Statins are hydroxymethylglutaryl-coenzyme A reductase inhibitors inhibit denovo cholesterol synthesis leading to reduction of serum cholesterol and low density lipoprotein as well as elevation of high density lipoprotein level. Statins are used in the treatment of dyslipidaemia, prevention of major cardiovascular events and complications. The potential role of statins in the induction of peripheral neuropathy has not been verified as most of statins induced-peripheral neuropathy had been reported as case reports. Also, statins therapy leads to noteworthy reduction of Coenzyme Q10, causing impairment of neuronal energy. The incidence of polyneuropathy was high with atorvastatin (65%) which is lipophilic, and relatively less with fluvastatin (54%) which is hydrophilic. Long-term statins therapy, mainly with atorvastatin and simvastatin, is linked with thedevelopment of peripheral neuropathy.
Keywords: Statins, Peripheral neuropathy, Dyslipidaemia.
Peripheral neuropathy (PN) is a term used to describe dysfunctions and disorders of the peripheral nervous system. PN leads to impairment of movements and/or sensations depending on the affected neurons. Single nerve neuropathy is called mono-neuropathy, while two or more affected neurons in different body areas are called mononeuritis multiplex.1 PN may be acute or chronic, depending on the time of its onset. PN is more precisely classified into motor, sensory and autonomic neuropathies. 2 Sensory symptoms comprise numbness, tingling and prickling sensations as well as positive sensory symptoms such as freezing, burning and throbbing sensations which are common in acquired neuropathy and rare in hereditary PN. 3 Motor neuropathy leads to muscle weakness, cramping, paresis and wasting. Autonomic neuropathy is characterised by constipation and/or diarrhoea, urinary retention, erectile dysfunction, dry eye, dry mouth, excessive sweating, postural hypotension and tachycardia. 4Electro-diagnostic investigations, including needle electromyography and nerve conduction studies, are recommended for accurate and precise diagnosis of PN. Drug-induced PN is one of the chief causes after diabetes mellitus, and it is of immense value in early diagnosis since; stopping the relevant drugs leads to significant recovery. Drugs that are implicated in the induction of PN including allopurinol, amiodarone, metronidazole, hydralazine, enalapril, colchicines and phenytoin. 5
Statins are hydroxymethylglutaryl-coenzyme A (HMGCoA) inhibitors that inhibit denovo cholesterol synthesis leading to reduction of serum cholesterol and low density lipoprotein (LDL) with an increase in high density lipoprotein (HDL) level. The statins family comprises synthetic statins, like atorvastatin, rosuvastatin, fluvastatin and cerivastatin, and natural statins, like mevastatin, lovastatin, prvastatin and simvastatin, which differ in their half-life, potency and lipophilicity. Regardless of their differences in the chemical structure, all bind HMG-CoA, leading to competitive inhibition of natural substrate of this enzyme. Therefore, conversion of mevalonic acid into cholesterol is reduced that activates expression of LDL receptor gene which helps in the reduction of circulating LDL and cholesterol. 6 Statins are used in the treatment of dyslipidaemia and the prevention of major cardiovascular events and complications. 7 Moreover; statins inhibit endothelial dysfunction and plaque-associated inflammatory reactions independent of its cholesterol-reducing effect, suggesting that statins have potential pleiotropic effects. 8 Pleiotropic effects including; improvement of endothelial function, preserve plaque stability, prevention of blood clot formation and modulation of inflammatory responses. 9 Recently, statins have been found to have significant anti-bacterial activity and have illustrated synergistic effects with different antibiotics. 10
Adverse Effects of Statins
Long-term statins therapy increases the risk of muscle damage which accounts for 10-15% of the users. Rhabdomyolysis, which is destruction of muscle cells, may occur rarely during statins therapy. Statins-inducedmuscle damage occurs more in old age, in people with hypothyroidism and concomitant use of fibrate. It has been reported that hydrophilic statins are less toxic than lipophilic statins as lovastatin increases expression of atrogin-1 gene which is linked with the induction of skeletal muscle fibre destruction. 11
Statins therapy might cause reversible cognitive deficits as reported by the Food and Drug Administration (FDA). 12 However, meta-analysis studies have concluded that the present evidences does not support the link between statins and cognitive deficits. Some studies have illustrated that statins therapy improves cognitive function and reduces the risk of dementia in patients with cardiovascular complications. 13
Type 2 Diabetes Mellitus (T2DM)
Prolonged use of statins increase the risk of type 2 diabetes mellitus (T2DM) due to the inhibition of peripheral glucose uptake through down-regulation of glucose uptake transporter-1 (GLT1) whose activity depends on cholesterol. Also, statins are thought to decrease insulin sensitivity and to inhibit insulin secretion due to damaged β-cells of islet of Langerhan. 14
High doses of statins, or when combined with niacin or fibrate, increase the risk of rhabdomyolysis. Bitter orange and grape fruit juice inhibits metabolism of certain statins. Besides, protease inhibitors inhibit statins metabolism and increase the risk of myopathy. 15 Consequently, extensive and broad usage of statins necessitates research into the significant side effects, such as PN.
Statins Induced-peripheral Neuropathy
These drugs may cause distal axonal damage, degeneration of the myelin sheath and nerve roots deterioration. Nevertheless, the potential role of statins in the induction of PN has not been verified as most of statins-induced PN cases have been reported as case reports. The main mechanisms of statins induced-PN are linked to the reduction of cholesterol which is necessary for the myelin sheath of peripheral neurons. 16 Also, statin therapy leads to significant reduction of coenzyme Q10 (CoQ10) which causes impairment of neuronal energy. CoQ10 is an endogenous anti-oxidant essential for the mitochondrial transport chain found in all cell membranes that participate in the regulation and prevention of lipid and protein peroxidation. 17 In rare circumstances, one case for every 2200 statin users developed large fibreneuropathy which might be due to neuronal mitochondrial dysfunction caused by the inhibition of ubiquinone and/or depletion of neuronal membrane cholesterol. 18 The link between small fibre neuropathy and statins therapy is limited. Previously, a study confirmed the association between statins and painful PN. 19 On the contrary, another study reported significant ameliorative effects of statins on diabetic PN. 20 Moreover, statins induced-PN is never fibre length independent as statins lead to thigh sensory and autonomic neuropathy with sparing of distal axons in the feet. The reason behind this phenomenon is statin induced-ganglionopathy as statins may cause degeneration of sensory and autonomic ganglions. This type of ganglionopathy may be sub-acute or chronic,leading to neuropathic dysfunction due to the reduction of nerve fibre density. 21 The probable mechanisms of statins inducedganglionopathy and/or neuropathy are due to induction of neuronal apoptosis and necrosis as well as myelin sheath degeneration due to inhibiting the conversion of HMG-CoA into mevalonate which is essential for neuronal cholesterol. Besides, mevalonate is necessary for neuronal ubiquinone and adenosine triphosphate (ATP) production. Consequently, the reduction of mevalonate leads to the reduction of farnesyl-pyrophosphate which is involved in the production of geranyl-geranyl pyrophosphate which is responsible for the production of anti-apoptotic proteins that inhibit neuronal apoptosis.22,23 Additionally, epidemiological studies illustrated equivocal results in the association between statins and risk of PN, but remain indistinct whether hypercholesterolaemia or statins is the main cause of PN. 24However, a recent study reported dose-independent effect of statins in the induction PN, so there is no apparent dose-response pattern between statins and risk of PN which may give a clue for the negative association between statins and risk of PN. 25 Besides, a study reported that risk of statins induced-neuropathy is typically developed after long-term therapy and, therefore, statins induced neuropathy is cumulatively dose-dependent. 26 Astudy illustrated that statins induced-neuropathy sets in after two years of therapy and neuropathic manifestations are reduced and relieved by statins discontinuation. These symptoms reappear after resumption of the statins therapy. 27 Previously, in vitro studies have shown that fluvastatin led to neuritic degeneration for cultured spinal motor neurons. Simvastatin and pravastatin might cause neuritic degeneration only at a higher concentration. Besides, peripheral neurons are less susceptible to the toxic effect of statins compared to spinal neurons, suggesting different mechanism of neuronal toxicity. Hydrophilic statins, like pravastatin and rosuvastatin, demonstrated less peripheral neuronal damage compared with lipophilic statins, like simvastatin and rosuvastatin, due to the difference in the compartmental pharmacokinetics. 28 Tall et al’s animal model study confirmed that statins havea potential effect on mitochondrial membrane through inhibition of carnitine palmitoyl transferase leading to the reduction of the attachment of Ras-family protein (Rab5) which is involved in neuronal endocytosis. 29 Accumulating evidence supports a key role for extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in the development of the central nervous system (CNS) and in the regulation of peripheral neuron functions. ERK1/2, is one of the most well characterized members of the mitogen-activated protein kinase family, regulates a range of processes, from metabolism, motility and inflammation, to cell death and survival. In the nervous system, ERK1/2 regulates synaptic plasticity, brain development and repair of neuronal damage. ERK1/2 is also has a potent effect on of neuronal death and neuro inflammation in PN. 30Akt is one of the central kinases that perform a pivotal function in mediating survival signaling in a wide range of neuronal cell types in response to growth factor stimulation, it prohibits neuronal death. 31 Yanae et al illustrated that, statins provoke glioma cell line apoptosis and induce membrane damage through modulation of AKT and ERK1/2 pathways in the peripheral neurons, signifying different molecular pathways in normal and abnormal neuronal cells. 32Moreover, a recent study confirmed the usefulness of rosuvastatin in the PN management through the reduction of pro-inflammatory biomarkers. 33 In contrast, Carrillo-Ibarra et al reported that both simvastatin and rosuvastatin did not reduce the biomarkers of deoxyribonucleic acid (DNA) oxidative damage in patients with diabetic PN. 34 Furthermore, a previous double-blind, placebo-controlled clinical trial demonstrated that statins were not superior to placebo in the attenuation of diabetic PN after 16 weeks of intervention in spite of reduction of oxidative stress by statins. 35
Dyslipidaemia and the Risk of Statins
Dyslipidemia may be a risk factor in the development of PN regardless of the statins therapy. Oxidised LDL (oxLDL) serum levels are linked with the incidence and progression of PN. It has been reported that oxLDL isresponsible for neuronal damage through the induction of apoptotic injury, including activation of caspase-3 and cytochrome-c with the reduction of anti-apoptotic pathway. Besides, oxLDL reduces native protective neuronal LDL receptors. 36 Therefore, rosuvastatin but not atorvastatin improves symptoms and severity of PN due to reduction of oxLDL, lipid peroxidation and oxidative stress sera levels after three months of therapy,indicating that hydrophilic but not lipophilic statins are less associated with risk of PN. 37 Likewise, dyslipidaemia may be considered as an independent risk factor in the progression and development of PN. Animal model study confirmed that high-fat diet (HFD) in mice with leptin deficiency leads to dyslipidaemia and decreases nerve conduction velocity with potential sensory deficit. 38 Nevertheless, Vincent et al illustrated that apolipoprotein-knockout mice with dyslipidaemia did not develop PN. 39 It has been reported that statins might affect autononmic neurons since; atorvastatin but not rosuvastatin reduces sympathetic nerve activity due to the lipophilic property of atorvastatin. 40 This finding gives evidence that hydrophilic statins do not penetrate the neuronal membrane and do not produce an effect on neuronal metabolism and function. As well, the association between statins and risk of PN was high with atorvastatin (65%), which is lipophilic, and relatively less with fluvastatin (54%), which is hydrophilic. 41Hence, hyperlipidaemia and statins are inter-related as causative factors in the induction of PN, but statins are still used in patients with major cardiovascular events like myocardial infarction and ischaemic stroke. 42 Consequently, statins are mainly blamed for peripheral neuronal damage and PN. Therefore, large-scale studies are recommended to explore the effect of individual statins on nerve electrophysiology in normal healthy volunteers to precisely elucidate the effect of statins on nerve physiology.
Long-term statins therapy, mainly with atorvastatin and simvastatin, are associated with the development of peripheral neuropathy.
Acknowledgment: We are grateful to all the staff members of the Department of Clinical Pharmacology and Therapeutics, Al-Mustansiriya University, Baghdad, Iraq, for their cooperation and support.
Conflicts of Interest: None.
Source of Funding: None.
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