What are the current evidence‑based guidelines for managing dyslipidemia, including lifestyle modification, risk assessment, statin therapy, and use of non‑statin agents?

Dyslipidemia Treatment Guidelines

Lifestyle Modifications: Foundation of All Therapy

All patients with dyslipidemia should implement aggressive lifestyle modifications immediately, as these interventions provide additive lipid-lowering effects and reduce cardiovascular risk independent of pharmacotherapy. 1

Dietary Interventions

• Restrict saturated fat to <7% of total calories and trans fat to <1% of total calories, replacing with monounsaturated or polyunsaturated fats 1
• Limit dietary cholesterol to <200 mg/day to reduce LDL-C 1
• Increase soluble fiber to >10 g/day from sources like oats, beans, and vegetables, which lowers LDL-C by binding bile acids 1, 2
• Add plant stanols/sterols 2 g/day, which can reduce LDL-C by 6-15% through competitive inhibition of cholesterol absorption 2, 3
• Consume ≥2 servings per week of fatty fish (salmon, sardines, mackerel) rich in omega-3 fatty acids to reduce triglycerides 2, 4
• Restrict added sugars to <6% of total daily calories for patients with elevated triglycerides, as sugar intake directly increases hepatic triglyceride production 2, 4

Weight Management and Physical Activity

• Target 5-10% body weight reduction in overweight patients, which produces approximately 20% decrease in triglycerides and improves LDL-C 2, 4
• Engage in ≥150 minutes/week of moderate-intensity aerobic activity (or 75 minutes/week vigorous activity), which reduces triglycerides by ~11% and raises HDL-C by 5-14% 1, 2
• Limit or eliminate alcohol consumption, particularly in patients with triglycerides >200 mg/dL, as even 1 ounce daily increases triglycerides by 5-10% 2, 4

Risk Assessment and Screening

Measure fasting lipid profile at least annually in most adult patients; in adults with low-risk values (LDL-C <100 mg/dL, HDL-C >50 mg/dL, triglycerides <150 mg/dL), reassess every 2 years. 1

Risk Stratification for Treatment Decisions

• Calculate 10-year ASCVD risk using pooled cohort equations for patients aged 40-75 years without established ASCVD 1
• Identify risk-enhancing factors including family history of premature ASCVD, chronic kidney disease, metabolic syndrome, persistently elevated triglycerides ≥175 mg/dL, and inflammatory conditions 1
• Consider coronary artery calcium (CAC) scoring when risk-based treatment decision is uncertain (intermediate risk 7.5-19.9%), as CAC=0 may favor deferring statin therapy while CAC≥100 favors initiation 1
• Suspect familial hypercholesterolemia (FH) when LDL-C exceeds 190 mg/dL in adults, particularly with family history or tendon xanthomas; genetic testing or Dutch Lipid Clinic Network score should be used for diagnosis 1, 2

Statin Therapy: First-Line Pharmacologic Treatment

Statin therapy should be added to lifestyle modifications as first-line pharmacologic treatment for most patients with dyslipidemia, as statins provide the strongest evidence for reducing cardiovascular events and mortality. 1

Indications for Statin Therapy

• Patients with clinical ASCVD (secondary prevention): high-intensity statin therapy regardless of baseline LDL-C 1
• LDL-C ≥190 mg/dL (primary prevention): high-intensity statin therapy to achieve ≥50% LDL-C reduction 1, 2
• Diabetes mellitus aged 40-75 years: moderate-to-high intensity statin therapy regardless of baseline LDL-C 1
• 10-year ASCVD risk ≥7.5% (aged 40-75 years): moderate-to-high intensity statin therapy after clinician-patient discussion 1
• 10-year ASCVD risk 5-7.5% with risk-enhancing factors: consider moderate-intensity statin after shared decision-making 1

Statin Intensity Classification

• High-intensity statins (≥50% LDL-C reduction): atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily 1, 2
• Moderate-intensity statins (30-49% LDL-C reduction): atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg, pravastatin 40-80 mg daily 1

LDL-C Treatment Goals

• Primary prevention without ASCVD: LDL-C <100 mg/dL with at least 30% reduction from baseline 1
• Established ASCVD or very high risk: LDL-C <70 mg/dL (or <55 mg/dL for very high-risk European patients) with ≥50% reduction from baseline 1, 2
• Use adequate statin dose to achieve both percentage reduction and absolute LDL-C target 1

Critical Monitoring and Safety

• Monitor hepatic aminotransferases at baseline and periodically during therapy, though routine monitoring is no longer mandated 1
• Assess for muscle symptoms at each visit; obtain creatine kinase only if symptomatic 1, 2
• Do not delay statin initiation while attempting lifestyle modifications alone in high-risk patients—both should proceed concurrently 2, 4

Non-Statin Lipid-Lowering Agents

Ezetimibe: Second-Line for LDL-C Lowering

If LDL-C remains ≥70 mg/dL on maximally tolerated statin therapy in high-risk patients, add ezetimibe 10 mg daily, which provides additional 13-20% LDL-C reduction and has proven cardiovascular benefit. 1, 2

• Ezetimibe inhibits intestinal cholesterol absorption at the NPC1L1 transporter 5
• The IMPROVE-IT trial demonstrated cardiovascular event reduction when ezetimibe was added to simvastatin post-ACS 5
• Ezetimibe is well-tolerated with minimal adverse effects and no significant drug interactions 5

PCSK9 Inhibitors: For Very High-Risk or Statin-Intolerant Patients

For patients at very high cardiovascular risk who fail to achieve LDL-C goals despite maximally tolerated statin plus ezetimibe, or for statin-intolerant patients, PCSK9 inhibitors provide an additional 50-60% LDL-C reduction. 1, 2

• Evolocumab and alirocumab are monoclonal antibodies administered subcutaneously every 2 weeks 2
• Inclisiran is a small interfering RNA (siRNA) administered subcutaneously every 6 months after initial loading doses, providing ~50% LDL-C reduction 5
• PCSK9 inhibitors demonstrated cardiovascular event reduction in the FOURIER and ODYSSEY OUTCOMES trials 2

Bempedoic Acid: Alternative for Statin-Intolerant Patients

Bempedoic acid 180 mg daily can be added to maximally tolerated statin therapy or used as monotherapy in statin-intolerant patients, providing ~20% LDL-C reduction without muscle-related adverse effects. 5

• Bempedoic acid inhibits ATP citrate lyase upstream of HMG-CoA reductase but is only activated in the liver, not muscle 5
• Approved for primary hypercholesterolemia, mixed dyslipidemia, heterozygous FH, and patients with ASCVD requiring additional LDL-C lowering 5
• Monitor for hyperuricemia and gout, as bempedoic acid can increase uric acid levels 5

Bile Acid Sequestrants: Limited Use Due to Tolerability

Bile acid sequestrants (cholestyramine, colesevelam, colestipol) lower LDL-C by 15-30% but have limited use due to gastrointestinal side effects; they may be considered for statin-intolerant patients or as add-on therapy. 1, 5

• Contraindicated when triglycerides >200 mg/dL, as they can worsen hypertriglyceridemia 1, 4
• Multiple drug interactions require careful timing of other medications 1

Triglyceride Management

Classification and Treatment Thresholds

• Normal: <150 mg/dL 4
• Mild elevation: 150-199 mg/dL (cardiovascular risk-enhancing factor) 4
• Moderate elevation: 200-499 mg/dL (increased cardiovascular risk) 1, 4
• Severe elevation: 500-999 mg/dL (pancreatitis risk ~14%) 4
• Very severe elevation: ≥1000 mg/dL (high pancreatitis risk) 4

Triglyceride-Specific Lifestyle Modifications

• For moderate hypertriglyceridemia (200-499 mg/dL): restrict added sugars to <6% of calories, limit total fat to 30-35% of calories 4
• For severe hypertriglyceridemia (500-999 mg/dL): restrict fat to 20-25% of calories, eliminate all added sugars and alcohol completely 4
• For very severe hypertriglyceridemia (≥1000 mg/dL): implement very low-fat diet (10-15% of calories) until triglycerides <1000 mg/dL 4

Fibrates: First-Line for Severe Hypertriglyceridemia

For triglycerides ≥500 mg/dL, initiate fenofibrate 54-160 mg daily immediately as first-line therapy before addressing LDL-C, to prevent acute pancreatitis; fibrates provide 30-50% triglyceride reduction. 1, 4

• Fenofibrate is preferred over gemfibrozil when combining with statins, as fenofibrate has significantly lower myopathy risk because it does not inhibit statin glucuronidation 4
• Adjust fenofibrate dose based on renal function: contraindicated if eGFR <30 mL/min/1.73m², maximum 54 mg daily if eGFR 30-59 mL/min/1.73m² 4
• Monitor renal function within 3 months after initiation and every 6 months thereafter 4
• For moderate hypertriglyceridemia (200-499 mg/dL), consider fenofibrate only after 3 months of optimized lifestyle modifications and statin therapy if triglycerides remain elevated 4

Prescription Omega-3 Fatty Acids: Cardiovascular Risk Reduction

Icosapent ethyl (purified EPA) 2 g twice daily is indicated as adjunct to maximally tolerated statin therapy for patients with triglycerides ≥150 mg/dL who have established ASCVD or diabetes with ≥2 additional cardiovascular risk factors; the REDUCE-IT trial demonstrated 25% reduction in major adverse cardiovascular events. 4

• Icosapent ethyl is the only triglyceride-lowering therapy FDA-approved for cardiovascular risk reduction, distinct from other omega-3 formulations 4
• Monitor for increased risk of atrial fibrillation (3.1% vs 2.1% on placebo) 4
• Over-the-counter fish oil supplements are NOT equivalent to prescription formulations and should not be substituted 4
• Mixed EPA/DHA formulations (omega-3 acid ethyl esters, omega-3 carboxylic acid) are FDA-approved only for severe hypertriglyceridemia (≥500 mg/dL) as adjunct to diet, not for cardiovascular risk reduction 4

Non-HDL-C as Secondary Target

When triglycerides are 200-499 mg/dL, calculate non-HDL-C (total cholesterol minus HDL-C) with a target goal of <130 mg/dL (or <100 mg/dL for very high-risk patients). 1, 4

Special Populations

Diabetes Mellitus

All diabetic patients aged 40-75 years should receive at least moderate-intensity statin therapy regardless of baseline LDL-C; those with 10-year ASCVD risk ≥20% or multiple risk factors should receive high-intensity statin therapy. 1

• Optimize glycemic control as priority in diabetic patients with severe hypertriglyceridemia, as poor glucose control is often the primary driver; improving HbA1c can reduce triglycerides by 20-50% independent of lipid medications 4
• For diabetic patients aged 20-39 years with additional ASCVD risk factors (family history, albuminuria, smoking, hypertension), consider moderate-intensity statin therapy 1

Chronic Kidney Disease

Initiate lipid-lowering therapy for CKD stages 3-5 (not on dialysis); do NOT initiate statins in dialysis-dependent patients. 1

• Use statins as first-line therapy in non-dialysis CKD patients 1
• Consider non-statin therapy for statin-intolerant patients or those at high ASCVD risk not achieving goals on maximally tolerated statin 1

Older Adults

For patients >75 years (or ≥70 years per European guidelines), primary prevention with statins may be considered if high-risk category or above, after clinical assessment and risk discussion. 1

• Continue statin therapy in older adults already on treatment with good tolerability 1
• Use lower statin doses when combining with fibrates in elderly patients to minimize myopathy risk 4

Pregnancy

ACE inhibitors and ARBs are contraindicated during pregnancy; for pregnant patients with chronic hypertension, target BP 110-129/65-79 mmHg using methyldopa, labetalol, diltiazem, clonidine, or prazosin. 1

• Statins are contraindicated in pregnancy; discontinue before conception 1

Common Pitfalls and Caveats

• Do NOT reduce or discontinue statins in favor of fibrate monotherapy for patients with cardiovascular risk, as statins provide proven mortality benefit through LDL-C reduction 4
• Do NOT start with statin monotherapy when triglycerides ≥500 mg/dL, as statins provide only 10-30% triglyceride reduction—insufficient for preventing pancreatitis; initiate fibrates first 4
• Do NOT use gemfibrozil when combining with statins due to significantly higher myopathy risk; use fenofibrate instead 4
• Do NOT use over-the-counter fish oil supplements expecting cardiovascular benefit equivalent to prescription icosapent ethyl 4
• Do NOT ignore secondary causes of dyslipidemia (uncontrolled diabetes, hypothyroidism, nephrotic syndrome, medications) before initiating or intensifying lipid-lowering therapy 4
• Do NOT use bile acid sequestrants when triglycerides >200 mg/dL, as they worsen hypertriglyceridemia 1, 4
• When combining statin with fibrate, use lower statin doses (e.g., atorvastatin 10-20 mg maximum) to minimize myopathy risk, particularly in patients >65 years or with renal disease 4