Cardiovascular · PANCE / PANRE

Hyperlipidemia

Written & clinically reviewed by Ryan Busch, PA-C · Updated August 2026 · Report an error

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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Question 1CardiovascularEasy
A 60-year-old man started rosuvastatin 40 mg daily. At 3 months he reports bilateral thigh and calf muscle aches with weakness. Creatine kinase (CK) is 4,800 U/L (reference <200 U/L). Which of the following is the most appropriate next step?
  • AReduce rosuvastatin to 10 mg daily
  • BDiscontinue rosuvastatin promptly
  • CAdd coenzyme Q10 supplementation
  • DSwitch immediately to pravastatin
Reveal answer & full explanation
Correct answer: B — Discontinue rosuvastatin promptly
  • AReduce rosuvastatin to 10 mg daily
  • BDiscontinue rosuvastatin promptly✓
  • CAdd coenzyme Q10 supplementation
  • DSwitch immediately to pravastatin

Why Discontinue rosuvastatin promptly is correct

  • Statin-associated myopathy with a CK greater than 10 times the upper limit of normal (here ~24×) plus muscle symptoms mandates stopping the statin immediately to prevent progression to rhabdomyolysis, myoglobinuria, and acute kidney injury
  • After stopping, hydrate and trend CK and renal function until CK normalizes; check TSH because hypothyroidism predisposes to statin myopathy
  • A lower-myopathy-risk statin (e.g., pravastatin) may be cautiously reintroduced once CK has normalized

Why the others are wrong

  • Reduce rosuvastatin to 10 mg daily — dose reduction is a reasonable strategy for tolerable myalgias with a normal or minimally elevated CK, but CK >10× ULN with weakness requires stopping the drug entirely and trending CK and renal function (right-strategy-wrong-severity)
  • Add coenzyme Q10 supplementation — CoQ10 is not an evidence-based treatment for statin myopathy and does not remove the offending drug (buzzword-matching myalgia to a supplement)
  • Switch immediately to pravastatin — any rechallenge must wait until CK normalizes and renal function is confirmed stable; switching now perpetuates exposure during active myopathy (right-idea-wrong-timing)
Question 2CardiovascularEasy
A 65-year-old man with stable coronary artery disease (CAD) is taking maximally tolerated atorvastatin 80 mg daily for secondary prevention, with a treatment goal of LDL cholesterol below 70 mg/dL. His current LDL cholesterol is 118 mg/dL, and he asks about additional LDL-lowering therapy. Which of the following is the most appropriate next step in management?
  • AAdd PCSK9 inhibitor therapy
  • BSwitch to pravastatin 80 mg
  • CAdd niacin 1000 mg daily
  • DAdd ezetimibe 10 mg daily
Reveal answer & full explanation
Correct answer: D — Add ezetimibe 10 mg daily
  • AAdd PCSK9 inhibitor therapy
  • BSwitch to pravastatin 80 mg
  • CAdd niacin 1000 mg daily
  • DAdd ezetimibe 10 mg daily✓

Why Add ezetimibe 10 mg daily is correct

  • Secondary prevention LDL target is <70 mg/dL (ideally <55 mg/dL for very high risk)
  • After a maximally tolerated high-intensity statin (atorvastatin 80 mg or rosuvastatin 40 mg), the next step is to add ezetimibe
  • Ezetimibe provides a 15-25% LDL reduction and reduces cardiovascular (CV) events (IMPROVE-IT trial), per current ACC/AHA cholesterol guidance

Why the others are wrong

  • Add PCSK9 inhibitor therapy — A proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (evolocumab, alirocumab) is added if LDL remains above goal after ezetimibe (FOURIER, ODYSSEY trials); it is the third step, not the second (right-drug-wrong-step)
  • Switch to pravastatin 80 mg — Pravastatin 80 mg is moderate-intensity and would represent a step down from high-intensity atorvastatin 80 mg (premature closure on 'just change the statin')
  • Add niacin 1000 mg daily — Niacin does not reduce CV events when added to statins (AIM-HIGH, HPS2-THRIVE trials) and is no longer recommended (outdated-practice trap)
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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

GroupPopulationRecommended Therapy
1Clinical ASCVD (MI, stroke, PAD, revascularization)HIGH-intensity statin (atorvastatin 40-80 / rosuvastatin 20-40)
2LDL ≥190 (untreated)HIGH-intensity statin
3Diabetes, age 40-75, LDL 70-189MODERATE-intensity (HIGH if multiple risk factors or 10-yr ASCVD risk ≥20%)
4Primary 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 statinAdd 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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Related Cardiovascular diagnoses

Acute Coronary Syndrome (ACS)Stable AnginaHeart Failure with Reduced Ejection Fraction (HFrEF)Heart Failure with Preserved Ejection Fraction (HFpEF)Atrial FibrillationAtrial FlutterHypertensionAortic StenosisMitral RegurgitationAortic Regurgitation (AR)Mitral Stenosis (MS)Mitral Valve Prolapse (MVP)Infective Endocarditis (IE)Acute Pericarditis

Differentials & related conditions

Hypothyroidism (Hashimoto Thyroiditis)Nephrotic SyndromeAlcohol Use Disorder (AUD)Anorexia Nervosa

Educational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA or PAEA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants; End of Rotation™ is a program of the Physician Assistant Education Association.