simvastatin

MECHANISM: Simvastatin competitively inhibits HMG-CoA reductase, the rate-limiting enzyme converting HMG-CoA to mevalonate. Lower intrahepatic cholesterol upregulates LDL receptors on hepatocytes (via SREBP-2 activation), increasing LDL clearance from plasma. Effects on lipids: LDL decreases most (about 20-55% depending on dose/intensity), TG decreases modestly, and HDL increases slightly. Statins also have "pleiotropic" effects (improved endothelial function, plaque stabilization, anti-inflammatory effects, reduced CRP).

PHARMACOKINETICS: Simvastatin (and lovastatin) are lactone prodrugs activated by hydrolysis to the active beta-hydroxy acid form. They are lipophilic, with extensive first-pass hepatic metabolism, mainly via CYP3A4. Because cholesterol synthesis peaks at night, short-half-life statins like simvastatin are classically dosed in the evening. Pravastatin and rosuvastatin are more hydrophilic and are not significantly metabolized by CYP3A4 (pravastatin is not CYP-metabolized; rosuvastatin minimally via CYP2C9). Atorvastatin is also CYP3A4-metabolized.

CLINICAL USES: Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD: MI, stroke, PAD); hyperlipidemia (especially elevated LDL, familial hypercholesterolemia); diabetes mellitus in patients aged 40-75; chronic kidney disease. Simvastatin is moderate intensity at 20-40 mg. High-intensity statins are atorvastatin 40-80 mg and rosuvastatin 20-40 mg. Landmark trial: 4S (Scandinavian Simvastatin Survival Study) showed reduced mortality in patients with CAD. Simvastatin 80 mg is no longer recommended because of myopathy risk.

ADVERSE EFFECTS: - Myopathy/myalgia, and rarely rhabdomyolysis (muscle pain, elevated CK, myoglobinuria, AKI). Risk is increased by drug interactions, hypothyroidism, renal impairment, older age, and high dose. - Hepatotoxicity: elevated transaminases (check baseline LFTs; monitor if symptomatic). - Slightly increased risk of new-onset type 2 diabetes mellitus (small hyperglycemia effect). - Teratogenicity: formerly pregnancy category X; contraindicated in pregnancy historically (FDA removed the blanket contraindication in 2021, but it is still generally avoided in pregnancy and breastfeeding, so know the classic board teaching).

DRUG INTERACTIONS (high-yield): CYP3A4 inhibitors increase simvastatin levels and risk of rhabdomyolysis: macrolides (clarithromycin, erythromycin), azole antifungals (ketoconazole, itraconazole), protease inhibitors, grapefruit juice, cyclosporine, and diltiazem/verapamil (dose limits apply). Amlodipine limits simvastatin to 20 mg. Amiodarone limits it to 20 mg. Gemfibrozil (fibrate) greatly increases myopathy risk (inhibits glucuronidation). Niacin also raises the risk. CYP3A4 inducers (rifampin, phenytoin, carbamazepine) lower statin levels.

COMBINATIONS: Ezetimibe/simvastatin (Vytorin) is used for additive LDL lowering (ezetimibe blocks NPC1L1-mediated intestinal cholesterol absorption). The IMPROVE-IT trial showed added benefit after ACS.

BOARD PEARLS: - Statins are the first-line agents for LDL lowering and the only lipid-lowering class with the strongest mortality benefit. - Statins lower LDL the most; fibrates lower TG the most; niacin raises HDL the most. - A patient on a statin who starts clarithromycin and develops muscle weakness and dark urine has rhabdomyolysis. Management: stop the statin, give IV fluids, and check CK and renal function. - Mnemonic: "Statins: HMG-CoA reductase inhibitors; Lovastatin, simvastatin... 'Lova-Simva'." Avoid taking with grapefruit juice. - If a statin is not tolerated because of myalgias, check TSH/vitamin D, consider a lower dose or a different statin (e.g., pravastatin, rosuvastatin), or use ezetimibe or a PCSK9 inhibitor.