions (diabetes, chronic kidney disease, familial hypercholesterolemia, prior CABG or PCI outside of the major ASCVD event)

If very high-risk: Target LDL-C <55 mg/dL 1, 2

If standard ASCVD risk: Target LDL-C <70 mg/dL 1

The Evidence Against Simply Increasing Statin Dose

Do not increase the statin dose to chase numerical LDL-C targets—this strategy lacks randomized trial evidence. 3 The 2013 ACC/AHA guideline explicitly states that no direct RCT data confirm the efficacy of using LDL-C goals to guide therapy through dose titration. 3 Current guidelines recommend fixed-dose intensity strategies (high-intensity, moderate-intensity, or low-intensity statin therapy) rather than titrating to arbitrary numerical targets. 3

High-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) should achieve ≥50% LDL-C reduction from baseline. 1 Once on maximally tolerated high-intensity statin therapy, the evidence-based next step is adding non-statin therapy, not further dose escalation. 3

Add Ezetimibe as First-Line Non-Statin Therapy

For patients with clinical ASCVD and LDL-C ≥70 mg/dL on maximally tolerated statin therapy, adding ezetimibe is reasonable (Class IIa, Level B-R). 1, 3 Ezetimibe provides an additional 15-20% LDL-C reduction through complementary cholesterol absorption inhibition. 3, 4 In clinical trials, ezetimibe added to ongoing statin therapy significantly lowered LDL-C by an additional 25% compared to statin alone. 4

For very high-risk patients with LDL-C ≥55 mg/dL, consider adding ezetimibe even at this lower threshold. 2 Individuals achieving LDL-C <55 mg/dL experience lower cardiovascular event rates than those with higher levels. 2

The "Lower is Better" Principle Has No Lower Threshold

There is no LDL-C level below which cardiovascular benefit ceases. 2 Lifelong very low LDL-C levels (15-30 mg/dL) in patients with genetic conditions and in clinical trials show lower ASCVD incidence without adverse effects. 2 For every 1% reduction in LDL-C levels, relative risk for major coronary events is reduced by approximately 1%, and this relationship holds even for LDL-C levels below 100 mg/dL. 2

The FOURIER trial demonstrated that patients achieving median LDL-C of 30 mg/dL on background statin plus PCSK9 inhibitor experienced additional ASCVD event reduction benefits. 5 Multiple IVUS imaging studies show atheroma regression continues as LDL-C is lowered below 70 mg/dL. 5

Consider PCSK9 Inhibitors for Persistent Elevation

If LDL-C remains ≥70 mg/dL (or ≥55 mg/dL in very high-risk patients) despite maximally tolerated statin plus ezetimibe, adding a PCSK9 monoclonal antibody is reasonable (Class 2a, Level A). 1 PCSK9 inhibitors provide substantial additional LDL-C lowering (50-60% reduction). 6

Alternative: Bempedoic acid may be considered as an addition or alternative if PCSK9 inhibitors are not accessible. 2

Treatment Algorithm

1. Confirm maximally tolerated high-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg achieving ≥50% LDL-C reduction from baseline). 1

2. Assess adherence to medications and lifestyle modifications (reduced saturated fat <7% of calories, trans fat <1%, cholesterol <200 mg/day, daily physical activity). 1, 3

3. Determine risk category:

   • Very high-risk → Target LDL-C <55 mg/dL 1, 2
   • Standard ASCVD → Target LDL-C <70 mg/dL 1

4. At LDL-C 70 mg/dL:

   • Standard ASCVD risk: Add ezetimibe 1, 3
   • Very high-risk: Add ezetimibe (already above 55 mg/dL threshold) 2

5. If LDL-C remains elevated after statin + ezetimibe:

   • Add PCSK9 inhibitor if ≥70 mg/dL (standard risk) or ≥55 mg/dL (very high-risk) 1, 2

6. Monitor lipid response 4-12 weeks after adding therapy, then every 3-12 months. 2, 3

Consider Apolipoprotein B Testing

Apolipoprotein B (apoB) testing provides superior assessment of residual cardiovascular risk in statin-treated patients compared to LDL-C alone, particularly in those with elevated triglycerides or low HDL-C. 2, 3 If apoB is elevated despite LDL-C near target, this indicates residual risk and should prompt discussion about add-on therapy. 2

Target apoB <70 mg/dL for extreme risk patients, or <80 mg/dL for very high-risk patients. 5

Common Pitfalls to Avoid

Do not assume LDL-C of 70 mg/dL is "good enough" for very high-risk patients. 2 The 2025 ACC guideline recommends a lower threshold of ≥55 mg/dL for considering nonstatin therapies in very high-risk patients. 2

Do not increase statin dose beyond maximally tolerated therapy to chase LDL-C targets. 3 This lacks RCT evidence and increases adverse effect risk without proven incremental benefit compared to adding non-statin therapy. 3

Do not delay adding ezetimibe while attempting lifestyle modifications alone. 1 In patients with established ASCVD, pharmacologic intensification should occur promptly when LDL-C is above goal on maximally tolerated statin. 1

Do not ignore non-HDL-C and triglycerides. 1 If triglycerides ≥200 mg/dL, non-HDL-C should be <100 mg/dL for very high-risk patients. 1