Reducing atherosclerotic cardiovascular disease risk: A focus on lipid lowering drugs

In the ensuing piece, l will be using lots of materials from Wilkinson et al. Evolving Management of Low-Density Lipoprotein Choles­terol: A Personalised Approach to Preventing Atherosclerotic Cardio­vascular Disease Across the Risk Continu­um. J. Am. Heart Assoc 2023.

Cardiovascular disease (CVD) is a leading cause of death globally. In 2020, CVD re­sulted in about 19 million deaths, an increase of 18.7 per cent over 10 years. More than 80 per cent of these deaths were attributable to atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein choles­terol (LDL-C) is a major causal factor in the pathophysiology of atherosclerotic cardio­vascular disease (ASCVD). Elevated LDL-C is a key modifiable risk factor contributing to CVD burden. There is a linear relationship between LDL-C levels and the risk of ASC­VD. Management of LDL-C levels is central to ASCVD prevention strategies.

Several studies have shown that it is not only the magnitude of LDL-C elevation but also the duration of exposure to elevated LDL-C that is associated with ASCVD risk. This makes the timing of implement­ing strategies to decrease lipid levels key to slowing the progression of atherosclerotic plaques and reduction of risk of ASCVD events. Persons who maintain lifetime ex­posure to low plasma levels of LDL-C have low lifetime risk of ASCVD. It means that making lifetime choices of low exposure to LDL-C translates into significant reduction in the risk CV events. Furthermore where pharmacotherapy is clearly indicated the use is less.

Even for persons who are given lipid-low­ering therapies the management is subop­timal with many not receiving appropriate treatment intensity or available combination therapies needed to achieve LDL-C goals. Another study of about 1.5 million patients with a history of >1 major ASCVD event reported that >50% of patients meeting the 2018 American Heart Association (AHA) American College of Cardiology (ACC) guideline very high-, risk criteria had LDL-C levels >1.8mmol/L despite receiving statins and/or ezetimibe. In the GOULD (Getting to an improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidaemia Management) registry over a 2-year period, two-thirds of patients with ASCVD remained with LDL-C levels above 1.8mmol/L and only 17% received treatment intensification.

Pooled analyses of lipid-lowering thera­pies have shown a linear association be­tween achieved LDL-C levels and absolute coronary heart disease event rates. Every 1.0-mmol/L reduction in LDL-C confers about 22% reduction in the risk of major vascular events.

There are several barriers to the use of lipid-lowering therapy. These include poor patient adherence, lack of health profession­al familiarity, uncertainty about treatment recommendations, time constraints, clinical inertia, and cost issues, others are inadequate patient education, and adverse effects.

Lipid lowering with statin therapy (e. g. Atorvastatin, Rosuvastatin) has been the cornerstone of the prevention and treatment of ASCVD for several years. High-intensity statins can reduce LDL-C levels by >50% with a consequent significant risk reduction of major ASCVD events. The magnitude of LDL-C lowering is directly linked to efficacy of the selected lipid-lowering therapy. At the same time data from JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) confirm wide variation in the degree of LDL-C reduction achieved among individu­als treated with statins.

The goal of lipid-lowering therapy is to reduce the risk of atherosclerotic cardio­vascular disease (ASCVD). Low-density lipoprotein (LDL) is a well-known causal factor of ASCVD. Statins are administered as first-line agents to lower plasma LDL cholesterol (LDL-C) levels. A number of outcome trials have demonstrated that statins have a consistent benefit in reducing the risk of ASCVD in primary and second­ary prevention. Therefore, current guidelines on the management

of blood cholesterol recommend statin administration in all patients treated for secondary prevention, patients with familial hypercholesterolemia, patients aged 40 to 75 years with diabetes and plasma LDL-C ?1.81mmol/L, and patients treated for primary prevention without diabetes and with estimated 10-year ASCVD risk ?7.5%. However, despite optimal statin therapy, a significant residual ASCVD risk remains. Therefore, there is a clinical need for ad­ditional agents which will help in lowering plasma LDL-C and other atherogenic parti­cles effectively.

Ezetimibe reduces cholesterol absorption from the intestine. Ezetimibe in combination with statins is well tolerated and significantly reduces LDL-C levels by up to an additional 24% compared to statins alone.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme predominantly produced in the liver, binds to the LDL receptor (LDLR) present on the surface of the hepatocytes, leading to its degradation and a subsequent increase in plasma LDL-C levels. Thus, inhibition of PCSK9 causes an increase in LDLR number and a subsequent decrease in plasma LDL-C levels. Monoclo­nal antibodies that target PCSK9 (proprotein convertase subtilisin/kexin type 9) e.g. Ali­rocumab, Evolocumab, reduce LDL-C levels by about 60% when added to statin therapy in very high risk patients.

ATP-citrate lyase (ACLY) catalyses the ATP-dependent conversion of citrate and coenzyme A (CoA) to oxaloacetate and acetyl-CoA. Acetyl-CoA, the precursor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), is crucial for the biosynthesis of cholesterol. Thus, inhibition of ACLY leads to a reduction of acetyl-CoA and cholesterol synthesis, resulting in an increased number of LDLRs, causing a subsequent reduction of plasma cholesterol. Bempedoic acid is an oral, once-daily, hypolipidaemic prodrug that targets cholesterol synthesis in the liver by inhibiting ATP-citrate lyase. It is used as an adjunct treatment to maximally tolerated statins. In the CLEAR (Cholesterol Lower­ing via Bempedoic Acid, an ACL (ATP-Ci­trate Lyase-Inhibiting Regimen) Harmony trial of patients with ASCVD, HeFH, or both, bempedoic acid added to statin thera­py reduced LDL-C levels by 18.1 per cent.

Inclisiran is a first-in-class small interfering RNA that uses RNA interference to degrade PCSK9 mRNA, reducing the hepatic synthe­sis of PCSK9 protein and thereby increasing hepatic LDL receptor expression. The mag­nitude of LDL-C lowering with inclisiran is about 50 per cent, slightly less than the levels achieved with anti-PCSK9 monoclonal antibodies and greater than for bempedoic acid as monotherapy and in combination with ezetimibe.

Elevated plasma triglycerides (TG) level is associated with increased risk of ASCVD. However, TG can be degraded by most cells in the body and, therefore, does not accumulate in the atherosclerotic plaque. Therefore, TG itself is unlikely the cause of atherosclerosis. Instead, TG-rich lipoproteins enter into the arterial intima and contribute to plaque formation, eventually leading to a high ASCVD risk. American guidelines recommend the administration of fibrates or omega-3 fatty acids in patients with per­sistently elevated severe hypertriglyceridemia (TG ?565mmol/L) to prevent pancreatitis. European guidelines recommend the admin­istration of n-3 polyunsaturated fatty acids (icosapent ethyl 2×2 g/day) in combination with a statin in high-risk (or above) patients with TG levels between 1.52mmol/L and 5.63mmol/L despite statin treatment (Kim et al. New Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins. Diabetes Metab J. 2022;46:517-53).

Overall, although statins form the back­bone of therapy, achieving a >50% reduc­tion in LDL-C levels with high-intensity statins is often insufficient for patients at the highest risk of ASCVD events. It is there­fore critical to identify high-risk and provide the most effective lipid lowering combina­tion to reduce the ASCVD risk aggressively. Polyphenol-rich cocoa protect LDL from oxidation and enhance high-density lipo­protein cholesterol (HDL-C) concentration. Regular consumption of polyphenol-rich cocoa is beneficial in the prevention of ASCVD (Baba et al. Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative suscepti­bility and has beneficial effects on plasma HDL-cholesterol concentrations in humans. Am J Clin Nutr 2007;85:709 –17)

BY DR EDWARD O. AMPORFUL

CHIEF PHARMACIST

COCOA CLINIC

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