What is the relationship between Low-Density Lipoprotein (LDL) lowering and the prevention of coronary heart disease (CHD)?

From the Guidelines

Lowering LDL cholesterol to very low levels (<30 mg/dL) is safe and associated with a significant reduction in major adverse cardiovascular events, making aggressive LDL management a cornerstone of heart disease prevention. The primary recommendation is to target LDL levels below 100 mg/dL for most adults, and below 70 mg/dL for those with existing heart disease or diabetes, but recent evidence suggests that even lower levels may be beneficial 1. This can be achieved through a combination of lifestyle modifications and medications, including statins, ezetimibe, PCSK9 inhibitors, and bempedoic acid. Lifestyle modifications should include a Mediterranean or DASH diet low in saturated fats, regular exercise (150 minutes weekly of moderate activity), weight management, smoking cessation, and limited alcohol consumption.

Some key points to consider when managing LDL cholesterol include:

• The use of high-intensity statins, statin/ezetimibe combination, and PCSK9 inhibitors to achieve very low LDL-C levels 1
• The importance of regular exercise and a healthy diet in maintaining low LDL-C levels 1
• The need for individualized treatment plans, taking into account the patient's risk factors and medical history
• The potential benefits of achieving very low LDL-C levels, including a significant reduction in major adverse cardiovascular events 1

It is essential to note that the evidence supporting the safety and efficacy of very low LDL-C levels is based on recent studies, and the most up-to-date guidelines recommend a more aggressive lipid-lowering approach in high-risk patients 1. Each 1 mmol/L (approximately 39 mg/dL) reduction in LDL is associated with about a 22% reduction in cardiovascular events, making aggressive LDL management a crucial aspect of heart disease prevention.

In terms of specific treatment options, statins are the first-line medication therapy, with options including atorvastatin (10-80 mg daily), rosuvastatin (5-40 mg daily), and simvastatin (10-40 mg daily) 1. For patients who cannot tolerate statins or need additional LDL lowering, ezetimibe (10 mg daily), PCSK9 inhibitors (evolocumab or alirocumab by injection every 2-4 weeks), or bempedoic acid (180 mg daily) may be added.

Overall, the goal of LDL cholesterol management is to reduce the risk of heart disease and improve patient outcomes, and the most recent evidence suggests that achieving very low LDL-C levels is a safe and effective way to achieve this goal 1.

From the FDA Drug Label

To reduce the risk of: Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD. Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD. As an adjunct to diet to reduce low-density lipoprotein (LDL-C) in: Adults with primary hyperlipidemia

LDL lowering and heart disease are directly related, as reducing LDL-C levels can decrease the risk of myocardial infarction, stroke, and other cardiovascular events.

• The use of atorvastatin 2 and evolocumab 3 can help reduce LDL-C levels and lower the risk of major adverse cardiovascular events.
• Key benefits of these medications include reducing the risk of myocardial infarction, stroke, and revascularization procedures in adults with multiple risk factors for coronary heart disease.

From the Research

LDL Lowering and Heart Disease

• There is evidence that high LDL cholesterol levels cause atherosclerotic heart disease, and current guidelines recommend an LDL cholesterol target of 70 mg/dL for patients at high or very high risk 4.
• Epidemiologic studies have shown that very low LDL cholesterol levels (lower than 70 mg/dL) are associated with a very low risk of cardiovascular disease, and analyses of randomized clinical trials have shown a greater benefit in reducing the risk of cardiovascular disease among those with very low achieved LDL (below 40 mg/dL) 4.
• High-intensity statin therapy is associated with a higher rate of transaminase elevations, but no hepatic failure, a very small risk of myopathy, and an increased risk of developing diabetes, although the small increase in the risk of developing diabetes is much smaller than the marked lowering of cardiovascular risk 4.

Treatment Options

• Statins inhibit 3-hydroxyl-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) to reduce low-density lipoprotein (LDL) by about 20% to 45% 5.
• Ezetimibe inhibits cholesterol absorption by targeting the Niemann-Pick C1-like 1 protein (NPC1L1), which is related to cholesterol absorption in the intestines, and lowers LDL by about 18% when used alone and by an additional 25% when combined with statin therapy 5.
• Evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody, can reduce LDL from baseline by 53% to 56% 5.
• Combining any of these drugs with the two other drugs on the basis of statin treatment has improved the lipid-lowering effect 5.

LDL Targets and Treatment Goals

• Guidelines provide different LDL-C levels to strive for, depending on the CVD risk, and in patients who do not reach the LDL-C target, combination therapy with additional LDL-C lowering drugs should be considered 6.
• Current European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidemias have further reduced low density lipoprotein-cholesterol (LDL-C) targets, and the use of proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) treatment is recommended for very high-risk ASCVD patients who are not achieving treatment goals on a maximum tolerated dose of a statin and ezetimibe 7, 8.
• However, the lipid management and LDL-C targets attainment is largely suboptimal in very high-risk patients with established atherosclerotic cardiovascular disease 7.