What are the treatment options for high cholesterol?

Treatment Options for High Cholesterol

Start all patients with therapeutic lifestyle changes (TLC) including dietary modifications (<7% saturated fat, <200 mg/day cholesterol, 10-25 g/day fiber) and regular physical activity, then add high-potency statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) if LDL-cholesterol goals are not achieved after 12 weeks, with ezetimibe as the next addition if targets remain unmet. 1, 2

Risk-Based LDL-Cholesterol Treatment Goals

Your treatment intensity depends on cardiovascular risk stratification 1:

• High-risk patients (established coronary heart disease or risk equivalents): LDL-C goal <100 mg/dL 3, 1
• Very high-risk patients (acute coronary syndrome, multiple risk factors): LDL-C goal <70 mg/dL 3, 1
• Familial hypercholesterolemia with clinical atherosclerotic cardiovascular disease: LDL-C goal <1.4 mmol/L (<55 mg/dL) 3
• Recurrent cardiovascular events within 2 years on maximal statin: Consider LDL-C goal <1.0 mmol/L (<40 mg/dL) 3

Step 1: Therapeutic Lifestyle Changes (First-Line for All Patients)

Initiate TLC immediately in all patients with elevated LDL-cholesterol 3, 1:

• Dietary modifications 3, 1:

  • Reduce saturated fat to <7% of total daily calories
  • Limit dietary cholesterol to <200 mg/day
  • Increase viscous fiber intake to 10-25 g/day
  • Increase omega-3 fatty acid consumption

• Physical activity: Minimum 30-60 minutes daily or at least 3-4 times weekly 3, 1

• Weight management: Target BMI 18.5-24.9 kg/m² 3

Critical pitfall: Only 20% of patients with hypercholesterolemia successfully comply with Step II dietary recommendations in real-world settings 4. Do not delay pharmacological therapy beyond 12 weeks if lifestyle changes alone are insufficient 1.

Step 2: High-Potency Statin Therapy (Primary Pharmacological Treatment)

If LDL-cholesterol goals are not achieved after 12 weeks of TLC, initiate statin therapy 1, 2:

• Preferred agents: Atorvastatin 40-80 mg or rosuvastatin 20-40 mg 3, 2
• Target reduction: At least 30-40% reduction in LDL-C, with high-potency statins achieving ≥50% reduction 1, 2

For combined hyperlipidemia (elevated LDL-C >100 mg/dL AND triglycerides >150 mg/dL): Start immediately with atorvastatin 40 mg or rosuvastatin 20 mg without delaying for lifestyle changes alone 2. Higher-dose statins provide dual benefit by lowering both LDL-cholesterol and triglycerides 2.

Monitoring requirements 3:

• Measure hepatic aminotransferases before starting therapy
• Monitor creatine kinase if musculoskeletal symptoms develop
• Recheck lipid panel at 4-12 weeks, then every 6-12 months once goals achieved

Step 3: Add Ezetimibe (Second-Line Addition)

If LDL-cholesterol goals remain unmet on maximally tolerated statin therapy, add ezetimibe 10 mg daily 3, 5:

• FDA-approved indications: Combination with statin for primary hyperlipidemia and heterozygous familial hypercholesterolemia 5
• Mechanism: Inhibits intestinal cholesterol absorption, providing additional 15-20% LDL-C reduction 5
• Pediatric use: Approved for patients ≥10 years old with familial hypercholesterolemia 5

Step 4: PCSK9 Inhibitors (Third-Line for Refractory Cases)

Add PCSK9-targeted therapy (monoclonal antibodies or inclisiran) if LDL-cholesterol goals are not achieved with maximally tolerated statin plus ezetimibe 3:

• Indications: Patients with extremely high-risk (post-myocardial infarction, multivessel coronary disease, polyvascular disease) may require combination statin + ezetimibe + PCSK9 inhibitor as first-line treatment 3

Step 5: Additional Adjunctive Therapies

If further LDL-cholesterol lowering is needed 3:

• Bempedoic acid: Can be added to statin ± ezetimibe 3
• Bile acid sequestrants (colesevelam): May be considered as adjunctive therapy 3
• Plant sterols/stanols: May provide modest additional benefit 3

Special Population: Isolated Hypertriglyceridemia (Normal LDL-C, Elevated Triglycerides)

For triglycerides 200-499 mg/dL with normal LDL-cholesterol 3, 6, 7:

1. First: Optimize therapeutic lifestyle changes for 12 weeks (reduce saturated fat, limit alcohol to ≤2 drinks/day men or ≤1 drink/day women, increase physical activity) 6

2. Second: If triglycerides remain elevated, add fenofibrate as preferred first-line pharmacological therapy 6, 7

3. Alternative: Niacin can be considered, but use with caution in diabetic patients 6

Emergency threshold: If triglycerides exceed 500 mg/dL, initiate immediate pharmacological treatment with fibrate or niacin to reduce pancreatitis risk 3, 6

Critical pitfall: Avoid gemfibrozil in combination with any statin due to significantly increased myopathy risk; fenofibrate is safer for combination therapy 2.

Special Population: Familial Hypercholesterolemia

For heterozygous familial hypercholesterolemia 3:

• Start with maximally tolerated high-potency statin + ezetimibe + bempedoic acid (if available) 3
• Add PCSK9 inhibitor if goals not achieved 3
• Consider lipoprotein apheresis for progressive atherosclerotic cardiovascular disease despite maximal medical therapy 3

For homozygous familial hypercholesterolemia 3:

• Lipoprotein apheresis should be undertaken in children (≥3 years) and adults who do not achieve guideline-recommended LDL-cholesterol goals despite maximally tolerated combination drug therapy 3

Monitoring and Ongoing Management

• Lipid panel reassessment: At 4-12 weeks after initiating or adjusting therapy, then every 6-12 months once stable 2
• Non-fasting lipid profiles: Acceptable for monitoring stable patients, but use fasting LDL-cholesterol when making treatment decisions, especially with concomitant hypertriglyceridemia 3
• Continue therapy during acute illness: Maintain cholesterol-lowering medications during respiratory infections (including COVID-19) unless specifically contraindicated 3