Cholesterol, an important lipid present in all cell-membranes, is mostly synthesized in the liver by an enzyme: 3-hydroxy3-methylglutaryl coenzyme A (HMG-CoA). Up to one gram of cholesterol can be synthesized per day. It is transported in the blood as a part of lipoprotein particles in different forms. Low density lipoproteins (LDL) account for 60-70% of total serum cholesterol, and is the most atherogenic. High density lipoproteins (HDL) account for 20-30% of total serum cholesterol, and its levels are inversely correlated with cardiovascular risk. Very low density lipoproteins (VLDL) and chylomicrons account for 10-15% of total serum cholesterol, and are rich in triglycerides, seemingly atherogenic.

     The normal range of total serum cholesterol is 120-220 mg / dl.The HDL normal range is 35 -100 mg / dl. The LDL levels of low, moderate, and high risk  are <130, 130-160, and > 160 mg / dl respectively. Cholesterol / HDL ratio represents risk factor 1 for CAD. A ratio of 3.3 - 4.4 represents low risk. A ratio of 4.5 - 7.0 represents an average risk. A ratio of 7.1-11.0 represents a moderate risk, while a ratio > 11.0 represents a high risk. LDL / HDL ratio represents risk factor 2 for CAD. Low, moderate, and high risks are represented by ratios of 0.5-3.0, 3.1-6.0, and > 6.0 respectively.The normal range for serum triglycerides is 40 - 150 mg / dl.

      With accumulating LDL, they begin to stick to the vessel wall, where the permeability of the endothelium increases allowing further accumulation. Macrophages then adhere to the lesion sites and more cholesterol accumulates forming fatty streaks. A plaque is formed when a fatty streak is overlaid with a layer of scar tissue. Large plaques can limit the blood flow at times of increased demand. Plaques are liable to be unstable and may rupture, particularly in the presence of high levels of LDL, and can cause most of the acute coronary artery disease (CAD) events. The process takes many years, and once symptoms are experienced, CAD is already established. Treatment should be targeted to primary or secondary prevention by lifestyle changes and pharmacotherapy. Attempts to reduce the incidence of CAD should start with education and lifestyle changes including stress reduction, stopping smoking, increased physical activity, weight reduction, and dietary modification. Comorbid conditions such as hypertension and diabetes should be controlled appropriately, and added statins can then contribute.

     Clinical trials data demonstrate that treatment with statins favourably alters the plaque size, cellular composition, chemical composition, and biological activities centered on inflammation and cholesterol metabolism, as well as the risk of clinical events due to atherosclerosis ⁽¹⁾.

Pharmacological properties:

        Statins represent a forefront strategy to manage dyslipidaemia with a pivotal role in the prevention of cardiovascular disease .Statins are a group of drugs that competitively and selectively inhibit the HMG-CoA reductase enzyme, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor for cholesterol. The primary site of action of mevalonate is the liver, the target organ for cholesterol lowering. Statins increase the number of hepatic LDL receptors on the cell-surface, enhancing the uptake and catabolism of LDL and inhibiting the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles. They reduce elevated LDL-cholesterol, total cholesterol, and triglycerides, but they increase HDL-cholesterol^(2,3).

        The therapeutic effect of statins to reduce cholesterol level is obtained within one  week following treatment initiation and the maximum response is achieved in four weeks, and is maintained there-after. As the cholesterol lowering effect is due to the selective inhibition of the HMG-CoA reductase  enzyme in the liver, cholesterol synthesis in non-hepatic cells is not inhibited, with the advantage of non-hepatic cell cholesterol formation needed for normal cell functioning.

       Statins are grouped into two categories according to their structure.

Type 1 statins resemble the first statin ever discovered, mevastatin. Examlpes are:  lovastatin , pravastatin , and simvastatin .

Type 2 statins are fully synthetic. Examples are fluvastatin , cerivastatin , atorvastatin , and  rosuvastatin.

           The differences in structure between the two types affect the pharmacological  properties such as their affinity, rates of entry into hepatic and non-hepatic cells, availability in the systemic circulation, and the routes and modes of metabolic transformation and elimination. Statins of the same type also show differences in physical properties. An example is that both pravastatin and simvastatin belong to type 1,but pravastatin is hydrophilic while simvastatin is lipophilic, and can cross the blood brain barrier.

       An ideal statin should have high affinity for the enzyme active site, marked selectivity of uptake into hepatic cells versus non-hepatic cells, low systemic availability of active inhibitory equivalents, and relatively prolonged duration of action.

      Most of the statins are metabolized by the liver, which causes their low systemic bioavailability. Cytochrome  P450  isoenzymes are involved in the oxidative metabolism of the statins, and may therefore avoid drug accumulation when one of the pathways is inhibited by co-administered drugs ⁽⁴⁾.

 

Side-effects:

Statins are well tolerated by most patients. The most common adverse effects are gastrointestinal disturbances and headache that are usually mild and transient. However, hepatic and skeletal muscle toxicity are of concern.

Statins can cause increased activity in hepatic transaminases, and occasionally this may lead to symptomatic injury. The effect appears to be dose-related and comparable amongst the various statin drugs. The prescribing advice in the setting of production information sheets indicates that any type of  liver disease is a contraindication to statin therapy.  Clinical management would  suggest that all patients should be investigated prior to the initiation of statin therapy, and be monitored closely thereafter.

Statins can also produce a variety of skeletal-muscle problems; the severity is variable and ranges from myalgia to myositis and the most severe form, rhabdomyolysis. The mechanism(s) of skeletal muscle toxicity remains unknown. However, depletion of cholesterol from skeletal muscle cell membranes or effects on metabolic intermediates have been proposed as potential mechanisms ⁽⁵⁾. Although all statins can cause muscle toxicity, the incidence varies with different drugs. Cerivastatin has been associated with the highest incidence of muscle problems, and induced rhabdomyolysis associated with approximately 100 fatalities, and was, so, withdrawn from the market in 2001.

Clinical Applications:

        The clinical applications of statins follow their classical cholesterol lowering effect, and/or other actions independent of their classical cholesterol lowering effect.

        The classical cholesterol lowering effect:

      Statins are indicated for the treatment of primary hypercholesterolemia or mixed dyslipedemia as an adjunct to diet when the response to diet and non- pharmacological treatments (as exercise and weight reduction) is inadequate. This is in the presence or absence of hypertriglyceridemia and regardless of race, sex, or age.

     The recommended start dose of statins is 5 or 10 mg orally once daily. An adjustment of  the next dose level can be made after four weeks. The maximum dose is 40 or 80 mg once daily (according to the type of statin  used) if tolerated without side effects. It takes 4-6weeks after the initiation of statin treatment for plasma lipid levels to show lower changes, and longer for lower tissue lipid levels to be attained.

       It is to be clear that a high level of cholesterol alone is not an indication of statin therapy, because hyperchoesterolemia is only one risk factor for heart disease. Other risk factors should be considered, including  smoking, hypertension, diabetes mellitus, excessive weight, age,  peripheral vascular disease, and sedentary lifestyle⁽⁶⁾.

       In case of success of  a statin to reduce the cholesterol level, it is likely to be needed for the rest of life. In case of combined increase of cholesterol and triglycerides, a statin is to be combined with niacin (nicotinic acid) or a fibric acid (fibrate), where the risk of muscle problem would be higher, and the statin dose would be reduced with a suitable synergistic effect of both drugs. Combinations of medications include: lovastatin+niacin, atorvastatin+ amlodipine, and simvastatin+ ezetimibe.

    Niacin is prescribed to lower LDL cholesterol and triglycerides, and to raise HDL cholesterol. Fibrates are best at lowering triglycerides, and in some cases increasing HDL cholesterol levels. They are not very effective in lowering LDL cholesterol levels. Ezetimibe belongs to a relatively new class of drugs known as the  selective cholesterol absorption inhibitors. These drugs work by preventing the absorption of cholesterol from the intestine. They are most effective at lowering LDL cholesterol, but they also have moderate effects in lowering high triglycerides, and raising HDL cholesterol levels.  Ezetimibe was approved in 2002 for the treatment of high cholesterol, and certain inherited abnormalities.

       Statins have not been yet evidence-based to prevent the associated complications of lipid abnormalities, such as CHD or heart failure. However, statins modulate the release and actions of vasoconstrictors as endothelin I and angiotensin II. Decreasing the levels of these vasoconistrictors potentially reduces the vascular resistance and improves the blood flow in both the coronary and systemic vascular beds.

 

      The effects independent of cholesterol lowering action :

      Statins have beneficial anti-inflammatory effects that are independent  of their classical actions on cholesterol. These effects include reduction in inflammation and enhancement of nitric oxide production in vascular endothelium due to upregulation of endothelial nitric oxide synthase enzyme. The anti-inflammatory effect is also due to reduction of acute phase proteins, including C-reactive protein (CRP), inflammatory cytokines, and cell adhesion molecules.

    Statins have anti-oxidant effects due to scavenging of superoxides, together with reservation of adequate levels of vitamin C and vitamin E, and endogenous anti-oxidants such as glutathione.

   Statins have  anti-thrombotic effects due to a shift in the fibrinolytic balance towards fibrinolysis and reduced platelet aggregation ⁽⁷⁾. They again have an anti-proliferative effect, due to inhibition of smooth muscle cell profiration.

     Clinical trials and animal studies have shown that statins reduce the progression of nephropathy, the development of diabetes, and the bone fracture rates ^(8,9).

 

 

 

The anti-inflammatory role of statins:

Sepsis results in a significant and time-dependent increase in leucocyte recruitement, adherence, and transmigration on the vascular endothelium, and the release of inflammatory mediators ⁽¹⁰⁾.

Statins affect the production of acute phase reactants, such as TNF alpha, IL-6, IL8, and  CRP. The latter is mainly produced by hepatocytes in response to IL-6. In an in vitro study, hepatocytes treated with statins showed significant inhibition of IL-6-induced by CRP production⁽¹¹⁾. Patients with acute coronary syndrome treated with atorvastatin 40 mg/ day showed a rapid reduction in CRP, four days after initiation of treatment compared with placebo⁽¹²⁾. In a double-blinded, placebo-controlled, randomized study, atorvastatin (20 mg/ day) given for three weeks before surgery significantly reduced IL-6, CRP, IL-8 release, and neutrophil adhesion to the venous endothelium in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass ⁽¹³⁾.

In inflammatory conditions other than ischemic heart disease, statins have been shown to improve disease activity. For example, the trial of atorvastatin (40 mg/ day) in 116 patients with active rheumatoid arthritis demonstrated a significant improvement in clinical disease activity score, CRP level, and erythrocyte sedimentation rate ⁽¹⁴⁾.

Recent clinical trials have indicated that statins significantly reduced stroke risk in patients with vascular disease. It is not yet known if this is due to a cholesterol lowering  effect  or to a pleiotropic effect of statins such as improved endothelial function, decreased  platelet  aggregability, and reduced vascular inflammation⁽¹⁵⁾.

 

 

The role of statins in sepsis:

Almog et al in 2004 ⁽¹⁶⁾ had conducted a prospective observational cohort study including 361 consecutive patients admitted with suspected or documented acute bacterial infection, and noticed that severe sepsis developed in 19% of patients in the no pre-statin group compared with only 2.4% of patients in the pre-statin group.

         Fernandez et al in 2006 ⁽¹⁷⁾ analyzed data from 438 patients at high risk of  ICU-acquired infection, being receiving mechanical ventilation for more than four days, 38 of whom (8.7%) had been treated with statins prior to and during ICU admission. The ICU-acquired infection rate in statin-treated patients was non-significantly lower (29% versus 38%).

          A recent  study ⁽¹⁸⁾ was conducted on a small number of 50 critically ill patients admitted to the Critical Care Department, Cairo Faculty of Medicine, with early sepsis, as a prospective  randomized controlled study over one year (Sept 2007 – Sept 2008). Of those; 25patients were enrolled into a statin group (receiving atorvastatin 80 mg/day for four days), while the other 25 patients were enrolled into a control group. The study examined the anti-inflammatory effect when the drug is given orally or via a nasogastric tube because iv forms are not widely available, as guided by measuring serum levels of  CRP  and  procalcitonine (PCT)  at  study day  one and four .The mean levels of CRP and PCT in day four decreased in both groups but were significantly lower in the statin group as compared to the control group. In the same study, the effect of early statin therapy on the clinical course of sepsis was determined by the need for organ supportive measures, which showed that the statin group exhibited significant decrease in the need for vasopressors  (P value = 0.001) and mechanical ventilation (P value = 0.044); and a non-significant decrease in the need for acute hemodialysis. The conclusion was that a short term statin regimen can be associated with a significant reduction in the rate of severe sepsis, if used as an adjunctive therapy in early sepsis.

         Overview:

       Statins are looked upon by some as the aspirin of the 21^st century, because in addition to the above-described actions, it is hypothesized to play a role in slowing the progression of Alzheimer's disease  and dementia ⁽¹⁹⁾ and in decreasing the overall cancer risk⁽²⁰⁾. However, such assumptions, and the overall role of statins in medical practice need to be evidence-based.

      One should know that statins are expensive. However, the health economics of statins address the absolute cost in terms of lives saved. We may assume that the higher the level of patient risk, the more effective the statin therapy would be. But, one should also remember that although the percentage reduction in LDL cholesterol, for example, is a major problem, the paucity of quality data from large numbers of randomized clinical trials represent a more major problem. So again, we are in need to evidence-based  proofs, regarding cost-effectiveness.

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