Statins

Statins are recommended as the first-line pharmacological treatment for hypercholesterolaemia and moderate hypertriglyceridaemia. Evidence has proven that statins can lower LDL-C levels by 30-50% and reduce the risk of major vascular events, thereby preventing cardiovascular disease.^1,2 Statins competitively inhibit the enzyme, called HMG-CoA reductase, which reduces the synthesis of cholesterol. Consequently, it enhances the LDL receptor's expression on liver cells to uptake LDL from the blood, decreasing the levels of LDL in the plasma.

Statins are categorised by their LDL-C-lowering potency into three groups. High-intensity statins include atorvastatin 40-80 mg and rosuvastatin 20-40 mg. Moderate-intensity statins are simvastatin 20-40mg and lovastatin 40 mg. Simvastatin 10 mg is a low-intensity statin.

Even though statins are generally safe and effective medications to treat hyperlipidemia, there are some limitations for certain patients. First, the potential side effects include muscle pain and abnormally elevated liver enzymes. Certain statins might also interact with other medicines, such as antibiotics, immunosuppressants or cardiovascular drugs. Moreover, statins are not recommended for pregnant people assigned female at birth.

In some cases, patients may be intolerant to statin therapy, or their lipid profile cannot be controlled in the targeted range even with the maximal tolerated doses. In such situations, alternative or adjunctive lipid-lowering medications should be considered.

Other lipid-lowering agents

Several other pharmacological options are available for the management of hyperlipidaemia; each of them with distinct mechanisms of action, clinical indications, and safety profiles. These agents are particularly valuable for patients with statin intolerance, familial lipid disorders, or persistent dyslipidaemia despite optimised statin therapy.

Bile acid sequestrants

Bile acid sequestrants, such as colesevelam, colestipol, and colestyramine, can be used as monotherapy or in combination with statins to manage hypercholesterolemia, which is a condition that causes abnormally high blood cholesterol. At full doses, they can reduce LDL-C levels by 15-30%. These agents bind bile acids in the intestine and prevent bile acids reabsorption. This causes a decrease in bile acid concentration in enterohepatic circulation, and consequently, enhances the liver to convert cholesterol into bile acids, thereby lowering cholesterol levels.

Bile acid sequestrants are taken orally- typically divided into two to three doses daily with meals. They cannot be absorbed into the body; however, common adverse effects include gastrointestinal upset, such as constipation, stomachache, and bloating. They may also affect the absorption of fat-soluble vitamins and many drugs. To minimise interactions, it is suggested to take other medicines separately at least an hour before or four hours after the bile acid sequestrants.^3,4

Ezetimibe

Ezetimibe is a cholesterol absorption inhibitor that acts in the small intestines to lower LDL-C by 13-20%. It can be used as an ‘add-on’ therapy with statins for better LDL control or as monotherapy in patients who are intolerant to statins. With a longer half-life, ezetimibe provides longer action and is taken orally once a day. Common side effects include headache, runny nose and a sore throat.^3,5,6

Fibrates

Fibrates, such as fenofibrate, bezafibrate, ciprofibrate and gemfibrozil, are used to lower cholesterol and triglycerides, and increase HDL by 5-15%, which is considered “good” cholesterol. Their primary mechanism involves activation of peroxisome proliferator-activated receptor alpha (PPARα), a key regulator of lipid metabolism. It stimulates adipose tissue to produce more lipoprotein lipase, which converts triglycerides into fatty acids, thereby reducing triglyceride levels. In the liver, fibrates enhance haptic fatty acid oxidation, promoting the breakdown of triglycerides. Because of their less potency in lowering cholesterol, fibrates are used as adjunct therapy. Common side effects include nausea, vomiting, flatulence and abdominal pain. Notably, because of the increased risk of myopathy, fibrates cannot be taken with statins.^3,7,8

Nicotinic Acid (Niacin)

Nicotinic acid, also called vitamin B3, is a lipid-modifying drug that lowers LDL-C, triglycerides, and lipoproteins, while raising HDL levels to treat various lipid disorders. There are several mechanisms of action, including inhibition of lipolysis in the adipose tissue, inhibition of hepatic triglyceride synthesis and lowering breakdown of HDL. Nicotinic acid can be used alone in statin-intolerant patients or as an adjuvant therapy with statins in selected cases. 

There are three available formulations: immediate-release, sustained-release and extended release. Common side effects include flushing, gastrointestinal discomfort, hyperglycaemia, hyperuricaemia and hepatotoxicity, which should be used with caution in patients with diabetes, gout or liver disease.^8,9

PCSK9 Inhibitors

PCSK9 inhibitors, such as alirocumab and evolocumab, are emerging lipid-modifying drugs first approved in 2015. They are monoclonal antibodies that are administered via subcutaneous injection every two to four weeks. PCSK9 is a protein that regulates the number of LDL receptors on liver cells. It binds to LDL receptors and facilitates the degradation, which reduces LDL receptor expression and the clearance of LDL-C. Therefore, alirocumab and evolocumab bind to PCSK9 as inhibitors to prevent the degradation of LDL receptors. Common side effects include hypersensitivity, muscle pain and flu-like symptoms.^3,10,11

Small interfering RNA (siRNA) therapy

Inclisiran is a small interfering RNA (siRNA) that binds to mRNA, inhibiting intracellular PCSK9 synthesis and consequently increasing the presence of LDL receptors to increase the clearance of LDL-C from the blood. It is administered subcutaneously as a 300 mg initial dose, then a second dose three months later and every six months thereafter. Common side effects are injection site reactions, pain and redness. Notably, Inclisiran is not suggested for use in pregnant women.^3,12

Bempedoic Acid

Bempedoic acid is an oral prodrug that is converted in the liver to its active form. Where it acts as an enzyme inhibitor to decrease cholesterol synthesis. It is taken once a day and is used as an adjunct therapy for patients requiring additional LDL-C reduction even under a maximal tolerated statin dose. Clinical studies have shown a 17-28% LDL-C reduction after 12 weeks of treatment. Due to a lack of available data, bempedoic acid is not recommended for use during pregnancy. Common side effects include hyperuricemia, tendon rupture and anaemia.^3,13

Evinacumab

Evinacumab is a monoclonal antibody that binds to angiopoietin-like protein 3 (ANGPTL3), thereby enhancing the clearance of VLDL and other lipoproteins. It is approved as an adjunct therapy for patients with homozygous familial hypercholesterolemia, which is a genetic disease characterised by elevated LDL-C levels due to reduced or absent LDL receptor function. Evinacumab is administered as an intravenous infusion every four weeks, with the dose adjusted according to body weight. The product should be stored between two and eight degrees Celsius. Common side effects are hypersensitivity reactions, influenza-like illness and nausea.^3,14

Lomitapide

Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that reduces the production of lipoproteins, thereby lowering LDL-C levels. It is approved as an adjunct therapy for patients with homozygous familial hypercholesterolaemia. Lomitapide is taken orally once daily, at least two hours after the evening meal, to minimise gastrointestinal side effects.

 Common adverse effects include gastrointestinal discomfort, elevated liver enzymes, and increased risk of infection. Moreover, lomitapide cannot be concomitant with grapefruit juice and certain medicines, such as clarithromycin, ketoconazole and ciprofloxacin, as they are CYP3A4 inhibitors, which can significantly increase plasma concentrations of lomitapide and the risk of toxicity.^3,15

Icosapent ethyl (IPE)

Icosapent ethyl is a highly purified form of eicosapentaenoic acid (EPA), one of the principal omega-3 fatty acids found in fish oil. It is approved as an adjunct to statin therapy for the prevention of cardiovascular events in patients with hyperlipidaemia. The cardioprotective effects of icosapent ethyl are thought to arise from multiple mechanisms, including reduction of triglyceride levels, inhibition of platelet aggregation, anti-inflammatory and antioxidant actions, stabilisation of atherosclerotic plaques (buildup of fats in arteries), and reduction in blood pressure. It is supplied in capsule form and is typically administered as two capsules twice a day, with or after meals. Possible side effects include atrial fibrillation (heart rhythm problems), allergic reactions, and an increased risk of bleeding.^3,16

Volanesorsen

Volanesorsen is an antisense oligonucleotide, which is a short synthetic strand of RNA, that binds to apolipoprotein C-III (ApoC-III) messenger RNA, thereby inhibiting its production and reducing plasma triglyceride levels. It is indicated for the treatment of familial chylomicronaemia syndrome, a rare genetic disorder caused by a deficiency of lipoprotein lipase, leading to extremely elevated triglyceride concentrations. 

Volanesorsen is administered via subcutaneous injection once weekly for the first three months, followed by a maintenance dose every two weeks. Patients whose body weight is less than 70 kilograms should use volanesorsen with caution, as it increases the risk of thrombocytopenia, which is a decreased platelet count and will impact the blood stability and clotting function. Common adverse effects include injection site reactions, headache and gastrointestinal discomfort.^3,17

Summary

Statins are the main medicines used to lower cholesterol and reduce the risk of heart disease. They are very effective, but some people cannot take particular variations or still have high cholesterol despite the highest safe dose. In these cases, other medicines are available to help lower cholesterol and fats in the blood. These include tablets, injections, and other treatments that work in different ways.

With more treatment options now available, doctors can choose the right medicine or combination of medicines to match each person’s needs, health conditions, and tolerance.