How should I evaluate and treat hypercholesterolemia in an adult with LDL‑C ≥190 mg/dL and no known atherosclerotic cardiovascular disease?

Evaluation and Treatment of LDL-C ≥190 mg/dL Without Known ASCVD

Initiate high-intensity statin therapy immediately without delay—this patient has severe primary hypercholesterolemia conferring a lifetime ASCVD risk equivalent to established cardiovascular disease, and treatment should begin at diagnosis regardless of calculated 10-year risk. 1

Initial Evaluation

Rule out secondary causes before confirming primary hypercholesterolemia:

• Obtain a repeat fasting lipid panel to confirm LDL-C ≥190 mg/dL on two separate occasions 1
• Screen for hypothyroidism (TSH, free T4), chronic kidney disease (creatinine, eGFR), nephrotic syndrome (urinalysis for proteinuria), obstructive liver disease (liver function tests), and poorly controlled diabetes (HbA1c, fasting glucose) 1
• Review medications that elevate LDL-C: diuretics, cyclosporine, glucocorticoids, amiodarone 1
• Assess for familial hypercholesterolemia (FH) by evaluating family history of premature ASCVD (onset <55 years in male first-degree relatives or <65 years in female first-degree relatives), presence of tendon xanthomas, and corneal arcus before age 45 1

Immediate Pharmacologic Management

Start high-intensity statin therapy at diagnosis:

• Atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily to achieve ≥50% LDL-C reduction from baseline 1
• The treatment goal is ≥50% LDL-C reduction, with an optimal achieved LDL-C <100 mg/dL 1
• Do not calculate 10-year ASCVD risk—patients with LDL-C ≥190 mg/dL require treatment based on their markedly elevated lifetime risk regardless of short-term risk estimates 1

Baseline safety monitoring before statin initiation:

• Obtain ALT, AST (liver enzymes), creatine kinase (CK), and creatinine 1
• Routine monitoring of ALT or CK during therapy is not recommended unless the patient develops symptoms 1

Lifestyle Modification (Concurrent with Statin Therapy)

Implement intensive dietary and lifestyle changes simultaneously—not as a prerequisite to medication:

• Saturated fat <7% of total calories and dietary cholesterol <200 mg/day 1
• Add 10-25 g/day soluble fiber and 2 g/day plant stanols/sterols for additional 5-15% LDL-C reduction 1, 2
• ≥150 minutes/week moderate-intensity aerobic exercise (e.g., brisk walking) 2, 3
• Achieve and maintain healthy body weight if overweight or obese 1

Follow-Up and Treatment Intensification

Reassess response 4-12 weeks after statin initiation:

• Obtain fasting lipid panel to assess LDL-C reduction 1
• Expected response: ≥50% LDL-C reduction with high-intensity statin 1
• If adherence is confirmed but LDL-C reduction is <50% or LDL-C remains ≥100 mg/dL, add ezetimibe 10 mg daily for an additional 15-20% LDL-C reduction 1

For patients with confirmed or suspected FH and LDL-C ≥100 mg/dL despite maximally-tolerated statin plus ezetimibe:

• Consider adding a PCSK9 inhibitor (evolocumab 140 mg subcutaneously every 2 weeks or 420 mg monthly; alirocumab 75-150 mg subcutaneously every 2 weeks) for an additional 50-60% LDL-C reduction 1, 4
• PCSK9 inhibitors are particularly indicated if the patient has clinical or genetic confirmation of heterozygous FH 1

Alternative non-statin option if statins are not tolerated:

• Bile acid sequestrants (cholestyramine 4-24 g/day) can reduce LDL-C by 15-30% but are less effective than statins and have significant gastrointestinal side effects 5
• Use only if triglycerides <300 mg/dL, as bile acid sequestrants can worsen hypertriglyceridemia 5

Ongoing Monitoring Strategy

Long-term follow-up schedule:

• Reassess lipid panel and adherence every 3-12 months once stable on therapy 1
• Continue to reinforce lifestyle modifications and address other cardiovascular risk factors (blood pressure, smoking cessation, diabetes management) at each visit 1
• Screen for statin-associated muscle symptoms (myalgia, weakness, dark urine) at every encounter—occurs in 5-10% of patients 2
• Monitor for new-onset diabetes in patients on high-intensity statins (approximately 0.3 excess cases per 100 treated patients per year), but recognize that ASCVD risk reduction far outweighs this risk 1

Family Screening

Cascade screening is essential:

• Measure lipid panels in all first-degree relatives (parents, siblings, children) because FH is inherited in an autosomal dominant pattern with 50% transmission risk 1, 6
• Children of a parent with confirmed FH should be screened by age 8-10 years and offered treatment if LDL-C >190 mg/dL 1

Critical Pitfalls to Avoid

• Do not delay statin therapy to attempt lifestyle modification alone—patients with LDL-C ≥190 mg/dL have been exposed to severely elevated cholesterol since birth and require immediate pharmacologic intervention 1
• Do not use 10-year ASCVD risk calculators to decide on treatment—these patients are automatically high-risk based on LDL-C alone 1
• Do not accept LDL-C >100 mg/dL as adequate in patients with genetic hypercholesterolemia—intensify therapy with ezetimibe and consider PCSK9 inhibitors 1
• Do not overlook secondary causes—hypothyroidism, nephrotic syndrome, and medications can masquerade as primary hypercholesterolemia and require different management 1