High blood levels of low-density lipoprotein cholesterol (LDL-C) is a major causative factor of coronary artery disease. Drug and/or diet-mediated lowering of the LDL level is known to reduce the risk of cardiovascular disease. The effectiveness of low LDL in reducing the risk of atherosclerotic vascular events has been discussed in a recently published article in the journal Clinics of Endocrinology and Metabolism of North America†
Hypercholesterolemia is a medical condition characterized by very high levels of LDL in the blood. LDL is considered “bad” cholesterol because it builds up in the walls of arteries, leading to narrowing and hardening of arteries and obstruction of blood flow. Based on population statistics, a blood cholesterol level of 300 mg/dL was initially considered the upper limit of normal.
Nearly all nucleated mammalian cells can synthesize cholesterol, and LDL is only needed to recycle it. Human newborn babies have very low levels of LDL compared to young children and adults. The large amounts of cholesterol necessary for fetal brain development are synthesized in the brain.
Diseases caused by mutations in LDL receptors, such as familial hypercholesterolemia, can significantly increase blood LDL levels, leading to the development of myocardial infarction and other atherosclerotic events.
The effectiveness of lowering blood LDL levels in reducing the risk of coronary heart disease was first discussed at a National Institutes of Health (NIH) consensus conference held in 1984. In 1987, lovastatin, the first statin drug, was introduced to the market and showed significant efficacy in controlling LDL levels in the blood. Since then, many cholesterol-lowering drugs with high efficacy have been developed, including atorvastatin and rosuvastatin, ezetimibe.
Most cholesterol-lowering drugs have shown significant efficacy in lowering LDL levels in the blood, which in turn reduces the risk of myocardial infarction, stroke and other atherosclerotic events. Treatment with PCSK9 (a liver protease) targeting monoclonal antibodies (alirocumab and evolocumab) in combination with statin drugs has been shown to reduce LDL levels by 50%.
According to current European guidelines, a blood LDL level of 40 mg/dL is considered a target threshold for the treatment of patients who have experienced two or more serious atherosclerotic events.
Safety profiles of cholesterol-lowering drugs
Statins, which are the backbone of cholesterol-lowering therapy, are associated with some adverse side effects, including muscle injury and new-onset diabetes. However, there is ample evidence to suggest that statin treatment-related muscle symptoms develop as a result of the nocebo effect (negative treatment outcome due to the patient’s disbelief in the treatment).
Treatments with alirocumab for more than 6 months have been shown to lower LDL levels below 15 mg/dL without causing serious side effects, including cognitive impairment, new-onset diabetes and hemorrhagic stroke. Similar results have been observed with evolocumab treatment.
Incisiran (siRNA) mediated reduction in PCSK9 blood level by 80% – 90% has been shown to cause a 50% reduction in LDL level without causing serious side effects. Taken together, these observations indicate that ultra-low LDL levels achieved by cholesterol-lowering treatments are not associated with major health risks.
Usefulness of ultra-low LDL level
Many clinical studies have been conducted to investigate the impact of lowering LDL levels on cardiovascular risk reduction. According to these studies, the risk of cardiovascular events can be reduced by 22% per 1 mmol/L reduction in LDL level. A blood LDL level of 25-50 mg/dL is considered optimal in patients with atherosclerotic vascular disease. However, lowering LDL levels below 25 mg/dL has been observed to provide no additional treatment benefit in these patients.
Based on available evidence collected from large-scale clinical trials of cardiovascular outcomes, an LDL level of 40 mg/dL or lower is considered beneficial in terms of significantly reducing the risk of cardiovascular events.
In the current paper, two important points have emerged based on findings from large-scale clinical trials. A blood LDL level of 40 mg/dL or lower has been set as a target threshold for cholesterol-lowering drugs in patients who have had two or more atherosclerotic events.
Although no adverse side effect has been documented in response to an LDL level of 25 mg/dL, further reduction of LDL level may not provide additional benefit in patients with cardiovascular disease.