INTRODUCTION:

Statins introduced in late 1980s, its effect in reduction of serum lipids has been reported by many landmark studies.¹Being introduced into the market as lipid lowering agents,they have been shown to reduce mortality and morbidity.²

Statins or HMG CoA inhibitor forms a class of hypolipideimic drugs which are used to lower the cholesterol level in people having or at higher risk of cardio vascular diseases.Cholesterol lowering is achieved by inhibition of HMG CoA reductase enzyme which represents the rate limiting enzyme of mevolonate pathway of cholesterol synthesis.³

Statins represent the mainstay of dislipidemic treatment,therapeutic potential might extend it to have modest effect on lowering triglycerides and raising HDL cholesterol some of its clinical benefits are independent of cholesterol lowering effects. These are called as pleiotropic effects.⁴That is producing or having multiple effects from a single gene. All these effects are achieved by non-LDL mediated pathways, which include its action on inflammatory disorders on conditions such as rheumatoid arthritis, transplantation, multiple sclerosis and chronic kidney disease to emerging evidences which supports the existence of other mechanism of action namely immunosuppressive properties, reducing the risk of osteoporotic fractures in women, effects on atherosclerotic plaque development, and stabilisation, antioxidant actions, favourable coagulation profile, endothelial function, oxidative stress, preventing platelet aggregation and normalising sympathetic outflow.^5-6In addition to this, clinical trials indicates its therapeutic potential as immunosuppressive agents.

Understanding various pleiotropic effect of statin made as aware about their use to treat or prevent wide range of chronic and life threatening disorders. Although the beneficial non lipid effects seem promising clinical trials are needed to validate their use for indication other than the prevention of primary and secondary vascular disease.⁷

Anti-Oxidant effect of Statin

LDL oxidation disrupts vascular tone, which impairs normal relaxation of blood vessel.⁸Endothelium derived NO(Nitric Oxide) production is interfered by this mechanism. Normal endothelial function involves a balance between NO and other oxidants.⁹Statins prevent oxidized LDL(Ox-LDL) with help of endogenous antioxidant system like superoxide dismutase. NO acts as a scavenger antagonising vasoconstrictive property of ROS(Reactive Oxygen Species).¹⁰Thus statins exerts antioxidant effects by suppressing distinct oxidation pathways; decreasing lipid peroxidation and ROS production and increasing NO bioavailability.¹¹

Statins as Immunomodulatory and Anti-Inflammatory

Hypercholestrolemia is a risk factor for CAD(Coronary Artery Disease) and atherosclerosis. Such patients are having higher plasma level of inflammatory cytokines, macrophages, circulating leukocytes and T cells which are modified into atherosclerotic plaques.Although statins are popular for their hypolipideimic effect, evidences support that statins possess immunomodulatory and anti-inflammatory effects. Immunomodulatory effect is achieved by preventing the activation of T lymphocyte by reducing expression of MHC-II (Major Histocompatibility Complex) and also by preventing lymphocyte function associated antigen-1 whereas anti-inflammatory effect is by reducing expression of IL-1(Interleukin-1) and IL-6 (Interleukin-6) in primary human endothelial cells.^12-13

Thus by reducing expression of MHC-II on APC and MHC-II mediated Tcell activation, statins reduce production of inflammatory cytokines like TNF-α(Tumour Necrosis Factor-α) and chemotactic cytokines, these hypolipideimic agents are expected to be useful in rheumatoid arthritis(RA).

Another mechanism suggesting statin use in RA is by disrupting oxidative stress or inflammation cycle, it inhibit lipid peroxidation and release of inflammatory mediator like peroxisome proliferator activated receptor(PPAR) α and Ɣ and when given at proper time having a beneficial effect on vasculature.

Statin helps to get rid of symptoms, inhibits joint destruction and also reduces the risk of cardiovascular events in Rates are having an overall favourable cardio protective effect.¹⁴

Role of statin in Osteoporosis

Osteoporosis, a skeletal disorder characterised by compromised bone strength predisposing individuals in increased fracture risk. Osteoporotic fractures are common cause of disability and associated with high health care expenditure. Drugs used for osteoporosis are capable of preventing execissive bone loss and also inhibit bone desorption but not formation of new bones. Recent studies reported HMG CoA reductase inhibitor accelerates production of bone morphogenetic protein(BMP-2) a regulating protein is osteoblast differentiating and activity. These agents are having an anabolic effect on bones, which increases the bone mineral density especially in hip and spines with reduced risk of fractures. Thus promoting bone formation.¹⁵

Statins as Anti-Thrombotic Agent

Anti-thrombotic effect of statin is by inhibiting production of thromboxane A2 (TXA2). By increasing expression of COX-2 enzyme, statins increase synthesis of anti-aggregant, vasodilating agent prostacyclin. Also reduces chromogenic potential in patients having atherosclerosis by up regulating NO and eNOS. Because this patients are having increased thrombotic potential due to increased production of TXA2.Statins also helps in increasing fibrinolytic activity by raising levels of t-PA and by inhibiting expression of plasminogen activator inhibitor-1(PAI-1)¹⁶

Statins in Immunosuppression and Transplantation

Statins exerts immunosuppressive property by effect on lymphocytes, vascular smooth muscle and endothelial function.¹⁷Repressing induction of MHC-II expression by interferon . If L-Mevolonate is present; MHC-II expression is inhibited stating that the action of statin as HMG CoA reductase inhibitor which mediates repression of MHC-II.T-lymphocyte proliferation by monoclonal antibodies against MHC-II can be blocked through mixed lymphocyte reaction. All these effects are specific for MHC-II and not for MHC-I expression.

Role of statin in Sepsis

Mainly used for bacterial induced sepsis by interference with leukocyte endothelium interaction, modulation of endothelial function and prevention of toxin induced cellular damage.

Trans-migration of leukocytes from vasculature to tissue is the critical event in leukocyte endothelial interaction. Statins increase the levels of endothelial NO and inhibit adhesion of monocytes to endothelium and also inhibit release of PMN cell chemo attractants.

Statins are also active agent α-toxin in septic patients released by staphylococcus aureus. These α-toxins may provoke CV collapse by activating various inflammatory mediators. Also exert its action by negative inotropic and coronary vasoconstriction. Increase in production of thromboxane and by up regulation of adhesion molecules Pselectin and ICAM-1 alpha toxin activity is mediated.^18-19

Statins and Chronic Kidney Disease

Statins are useful in reducing mortality and morbidity in patients having normal renal function. Diabetes could be the prime cause of chronic kidney disease. The mechanism by which statins slows down the rate of renal function is with the levels of soluble tumour necrosis factor receptor II and C reactive protein.^20-21

Diabetic Nephropathy is a leading cause of renal impairment. In this disease, there will be leukocyte infiltration into the glomeruli and accumulation of extracellular matrix around the glomeruli. Statins exert their effect in diabetic nephropathy by inhibiting expression of leukocyte adhesion molecule in glomerular endothelial cells and decreasing migration of macrophage into glomeruli.

Statins can be also useful in chronic glomerulonephritis. This is a disease in which there will be damage to podocytes which are important for structure and function of glomerulus. Statins prevent the damage by platelet activation within and monocyte infiltration into the glomeruli.²²

Statins and Cancer

Statins help to induce apoptosis and inhibit proliferation. Anti-tumour effects of statins therefore exists and helps in inhibition of metastasis and retardation of tumour growth.

Mechanism behind this is not clearly known, but may be by interfering with function of Ras and Rho family. GTPases, by inhibition of cyclic dependant kinases (CDK) and activation of CDK inhibitions. Mevalonate an intermediate in cholesterol synthesis plays major role in cell proliferation and thereby increasing the activity of HMG CoA reductase suggesting a new chemotherapy for cancer.

Anti-tumour property of statins can be related to reduction of non-steroidal isoprenoid compounds. As a result of its overall potent effect, statins are now used in combination with chemotherapeutic or other molecular targeted agents,in chemo preventive therapy. Maintenance therapy in minimal disease status and also in combination with radiotherapy.^23-25

Psychological Well Being

Recent studies reported the evidence of reduced risk of depression in patients with CAD being treated with statins. The impact on psychological status by lipophilic statins is by crossing the blood brain barrier. Another possible explanation is by indirect effects, by reducing risk of depression and through improved quality of life due to more health consciousness or increased incidence of cardio vascular events and compliance.²⁶

Stroke

Statins play an important role in stroke prevention. Many mechanism explains its preventive action on stroke. This includes lipid lowering effects and cholesterol independent mechanisms such as neuroprotective effects via modulating inflammatory mediators.

Anti-oxidative property of statin is a mechanism to protect neuron. This anti-oxidants are released from damaged cells during ischaemic stroke.

On matrix metalloproteases (MMPs), an enzyme that destroys from extracellular proteins like collagen, which release thrombotic stuff into peripheral blood stream produces a neuro inflammatory response. Statins stop the up regulation of MMPs which causes reduction of MMP mediated blood brain barrier permeability.

Activation of eNOS (Endothelial Nitric Oxide Synthase) mediated pathway by statins results in production of eNOS causing a vasodilatory effect which increases the blood flow to cerebrum. Statins thus increase NO production via eNOS and stops over production of NO by iNOS (Inducable Nitric Oxide Synthase) and nNOS (Neuronal Nitric Oxide Synthase).^27-28

Statins also decreases the incidence of ischaemic stroke by stabilising of atherosclerotic, anti-thrombotic and haematological properties which induce thromboembolism and plaque disruption from artery to artery.^29-30

Congestive Heart Failure

Congestive Heart Failure (CHF) is the impairment of heart function with inflammation, endothelial dysfunction and neuro-hormonal imbalance. The use of statins helps in lowering levels of β-natriuretic peptide and inflammatory mediators TNF-α. This decrease in the levels of cytokines may reduce peripheral blood flow and may lead to cardiac cachexia, rise in this markers may cause increased mortality. Statins also helps to improve endothelial function.

Ischemic and non-ischemic heart failure patients who used statins shows decreased evidences of mortality and thus needs urgent organ transplantation.

Their use also helps in prevention of cardiac hypertrophy by inhibition of isoprenylation of intracellular signalling proteins like Ras, Rho and Rac, which helps in modulation of hypertrophic responses and blocks release of oxidative stressors which modulate cardiac hypertrophy. Thus the benefits of statin therapy have been reported in high risk patient irrespective of their high cholesterol levels.^31-34

Hypertension

Statins promotes synthesis of NO which is a mediator of homeostasis and blood flow. Their decreased synthesis in endothelial cells induces platelet aggregation, vasoconstriction and leukocyte recruitment and adhesion.

In vitro experiments are conducted with vascular endothelial cells and results reported that statins helps in inhibition of thrombin induced activation of endothelin-1, a potent vasoconstrictor as well as procoagulant tissue factor and mitogenic molecule that regulates vascular tone and remodelling.

Renin Angiotensin System(RAS) also play a major role in blood pressure regulation in hypercholestrolemic patients, high cholesterol level induce AT1 over expression, resulted in enhancement of angiotensin II induced blood pressure elevation. Statin mediated decrease in AT1 receptor helps is improved endothelial function, reduced angiotensin II driven vasoconstriction and lowering of blood pressure.^35-38

Statins in Peripheral Arterial Diseases

By increasing production of nitric oxide in endothelium, statins have a vasodilatory property beyond its anti-thrombogenic, anti-proliferative and leukocyte adhesion inhibiting effect. Statins also influence atherosclerosis by other mechanism including endothelium dependent relaxation enhancement and inhibition of platelet function,endothelin-1 and nitrogen. Statins may this improve lower extremity functioning in PAD by retarding deleterious effects of atherosclerosis on by arteries^.39-40

Plaque Stability

Unstable plaque ruptures is a major cause of Myocardial Infraction (MI). Statin therapy helps in stabilization of atherosclerotic lesion. Characteristic of atherosclerotic plaque include a large lipid rich core and an intensive inflammatory response in this fibrous cap with macrophages and its ability to degrade collagen containing fibrous cap with help of proteolytic enzymes.

Statins decrease size of lipid core by effective lipid lowering capacity and by reducing intracellular lipid accumulation by inhibiting cholesterol esterification. Inhibitory effect of statin in inflammation, coagulation and thrombogenicity also reduces risk of plaque rupture.^41-43

CNS Disease

Although statins are well effective in cardio vascular disorders, this are also suggested for use in cerebrovascular accidents, in congenital disorders, stabilization of pre-cerebral atheroma in aorta and carotid arteries and inhibition of platelet activity.

This beneficial effects in CNS may be due NO production, as this may improve cerebral vasodilator response, enhance CNS collateral blood flow and also helps prevent apoptosis.^44-46

In alzheimer’s disease, CNS cholesterol level is elevated which accelerate amyloid precursor protein(APP),cleavage to beta amyloid (Aβ) considered cytotoxic to oligodendrocytes and neurons.^47-49

CONCLUSION:

Statins are effective medications, which have shown great promise beyond their hypolipideimic effects. A number of experimental and clinical data give evidences for their broader therapeutic benefit. Despite their safety, efficacy and cost effectiveness right patients are not getting adequate treatment with the use of this drug. The causes behind their underutilization and treatment may be related to their efficacy, safety, adverse drug reaction, failure to prescribe right medication or dose and non-compliance with therapy. Understanding of lipid and non-lipid mechanism helps in development of newer therapies, which can provide additional benefit in form of risk reduction. Although a number of drug are available, statin establish their supremacy over other lipid lowering agents because they are best tolerated and can provide cardio protective effects independent of their lipid lowering action.

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Received on 14.04.2016 Modified on 16.05.2016

Research J. Pharm. and Tech. 2016; 9(7):977-981.

DOI: 10.5958/0974-360X.2016.00187.6