Statin

According to the World Health Organization (WHO), ischemic heart disease and stroke are the two major causes of death. Apart from age, gender, and family history, the majority of these cardiovascular events are caused by modifiable risk factors; high blood pressure, tobacco use, overweight/obesity, lack of physical activity, diabetes, and high blood cholesterol levels. Reducing cholesterol levels is therefore one of the therapeutic targets in reducing the prevalence of cardiovascular mortality. The medication group statins can reduce cholesterol plasma levels by at least 20 percent due to the inhibition of the enzyme 3-hydroxy-3-methylglutaryl CoA (HMG CoA). This enzyme is responsible for the irreversible step in the biosynthesis of cholesterol. Furthermore, statins reduce the risk of thrombosis and stenosis by their interaction with the atherothrombotic process. Statins are therefore the first choice of pharmacotherapeutical cholesterol-lowering agents in the prevention of cardiovascular events.

Background

Cholesterol is an essential component of the cell membranes, where it fulfills its role as a transporting and signaling molecule. It is also a precursor molecule of fat soluble vitamins and bile. Cholesterol can be synthesized by the liver (endogenous) or can be obtained from food such as animal fats (exogenous). Dietary cholesterol is transported to the liver by chylomicrons. These are a type of lipoproteins—molecules that can carry cholesterol through the blood. Lipoproteins vary in density from very low (VLDL) to high density lipoproteins (HDL). The liver can regulate its endogenous cholesterol production according to the amount of dietary cholesterol intake. It can also remove cholesterol to extrahepatic tissues in the form of VLDL particles. After splitting triglycerides from VLDL-particles by hydrolysis, low density lipoproteins (LDL particles) remain in the blood plasma. Cholesterol, packed in LDL particles, accounts for 70 percent of the plasma cholesterol in most individuals and is considered "bad cholesterol." Cholesterol from the cells can be transported to the liver. High density lipoprotein-particles (HDL particles) adapt cholesterol from cell membranes and transport it back to the liver. HDL particles can be considered "good cholesterol." The sum of LDL and HDL in blood plasma is referred to as the total cholesterol (TC). TC is expressed in mg/dl and is recommended to be lower than 200 mg/dl.

William Insull explained in his 2009 report, "The pathology of Atheroslerosis: Plaque development and plaque responses to medical treatment," that the LDL particles, as part of the TC, can provoke or intensify the process of atherosclerosis. Because of an excess of cholesterol in the bloodstream (hypercholesterolemia), LDL particles accumulate in the arterial walls. This accumulation of cholesterol is followed by a gradual process of chronic inflammation in the walls. This creates plaques that compromise the blood flow and ultimately can lead to thrombosis or stenosis. In sum, the amount of LDL particles in the blood is a strong predictor of cardiovascular events.

Statins can reduce the cardiovascular risk by the inhibition of the biosynthesis of endogenous cholesterol and additionally, by the retardation and stabilization of the plaque development in arterial walls. The biosynthesis of cholesterol predominantly takes place in the liver. First, the molecules acetyl CoA and acetoacetyl CoA are dehydrated, forming 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). This intermediate molecule is then reduced to the molecule mevalonate by the enzyme HMG-CoA. Statins inhibit this enzyme and thereby block the irreversible step in the cholesterol synthesis. This results in a reduction of TC, including LDL. Statins are preferably taken in the evening, since cholesterol is produced by the liver during the night.

Overview

Statins have demonstrated their therapeutic benefits both in patients with no history of cardiovascular diseases (primary prevention), and in patients who have already experienced a cardiovascular event (secondary prevention). Despite underreporting of side effects, it is believed that the potential benefits of statins may outweigh their potential risks.

When statins were used for primary prevention, a significant reduction was observed in the prevalence of cardiovascular events and mortality rates in patients with a high cardiovascular risk profile. This finding is confirmed by a systematic literature review conducted in 2013 by the Cochrane Collaboration, led by Huffman Taylor et al. Patients with a high initial cardiovascular risk show greater cardiovascular absolute risk reductions caused by statins than those with lesser initial risk. This was demonstrated by the Cholesterol Treatment Trialists in 2012, which stated that for each reduction of 40mg/dl LDL caused by statins, a relative risk reduction of 21 percent in major vascular events was documented in patients. A relative risk reduction in vascular mortality of 12 percent was documented. In terms of age, there is little evidence supporting that the use of statins in elderly patients in primary prevention has net benefits. A meta-analysis conducted by Gotto Savarese et al. ("Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis") in 2013, stated that in the case of the elderly who have a high cardiovascular risk yet no established cardiovascular diseases, statins did not seem to prolong life in the short term, even though the incidence of myocardial nfarction (MI) and stroke was reduced.

In secondary prevention, statins are proven to be effective in the prevention of subsequent major coronary events for almost all patients. In patients with a history of ischemic stroke or patients with coronary heart diseases (MI, heart attack, angina), statin therapy showed a significant reduction in the incidence of subsequent vascular events. Statin therapy showed a reduction in cardiovascular mortality only in patients with coronary heart diseases. Previous cardiovascular benefits are not demonstrated in patients with a history of hemorrhagic stroke.

In terms of clinical efficacy, there is no clear distinction between different types of statins. Similarly, in 2011, O’Regan Mills et al. documented in "Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of >40000 patients" that there is no evidence of a significant difference in mortality between highly dosed statin therapy and moderate-dosed therapy.

Despite all the documented benefits. Muscle effects are the most reported and documented adverse effect (AE) of statin therapy and are dose-dependent. 5 to 10 percent of patients suffer from myalgia and 0.1 percent from myositis. When severe muscle damage is determined, this can lead to renal dysfunction and renal failure (rhabdomyolysis), sometimes causing death. Rhabdomyolysis is a rare AE, but can be amplified by drug interactions that affect the metabolic pathway of statins, called cytochrome P450 (CYP) 3A4. Inhibitors of this CYP-system (e.g., fibrates and grapefruit) increase the risk of AE by elevating statin plasma levels. Due to pharmacogenomic differences, patients’ tolerance for CYP-drug-interactions can differ. In addition, other organs such as the brain, liver, and heart can be affected by statins. Cognitive problems and elevated transaminase levels (indicator of liver damage) are reported. Statins in high doses may also increase the incidence of type 2 diabetes, but this AE does not outweigh its cardiovascular benefits. Observational and limited data suggest that supplementation of coenzyme Q10 may lead to an improvement of statin-induced AEs.

Bibliography

Cholesterol Treatment Trialists et al. "The Effects of Lowering LDL Cholesterol with Statin Therapy in People at Low Risk of Vascular Disease: Meta-Analysis of Individual Data from 27 Randomised Trials." TheLancet 380 (2012): 581–90. Print.

Golomb, Beatrice, and Marcella Evans. "Statin Adverse Effects: A Review of the Literature and Evidence for Mitochondrial Mechanism." American Journal of Cardiovascular Drugs 8.6 (2008): 373–418. Print.

Insull, William. "The Pathology of Atheroslerosis: Plaque Development and Plaque Responses to Medical Treatment." The American Journal of Medicine 122.1 (2009): 3–14. Print.

Manktelow, Bradley, and J. F. Potter. "Interventions in the Management of Serum Lipids for Preventing Stroke Recurrence." The Cochrane Library 3 (2009). Print.

Mills, O’Regan, et al. "Intensive Statin Therapy Compared with Moderate Dosing for Prevention of Cardiovascular Events: A Meta-Analysis of >40000 Patients." European Heart Journal 32.11 (2011): 1409–15. Print.

Pagano, Irwin S., and Nathan B. Strait. HDL and LDL Cholesterol: Physiology and clinical significance: Nova, 2009. Print.

Savarese, Gotto, et al. "Benefits of Statins in Elderly Subjects without Established Cardiovascular Disease: A Meta-Analysis." Journal of the American College of Cardiology 62.22 (2013): 2090–99. Print.

Taylor, Huffman, et al. "Statins for the Primary Prevention of Cardiovascular Disease." The Cochrane library 1 (2013). Print.

Ward, Lloyd Jones, et al. "A Systematic Review and Economic Evaluation of Statins for the Prevention of Coronary Events." Health Technology Assessment 11.14 (2007): 1–160. Print