Statins

What they are

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in hepatic cholesterol synthesis. Lower intracellular cholesterol up-regulates LDL receptors on the hepatocyte surface, increasing LDL clearance from the blood. Main agents: rosuvastatin, atorvastatin, simvastatin, pravastatin.

Why they matter

Lifetime atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death globally. The relationship between cumulative apoB exposure and ASCVD risk is essentially monotonic. Statins reliably reduce LDL by 30–60% and produce roughly a 20% relative reduction in major cardiovascular events per ~1 mmol/L LDL reduction.

Earlier and harder

Most ASCVD events come from decades of accumulated apoB exposure starting well before middle age. Modern lipidology argues for treating earlier and more aggressively in higher-risk individuals, often combined with ezetimibe and (when needed) PCSK9 inhibitors.

Safety

• Muscle symptoms (myalgia) reported in ~5–10% in clinical practice, though blinded RCTs (SAMSON) suggest most are nocebo.
• Hepatotoxicity is rare and usually mild.
• New-onset diabetes is small but real (~1 per 1,000 patient-years).
• Cognitive side effects are not supported by RCTs.

Combinations

• Ezetimibe: additional ~15–20% LDL reduction; RCT evidence (IMPROVE-IT).
• PCSK9 inhibitors: large additional LDL reduction; major event reduction (FOURIER, ODYSSEY).
• Bempedoic acid: alternative for statin-intolerant patients.

Related entries

ApoB, Lp(a), Cardiovascular disease, JUPITER trial, FOURIER trial.