Cardiovascular disease (CVD) is associated with the build-up of plaque (made of fats, cholesterol and other substances) leading to atherosclerosis which is narrowing of arteries. CVD is an umbrella term including the following conditions: Stroke Transient ischaemic attack (TIA) Myocardial infarction (MI) Angina Peripheral arterial disease Aortic disease. It is vital to optimise patients’ lipid levels to reduce the risk of cardiovascular disease. Dyslipidaemia, an imbalance of serum lipids, is associated with CVD and can be characterised by the following blood markers: High total cholesterol High low-density lipoprotein (LDL) cholesterol High triglycerides Low HDL cholesterol This article will discuss lipid lowering agents, their mechanism of action, common cautions and contraindications, side effects and clinically significant drug interactions. Adobe stock Fig. 1: Stages of atherosclerosis. Detailed illustration showing healthy artery and unhealthy arteries. Developing of plaque from fatty streak to calcification and thrombosis. General management Statins Statins are the most commonly used lipid-lowering agents. Common examples include atorvastatin, simvastatin, pravastatin, rosuvastatin and fluvastatin. Statins are classified into high, medium and low intensity depending on the LDL reduction rates. Statins reduce the synthesis of cholesterol in the liver by competitively inhibiting HMG CoA reductase (the rate-limiting enzyme of cholesterol biosynthesis). Reduction in intracellular cholesterol promotes increased LDL receptor expression at the surface of the hepatocytes, leading to increased uptake of LDL from the blood and decreased circulating LDL in plasma. Statins with short half-lives should be given at night, such as simvastatin which has a half-life of 1.9 hours, as cholesterol synthesis peaks at around midnight. By TeachMeSeries Ltd (2026) Fig. 2: Mechanism of actionStatins Cautions Statins can cause liver function derangement. Monitoring of transaminases should be undertaken at baseline and during treatment. If ALT or AST are more than three times the upper limit, statin treatment should not be initiated. If ALT or AST is above target range but less than three times the upper limit, ALT and AST should be monitored, as transient liver function derangement can occur after commencing statins and does not always require interruption of treatment. Myopathy and rhabdomyolysis are rare side effects from statin use, often characterised by muscle pain and weakness. Risk factors include high statin doses, advanced age, high alcohol intake, strenuous exercise, hypothyroidism and in the presence of interacting medications. Creatinine kinase should be monitored as this is a marker for rhabdomyolysis. MHRA alert: increased risk of myopathy associated with simvastatin 80mg daily; this dose should only be considered in patients with severe hypercholesterolaemia and high risk of cardiovascular complications, who have not achieved their treatment goals on lower doses, and benefits of treatment outweigh any potential risks. Statins can also cause hyperglycaemia and interstitial lung disease. Interactions Simvastatin and atorvastatin are metabolised by CYP3A4, therefore CYP3A4 inhibitors, when used concurrently with statins, may increase the risk of side effects such as myopathy and rhabdomyolysis. Recommendation for managing these interactions depends on which statin the patient is taking. A common example is withholding statin therapy if a patient needs a course of clarithromycin; use of clarithromycin and simvastatin together is contraindicated. Created with ChatGTP Fig 3: CYP3A4 inducers and inhibitors Ezetimibe Ezetimibe can also be used as a lipid lowering agent, as monotherapy or in combination with a statin. Ezetimibe inhibits the intestinal absorption of cholesterol by targeting the sterol transporter NPC1L1, this leads to a decrease in the delivery of intestinal cholesterol to the liver. Reduced cholesterol delivery promotes increased low-density lipoprotein (LDL) receptor expression, leading to increased clearance of LDL cholesterol from the blood. Cautions There are a few cautions to consider with ezetimibe therapy. Ezetimibe has significant biliary excretion and for patients with hepatic impairment, exposure to ezetimibe is increased, and therefore is not recommended in moderate or severe hepatic impairment. Rarely, there have been reported cases of myopathy and rhabdomyolysis with ezetimibe. Interactions There are less drug interactions with ezetimibe compared to statins, however the following are of note: Ciclosporin: Ezetimibe exposure is increased by ciclosporin Fibrates: increased risk of cholelithiasis and gallbladder disease with ezetimibe Warfarin: There are reports that ezetimibe increases INR with warfarin therapy Summary table The table below provides a side by side comparison of statins vs ezetimibe Feature Statins Ezetimibe Examples Atorvastatin, Simvastatin, Pravastatin, Rosuvastatin, Fluvastatin Ezetimibe Mechanism Inhibit HMG-CoA reductase → ↓ cholesterol synthesis → ↑ LDL receptor expression → ↑ LDL clearance Inhibit NPC1L1 transporter in intestine → ↓ cholesterol absorption → ↑ LDL receptor expression → ↑ LDL clearance LDL Reduction High (most effective for lowering LDL) Moderate (less potent alone, often add-on) Use First-line therapy for dyslipidaemia & CVD risk reduction Monotherapy if statins not tolerated; commonly used in combination with statins Dosing Notes Some short half-life statins (e.g., simvastatin) should be taken at night Once daily, timing not critical Cautions/adverse effects Liver dysfunction, myopathy, rhabdomyolysis, ↑ blood glucose, interstitial lung disease Contraindicated in moderate/severe hepatic impairment, rare myopathy/rhabdomyolysis Monitoring ALT/AST (liver enzymes) CK if muscle symptoms or fall with long lie LFTs in hepatic impairment Monitor INR if on warfarin Drug Interactions CYP3A4 inhibitors (↑ toxicity): clarithromycin, ketoconazole, ciclosporin, etc. CYP3A4 inducers (↓ effect): rifampin, St John’s wort Ciclosporin (↑ ezetimibe levels) Fibrates (↑ gallstones risk) Warfarin (↑ INR) MHRA Warning Simvastatin 80 mg/day → ↑ myopathy risk (only if benefits outweigh risks) None specific References MHRA 2014: Simvastatin: increased risk of myopathy at high dose (80 mg) https://www.gov.uk/drug-safety-update/simvastatin-increased-risk-of-myopathy-at-high-dose-80-mg accessed 28/8/24 SPC Ezetimibe 10 mg tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 4/9/24 SPC Atorvastatin 10 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 4/9/24 Statins | Prescribing information | Lipid modification – CVD prevention | CKS | NICE accessed 4/9/24 Ezetimibe | Prescribing information | Lipid modification – CVD prevention | CKS | NICE accessed 4/9/24 Do you think you’re ready? 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