Lipid Lowering Drugs

Lipid lowering drugs reduce circulating LDL cholesterol, triglycerides or both, lowering atherosclerotic events and, for severe hypertriglyceridaemia, pancreatitis. LDL cholesterol is the main target: each 1 mmol/L (about 39 mg/dL) fall in LDL cholesterol reduces major vascular events by about 20% to 25%, and benefit continues to very low levels.

Classification. Statins; cholesterol absorption inhibitor (ezetimibe); bempedoic acid; PCSK9 inhibitors (alirocumab, evolocumab) and inclisiran; fibrates; bile acid sequestrants; omega 3 fatty acids; niacin (little current role); lomitapide (homozygous familial hypercholesterolaemia).

Mechanism. Statins reduce hepatic cholesterol synthesis and raise LDL receptor expression. Ezetimibe blocks intestinal uptake. PCSK9 inhibitors prevent receptor degradation. Bile acid sequestrants increase bile acid loss. Fibrates activate PPAR alpha and lower triglycerides. Bempedoic acid inhibits ATP citrate lyase upstream of HMG-CoA reductase.

Targets. Very high risk (established atherosclerotic disease, diabetes with organ damage, familial hypercholesterolaemia with disease): LDL cholesterol under 1.4 mmol/L (55 mg/dL) with a 50% or greater reduction. High risk: under 1.8 mmol/L (70 mg/dL). Moderate risk: under 2.6 mmol/L (100 mg/dL). Triglycerides over 1.7 mmol/L (150 mg/dL) mark raised risk. Over 10 mmol/L (880 mg/dL) carries pancreatitis risk.

Regional context. Hyperlipidaemia is under-detected and under-treated in sub-Saharan Africa. Generic statins are the usual affordable option, and PCSK9 inhibitors are rarely available.

• Statins: first line for LDL lowering and event reduction.
• Ezetimibe: second line, additive to statins.
• PCSK9 inhibitors and inclisiran: third line, injectable, large LDL reduction.
• Bempedoic acid: statin intolerance, additive to ezetimibe.
• Fibrates, omega 3 fatty acids: triglyceride lowering.
• Bile acid sequestrants: add-on, pregnancy, children.
• Lomitapide: homozygous familial hypercholesterolaemia, specialist use.

• Start with an assessment: non-fasting lipid profile, risk estimate, and exclusion of secondary causes (hypothyroidism, nephrotic syndrome, cholestasis, diabetes, alcohol, obesity, and drugs such as corticosteroids, thiazides, ciclosporin, antiretrovirals and antipsychotics). Measure lipoprotein(a) once in adulthood.
• Lifestyle: diet low in saturated fat, weight loss, activity, stopping smoking and alcohol reduction. Lifestyle does not replace drug treatment in high-risk patients.
• Established atherosclerotic disease: high-intensity statin (atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg), adding ezetimibe 10 mg if LDL cholesterol stays over target after 4 to 6 weeks, then a PCSK9 inhibitor or inclisiran if still over target.
• Primary prevention: statin by risk estimate, with intensity to the target.
• Diabetes: moderate or high-intensity statin by age and risk.
• Familial hypercholesterolaemia: statin from childhood (age 8 to 10 years), with early combination therapy. Suspect with LDL cholesterol over 5 mmol/L, tendon xanthomata or a family history of early heart disease.
• Severe hypertriglyceridaemia (over 10 mmol/L): fibrate, omega 3 fatty acids, strict reduction of alcohol, sugar and fat, glucose control, and treatment of secondary causes.
• Acute coronary syndrome: start or increase the statin dose before discharge.
• Pregnancy: stop statins; bile acid sequestrants are the option.
• Selection: match intensity to risk and aim at the LDL cholesterol target, combining agents early in very high risk.

Contraindications. Class-specific: pregnancy and breastfeeding (statins, ezetimibe with statin, PCSK9 inhibitors), active liver disease (statins, lomitapide), complete biliary obstruction (bile acid sequestrants), and severe renal or gallbladder disease (fibrates).

Adverse effects. Muscle symptoms, liver enzyme rise (statins, ezetimibe, lomitapide, fibrates), constipation (bile acid sequestrants), injection site reactions (PCSK9 inhibitors), gallstones (fibrates, ezetimibe), and raised creatinine (fibrates).

Interactions. Statins with CYP3A4 inhibitors, gemfibrozil, ciclosporin and some antiretrovirals; bile acid sequestrants bind many oral drugs; fibrates raise warfarin effect.

Monitoring. Lipid profile 4 to 12 weeks after starting or changing therapy, then yearly. Liver enzymes at baseline and when symptoms arise. Creatine kinase for muscle symptoms. Glucose or HbA1c in those at risk of diabetes.

Referral and escalation. LDL cholesterol over 10 mmol/L, tendon xanthomata in a young person, triglycerides over 20 mmol/L, or pancreatitis needs specialist care.

Special groups. Older adults: treat established disease and consider primary prevention by risk and frailty. Kidney disease: atorvastatin without dose adjustment, rosuvastatin reduced dose. HIV: check interactions with protease inhibitors and cobicistat. Children: familial hypercholesterolaemia under specialist care.