What is the management of hyperlipidemia?

Management of Hyperlipidemia

Initiate high-potency statin therapy (atorvastatin, rosuvastatin, or pitavastatin) as first-line treatment for hyperlipidemia, with LDL-C targets based on cardiovascular risk stratification: <1.4 mmol/L (<55 mg/dL) for very high-risk patients with clinical ASCVD, <1.8 mmol/L (<70 mg/dL) for high-risk patients with imaging evidence of ASCVD or major risk factors, and <2.5 mmol/L (<100 mg/dL) for moderate-risk patients without ASCVD. 1

Risk Stratification and Target Setting

Cardiovascular risk assessment drives treatment intensity:

• Very high-risk patients (clinical ASCVD, recurrent events within 2 years, multivessel coronary disease, or polyvascular disease): Target LDL-C <1.4 mmol/L (<55 mg/dL), or even <1.0 mmol/L (<40 mg/dL) for recurrent events on maximally tolerated statin therapy 1

• High-risk patients (imaging evidence of ASCVD alone, diabetes >40 years, chronic kidney disease with eGFR <60 mL/min/1.73 m² or albuminuria, chronic inflammatory conditions like rheumatoid arthritis or lupus): Target LDL-C <1.8 mmol/L (<70 mg/dL) 1

• Moderate-risk patients (absence of ASCVD but presence of other major risk factors): Target LDL-C <2.5 mmol/L (<100 mg/dL) 1

• Use SCORE risk estimation tools (preferably versions including HDL-C) for patients without established disease 1

First-Line Pharmacotherapy

Statin therapy forms the cornerstone of treatment:

• Initiate maximally tolerated high-potency statins (atorvastatin, rosuvastatin, or pitavastatin) to achieve at least 50% reduction in LDL-C 1

• Early initiation of statin therapy, even in young individuals with low absolute but high relative cardiovascular risk, provides the greatest long-term benefits through lifelong risk reduction 1

• In extremely high-risk patients (post-myocardial infarction, multivessel coronary atherosclerosis, polyvascular disease), consider combination therapy with high-potency statin + ezetimibe + PCSK9 inhibitor as first-line treatment 1

• Every 1.0 mmol/L (40 mg/dL) reduction in LDL-C associates with a 22% reduction in cardiovascular mortality and morbidity 1

Combination Therapy for Inadequate Response

When LDL-C targets are not achieved with maximally tolerated statin monotherapy:

• Add ezetimibe 10 mg daily as second-line agent, which improves cardiovascular protection without significant increase in adverse events 1, 2

  • Administer at least 2 hours before or 4 hours after bile acid sequestrants 2
  • Monitor liver enzymes and consider withdrawal if ALT/AST ≥3× ULN persist 2
  • Reassess lipid panel 4-12 weeks after initiation 2

• Add bempedoic acid (if available) for additional LDL-C lowering 1

• Add PCSK9 inhibitors (alirocumab or evolocumab, or inclisiran) if goals remain unmet despite statin + ezetimibe + bempedoic acid 1

  • These agents substantially reduce cardiovascular morbidity and are authorized for primary hyperlipidemia and secondary prevention 1

Management of Mixed Dyslipidemia and Hypertriglyceridemia

For patients with elevated triglycerides in addition to elevated LDL-C:

• Fenofibrate can reduce triglycerides by 30-50% and increase HDL cholesterol 3

  • Start at 54-160 mg daily for moderate hypertriglyceridemia 3
  • Use with caution in combination with statins due to increased myopathy risk; monitor closely for muscle symptoms and liver function 1, 3
  • Avoid in patients with autoimmune conditions due to small but reported risk of autoimmune adverse effects (thrombocytopenia, hepatitis) 1

• Icosapent ethyl is a promising treatment for hypertriglyceridemia that lowers ischemic events and cardiovascular death with good tolerability 1

• Alternative agents for triglyceride reduction include statins, ezetimibe, niacin, and omega-3 fatty acids 1

• Avoid bile acid sequestrants if triglycerides >200 mg/dL as they can further increase triglyceride levels 3

Special Populations

Familial Hypercholesterolemia (FH):

• Requires aggressive treatment with maximally tolerated high-potency statins with or without ezetimibe and/or bempedoic acid 1
• Add PCSK9-targeted therapy if LDL-C goals not achieved 1
• Consider genetic screening in specialized clinics 1
• Statins can be initiated in children aged >8 years with concerning family history or extremely elevated LDL-C or Lp(a), with informed shared decision-making 1

Nephrotic Syndrome/Glomerular Disease:

• Consider statin therapy as first-line for persistent hyperlipidemia, particularly with other cardiovascular risk factors (hypertension, diabetes) 1
• Assess ASCVD risk based on LDL-C, Apo B, triglycerides, Lp(a), age, and risk enhancers 1
• Align statin dosage intensity to ASCVD risk 1

Rheumatoid Arthritis:

• "High-risk RA" patients (seropositive, erosive disease, extra-articular manifestations, high cumulative disease activity/glucocorticoid dose) require reclassification into higher cardiovascular risk categories with lower LDL-C targets 1
• Target LDL-C <3 mmol/L (115 mg/dL) for all RA patients, <2.6 mmol/L (100 mg/dL) for many including high-risk RA, and <1.8 mmol/L (70 mg/dL) for some 1
• Rosuvastatin shows most prominent protection against acute coronary syndrome in RA patients 1

Diabetes:

• All diabetics >40 years should use statins; consider in younger diabetics with pronounced cardiovascular risk 1
• For impaired fasting glucose with hypertriglyceridemia, initiate metformin targeting HbA1c <7% to improve glucose control and triglyceride levels 3

Essential Lifestyle Modifications

Implement comprehensive lifestyle interventions as foundation of therapy:

• Dietary modifications:

  • Restrict added sugars to <6% of total daily calories 3
  • Limit total fat to 30-35% of total daily calories 3
  • Reduce saturated fat intake 3
  • Restrict dietary sodium to <2.0 g/day (<90 mmol/day) 1
  • Avoid red meat; consider plant-based diet 1

• Weight management: Target 5-10% weight loss, which can reduce triglycerides by approximately 20% 3

• Physical activity: Recommend at least 150 minutes/week of moderate-intensity or 75 minutes/week of vigorous aerobic activity 3

• Smoking cessation is imperative 1

• Alcohol moderation 4

Monitoring and Safety

Establish systematic monitoring protocols:

• Reassess fasting lipid panel 4-12 weeks after initiating or adjusting therapy, then every 3-12 months based on adherence and safety needs 1, 2

• Monitor liver enzymes (hepatic aminotransferases) at baseline and as clinically indicated; withdraw therapy if ALT/AST ≥3× ULN persist 1, 2

• Monitor creatine kinase for myopathy risk, especially with combination therapy 1, 3, 2

• Monitor glucose and creatinine levels 1

• For statin + fibrate combination, use cautiously with close monitoring for myopathy and liver function abnormalities 3, 2

Important Clinical Caveats

Avoid common pitfalls:

• Non-fasting lipid profiles can be used for monitoring stable patients, but use fasting LDL-C when making treatment decisions, especially with concomitant hypertriglyceridemia 1

• Secondary treatment goals based on non-HDL-cholesterol and apolipoprotein B may be considered, particularly in patients with hypertriglyceridemia 1

• There are no indications that drugs increasing HDL-C levels protect against cardiovascular events 1

• Plant sterols (stanols) or bile acid sequestrants (colesevelam) may be considered as adjunctive therapies if LDL-C goals not achieved, though bile acid sequestrants have high rates of gastrointestinal side effects 1, 2

• Counsel patients to hold ACE inhibitors/ARBs and diuretics during sick days when at risk for volume depletion (relevant for patients with concurrent hypertension) 1

• Proactive approach to diagnosing cardiovascular disease is critical in high-risk populations; ultrasonographic detection of carotid plaques can facilitate determining very-high cardiovascular risk 1