Treatment of Diabetic Cardiovascular Autonomic, Peripheral and Painful Neuropathy. Focus on the Treatment of Cardiovascular Autonomic Neuropathy with ACE Inhibitors

Author(s): Triantafyllos Didangelos*, Aristidis Veves

Journal Name: Current Vascular Pharmacology

Volume 18 , Issue 2 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Neuropathies of the peripheral and autonomic nervous systems affect up to half of all people with diabetes mellitus, and are major risk factors for foot ulceration, amputation and cardiovascular dysfunction. Peripheral neuropathies manifest with either painful or painless symptoms, but many patients experience both. Once diagnosed appropriately, painful diabetic neuropathy management presents a unique challenge for physicians and should be considered as a syndrome, clinically distinct from diabetic peripheral neuropathy. The aetiology is multifactorial: metabolic changes in diabetes may directly affect neural tissue and neurodegenerative changes are precipitated by compromised nerve vascular supply. Metabolic changes include the elevated polyol pathway activity, the increased oxidative stress, the formation of advanced glycation and lipoxidation end products, and various pro-inflammatory changes. These mechanisms work in combination and interact in a mutually facilitatory fashion. This review focuses on the current therapies for the management of peripheral and cardiovascular autonomic neuropathy and of painful neuropathy as a distinct entity, based on the current knowledge of diabetic neuropathy. Moreover, the role of ACE inhibition has been explored in the treatment of Cardiovascular Autonomic Neuropathy.

Keywords: Diabetes, neuropathy, treatment, ACE inhibitors, DAN, DPN.

Shaw JE, Zimmet PZ. Epidemiology of diabetic neuropathy. Diabetes Rev 1999; 7: 245-52.
Abbott CA, Malik RA, van Ross ER, et al. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the UK. Diabetes Care 2011; 34: 2220-4.
Veves A, Manes C, Murray HJ, et al. Painful neuropathy and foot ulceration in diabetic patients. Diabetes Care 1993; 16: 1187-9.
Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: Epidemiology, pain description, and quality of life. Diabetes Res Clin Pract 2000; 47: 123-8.
Gordois A, Scuffham P, Shearer A, et al. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care 2003; 26: 1790-5.
Didangelos T, Doupis J, Veves A. Oxidative stress in diabetes mellitus and possible interventions in obrosova I, Stevens M., Yorek M (eds.), Studies in Diabetes, Oxidative Stress in Applied Basic Research and Clinical Practice, ©Springer Science+Business Media New York 2014, pp 237-61.
Sugimoto K, Yasujima M, Yagihashi S. Role of advanced glycation end products in diabetic neuropathy. Curr Pharm Des 2008; 14: 953-61.
Nedić O1. Rattan SI, Grune T, Trougakos IP. Molecular effects of advanced glycation end products on cell signalling pathways, ageing and pathophysiology. Free Radic Res 2013; 47(Suppl. 1): 28-38.
Duran-Jimenez B, Dobler D. Moff att S, et al. Advanced glycation end products in extracellular matrix proteins contribute to the failure of sensory nerve regeneration in diabetes. Diabetes 2009; 58: 2893-903.
Chilelli NC, Burlina S, Lapolla A. AGEs, rather than hyperglycemia, are responsible for microvascular complications in diabetes: A “glycoxidation-centric” point of view. Nutr Metab Cardiovasc Dis 2013; 23(10): 913-9.
Kim B, Feldman EL. Insulin resistance in the nervous system. Trends Endocrinol Metab 2012; 23: 133-41.
Sima AA, Zhang W, Grunberger G. Type 1 diabetic neuropathy and C-peptide. Exp Diabesity Res 2004; 5: 65-77.
Vincent AM, Hinder LM, Pop-Busui R, Feldman EL. Hyperlipidemia: A new therapeutic target for diabetic neuropathy. J Peripher Nerv Syst 2009; 14: 257-67.
Wiggin TD, Sullivan KA, Pop-Busui R, Amato A, Sima AA, Feldman EL. Elevated triglycerides correlate with progression of diabetic neuropathy. Diabetes 2009; 58: 1634-40.
McCall KD, Holliday D, Dickerson E, et al. Phenylmethimazole blocks palmitate-mediated induction of inflammatory cytokine pathways in 3T3L1 adipocytes and RAW 264.7 macrophages. J Endocrinol 2010; 207: 343-53.
Lontchi-Yimagou E, Sobngwi E, Matsha TE, Kengne AP. Diabetes mellitus and inflammation. Curr Diab Rep 2013; 13(3): 435-44.
Doupis J, Rahangdale S, Gnardellis C, Pena SE, Malhotra A, Veves A. Effects of diabetes and obesity on vascular reactivity, inflammatory cytokines and growth factors. Obesity 2011; 19(4): 729-35.
The effect of intensive diabetes therapy on the development and progression of neuropathy. The diabetes control and complications trial research group. Ann Intern Med 1995; 15; 122(8): 561-8.
Tesfaye S, Chaturvedi N, Eaton SEM, et al. Vascular risk factors and diabetic Neuropathy. N Engl J Med 2005; 352: 341-50.
Papanas N, Ziegler D. Prediabetic neuropathy: Does it exist? Curr Diab Rep 2012; 12: 376-82.
Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielk A. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy. Diabetes Care 2008; 31: 464-9.
Witte DR, Tesfaye S, Chaturvedi N, et al. Risk factors for cardiac autonomic neuropathy in type 1 diabetes mellitus. Diabetologia 2005; 48: 164-71.
Boulton AJM. Management of diabetic peripheral neuropathy. Clin Diabetes 23: 9-15.
Partanen J, Niskanen L, Lehtinen J, et al. Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1995; 333: 89-94.
Didangelos T, Doupis J, Veves A. Painful diabetic neuropathy: Clinical aspects. Handb Clin Neurol 2014; 126: 53-61.
Albers JW, Herman WH, Pop-Busui R, et al. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventionsand Complications (EDIC) Study. Diabetes Care 2010; 33: 1090-6.
Pop-Busui R, Low PA, Waberski BH, et al. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC). Circulation 2009; 119: 2886-93.
Linn T, Ortac K, Laube H, Federlin K. Intensive therapy in adult insulin-dependent diabetes mellitus is associated with improved insulin sensitivity and reserve: A randomized, controlled, prospective study over 5 years in newly diagnosed patients. Metabolism 1996; 45: 1508-13.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-53.
The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560-72.
Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycemia on micro vascular outcomes in type 2 diabetes: an analysis of the ACCORD randomized trial. Lancet 2010; 376: 419-30.
Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360: 129-39.
Pittenger G, Vinik A. Nerve growth factor and diabetic neuropathy. Exp Diabesity Res 2003; 4: 271-85.
Apfel SC, Schwartz S, Adornato BT, et al. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: A randomized controlled trial. rhNGF Clinical Investigator Group. JAMA 2000 Nov 1; 284(17): 2215-21.
Tesfaye S. Recent advances in the management of diabetic distal symmetrical polyneuropathy. J Diabetes Investig 2011; 2(1): 33-42.
Casellini CM, Barlow PM, Rice AL, et al. A 6-month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-beta inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy. Diabetes Care 2007; 30(4): 896-902.
Bansal D, Badhan Y, Gudala K, Schifano F. Ruboxistaurin for the treatment of diabetic peripheral neuropathy: A systematic review of randomized clinical trials. Diabetes Metab J 2013; 37(5): 375-84.
Spallone V, Ziegler D, Freeman R, et al. Cardiovascular autonomic neuropathy indiabetes: Clinical impact, assessment, diagnosis and management. Diabetes Metab Res Rev 2011; 27: 639-53.
Pfeifer MA, Weinberg CR, Cook DL, et al. Autonomic neural dysfunction in recently diagnosed diabetic subjects. Diabetes Care 1984; 7: 447-53.
Maser RE, Mitchell BD, Vinik AI, et al. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: A meta-analysis. Diabetes Care 2003; 26: 1895-901.
Ziegler D, Zentai CP, Perz S, et al. Prediction of mortality using measures of cardiac autonomic dysfunction in the diabetic and nondiabetic population: The MONICA/KORA Augsburg Cohort Study. Diabetes Care 2008; 31: 556-61.
Lykke JA, Tarnow L, Parving HH, et al. A combined abnormality in heart rate variation and QT corrected interval is a strong predictor of cardiovascular death in type 1 diabetes. Scand J Clin Lab Invest 2008; 68: 654-9.
Rennings AJ, Smits P, Stewart MW, et al. Autonomic neuropathy predisposes to rosiglitazone-induced vascular leakage in insulin-treated patients with type 2 diabetes: a randomized, controlled trial on thiazolidinedione-induced vascular leakage. Diabetologia 2010; 53: 1856-66.
Didangelos TP, Arsos GA, Karamitsos DT, Athyros VG, Karatzas ND. Left ventricular systolic and diastolic function in normotensive type 1 diabetic patients with or without autonomic neuropathy: A radionuclide ventriculography study. Diabetes Care 2003; 26(7): 1955-60.
Didangelos TP, Arsos G, Karamitsos T, et al. Left ventricular systolic and diastolic function in normotensive type 2 diabetic patients with or without autonomic neuropathy: A radionuclide ventriculography study. Angiology 2014; 65(10): 877-82.
Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation 2007; 115: 387-97.
Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years’ experience in diabetes. Diabetes Care 1985; 8: 491-8.
Gerritsen J, TenVoorde BJ, Dekker JM. Dekker et al. Measures of cardiovascular autonomic nervous function: Agreement, reproducibility, and reference values in middle age and elderly subjects. Diabetologia 2003; 46(3): 330-8.
Gaede P, Vedel P, Parving HH, et al. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 1999; 353: 617-22.
Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348: 383-93.
Gaede P, Lund-Andersen H, Parving HH, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358: 580-91.
Oellgaard J, Gaede P, Rossing P, et al. Reduced risk of heart failure with intensified multifactorial intervention in individuals with type 2 diabetes and microalbuminuria: 21 years of follow-up in the randomised Steno-2 study. Diabetologia 2018; 61: 1724-33.
Gaede P, Oellgaard J, Carstensen B, et al. Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial. Diabetologia 2016; 59: 2298-307.
Kontopoulos AG, Athyros VG, Didangelos TP, et al. Effect of chronic quinapril administration on heart rate variability in patients with diabetic autonomic neuropathy. Diabetes Care 1997; 20(3): 355-61.
Athyros VG, Didangelos TP, Karamitsos DT, et al. Long-term effect of converting enzyme inhibition on circadian sympathetic and parasympathetic modulation in patients with diabetic autonomic neuropathy. Acta Cardiol 1998; 53(4): 201-9.
Didangelos TP, Arsos GA, Karamitsos DT, et al. Effect of quinapril or losartan alone and in combination on left ventricular systolic and diastolic functions in asymptomatic patients with diabetic autonomic neuropathy. J Diabetes Complications 2006; 20(1): 1-7.
Didangelos T, Tziomalos K, Margaritidis C, et al. Efficacy of administration of an angiotensin converting enzyme inhibitor for two years on autonomic and peripheral neuropathy in patients with diabetes mellitus. J Diabetes Res 2017; 2017: 6719239
Selby JV, Peng T, Karter AJ, et al. High rates of co-occurrence of hypertension, elevated low-density lipoprotein cholesterol, and diabetes mellitus in a large managed care population. Am J Manag Care 2004; 10(part 2): 163-70.
Ziegler D, Low PA, Freeman R, Tritschler H, Vinik AI. Predictors of improvement and progression of diabetic polyneuropathy following treatment with α-lipoic acid for 4 years in the NATHAN 1 trial. J Diabetes Complications 2016; 30(2): 350-6.
A. Papageorgiou, A Karayiannis, V Athyros, et al. A comparative study of the efficacy and safety of quinapril and lisinopril in patients with mild to moderate hypertension. Drug Investig 1994; 7(1): 13-7.
Yozgatli K, Lefrandt JD, Noordzij MJ, et al. Accumulation of advanced glycation end products is associated with macrovascular events and glycaemic control with microvascular complications in Type 2 diabetes mellitus. Diabet Med 2018.
Forbes JM, Cooper ME, Thallas V, et al. Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy. Diabetes 2002; 51: 3274-82.
Forbes JM, Thorpe SR, Thallas-Bonke V, et al. Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy. J Am Soc Nephrol 2005; 16(8): 2363-72.
Adler AI, Stevens RJ, Neil A, Stratton IM, Boulton AJ, Holman RR. UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes Care 2002; 25(5): 894-9.
Didangelos TP, Athyros VG, Karamitsos DT, et al. Effect of aldose reductase inhibition on heart rate variability in patients with severe or moderate diabetic autonomic neuropathy. Clin Drug Investig 1998; 15(2): 111-21.
Didangelos TP, Karamitsos DT, Athyros VG, Kourtoglou GI. Effect of aldose reductase inhibition on cardiovascular reflex tests in patients with definite diabetic autonomic neuropathy over a period of 2 years. J Diabetes Complications 1998; 12(4): 201-7.
Merskey H, Bogduk N. Classification of chronic pain: Descriptions of chronic pain syndromes and definitions of pain terms. 2nd ed. Seattle, WA: IASP Press 1994.
Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurology 2008; 70: 1630-5.
Pavy FW. Introductory address to the discussion on the clinical aspect of glycosuria. Lancet 1885; 126: 1085-7.
Veves A, Backonja M, Malik RA. Painful diabetic neuropathy: Epidemiology, natural history, early diagnosis and treatment options. Pain Med 2008; 9(6): 660-74.
Said G, Bigo A, Ameri A, et al. Uncommon early-onset neuropathy in diabetic patients. J Neurol 1998; 245: 61-8.
Oyibo SO, Prasad YD, Jackson NJ, Jude EB, Boulton AJ. The relationship between blood glucose excursions and painful diabetic peripheral neuropathy: a pilot study. Diabet Med 2002; 19(10): 870-3.
Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010; 17: 1113-23.
Bril V, England J, Franklin GM, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and electro diagnostic medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011; 76: 1758-65.
Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: A double-blind, placebo-controlled trial. Pain 2004; 110: 628-38.
Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful diabetic neuropathy: A randomized controlled trial. Neurology 2004; 63: 2104-10.
Richter RW, Portenoy R, Sharma U, et al. Relief of painful diabetic peripheral neuropathy with pregabalin: A randomized, placebo-controlled trial. J Pain 2005; 6: 253-60.
Freynhagen R, Strojek K, Griesing T, et al. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo controlledtrial of flexible- and fixed-dose regimens. Pain 2005; 115: 254-63.
Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial. JAMA 1998; 280: 1831-6.
Raskin J, Pritchett YL, Wang F, et al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med 2005; 6: 346-56.
Harati Y, Gooch C, Swenson M, et al. Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy. J Diabetes Complications 2000; 14: 65-70.
Watson CP, Moulin D, Watt-Watson J, et al. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain 2003; 105: 71-8.
Ziegler D, Low PA, Boulton AJ. Antioxidant treatment with alpha-lipoic acid in diabetic polyneuropathy: A 4-year randomized double-blind trial (NATHAN 1). Diabetologia 2011; 50: S63.
Backonja M, Wallace MS, Blonsky ER, et al. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: A randomized, double-blind study. Lancet Neurol 2008; 7: 1106-12.
Baron R, Mayoral V, Leijon G, et al. Efficacy and safety of combination therapy with 5% lidocaine medicated plaster and pregabalin in post-herpetic neuralgia and diabetic polyneuropathy. Curr Med Res Opin 2009; 25: 1677-87.
Tesfaye S, Wilhelm S, Lledo A, et al. Duloxetine and pregabalin: High-dose mono therapy or their combination? The “COMBO-DN study”--a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain 2013; 154(12): 2616-25.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 27 January, 2020
Page: [158 - 171]
Pages: 14
DOI: 10.2174/1570161117666190521101342
Price: $65

Article Metrics

PDF: 37