Cholesterol control

Pharmacists have an increasingly important role in optimising cardiovascular outcomes, writes Damien O’Brien MPSI

Introduction

Cardiovascular disease is one of the leading causes of morbidity and mortality worldwide. Elevated low-density lipoprotein (LDL) cholesterol is an important modifiable risk factor for atherosclerotic cardiovascular disease. Evidence shows that lowering LDL cholesterol reduces the risk of myocardial infarction, stroke and cardiovascular death.

The identification and management of dyslipidaemia are important aspects of primary and secondary prevention. Community pharmacists, as knowledgeable and accessible healthcare professionals, have an important role in identifying patients who may benefit from cholesterol screening, encouraging lifestyle modifications, optimising pharmacological therapy and providing patient education. This article will provide an overview of cholesterol and dyslipidaemia, discuss evidence-based lifestyle and pharmacological treatment strategies, and examine the important role of the pharmacist in optimising cardiovascular outcomes.

Background on cholesterol

Cholesterol is a lipophilic molecule that plays an essential role in normal physiological function. It is a vital component of cell membranes and is necessary for the synthesis of sex hormones, steroid hormones, vitamin D and bile acids. Cholesterol is obtained from dietary sources and endogenous synthesis, primarily in the liver. As cholesterol is lipophilic, it is transported through the body by lipoproteins — mainly low-density lipoprotein (LDL), high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL). These lipoproteins can be measured to estimate blood cholesterol levels.

Cholesterol is important for many normal physiological functions, but it can also be harmful at abnormal blood concentrations. Hypercholesterolaemia occurs when LDL cholesterol levels are elevated and is a major risk factor for atherosclerotic cardiovascular disease. Elevated LDL cholesterol contributes to the formation of atherosclerotic plaques within arterial walls, increasing the risk of coronary heart disease, ischaemic stroke and peripheral arterial disease.

LDL cholesterol is the main atherogenic lipoprotein and the primary target of lipid-lowering therapy. HDL cholesterol has often been referred to as ‘good cholesterol’ due to its role in reverse cholesterol transport. However, evidence suggests that simply increasing HDL cholesterol concentrations does not necessarily reduce cardiovascular risk. Therefore, treatment guidelines primarily target lowering LDL cholesterol, with treatment intensity and targets determined by an individual’s overall cardiovascular risk, with lower LDL cholesterol targets recommended for those at highest risk.

Non-pharmacological management

Lifestyle modification is a crucial component of cholesterol management and is recommended for all patients with hypercholesterolaemia. Lifestyle interventions may be used as monotherapy to reduce LDL cholesterol, or they may be combined with lipid-lowering pharmacological therapy.

Dietary modification is an important aspect. A Mediterranean-style diet is recommended, rich in fruit, vegetables, whole grains, legumes, nuts, olive oil and oily fish, while limiting foods high in saturated and trans fats. Saturated fats should be replaced with unsaturated fats to help reduce LDL cholesterol levels. Increasing soluble fibre in the diet can also reduce LDL cholesterol by reducing intestinal cholesterol absorption and increasing bile acid excretion.

Maintaining a healthy body weight and engaging in regular physical activity are also important. Weight loss in overweight or obese individuals may modestly improve lipid profiles, as well as reducing overall cardiovascular risk. Regular physical activity may also have a modest effect on LDL cholesterol. Patients should be encouraged to undertake at least 150 minutes of moderate aerobic exercise per week and limit sedentary time. Although smoking cessation and reducing alcohol consumption have little direct effect on LDL cholesterol, both are important for reducing overall cardiovascular risk.

Many dietary products and supplements are marketed to reduce cholesterol. There is good evidence that plant sterols and stanols, consumed at doses of approximately 2g daily, can reduce LDL cholesterol. They act by competing with dietary and biliary cholesterol for absorption in the small intestine. They may be used as an adjunct to lifestyle modification in certain patients but should not replace lipid-lowering medication where indicated. They are available as supplements and in fortified foods.

Soluble fibre supplements, such as psyllium, have evidence for modest reduction in LDL cholesterol and may be recommended as part of an overall dietary approach. Red yeast rice also lowers LDL cholesterol because it naturally contains monacolin K, a compound chemically identical to lovastatin. However, there are concerns regarding variability between products, quality control and the lack of monitoring of adverse effects and drug interactions. Therefore, it is not routinely recommended for cholesterol management.

Omega-3 supplements may reduce blood triglyceride concentrations but have little effect on LDL cholesterol. They are not recommended solely for LDL cholesterol- lowering. Supplements such as lecithin, garlic and coenzyme Q10 do not have consistent clinical evidence of significant reductions in LDL cholesterol levels, and current guidelines do not support
their routine use for lipid management. Community pharmacists are ideally placed to counsel patients on evidence-based lifestyle interventions and over-the- counter products.

Pharmacological management

Despite the importance of lifestyle modification, many patients require pharmacological treatment to achieve LDL cholesterol targets, particularly those at high cardiovascular risk. Guidelines typically individualise cholesterol targets, with progressively lower LDL cholesterol goals according to a patient’s overall cardiovascular risk. More intensive lipid- lowering therapy is typically recommended in patients with established atherosclerotic cardiovascular disease and other high-risk conditions. Pharmacists play an important role in optimising pharmacological therapy, improving adherence, identifying adverse effects and reinforcing lifestyle interventions alongside medication use.

Statins

Statins are a first-line treatment option for the management of hypercholesterolaemia. Examples of commonly used statins include atorvastatin, rosuvastatin, simvastatin, pravastatin and fluvastatin. They reduce total cholesterol, LDL cholesterol and blood triglyceride concentrations. They have a strong evidence base demonstrating reductions in myocardial infarction, stroke and cardiovascular mortality. They exert their effects by inhibiting hydroxymethylglutaryl- coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in hepatic cholesterol synthesis. This results in upregulation of LDL receptors and increased hepatic uptake of LDL cholesterol.

Statins are generally well tolerated. Common adverse effects include myalgia, headache and gastrointestinal disturbances. Myopathy, rhabdomyolysis and hepatotoxicity are rarer but serious adverse effects. Muscle symptoms are often reported with statin treatment, although true statin intolerance is relatively uncommon. Pharmacists should encourage patients not to discontinue therapy without medical review. Options such as switching to an alternative statin, dose reduction or intermittent dosing may allow continued therapy.

There are many clinically significant drug interactions with statins, including macrolide antibiotics, azole antifungals, amiodarone and ciclosporin. Grapefruit juice should be avoided with simvastatin and high doses of atorvastatin due to CYP3A4 inhibition. Because hepatic cholesterol synthesis predominantly occurs overnight, evening administration is recommended for fluvastatin, pravastatin and simvastatin. Atorvastatin and rosuvastatin do not require specific time of administration but should be taken at the same time every day. Statins remain the cornerstone of lipid-lowering therapy due to their extensive evidence base and cost-effectiveness.

Ezetimibe

Ezetimibe is a commonly used lipid- lowering medication for the treatment of hypercholesterolaemia. It works by selectively inhibiting cholesterol absorption in the small intestine, thereby reducing cholesterol delivery to the liver and increasing hepatic LDL receptor expression. This results in reductions in total cholesterol and LDL cholesterol, with a modest effect on triglycerides.

Ezetimibe is the most commonly used non-statin lipid-lowering drug. It is commonly used in combination with a statin in patients in whom LDL cholesterol targets are not achieved with statin therapy alone and is available in fixed-dose combination products with several statins. It may also be used as monotherapy in patients who cannot tolerate statins. The recommended dose is 10mg once daily. Ezetimibe is generally well tolerated, with the most common adverse effects including headache, sore throat and abdominal discomfort. Pharmacists should encourage adherence, as ezetimibe provides additive LDL cholesterol reduction when combined with statins and contributes to further cardiovascular risk reduction.

Bempedoic acid

Bempedoic acid is a newer lipid-lowering medication. It works by inhibiting adenosine triphosphate-citrate lyase (ACL), an enzyme involved in hepatic cholesterol synthesis upstream of HMG-CoA reductase. It is useful in patients who require additional LDL cholesterol reduction despite maximally- tolerated statin therapy. It can also be used as monotherapy or combined with ezetimibe in patients who cannot tolerate statin therapy.

It is administered as a 180mg oral tablet once daily. Common adverse effects include hyperuricaemia, gout and increased liver enzymes, while tendon rupture is a rarer but potentially serious adverse effect. Bempedoic acid should not be co-administered with simvastatin at doses greater than 20mg or pravastatin at doses greater than 40mg due to an increased risk of muscle-related adverse effects.

Fibrates

Fibrates primarily work by activating peroxisome proliferator-activated receptors, which regulates lipid metabolism. They are generally not considered first-line treatment but may be used as an adjunct to lifestyle modification and other lipid-lowering therapies to achieve treatment targets. They have a relatively modest effect on LDL cholesterol and are often reserved for patients with significant hypertriglyceridaemia.

Examples of fibrates commonly used include fenofibrate and bezafibrate. Adverse effects include abdominal
pain, gallstone formation, elevated liver enzymes and myopathy. The risk of muscle toxicity is increased when fibrates are combined with statins.

PCSK9 inhibitors

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of LDL receptor metabolism. Evolocumab and alirocumab are monoclonal antibodies that inhibit PCSK9 and are administered by subcutaneous injection, typically every two weeks or monthly. They increase hepatic LDL receptor recycling, producing substantial reductions in LDL cholesterol and reducing cardiovascular events. These agents are usually reserved for patients with established cardiovascular disease
or familial hypercholesterolaemia who remain above LDL cholesterol targets despite maximally tolerated oral lipid- lowering therapy. They may be used as monotherapy or in combination with other lipid-lowering therapies.

An important advantage is their lack of clinically significant drug interactions. Injection-site reactions, nasopharyngitis and headache are the most common adverse effects, while hypersensitivity reactions and angioedema are rarer

but potentially serious. Pharmacists should counsel patients regarding correct storage, injection technique and adherence to the dosing schedule.

Inclisiran has a similar clinical effect but works via a slightly different mechanism. It is a small interfering RNA (siRNA) therapy that reduces hepatic production of PCSK9, increasing LDL receptor expression and lowering circulating LDL cholesterol. Initial doses are administered at baseline and three months, followed by maintenance treatment every six months. The administration schedule and adverse effect profile are broadly similar to those of the PCSK9 inhibitors.

Pharmacist’s role and conclusion

Community pharmacists play a crucial role in the prevention and management of cardiovascular disease through the early identification and ongoing support of patients with hypercholesterolaemia. They are ideally placed to encourage cholesterol screening, provide guidance on evidence- based lifestyle modification and optimise pharmacological therapy.

Lifestyle modification is often the first intervention in cholesterol management, with pharmacists offering advice on the importance of diet, exercise and maintaining a healthy body weight. Pharmacists can also counsel patients on over-the-counter cholesterol supplements and provide evidence-based advice regarding their efficacy and safety.

Medication adherence is one of the biggest challenges in cholesterol management. Hypercholesterolaemia is generally asymptomatic, with the benefits of treatment not immediately apparent. Pharmacists can reinforce the importance of long-term adherence and address concerns regarding adverse effects. They can also identify clinically significant drug interactions and advise on appropriate monitoring requirements.

Through lifestyle counselling, medication optimisation and patient education, pharmacists can make a significant contribution to improving cardiovascular outcomes.