Cardiovascular · PANCE / PANRE

Hyperlipidemia

Elevated LDL or triglycerides; statin therapy stratified by ACC/AHA risk groups.

Also known as: dyslipidemia, hypercholesterolemia, high cholesterol, LDL, statin

Overview

Elevated serum lipid levels — total cholesterol, LDL, or triglycerides — or low HDL. Primary modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD). Severe hypertriglyceridemia (TG ≥500 mg/dL) carries a distinct risk of acute pancreatitis.

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Risk factors

Primary (genetic):
• Familial hypercholesterolemia (FH) — most common autosomal dominant disorder; LDL often >190; tendinous xanthomas, premature ASCVD
• Familial combined hyperlipidemia, dysbetalipoproteinemia
Secondary causes:
• Hypothyroidism (always check TSH before starting statin)
• Nephrotic syndrome
• Cholestatic liver disease
• Uncontrolled diabetes (both LDL and TG)
• Alcohol use (TG ↑↑)
• Medications: thiazides, beta-blockers, atypical antipsychotics, protease inhibitors, oral estrogens

Pathophysiology

LDL particles infiltrate the arterial intima, where they undergo oxidation. Oxidized LDL is engulfed by macrophages → foam cells → fatty streaks → atherosclerotic plaque. Plaque progression narrows the lumen (stable angina) or destabilizes and ruptures (acute coronary syndrome). High TG ≥500 directly causes pancreatic ductal injury via free-fatty-acid release and chylomicronemia.

Clinical presentation

Symptoms

Almost always asymptomatic until ASCVD complication develops
Tendinous xanthomas, xanthelasma, corneal arcus (especially premature) — physical signs of severe / familial forms
Eruptive xanthomas on extensor surfaces — suggest TG >1000
Lipemic serum (milky appearance) when TG very high

Signs / physical exam

Xanthelasma (lipid deposits on eyelids)
Corneal arcus before age 45 — suspect FH
Tendinous xanthomas (Achilles, knuckle extensors) — FH
Acanthosis nigricans suggests metabolic syndrome

Differential diagnosis

Familial hypercholesterolemia (FH) — Autosomal dominant LDL >190, tendinous xanthomas, premature ASCVD family history (<55 men / <65 women); cascade screen first-degree relatives
Hypothyroidism — LDL can rise markedly and fully reverses with levothyroxine; always check TSH BEFORE starting a statin
Nephrotic syndrome — Heavy proteinuria, hypoalbuminemia, edema; treat underlying glomerular disease
Cholestatic liver disease (primary biliary cholangitis) — Elevated alkaline phosphatase, pruritus, anti-mitochondrial antibody positive
Uncontrolled diabetes mellitus — Mixed dyslipidemia (↑ TG, ↓ HDL, small dense LDL); improves with glycemic control
Alcohol use disorder — Predominantly hypertriglyceridemia; counsel reduction or cessation
Medication-induced — Thiazide diuretics, atypical antipsychotics, oral estrogens, protease inhibitors, beta-blockers (mild ↑TG, ↓HDL), corticosteroids
Anorexia nervosa — Paradoxical elevation of cholesterol in severe restrictive eating; weight restoration normalizes

Diagnostic workup

Labs

Fasting lipid panel (10-12 h fast): total cholesterol, HDL, triglycerides, calculated LDL
Non-fasting acceptable for screening (per most current guidelines) — fasting required if TG >400 or for accurate LDL calculation
TSH (rule out hypothyroidism), A1c, BMP, LFTs (baseline before statin)
ApoB or Lp(a) in selected patients (FH, recurrent ASCVD on therapy)
Calculate 10-year ASCVD risk (Pooled Cohort Equation) for patients 40-75 without ASCVD or DM

Diagnostic algorithm

Group	Population	Recommended Therapy
1	Clinical ASCVD (MI, stroke, PAD, revascularization)	HIGH-intensity statin (atorvastatin 40-80 / rosuvastatin 20-40)
2	LDL ≥190 (untreated)	HIGH-intensity statin
3	Diabetes, age 40-75, LDL 70-189	MODERATE-intensity (HIGH if multiple risk factors or 10-yr ASCVD risk ≥20%)
4	Primary prevention, age 40-75, 10-yr ASCVD risk ≥7.5%	MODERATE-to-HIGH intensity statin
—	10-yr risk 5-7.5% (borderline)	Consider statin with risk enhancers (FH+, CKD, CAC scoring, Lp(a) elevated)
—	LDL goal not met on max statin	Add ezetimibe → PCSK9 inhibitor (high-risk ASCVD)

ACC/AHA Statin Benefit Groups — the framework for deciding who needs statin therapy and at what intensity.

Treatment

First-line

Lifestyle: Mediterranean/DASH diet, reduced saturated fat (<6% calories), eliminate trans fat, exercise, weight loss, smoking cessation
Statin therapy based on ACC/AHA 4 statin benefit groups:
• Group 1 (Secondary prevention): clinical ASCVD — MI, stable angina, stroke, TIA, PAD, revascularization → HIGH-intensity statin
• Group 2 (Severe primary hyperlipidemia): LDL ≥190 → HIGH-intensity statin
• Group 3 (Diabetes): age 40-75 with diabetes → MODERATE-intensity (HIGH if multiple risk factors or ASCVD risk ≥20%)
• Group 4 (Primary prevention): age 40-75 without DM, LDL 70-189, 10-yr ASCVD risk ≥7.5% → MODERATE-to-HIGH intensity (shared decision-making 5-7.5%)
High-intensity statins: atorvastatin 40-80, rosuvastatin 20-40 (≥50% LDL reduction)
Moderate-intensity: atorvastatin 10-20, rosuvastatin 5-10, simvastatin 20-40, pravastatin 40-80 (~30-49% reduction)

Second-line / adjunct

Add-on therapies if LDL goal not met or statin-intolerant:
• Ezetimibe — first add-on, ~15-20% additional LDL drop
• PCSK9 inhibitors (evolocumab, alirocumab) — high-risk ASCVD or FH on max statin + ezetimibe
• Inclisiran (siRNA against PCSK9) — twice-yearly injection
• Bempedoic acid — statin-intolerant patients
TG-targeted therapy (TG ≥500 to prevent pancreatitis; TG 150-500 secondary after LDL goal met):
• Fibrates (fenofibrate preferred over gemfibrozil for combination with statin)
• High-dose omega-3 fatty acids (icosapent ethyl — REDUCE-IT trial showed CV benefit)
• Niacin — rarely used due to side effects (flushing, hepatotoxicity, glycemia)

Complications

Atherosclerotic cardiovascular disease (MI, stroke, PAD)
Acute pancreatitis (TG ≥500-1000)
Statin-associated muscle symptoms (mild myalgia common; true rhabdomyolysis rare)
Hepatotoxicity (mild ALT elevation common, hepatitis rare)
New-onset diabetes (small absolute risk increase, outweighed by CV benefit in most)

PANCE pearls

Check baseline LFTs and CK before starting a statin; routine surveillance LFTs are NO LONGER recommended unless symptomatic.
Statin myopathy: check CK if muscle symptoms; stop if CK >10× ULN or symptoms severe. Many patients tolerate a lower-intensity or different statin on re-challenge.
Drug interactions: statins metabolized by CYP3A4 (simvastatin, atorvastatin, lovastatin) interact with macrolides, azoles, amiodarone, grapefruit juice → ↑ rhabdo risk. Pravastatin and rosuvastatin avoid this pathway.
Lipoprotein(a) — genetically determined, not modified by lifestyle. Elevated Lp(a) is independent ASCVD risk; PCSK9 inhibitors lower it ~25%.
Familial hypercholesterolemia: cascade screen first-degree relatives. Early aggressive treatment (high-intensity statin starting in childhood/adolescence for affected family members) prevents premature ASCVD.

References

AHA/ACC 2018 — 2018 AHA/ACC Guideline on the Management of Blood Cholesterol (Grundy et al., Circulation 2019)
FOURIER — Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease (Sabatine et al., NEJM 2017)
ODYSSEY OUTCOMES — Alirocumab and Cardiovascular Outcomes after ACS (Schwartz et al., NEJM 2018)
REDUCE-IT — Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia (Bhatt et al., NEJM 2019)
Pooled Cohort Equations — 2013 ACC/AHA ASCVD Risk Calculator (Goff et al., Circulation 2014)

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