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% over 10 years. More than 80% of these deaths were attributable to atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C), which is usually referred to as ‘bad’ cholesterol, 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 therefore 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 reducing of risk of ASCVD events. Persons who maintain lifetime exposure to low plasma levels of LDL-C have a low lifetime risk of ASCVD.

It means that making lifetime choices of low exposure to LDL-C translates into a significant reduction in the risk of CV events. The challenge in current practice is that 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. 

Study

A study of about 1.5 million patients with a history of more than one (>1) major ASCVD event reported that more than 50% (>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 2 years, 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. 

Barriers

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 more than 50% (>50%) with a consequent significant risk reduction of major ASCVD events.

 The magnitude of LDL-C lowering is directly linked to the 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).  Statins are administered as first-line agents to lower plasma LDL cholesterol (LDL-C) levels. 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%. 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 (liver cells), leading to its degradation and a subsequent increase in plasma LDL-C levels.

The 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, and Evolocumab, reduce LDL-C levels by about 60% when added to statin therapy in very high-risk patients.

ATP-citrate lyase (ACLY) catalyzes 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, Heterozygous Familial Hypercholesterolaemia (HeFH), or both, bempedoic acid added to statin therapy reduced LDL-C levels by 18.1%.

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%, slightly less than the levels achieved with anti-PCSK9 monoclonal antibodies and greater than for bempedoic acid as monotherapy and in combination with ezetimibe. 

High ASCVD risk

Elevated plasma triglycerides (TG) level is associated with an 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 persons and provide the most effective lipid-lowering combination to reduce the ASCVD risk aggressively. Polyphenol-rich cocoa protects LDL from oxidation and enhances 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).

The Writer Is Chief Pharmacist
Cocoa Clinic