What is the recommended treatment for an adult without known atherosclerotic cardiovascular disease who has elevated LDL cholesterol (LDL‑C ≥190 mg/dL or 10‑year ASCVD risk ≥7.5%)?

Treatment of Elevated LDL Cholesterol in Adults Without Known ASCVD

For adults with LDL-C ≥190 mg/dL, initiate high-intensity statin therapy immediately without risk calculation; for those with 10-year ASCVD risk ≥7.5%, begin moderate-intensity statin therapy after 3-6 months of intensive lifestyle modification. 1, 2

Immediate High-Intensity Statin Therapy (LDL-C ≥190 mg/dL)

Patients with LDL-C ≥190 mg/dL require immediate high-intensity statin therapy without prior risk assessment or lifestyle trial. 1, 2 This threshold identifies likely familial hypercholesterolemia and represents a lifetime of elevated ASCVD risk that warrants aggressive pharmacotherapy. 1

High-Intensity Statin Options:

• Atorvastatin 40-80 mg daily (achieves ≥50% LDL-C reduction) 1
• Rosuvastatin 20-40 mg daily (achieves ≥50% LDL-C reduction) 1

When High-Intensity Statin Alone Is Insufficient:

If <50% LDL-C reduction is achieved on maximally tolerated high-intensity statin, add ezetimibe 10 mg daily as the preferred second agent. 1 Ezetimibe provides an additional 15-20% LDL-C lowering with excellent safety and tolerability. 1

PCSK9 inhibitors should be reserved only for patients who remain at very high risk despite maximally tolerated statin plus ezetimibe, as cost-effectiveness data in primary prevention remain limited. 1

Risk-Based Statin Therapy (10-Year ASCVD Risk ≥7.5%)

Step 1: Calculate 10-Year ASCVD Risk

Use the ACC/AHA Pooled Cohort Equations incorporating: age, sex, race, total cholesterol, HDL-C, systolic blood pressure, antihypertensive medication use, diabetes status, and smoking status. 2

Step 2: Intensive Lifestyle Modification (3-6 Months)

Before initiating statin therapy in primary prevention, implement intensive lifestyle changes for 3-6 months: 2

• Saturated fat <7% of total calories 3, 2, 4
• Dietary cholesterol <200 mg/day 3, 2, 4
• Soluble fiber 10-25 g/day (oats, beans, psyllium) 3, 2, 4
• Plant stanols/sterols up to 2 g/day 2
• Aerobic exercise ≥150 minutes/week of moderate intensity 3, 2, 4
• Resistance training 2 days/week (8-10 exercises, 10-15 repetitions) 2
• Weight loss ≥10% body weight if BMI ≥30 kg/m² 2

Step 3: Reassess After Lifestyle Trial

Recalculate 10-year ASCVD risk and lipid profile after 3-6 months. 2 If risk remains ≥7.5%, proceed with statin therapy. 2

Step 4: Initiate Moderate-Intensity Statin

Start moderate-intensity statin therapy aiming for 30-40% LDL-C reduction: 1, 3, 2

• Atorvastatin 10-20 mg daily 1, 3
• Rosuvastatin 5-10 mg daily 1, 3

Step 5: Assess Response and Consider Intensification

Recheck lipid profile 4-12 weeks after statin initiation. 3, 4

If <30% LDL-C reduction is achieved (or LDL-C remains ≥100 mg/dL): 1

1. Assess adherence (number of missed doses per month) 1
2. Intensify lifestyle modifications 1
3. Evaluate for secondary causes (hypothyroidism, nephrotic syndrome, cholestatic liver disease) 1
4. Increase to high-intensity statin if tolerated 1

If <50% LDL-C reduction on high-intensity statin (or LDL-C ≥70 mg/dL) in patients with high-risk markers, consider adding ezetimibe 10 mg daily. 1

High-Risk Markers That Favor More Aggressive Therapy

In primary prevention patients with 10-year ASCVD risk ≥7.5%, the following markers support consideration of combination therapy: 1

• 10-year ASCVD risk ≥20% 1
• Baseline LDL-C ≥160 mg/dL 1
• Family history of premature ASCVD (men <55 years, women <65 years) 1, 2
• Elevated lipoprotein(a) 1
• Coronary artery calcium score ≥100 Agatston units or ≥75th percentile for age/sex 1, 2
• High-sensitivity CRP ≥2.0 mg/L 1
• Chronic kidney disease 1
• Chronic inflammatory disorders (rheumatoid arthritis, psoriasis, HIV) 1

Role of Coronary Artery Calcium Scoring

For patients with borderline risk (5% to <7.5%) or intermediate risk (7.5% to <20%) where treatment decisions remain uncertain after lifestyle modification, CAC scoring is reasonable: 1, 2

• CAC = 0 Agatston units: Defer statin therapy; reassess in 3-5 years (unless diabetes, active smoking, or strong family history present) 1, 2
• CAC 1-99 AU and <75th percentile: Moderate-intensity statin reasonable 1
• CAC ≥100 AU or ≥75th percentile: Moderate- to high-intensity statin recommended 1, 2

Do not obtain CAC in patients with <5% risk (low yield) or >20% risk (will not change management). 1

Special Populations

Patients with Diabetes (Age 40-75 Years)

All patients with diabetes aged 40-75 years and LDL-C 70-189 mg/dL should receive at least moderate-intensity statin therapy regardless of calculated ASCVD risk. 1, 2 Diabetes is considered a coronary heart disease risk equivalent. 1

If <50% LDL-C reduction or LDL-C ≥100 mg/dL on maximally tolerated statin, consider adding ezetimibe 10 mg daily. 1 Although outcome data for ezetimibe in primary prevention with diabetes are limited, the safety profile and additional LDL-C lowering support its use. 1

Patients >75 Years of Age

Initiation of statin therapy for primary prevention in adults >75 years requires careful consideration of: 1

• Competing risks for non-cardiovascular death 1
• Patient frailty and functional status 1
• Polypharmacy and drug-drug interactions 1
• Patient goals and preferences 1

Evidence supporting statin initiation for primary prevention in this age group is limited. 1 However, continuation of statins in patients already tolerating therapy is supported. 1

Critical Pitfalls to Avoid

Do not prescribe statins as a substitute for lifestyle modification in lower-risk patients. 2 Lifestyle changes initiated at younger ages have greater long-term benefit than delayed pharmacotherapy. 2

Do not add nonstatin therapy routinely in primary prevention without first maximizing statin intensity and ensuring adherence. 1 The incremental benefit of combination therapy in primary prevention is modest and cost-effectiveness is limited. 1

Do not use PCSK9 inhibitors in primary prevention except in rare circumstances (e.g., severe familial hypercholesterolemia unresponsive to statin plus ezetimibe). 1 Efficacy data and cost-effectiveness in primary prevention are insufficient. 1

Do not routinely add bile acid sequestrants, fibrates, or niacin to statins in primary prevention. 1 No randomized controlled trial data support ASCVD event reduction from these combinations in primary prevention. 1

Evaluate and document statin intolerance systematically before labeling a patient as statin-intolerant. 1 Consider referral to a lipid specialist for patients unable to tolerate even low-dose statin therapy. 1

Monitoring Strategy

Reassess lipid profile and adherence every 3-6 months initially, then annually once stable. 3, 4 Monitor for statin-related adverse effects including myalgias, elevated liver enzymes, and new-onset diabetes. 1

Recalculate 10-year ASCVD risk every 4-6 years, as risk increases with age and may eventually warrant therapy initiation or intensification. 2