Antidyslipidaemics: Statins

Dyslipidaemia is defined as abnormal levels of lipids in the bloodstream, particularly elevated LDL or low HDL, which increases cardiovascular disease risk. There is a high association between dyslipidaemia and CV disease, particularly in diabetes. Hypercholesterolaemia is a major modifiable risk factor for CHD, hypertension, and atherosclerosis.

Lipoproteins transport cholesterol around the body. LDL is the principal carrier of cholesterol to peripheral tissues and liver and is the most atherogenic lipoprotein. HDL performs reverse cholesterol transport — scavenging excess cholesterol from peripheral tissues and delivering it to the liver for excretion or repackaging.

At the cellular level, LDL binds to LDL receptors (LDL-R) via ApoB-100, is internalised by endocytosis, and broken down in lysosomes. Elevated intracellular cholesterol: (1) inhibits HMG-CoA reductase (the rate-limiting enzyme in de novo cholesterol synthesis); (2) activates ACAT (storing cholesterol as cholesteryl esters); (3) inhibits LDL-R gene transcription (reducing further uptake). PCSK9 enzyme binds LDL-R and promotes its degradation, reducing LDL uptake.

High LDL leads to atherosclerosis: LDL enters the tunica intima; macrophages take it up, become foam cells; foam cells release growth factors (promoting vascular smooth muscle proliferation and narrowing the lumen) and metalloproteinases (degrading the matrix, increasing vessel vulnerability). High BP + atherosclerosis can cause plaque rupture → thrombosis → rapid vessel occlusion.

Atorvastatin is the prototypical statin — a pleiotropic drug (multiple MOAs). Primary mechanism: structural analogue of HMG-CoA → reversible, competitive HMG-CoA reductase inhibition → decreased hepatic de novo cholesterol synthesis → decreased intracellular cholesterol → protease activation → SREBP activation → upregulation of LDL-R gene → increased LDL-R expression → increased plasma LDL and IDL clearance → decreased plasma LDL-cholesterol and TAG. Secondary (pleiotropic) effects: anti-inflammatory (reduces NFkB binding, reduces CRP); increases endogenous NO release; inhibits CETP → raises HDL; activates PPARs (alpha: reduces TAGs; gamma: improves insulin sensitivity).

Atorvastatin PK: oral; 14% bioavailability; highly protein bound (98%); extensive CYP3A4 first-pass hepatic metabolism to active hydroxylated metabolites; cleared in bile; T½ atorvastatin ~14h, active metabolites ~25h. Hepatic impairment increases drug retention; renal impairment has minimal impact.

ADRs: myopathy and rhabdomyolysis (rare but serious — intense myalgia, fatigue, myoglobinuria, AKI); mild reversible cognitive impairment; elevated liver enzymes (AST, ALT in <1%); avoid in pregnancy (teratogenic). Major drug interaction risk via CYP3A4.

Other antidyslipidaemic drugs: ezetimibe (cholesterol re-uptake inhibitor — blocks enterocyte brush border absorption → decreased hepatic cholesterol → LDL-R upregulation); alirocumab (PCSK9 monoclonal antibody inhibitor — prevents PCSK9-LDL-R binding → less LDL-R degradation → increased LDL clearance; given by subcutaneous injection; for patients maxed out on statins); bile acid binding resins — colestipol and cholestyramine (oral; sequester bile acids in GI tract → interrupt enterohepatic circulation → increased cholesterol conversion to bile acids → decreased plasma LDL).