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Dyslipidemia: Basic to Clinical

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1. Definition

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2. Lipid Biochemistry (Basic Science)

Lipoproteins and Their Roles

Cholesterol Metabolism

• Acetyl-CoA is the precursor for cholesterol synthesis via the mevalonate pathway (rate-limiting enzyme: HMG-CoA reductase)
• Fatty acids can undergo beta-oxidation to acetyl-CoA, which can be used for cholesterol synthesis, ketone bodies, or the TCA cycle
• LDL receptors on hepatocytes remove LDL from circulation; their expression is inversely regulated by intracellular cholesterol
• Harper's Illustrated Biochemistry, 32nd Ed

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3. Fredrickson Classification (WHO Phenotypic System)

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4. Etiology and Classification

Primary (Genetic) Dyslipidemias

• Caused by mutations in LDL receptor (LDLR), ApoB, or PCSK9 genes
• Heterozygous FH: ~20-fold higher lifetime ASCVD risk; premature ASCVD in 20s-30s untreated
• Homozygous FH: far more severe; tendon xanthomas appear in childhood
• Statin initiation in adolescence/early adulthood normalizes ASCVD rates to those of unaffected relatives

• Most common monogenic hyperlipidemia
• Non-HDL-C typically >220 mg/dL with TG 200-600 mg/dL
• Expressed with age and obesity; clinical ASCVD in 50s (men) or 60s (women) if untreated

• Caused by ApoE2/E2 homozygosity (1 in 10,000) - but requires a second hit (obesity, diabetes, hypothyroidism)
• LDL >190 mg/dL, TG often >500 mg/dL
• Responds well to fibrates + statin

• Severe TG >1000 mg/dL; risk of acute pancreatitis
• Due to LPL, ApoC-II, or GPIHBP1 deficiency
• Goldman-Cecil Medicine, 26th Ed; Harrison's Principles 22E (2025)

Secondary Dyslipidemias

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5. Pathophysiology and Links to Disease

Atherosclerosis

1. Endothelial dysfunction
2. Monocyte recruitment and foam cell formation
3. Smooth muscle cell migration and proliferation
4. Formation of atherosclerotic plaques

Metabolic Syndrome Dyslipidemia

• Excess free fatty acids from adipose tissue lipolysis → liver produces more VLDL TG
• This leads to: ↑TG, ↓HDL-C, and increased small dense LDL particles
• Hyperinsulinemia drives further hepatic TG production
• The dyslipidemia of metabolic syndrome is a major contributor to ASCVD
• Harrison's Principles 22E, Fig. 420-2 (metabolic syndrome pathophysiology)

Hypertriglyceridemia and Pancreatitis

• TG >500 mg/dL: intervention warranted to reduce pancreatitis risk
• TG >1000 mg/dL: high risk of acute pancreatitis
• Chylomicronemia syndrome: hallmark of severe TG elevation (chylomicrons do not clear between meals)

Dyslipidemia and CKD

• CKD causes: urinary loss of albumin and lipoprotein lipase activators → ↑LDL; impaired TG clearance → ↑TG
• Dyslipidemia independently promotes glomerulosclerosis and progression of CKD - Brenner & Rector's The Kidney

Cutaneous/Musculoskeletal Manifestations

• Tendon xanthomas: Achilles/extensor tendons (Type 2A FH) - correlate with 3.2-fold higher CVD risk
• Tubero-eruptive and palmar crease xanthomas: Type 3 (dysbetalipoproteinemia)
• Eruptive xanthomas: severe hypertriglyceridemia (Type 1, 5)
• Xanthelasma: periorbital deposits (associated with hypercholesterolemia but low specificity)
• Corneal arcus: premature (<45 years) suggests FH
• Arthritis: Type II dyslipidemia can cause transient migratory polyarthritis

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6. Diagnosis and Evaluation

Fasting Lipid Panel

Advanced Biomarkers (when standard lipids are borderline)

• ApoB: captures all atherogenic particle number; useful when TG >200 mg/dL, low LDL-C, or diabetes
• Lp(a): 2026 guidelines now recommend Lp(a) measurement at least once in all adults; Lp(a) ≥50 mg/dL is a risk-enhancing factor
• hs-CRP: ≥2.0 mg/L is a risk-enhancer for statin initiation decisions
• Coronary Artery Calcium (CAC) score: For patients aged ≥40 men / ≥50 women in borderline risk - CAC=0 indicates low near-term risk; elevated CAC justifies statin

Risk Assessment (2026 ACC/AHA Guideline Update)

• Replaces the 2018 guideline on Blood Cholesterol
• Now uses the PREVENT-ASCVD equations (replaces Pooled Cohort Equations) for 10-year and 30-year risk in adults aged 30-79 years
• Borderline risk (3 to <5% 10-year): LLT is reasonable after clinician-patient discussion
• Intermediate risk (5 to <10% 10-year): LLT is recommended after discussion
• LDL-C goals return explicitly: secondary prevention very high risk = <55 mg/dL

Risk-Enhancing Factors Favoring Statin Initiation

• Family history of premature ASCVD (M <55y, F <65y)
• Metabolic syndrome
• CKD (eGFR 15-59 mL/min/1.73m²)
• Chronic inflammatory conditions (psoriasis, RA, HIV/AIDS)
• Premature menopause (<40 years)
• Lp(a) ≥50 mg/dL; ApoB ≥130 mg/dL; hs-CRP ≥2.0 mg/L
• TG persistently ≥175 mg/dL; LDL-C 160-189 mg/dL
• Goldman-Cecil Medicine, Table 190-4

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7. Treatment

A. Lifestyle (First-Line for All)

• Emphasize vegetables, fruits, whole grains
• Low-fat dairy, fish, legumes, nontropical vegetable oils, nuts
• Limit sweets, sugar-sweetened beverages, red meats
• Reduce saturated fats to <5-6% of calories; eliminate trans fats

• 3-4 sessions/week, ~40 min each, moderate to vigorous aerobic activity
• Reduces LDL-C and non-HDL-C; also has independent cardiovascular benefits

• Weight loss (↓TG, ↑HDL)
• Alcohol reduction (↓TG)
• Control of secondary causes (thyroid, diabetes, medications)

B. Pharmacological Therapy

Elevated LDL-C

• Inhibit HMG-CoA reductase → ↓hepatic cholesterol synthesis → upregulate LDL receptors
• Extensive RCT evidence for reducing MI, stroke, and all-cause mortality
• Doubling the statin dose gives only ~6% additional LDL reduction ("rule of 6")
• Side effects: myalgia (3-5%), rarely myopathy/rhabdomyolysis; mild transaminase elevation; slight ↑incident T2DM (outweighed by ASCVD benefit)
• Contraindicated in pregnancy and lactation

• Inhibits intestinal cholesterol absorption (via NPC1L1 transporter)
• 10 mg/day reduces LDL-C by ~18%; additive with statins
• Added to statin: significantly reduces major cardiovascular events (IMPROVE-IT trial)
• Very well tolerated; consider as add-on or in statin-intolerant patients

• Monoclonal antibodies: Alirocumab (Praluent) and Evolocumab (Repatha), SC q2 weeks
• PCSK9 promotes LDL receptor degradation; antibodies preserve LDL receptor recycling
• Reduce LDL-C by ~60%; also modestly lower Lp(a)
• Reduce CV events when added to statins in established CAD
• Indicated: FH or ASCVD not reaching LDL-C target on statin ± ezetimibe
• siRNA alternative: Inclisiran (targets PCSK9 mRNA) - given SC every 6 months

• Inhibits ATP-citrate lyase (upstream of HMG-CoA reductase)
• ~12% reduction in CV events in statin-intolerant patients
• Should be combined with ezetimibe in statin-intolerant patients

• Cholestyramine, colestipol, colesevelam
• Interrupt enterohepatic circulation of bile acids → ↑LDL receptor expression
• Reduce LDL-C ~15-25%; can raise TG (avoid in hypertriglyceridemia)

Elevated Triglycerides

• Can cause myopathy, especially with statins (greatest risk with gemfibrozil; fenofibrate preferred with statins)
• Raise creatinine; increase gallstone risk; potentiate warfarin

• TG >500 mg/dL → pharmacotherapy indicated (pancreatitis prevention)
• Moderate HTG (150-500 mg/dL) → focus on ASCVD risk reduction with statins

Triglyceride-Lowering Drug Efficacy Comparison (Goldman-Cecil, Table 190-E1)

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8. Treatment Targets (2026 ACC/AHA Guideline)

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9. Special Populations

Pregnancy

• Statins and PCSK9 inhibitors are contraindicated
• Women with FH should be counseled about temporarily discontinuing statin during pregnancy/lactation; resume after

Children with FH

• Statin initiation as early as age 8-10 in homozygous FH; adolescence for heterozygous FH
• Earlier treatment is associated with ASCVD rates comparable to unaffected relatives

CKD / Dialysis

• Complex dyslipidemia pattern; statins remain beneficial in non-dialysis CKD
• Statin benefit in dialysis patients is less clear (4D and AURORA trials negative)

HIV on ART

• INSTIs (raltegravir, elvitegravir, dolutegravir) have favorable lipid effects
• Avoid ritonavir-boosted PIs when possible; switching can reduce TG
• Manage with statins, but watch for drug interactions (many statins are CYP3A4 substrates)

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10. Key Clinical Pearls

1. Non-HDL-C is a better atherogenic marker than LDL-C alone in patients with elevated TG; ApoB is the most direct measure of atherogenic particle number
2. Measure Lp(a) once in all adults (new 2026 guideline COR 1 recommendation) - it is genetically determined and not modifiable by statins
3. CAC = 0 in a low-to-intermediate risk patient (no diabetes, no smoking, no strong FH, LDL <130): justifies deferring statin
4. Statin myalgia (3-5%): check CK; do not routinely monitor CK without symptoms; try alternative statin (e.g., low-dose rosuvastatin, pravastatin) or bempedoic acid + ezetimibe
5. For mixed dyslipidemia with high TG: icosapent ethyl (EPA) is the only TG-lowering agent with proven CV benefit in statin era; avoid adding gemfibrozil to a statin (myopathy risk)
6. In statin-intolerant patients: bempedoic acid + ezetimibe is a proven alternative
7. Tendon xanthomas on clinical exam → always suspect familial hypercholesterolemia

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