DRUG THERAPY OF HYPERLIPIDEMIA 1. Inhibitiоn оf Chоlesterol Synthesis HMG-CoA Reductаse Inhibitors (Stаtins) Atorvаstatin, Rosuvastatin, Simvastatin, Pravastatin, Lovastatin Mechanism Inhibit HMG-CoA reductase → ↓ hepatic cholesterol synthesis ↑ LDL receptors → ↑ LDL uptake from blood ↓ LDL, ↓ VLDL, mild ↑ HDL Lipid effects ↓↓↓ LDL (20–60%) ↓ TG (10–30%) ↑ HDL (5–10%) Pleiotropic (non-lipid) benefits ↓ inflammation & ROS ↓ endothelial dysfunction ↓ platelet aggregation Stabilize atherosclerotic plaques Pharmacokinetics (high yield) Oral CYP3A4 metabolism: atorvastatin, simvastatin, lovastatin → many drug interactions Pravastatin/rosuvastatin → minimal CYP metabolism → safer interactions Biliary excretion (mostly) Dose adjustment in renal disease (except atorvastatin preferred in severe CKD) Uses All dyslipidemias (first-line) ASCVD prevention (CAD, stroke prevention) Combination therapy with ezetimibe or PCSK9 inhibitors Adverse effects Myopathy → myositis → rhabdomyolysis (↑ CK) Worse with: fibrates (esp. gemfibrozil), niacin, colchicine Hepatotoxicity (↑ LFTs) ↑ Risk of type 2 DM Contraindicated in active liver disease Avoid in pregnancy & breastfeeding 2. ↑ Lipoprotein Lipase (LPL) Activation — Fibrates Fenofibrate (preferred), Gemfibrozil Mechanism Activate PPAR-α → ↑ LPL activity ↑ TG breakdown → ↓ VLDL Lipid effects ↓↓↓ TG (35–50%) ↓ LDL (5–15%) ↑ HDL (5–20%) Uses Severe hypertriglyceridemia (pancreatitis prevention) Mixed dyslipidemia with high TG Adverse effects GI upset Myopathy (↑ with statins, especially gemfibrozil) Gallstones (↑ biliary cholesterol) Hepatotoxicity Possible ↑ CV risk (gemfibrozil concern) Key interaction Gemfibrozil ↑ statin toxicity (CYP inhibition) Pregnancy Avoid unless severe TG (>1000 risk pancreatitis) 3. Inhibition of Cholesterol Absorption Ezetimibe Mechanism Blocks NPC1L1 transporter in intestinal brush border ↓ cholesterol absorption → ↓ hepatic cholesterol → ↑ LDL receptors Lipid effects ↓ LDL (~15–20%) Mild ↓ TG Slight ↑ HDL Uses Add-on to statins (very common) Statin intolerance Adverse effects Diarrhea Mild ↑ LFTs Myalgia (rare, ↑ with statins) Contraindications Active liver disease Pregnancy (limited data) 4. PCSK9 Inhibitors (MOST POWERFUL LDL-Lowering Drugs) Alirocumab, Evolocumab Mechanism Inhibit PCSK9 → prevent LDL receptor degradation ↑ LDL receptors → massive LDL clearance Lipid effects ↓↓↓↓↓ LDL (40–70%) ↓ TG ↑ HDL Uses Familial hypercholesterolemia ASCVD patients needing additional LDL lowering Statin-resistant hyperlipidemia Adverse effects Injection site reactions URTI, nasopharyngitis Rare hypersensitivity Route Subcutaneous every 2–4 weeks 5. Omega-3 Fatty Acids Icosapent ethyl (EPA-only) Omega-3 acid ethyl esters (EPA + DHA) Mechanism ↓ hepatic VLDL synthesis ↑ fatty acid oxidation ↑ LPL activity Anti-inflammatory effects Lipid effects ↓↓↓ TG (25–45%) ↑ HDL Minimal LDL effect (EPA-only preferred) Uses Severe hypertriglyceridemia ASCVD risk reduction (especially EPA-only formulation) Adverse effects Fishy taste (compliance issue) GI upset ↑ bleeding time at high doses (platelet inhibition) Question: A 58-year-old man with a history of coronary artery disease is started on a medication that inhibits HMG-CoA reductase. Three weeks later, he reports muscle pain and weakness. Laboratory testing shows: Creatine kinase (CK): 12,300 U/L (normal: 30–200 U/L) AST/ALT: mildly elevated The patient is also taking gemfibrozil for hypertriglyceridemia. Which of the following best explains this patient’s condition?
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