What is the relationship between high Low-Density Lipoprotein (LDL) cholesterol and mortality?

From the Guidelines

High LDL cholesterol is strongly associated with increased mortality risk, and reducing LDL levels is crucial to prevent cardiovascular disease, with a target LDL level of < 70 mg/dL for high-risk patients. The relationship between LDL and mortality is well-established, with epidemiological studies and clinical trials confirming that lowering LDL cholesterol reduces cardiovascular risk 1. A meta-analysis of many trials shows a clear dose-dependent relative reduction in cardiovascular disease with LDL cholesterol lowering, with every 1.0 mmol/L reduction in LDL cholesterol associated with a corresponding 20–25% reduction in cardiovascular disease mortality and non-fatal myocardial infarction 1.

Recent studies have further confirmed the benefits of lowering LDL levels, with the FOURIER trial showing a statistically significant reduction in cardiovascular events even at very low LDL levels, with no evidence of a plateau in cardiovascular benefit down to LDL levels as low as 10 mg/dL 1. Additionally, a post hoc analysis of the ODYSSEY OUTCOMES trial showed that alirocumab reduced all-cause death, with all-cause mortality declining with lower achieved LDL-C levels, down to an LDL-C level of 30 mg/dL 1.

Treatment of high LDL cholesterol typically involves lifestyle modifications, including a heart-healthy diet, regular exercise, weight management, and smoking cessation. Medication therapy often starts with statins, such as atorvastatin or rosuvastatin, which can reduce LDL by 30-50%. For those who cannot tolerate statins or need additional LDL lowering, ezetimibe or PCSK9 inhibitors, such as evolocumab or alirocumab, may be added. The goal of treatment is to achieve an LDL level below 70 mg/dL for high-risk patients, with regular monitoring through lipid panels every 3-12 months to assess treatment effectiveness and adjust therapy as needed.

Key points to consider in the management of high LDL cholesterol include:

• The importance of lifestyle modifications in reducing cardiovascular risk
• The use of statins as first-line therapy for LDL lowering
• The potential benefits of adding ezetimibe or PCSK9 inhibitors for additional LDL lowering
• The need for regular monitoring of lipid levels to adjust therapy as needed
• The goal of achieving an LDL level below 70 mg/dL for high-risk patients.

Overall, the evidence supports the importance of reducing LDL levels to prevent cardiovascular disease and reduce mortality risk, with a focus on achieving an LDL level below 70 mg/dL for high-risk patients 1.

From the FDA Drug Label

The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group There was no significant difference between the treatment groups for all-cause mortality (Table 7). Atorvastatin calcium reduces total-C, LDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia

The answer to the question of high LDL and mortality is that high LDL is associated with increased risk of cardiovascular events and death.

• Key points:
  • Atorvastatin calcium 80 mg/day significantly reduced the rate of major cardiovascular events (MCVE) by 22% compared to 10 mg/day.
  • The reduction in MCVE was driven by significant reductions in non-fatal, non-procedure related MI and fatal and non-fatal stroke.
  • There was no significant difference in all-cause mortality between the two treatment groups.
  • Atorvastatin calcium reduces LDL-C and other lipid parameters in patients with hyperlipidemia. 2

From the Research

High LDL and Mortality

• High levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for cardiovascular disease and mortality 3, 4.
• Statins are commonly used to reduce LDL cholesterol levels, but may not be sufficient for all patients, particularly those at high risk of cardiovascular events 3, 5.
• The addition of non-statin therapies, such as ezetimibe, to statin therapy can provide further reductions in LDL cholesterol levels and improve cardiovascular outcomes 3, 6.
• Combination therapy with statins and ezetimibe has been shown to be effective in reducing cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, and stroke 6.
• The use of ezetimibe in combination with statins can also help to reduce the risk of cardiovascular events in patients with acute coronary syndromes 6.
• Rosuvastatin and ezetimibe combination therapy has been shown to be effective in treating hypercholesterolemia and mixed dyslipidemia, particularly in high-risk patients such as those with diabetes 7.

Treatment Options

• Statins are the first-line therapy for reducing LDL cholesterol levels and preventing cardiovascular disease 3, 4.
• Ezetimibe can be added to statin therapy to provide further reductions in LDL cholesterol levels and improve cardiovascular outcomes 3, 6.
• Other non-statin therapies, such as bile acid sequestrants, can also be used to reduce LDL cholesterol levels 5.
• Combination therapy with statins and ezetimibe can be used to treat patients with hypercholesterolemia and mixed dyslipidemia, particularly those at high risk of cardiovascular events 7.

Benefits and Risks

• The use of statins and ezetimibe can provide significant reductions in LDL cholesterol levels and improve cardiovascular outcomes 3, 6.
• Combination therapy with statins and ezetimibe can also reduce the risk of cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, and stroke 6.
• However, the use of statins and ezetimibe can also be associated with adverse effects, such as muscle pain and liver enzyme elevations 3, 6.
• The benefits and risks of treatment should be carefully considered for each patient, taking into account their individual risk factors and medical history 4, 7.