Pathophysiology & Treatment of Hyperlipidemia

Factors contributing to dyslipidemia

Multiple factors: genetics (SNPs causing ↑LDL and cholesterol deposition), and non-genetic factors (smoking, diabetes, HTN, obesity, inactivity, menopause, infections, inflammation, ↑homocysteine).

How LDL becomes atherogenic

LDL enters intima → binds proteoglycans → becomes oxidized → OxLDL cannot bind LDL receptor → removed by macrophage scavenger receptors → foam cell formation → inflammation.

Role of OxLDL in endothelial dysfunction

OxLDL damages endothelium, ↑adhesion molecules (VCAM-1, ICAM-1), attracts monocytes/lymphocytes → plaque formation.

Foam cell formation explained

Macrophages ingest OxLDL via scavenger receptors → accumulate cholesterol → die → release inflammatory signals → amplify atherosclerosis.

Role of CRP in CAD

CRP is an inflammatory marker with 18h half-life; elevated levels within normal range double CAD risk; indicates systemic inflammation, not cholesterol itself.

Steps of atherosclerotic plaque progression

Endothelial injury → LDL oxidation → platelets adhere → fibrous cap → plaque growth → potential rupture → thrombus → occlusion → MI/stroke.

Why ROS inhibitors failed in trials

ROS production is complex and redundant; antioxidants could not sufficiently prevent LDL oxidation in vivo.

Why stents do not reduce mortality

Stents relieve obstruction but do not address systemic atherosclerosis; medical therapy alone performs similarly.

Goal of antihyperlipidemic therapy

Reduce total cholesterol, LDL, TGs; increase HDL; reduce ASCVD risk; combined with diet/exercise.

Statin mechanism of action

Inhibit HMG-CoA reductase → ↓cholesterol synthesis → ↑SREBP → ↑LDL receptors → ↓LDL 25–55%.

Statin pleiotropic effects

Improved endothelial function, ↑NO, ↓oxidative stress, ↓inflammation, plaque stabilization.

Statin adverse effects

Myopathy, myositis, rhabdomyolysis, elevated liver enzymes; contraindicated in pregnancy/lactation.

Bempedoic acid mechanism

Prodrug activated in liver; inhibits ATP-citrate lyase upstream of HMG-CoA reductase; ↓LDL ~18%.

Bempedoic acid adverse effects

Tendon rupture, gout, joint pain, abdominal discomfort; alternative for statin intolerance.

PCSK9 inhibitor mechanism

mAbs bind PCSK9 → prevent LDL receptor degradation → ↑LDL receptors → ↓LDL 50–60%.

Inclisiran mechanism

siRNA reduces PCSK9 mRNA → ↓PCSK9 protein → ↑LDL receptors; dosed twice yearly.

PCSK9 inhibitor adverse effects

Injection site reactions, flu-like symptoms, muscle pain, UTI.

Bile acid sequestrant mechanism

Bind bile acids → prevent reabsorption → liver uses cholesterol to make more → ↑LDL receptors → ↓LDL 8–24% but ↑TGs.

BAS adverse effects

Bloating, dyspepsia, vitamin ADEK deficiency, drug binding interactions.

Ezetimibe mechanism

Inhibits NPC1L1 → ↓cholesterol absorption ~50% → ↓LDL 15–20%.

Ezetimibe use

Best add-on to statins; minimal side effects.

Fibrate mechanism

PPAR-α agonists → ↑LPL activity → ↓TGs ~50%, ↑HDL ~20%.

Fibrate adverse effects

GI upset, gallstones, rare myopathy (especially with statins), ↑LFTs.

Niacin mechanism

↓TG synthesis → ↓VLDL → ↓LDL; ↓HDL clearance → ↑HDL.

Niacin adverse effects

Flushing, hepatotoxicity, hyperuricemia, dyspepsia; rarely used today.

Omega-3 (Lovaza) components

EPA + DHA mixture; ↓TGs 26–47%; no major CV benefit.

Vascepa (EPA) effects

Pure EPA; ↓TGs ~33%; significantly ↓ischemic events and CV risk (REDUCE-IT).

Lomitapide mechanism

MTP inhibitor → ↓apoB lipoprotein formation → ↓LDL ~50%; used for HoFH; hepatotoxic.

Evinacumab mechanism

ANGPTL3 inhibitor → ↑LPL/EL activity → ↓LDL ~50% independent of LDL receptors; used for HoFH.

Natural products overview

Garlic, plant sterols, policosanol; modest LDL reductions; many ineffective; always ask patients about supplement use.

LDL ≥190 mg/dL treatment

High-intensity statin → add ezetimibe if needed → add PCSK9 inhibitor if still above goal.

ASCVD secondary prevention

High-intensity statin first; if LDL >70 add ezetimibe; then PCSK9 inhibitor.

Statin-intolerant patient options

Ezetimibe → bempedoic acid → PCSK9 inhibitor/inclisiran.

Triglycerides ≥500 mg/dL treatment

Fibrate (fenofibrate preferred) + omega-3 (Vascepa); statins added after TG <500.

Combined hyperlipidemia treatment

Statin + fibrate or omega-3; avoid statin + gemfibrozil.

Low HDL treatment

Niacin increases HDL but rarely used.

HoFH treatment

Evinacumab, lomitapide, PCSK9 inhibitors (less effective), LDL apheresis.

Safe lipid-lowering drug in pregnancy

Bile acid sequestrants (only non-systemic option).