SN1 SHORT NOTE 5M ★ High-yield

Classify hypolipidaemic drugs. Describe the mechanism, uses and adverse effects of statins.

Pharmacology · 2nd Professional — Para-Clinical

Definition and Classification

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis.

Class	Drugs	Chief effect
Statins	Atorvastatin, rosuvastatin, simvastatin, pravastatin	LDL reduced 30–55%; the most effective and the only class with unequivocal mortality benefit
Cholesterol absorption inhibitor	Ezetimibe	LDL reduced about 18%; added to a statin
Fibrates	Fenofibrate, gemfibrozil	Chiefly reduce triglycerides; raise HDL
Bile acid sequestrants	Cholestyramine, colestipol	Reduce LDL; not absorbed, so safe in pregnancy; cause bloating and bind other drugs
Nicotinic acid	Niacin	Raises HDL most; flushing limits use and outcome benefit is unproven
PCSK9 inhibitors	Evolocumab, alirocumab (monoclonal antibodies); inclisiran (siRNA)	LDL reduced 50–60% on top of a statin; injectable and expensive
Omega-3 fatty acids	Icosapent ethyl	Reduce triglycerides

Mechanism and Pleiotropic Effects

Statin competitively inhibits HMG-CoA reductase in the hepatocyte → Intracellular cholesterol falls → SREBP is activated → up-regulation of LDL receptors on the hepatocyte surface → Increased clearance of LDL from the plasma → Plus pleiotropic effects — plaque stabilisation, improved endothelial function, reduced inflammation (CRP falls) and antithrombotic actions

The pleiotropic effects explain why benefit appears within weeks, long before any change in plaque size — and why statins help even where the cholesterol is not markedly raised
Given at night for short-acting statins (simvastatin), since cholesterol synthesis peaks overnight; atorvastatin and rosuvastatin have long half-lives and may be taken at any time

CLINICAL PEARL

Statins are prescribed on risk, not on cholesterol. A patient with an unremarkable LDL but established coronary disease benefits more than someone with a high LDL and no other risk factor. Treating a number rather than a person is the commonest error in lipid management, and the reason risk scores exist.

Adverse Effects

Myopathy — from mild myalgia (common, and often not truly drug-related) through myositis with a raised creatine kinase to rhabdomyolysis with acute renal failure (rare but serious)
Risk of myopathy is increased by high dose, old age, small body size, hypothyroidism, renal impairment, and above all by interacting drugs — fibrates (especially gemfibrozil), macrolides, azoles, ciclosporin, amiodarone, verapamil and grapefruit juice
Hepatic — raised transaminases, usually transient; serious liver injury is rare
A small increase in new-onset diabetes, which is far outweighed by the cardiovascular benefit in those at risk
Contraindicated in pregnancy and lactation, since cholesterol is essential for fetal development

Uses

Secondary prevention — after myocardial infarction, stroke, or in established coronary, cerebrovascular or peripheral arterial disease; benefit is large and the case is unarguable
Primary prevention in those with sufficient calculated risk, in diabetes, and in chronic kidney disease
Familial hypercholesterolaemia — high-dose statin with ezetimibe, and PCSK9 inhibitors where available; family screening is essential, since it is autosomal dominant
Fibrates for very high triglycerides (above about 500 mg/dL) to prevent acute pancreatitis — a different indication from cardiovascular prevention

Applied Aspects

Check baseline liver enzymes and creatine kinase, and measure creatine kinase whenever a patient reports significant muscle pain, tenderness or weakness
Warn every patient to report unexplained muscle pain, especially with dark urine — that combination suggests rhabdomyolysis and demands immediate attention
Prefer fenofibrate to gemfibrozil when combining with a statin, as the myopathy risk is substantially lower
Statins are lifelong; stopping after a "good" cholesterol result loses the benefit entirely, and this must be explained clearly at the outset
Lifestyle measures remain essential alongside — diet, exercise, weight and smoking cessation; a statin does not license an unchanged diet
Cardiovascular disease occurs about a decade earlier in South Asians and at lower body mass index, so risk calculators developed in Western populations underestimate it, and thresholds for treatment are set lower

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