HMG-CoA Reductase — Statins

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyses the rate-limiting step in the mevalonate pathway — the conversion of HMG-CoA to mevalonate — which is the committed step in hepatic cholesterol biosynthesis. Statins are structural analogues of HMG-CoA that competitively inhibit HMG-CoA reductase with approximately 1,000-fold greater affinity than the natural substrate. Reduced intracellular cholesterol synthesis in hepatocytes triggers compensatory upregulation of LDLR expression via SREBP-2 transcription factor activation, increasing hepatocyte LDL-C uptake from plasma and lowering circulating LDL-C levels by 30-55% depending on statin potency and dose.

Statins are stratified by their intensity of LDL-C lowering: high-intensity statins (atorvastatin 40-80mg, rosuvastatin 20-40mg) reduce LDL-C by approximately 50% or more; moderate-intensity statins (atorvastatin 10-20mg, rosuvastatin 5-10mg, simvastatin 20-40mg) by 30-50%; and low-intensity statins by less than 30%. ESC/EAS 2019 guidelines and NICE guidance recommend specific LDL-C targets stratified by cardiovascular risk category, with very high-risk patients (established ASCVD, FH with ASCVD, or estimated 10-year CV mortality above 10%) requiring LDL-C below 1.4 mmol/L. The relationship between LDL-C lowering and MACE reduction is log-linear and consistent across baseline risk, statin type, and comorbidity — supporting the principle that lower is better within safe ranges.

Beyond LDL-C lowering, statins exert pleiotropic effects including improved endothelial function, reduced vascular inflammation (lowering hsCRP independent of LDL-C), plaque stabilisation, and antithrombotic properties — mediated through inhibition of isoprenoid intermediates (geranylgeranyl pyrophosphate, farnesyl pyrophosphate) that are required for Rho/Rac GTPase prenylation. Statin-associated muscle symptoms (SAMS) affect 5-10% of patients in clinical practice (lower in RCTs due to healthy user effects) and range from myalgia to rare rhabdomyolysis; CK measurement and dose adjustment or statin switching are the primary management strategies, with coenzyme Q10 depletion proposed but not confirmed as the mechanistic basis.