ABSTRACT
Statins, or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the mainstay
of treatment for hypercholesterolemia as they effectively reduce LDL-C levels and
risk of atherosclerotic cardiovascular disease. Apart from hyperglycemia, dyslipidemia
and HDL dysfunction are known risk factors for neuropathy in people with obesity and
diabetes. Although there are case reports of statin-induced neuropathy, ad hoc analyses
of clinical trials and observational studies have shown that statins may improve peripheral
neuropathy. However, large randomized controlled trials and meta-analyses of cardiovascular
outcome trials with statins and other lipid-lowering drugs have not reported on neuropathy
outcomes. Because neuropathy was not a prespecified outcome in major cardiovascular
trials, one cannot conclude whether statins or other lipid-lowering therapies increase
or decrease the risk of neuropathy. The aim of this review was to assess if statins
have beneficial or detrimental effects on neuropathy and whether there is a need for
large well-powered interventional studies using objective neuropathy end points.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical TherapeuticsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Prescribing statins to reduce cardiovascular disease: 10 common misconceptions.Am J Med. 2019; 132: 897-899
- Interpretation of the evidence for the efficacy and safety of statin therapy.Lancet. 2016; 388: 2532-2561
- Hyperlidaemia: Diagnosis & Management.3rd ed. CRC Press, 2007
- Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells.J Neurosci. 2002; 22: 1679-1689
- Statins an oft-prescribed drug is implicated in peripheral neuropathy: the time to know more.J Pak Med Assoc. 2019; 69: s108-s112
- Oxidized LDL causes endothelial apoptosis by inhibiting mitochondrial fusion and mitochondria autophagy.Front Cell Dev Biol. 2020; 8
- Hyperlipidemia: a new therapeutic target for diabetic neuropathy.J Peripher Nerv Syst. 2009; 14: 257-267
- The metabolic syndrome influences the risk of chronic complications in patients with type 2 diabetes.Diabetologia. 2001; 44: 1148-1154
- Vascular impairment of epineurial arterioles of the sciatic nerve: implications for diabetic peripheral neuropathy.Rev Diabet Stud. 2015; 12: 13-28
- Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy.Diabetologia. 1989; 32: 92-102
- Lipids and peripheral neuropathy.Curr Opin Lipidol. 2021; 32: 249-257
- Statin-associated peripheral neuropathy: review of the literature.Pharmacotherapy. 2004; 24: 1194-1203
- Statins: mechanism of action and effects.J Cell Mol Med. 2001; 5: 378-387
- Statin toxicity: mechanistic insights and clinical implications.Circ Res. 2019; 124: 328-350
- Enhanced cellular metabolism of very low density lipoprotein by simvastatin. A novel mechanism of action of HMG-CoA reductase inhibitors.Eur J Clin Invest. 1994; 24: 173-178
- Quantitative evaluation of statin effectiveness versus intolerance and strategies for management of intolerance.Atherosclerosis. 2020; 306: 33-40
- Optimising treatment of hyperlipidaemia: quantitative evaluation of UK, USA and European guidelines taking account of both LDL cholesterol levels and cardiovascular disease risk.Atherosclerosis. 2018; 278: 135-142
- Are recent statin recommendations to employ fixed doses and abandon targets effective for treatment of hypercholesterolaemia? Investigation based on number needed to treat.Eur J Prevent Cardiol. 2017; 24: 76-83
- Evidence for more intensive cholesterol lowering.Curr Opin Lipidol. 2017; 28: 291-299
- The discovery and development of HMG-CoA reductase inhibitors.J Lipid Res. 1992; 33: 1569-1582
- Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,00 participants in 26 randomised trials.Lancet. 2010; 376: 1670-1681
- Cholesterol, not just cardiovascular risk, is important in deciding who should receive statin treatment.Eur Heart J. 2015; 36: 2975-2983
- Hypercholesterolaemia and its management.BMJ. 2008; 337: a993
- A comparison of the effects of low- and high- dose atorvastatin on lipoprotein metabolism and inflammatory cytokines in type 2 diabetes: results from the Protection Against Nephropathy in Diabetes with Atorvastatin (PANDA) randomized trial.J Clin Lipidol. 2018; 12: 44-55
- Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.Lancet. 2008; 371: 117-125
- Primary Prevention of Cardiovascular Disease with Atorvastatin in Type 2 Diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.Lancet. 2004; 364: 685-696
- Molecular mechanisms underlying the effects of statins in the central nervous system.Int J Molecul Sci. 2014; 15: 20607-20637
- Adverse effects of statin therapy: perception vs. the evidence—focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract.Eur Heart J. 2018; 39: 2526-2539
- Current and emerging uses of statins in clinical therapeutics: a review.Lipid Insights. 2016; 9: 13-29
- The nocebo effect in the context of statin intolerance.J Clin Lipidol. 2016; 10: 739-747
- Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society consensus panel statement on assessment, aetiology and management.Eur Heart J. 2015; 36: 1012-1022
- Safety and efficacy of stating therapy.Nature Rev Cardiol. 2018; 15: 757-769
- Adverse events associate with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase.Lancet. 2017; 389: 2473-2481
- Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survery of 10,138 current and former statin users.J Clin Lipidol. 2012; 6: 208-215
- Identification and management of patients with statin-associated symptoms in clinical practice: a clinician survey.Atherosclerosis. 2016; 245: 111-117
- Misperception among physicians and patients regarding the risks and benefits of statin treatment: the potential role of direct-to-consumer advertising.J Clin Lipidol. 2008; 2: 51-57
- Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.JAMA. 2011; 305: 2556-2564
- Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.Lancet. 2010; 375: 735-742
- Are statins diabetogenic?.Curr Opin Cardiol. 2011; 26: 342-347
- The Diabetes Subpanel of the National Lipid Association Expert Panel. An assessment by the Statin Diabetes Safety Taskforce: 2014 update.J Clin Lipidol. 2014; 8: S17-S29
- HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.Lancet. 2015; 385: 351-361
- Statins: pros and cons.Medicina Clinica. 2018; 150: 398-402
- Acquired low cholesterol: diagnosis and relevance to safety of low LDL therapeutic targets.Curr Opin Lipidol. 2018; 29: 318-326
- Corneal confocal microscopy identifies small-fiber neuropathy in subjects with impaired glucose tolerance who develop type 2 diabetes.Diabetes Care. 2015; 38: 1502-1508
- Microvascular complications of impaired glucose tolerance.Diabetes. 2003; 52: 2867-2873
- Corneal confocal microscopy detects neuropathy in subjects with impaired glucose tolerance.Diabetes Care. 2014; 37: 2643-2646
- Association of HMG-CoA reductase inhibitors with neuropathy.Ann Pharmacother. 2003; 37: 274-278
- Peripheral neuropathy associated with simvastatin.J Neurol Neurosurg Psychiatry. 1995; 58: 625-628
- Are users of lipid-lowering drugs at increased risk of peripheral neuropathy?.Eur J Clin Pharmacol. 2001; 56: 931-933
- Statins and polyneuropathy revisited: case-control study in Denmark, 1999-2013.Br J Clin Pharmacol. 2017; 83: 2087-2095
- Statin use and peripheral nerve function—a prospective follow-up study.Basic Clin Pharmacol Toxicol. 2019; 126: 203-211
- Statins do not increase risk of polyneuropathy.Neurology. 2019; 92: e2136-e2e44
- Effect of rosuvastatin on diabetic polyneuropathy: a randomized, double-blind, placebo-controlled Phase IIa study.Diabetes Metab Syndr Obes. 2014; 7: 401-407
- Lipid-Lowering therapy and peripheral sensory neuropathy in type 2 diabetes: the Fremantle Diabetes Study.Diabetologia. 2008; 51: 562-566
- Statins and neuropathic pain: a narrative review.Pain Therapy. 2020; 9: 97-111
- Metabolic syndrome and peripheral neuropathy.Muscle Nerve. 2021; 63: 285-293
- Small fiber neuropathy associated with hyperlidemia: utility of cutaneous silent periods and autonomic tests.Int Sch Res Notices. 2014; 579242
- High-fat diet induced neuropathy of pre-diabetes and obesity: effects of 'healthy' diet and aldose reductase inhibition.Diabetes. 2007; 56: 2598-2608
- Diabetic neuropathy: cellular mechanisms as therapeutic targets.Nature Rev Neurol. 2011; 7: 573-583
- Vascular risk factors and diabetic neuropathy.N Engl J Med. 2005; 352: 341-350
- The contemporary prevalence of diabetic neuropathy in type 1 diabetes: findings from the T1D Exchange.Diabetes Care. 2020; 43: 806-812
- Obesity and hyperlipidemia are risk factors for early diabetic neuropathy.J Diabetes Complications. 2013; 27: 436-442
- Risk Factors for the Presence and Progression of Cardiovascular Autonomic Neuropathy in Type 2 Diabetes: ADDITION-Denmark.Diabetes Care. 2018; 41: 2586-2594
- Higher levels of small dense low-density lipoprotein (LDL) are associated with cardiac autonomic neuropathy in patients with type 2 diabetes.Diabetic Med. 2013; 30: 694-701
- Neuropathy associated with hypertriglyceridemia in patients with metabolic syndrome.Acta Endocrinologica. 2016; 12: 26-29
- Metabolic factors, lifestyle habits, and possible polyneuropathy in early type 2 diabetes: a nationwide study of 5,248 patients in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Cohort.Diabetes Care. 2020; 43: 1266-1275
- Explanations for less small fibre neuropathy in South Asian versus European subjects with type 2 diabetes in the UK.Diabetes Metab Res Rev. 2018; 34: e3044
- The role of abnormalities of lipoproteins and HDL functionality in small fibre dysfunction in people with severe obesity.Scientific Rep. 2021; : 11
- A systematic review and meta-analysis of the serum lipid profile in prediction of diabetic neuropathy.Sci Rep. 2021; 11: 499
- Corneal confocal microscopy as a tool for detecting diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes: ADDITION-Denmark.J Diabetes Complications. 2018; 32: 1153-1159
- Improvements in diabetic neuropathy and nephropathy after bariatric surgery: a prospective cohort study.Obes Surg. 2021; 31: 554-563
- Bariatric surgery leads to an improvement in small nerve fibre damage in subjects with obesity.Int J Obes (Lond). 2021; 45: 631-638
- Short-term metabolic change is associated with improvement in measures of diabetic neuropathy: a 1-year placebo cohort analysis.Diabetic Med. 2010; 27: 1271-1279
- Hypertriglyceridemia and peripheral neuropathy in neurologically asymptomatic patients.Neuro Endocrinol Lett. 2005; 26: 775-779
- The role of hyperlidemia on nerve conduction.J Fac Med Baghdad. 2008; 50: 105-109
- Statin safety and associated adverse events: a scientific statement from the American Heart Association.Arterioscler Thromb Vasc Biol. 2019; 39: e38-e81
- Treatment with statins and peripheral neuropathy: results of 36-months a prospective clinical and neurophysiological follow-up.Neuroendocrinol Lett. 2011; 32: 101-103
- Statins-related peripheral neuropathy among diabetic patients.Diabetes Metab Syndr Clin Res Rev. 2020; 14: 341-346
- lipid lowering drugs prescription and the risk of peripheral neuropathy: an exploratory case-control study using automated databases.J Epidemiol Community Health. 2004; 58: 1047-1051
- Association of statin use with peripheral neuropathy in the US population 40 years of age or older.J Diabetes. 2013; 5: 207-215
- Statin use before diabetes diagnosis and risk of microvascular disease: a nationwide nested matched study.Lancet Diabetes Endocrinol. 2014; 2: 894-900
- Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis.BMC Med. 2014; : 12
- Statin therapy and risk of polyneuropathy in type 2 diabetes: a Danish cohort study.Diabetes Care. 2020; 43: 2945-2952
- Neuropsychiatric adverse events associated with statins: epidemiology, pathophysiology, prevention and management.CNS Drugs. 2014; 28: 249-272
- Does simvastatin affect mood and steroid hormone levels in hypercholesterolemic men? A randomized double-blind trial.Psychoneuroendocrinology. 2003; 28: 181-194
- Long-term association of psychological well-being in a randomized placebo-controlled trial of cholesterol reduction with pravastatin.Arch Intern Med. 2000; 160: 3144-3152
- Lipid-lowering drugs (statins) and peripheral neuropathy.Electronic Physician. 2018; 10: 6527-6533
- Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism.Am J Cardiovasc Drugs. 2008; 8: 373-418
- Statins: multiple neuroprotective mechanisms in neurodegenerative diseases.Experimental Neurol. 2011; 230: 27-34
- Neuroprotection by pravastatin in acute ischemic stroke in rats.Brain Res Rev. 2008; 58: 48-56
- Brinton RD. Statin therapy and risk of Alzheimer's and age-related neurodegenerative diseases.Trans Res Clin Intervent. 2020; 6: e12108
- Statins in the prevention of dementia and Alzheimer's disease: a meta-analysis of observational studies and an assessment of confounding.Pharmacoepidemiol Drug Saf. 2012; 22: 345-358
- Tolerance and pharmacokinetics of single-dose atorvastatin, a potent inhibitor of HMG-CoA reductase, in healthy subjects.J Clin Pharmacol. 1996; 36: 728-731
- The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms.Transl Neurodegener. 2018; 7: 1-11
- Statin-associated memory loss: analysis of 60 case reports and review of the literature.Pharmacotherapy. 2003; 23: 871-880
- Statins: then and now.Methodist DeBakey Cardiovasc J. 2019; 15: 23-31
- 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.Lancet. 2012; 380: 581-590
- Lipids: a suitable therapeutic target in diabetic neuropathy?.J Diabetes Res. 2017; 2017: 1-9
- Therapeutic effects of fenofibrate on diabetic peripheral neuropathy by improving endothelial and neural survival in db/db mice.PLoS ONE. 2014; 9: 1-12
- Diagnosis of neuropathy and risk factors for corneal nerve loss in type 1 and type 2 diabetes: a corneal confocal microscopy study.Diabetes Care. 2021; 44: 150-156
- Elevated triglycerides correlate with progression of diabetic neuropathy.Diabetes. 2009; 58 (1634-0)
- Jonville-Bera A. Severe toxic neuropathy due to fibrates.J Neurol Neurosurg Psychiatry. 1999; 66: 410
- Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk.Circulation. 2015; 132: 1648-1666
- Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat Genet. 2003; 34: 154-156
- Cardiovascular efficacy and safety of bococizumab in high-risk patients.N Engl J Med. 2017; 376: 1527-1539
- Evolocumab and clinical outcomes in patients with cardiovascular disease.N Engl J Med. 2017; 376: 1713-1722
- Alirocumab and cardiovascular outcomes after acute coronary syndrome.N Engl J Med. 2018; 379: 2097-2107
- PCSK9 inhibitors for treating dyslipidemia in patients at different cardiovascular risk: a systematic review and meta-analysis.Intern Emerg Med. 2017; 12: 1043-1053
- Obesity and type 2 diabetes are associated with elevated PCSK9 levels in young women.Pediatr Diabetes. 2017; 18: 755-760
- PCSK9 is increased in youth with type 1 diabetes.Diabetes Care. 2017; 40: e85-ee7
- Calorically restricted diets decrease PCSK9 in overweight adolescents.Nutr Metab Cardiovasc Dis. 2017; 27: 342-349
- Relaxation of porcine retinal arterioles exposed to hypercholesterolemia in vivo is modified by hepatic LDL-receptor deficiency and diabetes mellitus.Exp Eye Res. 2013; 115: 79-86
- Nerve growth factor (NGF) and pro-NGF increase low-density lipoprotein (LDL) receptors in neuronal cells partly by different mechanisms: role of LDL in neurite outgrowth.J Neurochem. 2016; 136: 306-315
- Stress-induced upregulation of VLDL receptor alters Wnt-signaling in neurons.Exp Cell Res. 2016; 340: 238-247
- Hyperlipidemia-induced apoptosis of hippocampal neurons in apoE(-/-) mice may be associated with increased PCSK9 expression.Mol Med Rep. 2017; 15: 712-718
- The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis.Eur Heart J. 2016; 37: 536-545
- Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.N Engl J Med. 2015; 372: 1489-1499
- Design and rationale of the EBBINGHAUS trial: a phase 3, double-blind, placebo-controlled, multicenter study to assess the effect of evolocumab on cognitive function in patients with clinically evident cardiovascular disease and receiving statin background lipid-lowering therapy—a cognitive study of patients enrolled in the FOURIER trial.Clin Cardiol. 2017; 40: 59-65
FDA advises of adverse effects from new cholesterol drugs [Available from: http://www.wsj.com/articles/SB10001424052702304732804579425612487904436] 2022.
- Association of corneal nerve fiber measures with cognitive function in dementia.Ann Clin Transl Neurol. 2019; 6: 689-697
- Corneal nerve and brain imaging in mild cognitive impairment and dementia.J Alzheimers Dis. 2020; 77: 1533-1543
- PCSK9 monoclonal antibody treatment promotes small fibre regeneration in heterozygous familial hypercholesterolemia.Atherosclerosis. 2020; 315: e215
Article info
Publication history
Published online: July 06, 2022
Accepted:
March 26,
2022
Identification
Copyright
© 2022 Published by Elsevier Inc.
