How is hyperlipidemia diagnosed and treated?

Diagnosis of Hyperlipidemia

Hyperlipidemia is diagnosed by measuring fasting lipid levels, specifically total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides, with diagnosis requiring exclusion of secondary causes and consideration of familial forms when LDL-cholesterol is markedly elevated. 1, 2

Primary Lipid Panel for Diagnosis

The essential measurements for diagnosing hyperlipidemia include:

• Total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, and calculated non-HDL cholesterol constitute the primary diagnostic panel 3
• Obtain fasting lipid levels (12-hour fast preferred) for accurate diagnosis, though non-fasting samples may be used for initial screening 1, 2
• Measure lipids on at least two separate occasions (>2 weeks but <3 months apart) to confirm the diagnosis 1, 2
• If triglycerides exceed 400 mg/dL (4.5 mmol/L), use a direct LDL-cholesterol assay rather than the Friedewald equation 2

Diagnostic Thresholds

For LDL-Cholesterol (Primary Target)

• LDL-cholesterol ≥190 mg/dL (≥4.9 mmol/L) in adults without secondary causes strongly suggests familial hypercholesterolemia (FH) and warrants family screening 2
• In children, LDL-cholesterol >190 mg/dL recorded on two occasions with parental history of high LDL-cholesterol or premature cardiovascular disease indicates highly probable FH 1
• Use age-specific, sex-specific, and country-specific thresholds above the 95th percentile for population screening 2

For Triglycerides

The Endocrine Society defines hypertriglyceridemia as:

• 150-199 mg/dL (1.7-2.3 mmol/L): mild hypertriglyceridemia 1
• 200-999 mg/dL (2.3-11.3 mmol/L): moderate hypertriglyceridemia 1
• 1,000-1,999 mg/dL (11.3-22.6 mmol/L): severe hypertriglyceridemia 1
• ≥2,000 mg/dL (≥22.6 mmol/L): very severe hypertriglyceridemia 1

Excluding Secondary Causes

Before confirming primary hyperlipidemia, rule out secondary causes through targeted testing:

• Check thyroid-stimulating hormone (TSH), liver function tests, and urinalysis to exclude hypothyroidism, liver disease, and nephrotic syndrome 1
• Evaluate for diabetes mellitus (fasting glucose or HbA1c), renal disease (creatinine, urinalysis), and pregnancy 1
• Review medications that elevate lipids: thiazide diuretics, beta-blockers, estrogen, isotretinoin, corticosteroids, bile acid-binding resins, antiretroviral protease inhibitors, immunosuppressants, and antipsychotics 1
• Assess alcohol intake (excessive consumption raises triglycerides) 1

Diagnosing Familial Hypercholesterolemia

When FH is suspected based on markedly elevated LDL-cholesterol, apply structured diagnostic criteria:

Clinical Diagnostic Criteria (Adults)

Use the Dutch Lipid Clinic Network or Simon Broome criteria, which incorporate: 1, 2

• LDL-cholesterol levels (adjusted for lipid-lowering medications if pretreatment values unavailable) 2
• Family history of premature coronary artery disease (men <55 years, women <60 years) 2
• Physical stigmata: tendon xanthomas (especially Achilles tendon), corneal arcus <45 years, xanthelasma 1

Genetic Testing for FH

Genetic testing is the most accurate diagnostic method and should be performed in all suspected FH cases: 4, 2

• Test for pathogenic variants in LDLR, APOB, PCSK9, and LDLRAP1 genes using next-generation sequencing 2
• Include analysis for deletions and duplications in LDLR 2
• Testing must occur in a certified laboratory using accredited methods 2
• Offer pre-test and post-test genetic counseling to all patients 2

Cascade Testing

After identifying a pathogenic variant in the index patient (proband), offer cascade genetic testing for that specific variant to all first-degree relatives, then sequentially to second-degree and third-degree relatives 2

Additional Diagnostic Considerations

• Measure lipoprotein(a) at least once in all patients at cardiovascular risk, as it is included in LDL-cholesterol and may explain poor statin response 3
• Adjust LDL-cholesterol values upward if patient is already on lipid-lowering therapy (statins, ezetimibe, PCSK9 inhibitors) when pretreatment values are unavailable 2
• In children at risk for heterozygous FH, screen at or after age 5 years, or as early as age 2 years with strong family history of premature cardiovascular disease 2
• Test children with suspected homozygous FH (physical stigmata or both parents with FH) as early as possible—at newborn stage or by age 2 years 2

Common Pitfalls to Avoid

• Do not rely on non-fasting samples alone for definitive diagnosis, especially when triglycerides are elevated 2
• Do not use the Friedewald equation when triglycerides exceed 400 mg/dL; obtain direct LDL-cholesterol measurement 2
• Do not dismiss FH diagnosis if genetic testing is negative; polygenic hypercholesterolemia or unidentified variants may be present 4
• Do not overlook medication adjustment factors when interpreting LDL-cholesterol in patients already on therapy 2
• Do not skip family screening when FH is diagnosed; cascade testing is highly cost-effective and identifies at-risk relatives 4

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Treatment of Hyperlipidemia

High-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) is first-line treatment for hyperlipidemia, with ezetimibe added if <50% LDL-cholesterol reduction is achieved, and PCSK9 inhibitors reserved for patients who remain above goal despite maximal statin plus ezetimibe therapy. 4, 2

Treatment Goals

LDL-Cholesterol Targets

Primary treatment goal is LDL-cholesterol reduction based on cardiovascular risk: 1, 4

• LDL-cholesterol <100 mg/dL (2.6 mmol/L) for patients with 2+ risk factors and 10-year CHD risk ≥20%, or diabetes 1
• LDL-cholesterol <70 mg/dL (1.8 mmol/L) if atherosclerotic cardiovascular disease is present 4
• LDL-cholesterol <130 mg/dL if 1 risk factor present 1
• LDL-cholesterol <160 mg/dL if 0-1 risk factors present 1

Non-HDL Cholesterol and Triglyceride Targets

• After achieving LDL-cholesterol goal, target non-HDL cholesterol 30 mg/dL higher than LDL goal in patients with triglycerides 150-199 mg/dL 1
• For triglycerides 200-499 mg/dL, treat elevated non-HDL cholesterol with lifestyle changes and consider higher statin doses or adding niacin/fibrate 1
• For triglycerides ≥500 mg/dL, initiate fibrate or niacin immediately to reduce pancreatitis risk 1

Therapeutic Lifestyle Changes (First-Line for All Patients)

Initiate dietary modifications and lifestyle interventions before or concurrent with drug therapy:

Dietary Modifications

• Reduce saturated fat to <7% of total calories 1
• Limit dietary cholesterol to <200 mg/day 1
• Eliminate trans-fatty acids 1
• Substitute with grains, unsaturated fatty acids from fish, vegetables, legumes, and nuts 1
• Add plant stanols/sterols (up to 2 g/day) and viscous soluble fiber (10-25 g/day) for additional LDL-cholesterol lowering 1
• Limit salt intake to 6 g/day 1
• Limit alcohol to 2 drinks/day in men, 1 drink/day in women among those who drink 1

Physical Activity

• At least 30 minutes of moderate-intensity physical activity on most (preferably all) days of the week 1
• Moderate-intensity activities (40-60% maximum capacity) equivalent to brisk walking (15-20 minutes per mile) 1
• Add vigorous-intensity activity (≥60% maximum capacity) for 20-40 minutes on 3-5 days/week for additional benefits 1
• Resistance training with 8-10 different exercises, 1-2 sets per exercise, 10-15 repetitions at moderate intensity twice weekly 1

Weight Management

• Reduce body weight by 10% in first year for overweight/obese persons 1
• Goal: achieve and maintain BMI 18.5-24.9 kg/m² 1
• Target waist circumference <40 inches in men, <35 inches in women when BMI ≥25 kg/m² 1

Pharmacological Treatment Algorithm

Step 1: Initiate High-Intensity Statin

Start with high-intensity statin therapy as first-line drug treatment: 4, 2

• Atorvastatin 40-80 mg daily 4, 5
• Rosuvastatin 20-40 mg daily 4
• These doses typically lower LDL-cholesterol by 50% or more 6

Monitor for adverse effects:

• Check liver transaminases before starting and as clinically indicated 5
• Persistent transaminase elevations (≥3× ULN on two occasions) occur in 0.2-2.3% depending on dose 5
• Creatine kinase elevations (≥10× ULN) occur in 0.1-0.3% 5
• Myalgia occurs in 3.5% of patients; discontinue if rhabdomyolysis suspected 5

Step 2: Add Ezetimibe if Needed

Add ezetimibe 10 mg daily if <50% LDL-cholesterol reduction or target not achieved on maximally tolerated statin: 4, 7

• Ezetimibe provides additional 15-20% LDL-cholesterol reduction 6
• Common adverse reactions (≥2% and greater than placebo) when combined with statin: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%) 7
• Monitor liver transaminases; consecutive elevations ≥3× ULN occur in 1.3% with statin combination vs 0.4% with statin alone 7

Step 3: Add PCSK9 Inhibitor if Still Above Goal

Consider PCSK9 inhibitors if LDL-cholesterol remains ≥70 mg/dL despite statin plus ezetimibe: 4

• PCSK9 inhibitors provide additional 50-60% LDL-cholesterol reduction 6
• Reserved for high-risk patients due to cost considerations 6

Alternative and Adjunct Therapies

For patients with statin intolerance or specific lipid abnormalities:

Bile Acid Sequestrants

• Consider as alternative first-line therapy if statins not tolerated 1
• Can be combined with statins for additional LDL-cholesterol lowering 1

Niacin

• Consider for low HDL-cholesterol (<40 mg/dL in men, <50 mg/dL in women) 1
• Can be combined with statins or used for triglyceride lowering (200-499 mg/dL) 1

Fibrates

• First-line therapy for severe hypertriglyceridemia (≥500 mg/dL) to reduce pancreatitis risk 1
• Consider for moderate hypertriglyceridemia (200-499 mg/dL) if non-HDL cholesterol remains elevated 1
• Caution: cholecystectomy rate 1.7% with ezetimibe plus fenofibrate combination vs 0.6% with fenofibrate alone 7

Special Considerations for Familial Hypercholesterolemia

All FH patients require aggressive cholesterol-lowering therapy regardless of current atherosclerosis status, as lifetime risk remains high: 4

• Start with high-intensity statin plus ezetimibe as initial combination therapy 4
• Add PCSK9 inhibitor if LDL-cholesterol goals not achieved 4
• For homozygous FH or treatment-resistant heterozygous FH with established ASCVD, consider lipoprotein apheresis 4
• Refer all homozygous FH patients to specialist centers for comprehensive care planning 1

Monitoring and Follow-Up

• Reassess lipid panel after 12 weeks of therapeutic lifestyle changes before initiating or intensifying drug therapy 1
• Check liver function tests and creatine kinase before starting statins and as clinically indicated 5
• Regular cardiovascular imaging (CT coronary angiography every 5 years, Doppler echocardiography annually) to assess for atherosclerosis development in FH patients 4
• Do not use coronary artery calcium scoring to monitor treatment effectiveness; use only for initial risk assessment 4

Common Pitfalls to Avoid

• Do not use statins alone for severe hypertriglyceridemia (≥500 mg/dL); fibrates are required to prevent pancreatitis 1
• Do not delay treatment in FH patients waiting for atherosclerosis to develop; earlier treatment leads to greater ASCVD event reduction 4
• Do not overlook secondary causes before intensifying lipid-lowering therapy 1
• Do not continue statin if rhabdomyolysis develops (muscle pain with CK >10× ULN and creatinine elevation) 5
• Do not ignore low HDL-cholesterol; intensify lifestyle changes and consider HDL-raising drugs (niacin, fibrates) in higher-risk patients 1