Az autonóm neuropathia a cukorbetegség igen gyakori szövődménye, mely a diabetes kórfejlődése során már korán kialakul, sőt már a csökkent glükóztolerancia stádiumában is jelen lehet. A betegek életminőségére, a cardiovascularis morbiditásra és mortalitásra gyakorolt prognosztikus jelentősége, a többi szövődménnyel mutatott összefüggései miatt a cardiovascularis autonóm funkció károsodása a cukorbetegség szövődményei között kiemelt jelentőségű. A cardiovascularis autonóm neuropathia klinikai manifesztációi mint a nyugalmi tachycardia, az orthostaticus hypotonia, a néma myocardialis ischaemia és infarktus vagy éppen a QT-távolság megnyúlása miatt kialakuló ritmuszavarok mind hozzájárulnak a cardiovascularis autonóm neuropathia rossz prognózisához. Ezek a betegek gyakrabban szenvednek el hirtelen szívhalált, és a perioperatív légzés-keringésleállás kockázata is nagyobb. A szövődmény irányában végzett szűrővizsgálatok így alapvető jelentőségűek. A diagnosztikában a mai napig a hagyományos cardiovascularis reflextesztek tekinthetők arany standardnak, melyek egyszerű, noninvazív, jól reprodukálható, megfelelő szenzitivitással és specificitással rendelkező eszközös vizsgálatok. Az egyéb vizsgálati lehetőségek közül a szívfrekvencia-variabilitás és baroreflex-szenzitivitás a prognózis pontosabb megítélésére, illetve elsősorban klinikai tanulmányokban végpontokként használatosak. Az összefoglaló kitér emellett a betegek előszűrését szolgáló kérdőíves módszerekre és a diagnosztika egyszerűsítését célzó újabb lehetőségekkel kapcsolatos legfrissebb eredményekre. A cardiovascularis autonóm neuropathia kezelésének sarokkövét a megfelelő glykaemiás kontroll és a cardiovascularis kockázati tényezők kontrollja jelenti. További oki terápiás lehetőség az alfa-liponsav alkalmazása, melynek az autonóm funkcióra gyakorolt kedvező hatásait klinikai vizsgálat igazolta. A hagyományos értelemben vett glykaemiás kontrollon túl újabban a glykaemiás variabilitás és egyes antidiabetikumok idegi funkciókra gyakorolt pleiotrop hatásai kerültek előtérbe. A testsúlycsökkentés nemcsak a diabetes, de az autonóm neuropathia tekintetében is jótékony hatású, ugyanakkor az életmód-terápia további összetevőivel kapcsolatban nem egyértelműek az adatok. Orv Hetil. 2024; 165(16): 602–612.
Autonomic neuropathy is a common and early complication of diabetes mellitus that can be present at the time of diabetes diagnosis or before, at the stage of impaired glucose tolerance. Cardiovascular autonomic neuropathy has a special significance among diabetic complications given its detrimental effect on the quality of life, its associations with other diabetic complications and its prognostic value regarding cardiovascular morbidity and mortality. Clinical manifestations of cardiovascular autonomic neuropathy, such as resting tachycardia, orthostatic hypotension, silent myocardial ischaemia and infarction as well as cardiac arrhythmias as a consequence of QT-interval prolongation all contribute to its poor prognosis. Patients with cardiovascular autonomic neuropathy are more prone to have sudden cardiac death and they have a higher risk for perioperative cardiac and respiratory arrest. Hence, screening and diagnosis of cardiovascular autonomic neuropathy in diabetic patients is crucial. Nowadays, cardiovascular autonomic reflex tests are still the gold standard of cardiovascular autonomic assessment. These tests are easy-to-perform, non-invasive, reproducible instrumental tests with high sensitivity and specificity. Among other methods of cardiovascular autonomic testing, the assessment of heart rate variability and baroreflex sensitivity provide additional prognostic information and are used as endpoints in clinical trials. This review provides the latest information on some new facilities aiming at the simplification of the diagnostic procedure such as pre-screening questionnaires and new devices as well. Glycaemic control and treatment of cardiovascular risk factors are the cornerstone of cardiovascular autonomic neuropathy management. Administration of alpha-lipoic acid is a further, pathogenetically-based causal therapeutic option with its beneficial effects proven in clinical trial. Beyond traditional measures of glycaemic control, the role of glycaemic variability and pleiotropic effects of some antidiabetic medications on neural function are of growing interest. Weight reduction is beneficial not only for diabetes itself but for improving autonomic control as well. Meanwhile, data on the effect of other components of lifestyle modification on autonomic function in diabetes are rather conflicting. Orv Hetil. 2024; 165(16): 602–612.
Spallone V, Ziegler D, Freeman R, et al. Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011; 27: 639–653.
Sztanek F, Zöld E, Harangi M, et al. The classification and diagnosis of diabetic neuropathy according to recent international guidelines. [A diabeteses neuropathia osztályozása és diagnosztikája a legújabb nemzetközi ajánlások alapján.] Magyar Belorv Arch. 2018; 71: 193–200. [Hungarian]
Putz Zs, Kempler P, Jermendy Gy. Diabetes-specific complications in prediabetes. [Diabetesspecifikus szövődmények praediabetesben.] Orv Hetil. 2009; 150: 2139–2145. [Hungarian]
Németh N, Putz Z, Istenes I, et al. Is there a connection between postprandial hyperglycemia and IGT related sensory nerve dysfunction? Nutr Metab Cardiovasc Dis. 2017; 27: 609–614.
Zoppini G, Cacciatori V, Raimondo D, et al. Prevalence of cardiovascular autonomic neuropathy in a cohort of patients with newly diagnosed type 2 diabetes: the Verona newly diagnosed type 2 diabetes study (VNDS). Diabetes Care 2015; 38: 1487–1493.
Shah AS, El Ghormli L, Vajravelu ME, et al. Heart rate variability and cardiac autonomic dysfunction: Prevalence, risk factors, and relationship to arterial stiffness in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Diabetes Care 2019; 42: 2143–2150.
Spallone V, Morganti R, D’Amato C, et al. Validation of DN4 as a screening tool for neuropathic pain in painful diabetic polyneuropathy. Diabet Med. 2012; 29: 578–585.
Martin CL, Albers JW, Pop-Busui R, for the DCCT/EDIC research group. Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care 2014; 37: 31–38.
Vági OE, Svébis MM, Domján BA, et al. Association of cardiovascular autonomic neuropathy and distal symmetric polyneuropathy with all-cause mortality: a retrospective cohort study. J Diabetes Res. 2021: 2021: 6662159.
Andersen ST, Witte DR, Fleischer J, et al. Risk factors for the presence and progression of cardiovascular autonomic neuropathy in type 2 diabetes: ADDITION-Denmark. Diabetes Care 2018; 41: 2586–2594.
Benichou T, Pereira B, Mermillod M, et al. Heart rate variability in type 2 diabetes mellitus: a systematic review and meta-analysis. PLoS ONE 2018; 13: e0195166.
Hansen CS, Jensen JS, Ridderstråle M, et al. Vitamin B12 deficiency is associated with cardiovascular autonomic neuropathy in patients with type 2 diabetes. J Diabetes Complications 2017; 31: 202–208.
Hansen CS, Fleischer J, Vistisen D, et al. High and low vitamin D level is associated with cardiovascular autonomic neuropathy in people with type 1 and type 2 diabetes. Diabet Med. 2017; 34: 364–371.
Young LH, Wackers FJ, Chyun DA, et al. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA 2009; 301: 1547–1555.
Ziegler D. Diabetic cardiovascular autonomic neuropathy: prognosis, diagnosis and treatment. Diabetes Metab Rev. 1994; 10: 339–383.
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: 1895–1901.
Cardoso CR, de Oliveira VA, Leite NC, et al. Prognostic importance of cardiovascular autonomic neuropathy on cardiovascular and mortality outcomes in individuals with type 2 diabetes: the Rio de Janeiro type 2 diabetes cohort. Diabetes Res Clin Pract. 2023; 196: 110232.
Soedamah-Muthu SS, Chaturvedi N, Witte DR, et al. Relationship between risk factors and mortality in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study (PCS). Diabetes Care 2008; 31: 1360–1366.
Mancia G, Grassi G. Orthostatic hypotension and cardiovascular risk: defining the epidemiological and prognostic relevance. Eur Heart J. 2010; 31: 12–14.
Okin PM, Wachtell K, Kjeldsen SE, et al. Incidence of atrial fibrillation in relation to changing heart rate over time in hypertensive patients: the LIFE study. Circ Arrhythm Electrophysiol. 2008; 1: 337–343.
Mala S, Hoskovcova L, Riedlbauchova L, et al. Relationship between cardiac autonomic neuropathy and atherosclerosis in patients with diabetes mellitus. Curr Res Diabetes Obes J. 2018; 9: 14–19.
Wulsin LR, Horn PS, Perry JL, et al. Autonomic imbalance as a predictor of metabolic risks, cardiovascular disease, diabetes, and mortality. J Clin Endocrinol Metab. 2015; 100: 2443–2448.
Al-Humaidi G, Sarikaya I, Elgazzar AH, et al. Myocardial perfusion abnormalities in asymptomatic type 2 diabetic patients. J Saudi Heart Assoc. 2018; 30: 3–8.
Valensi P, Sachs RN, Harfouche B, et al. Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia. Diabetes Care 2001; 24: 339–343.
Kempler P, Jermendy Gy. Cardiovascular autonomic neuropathy in diabetes: clinical experiences in Hungary. Diabetol Hung. 2002; 10(Suppl 2): 37–43.
Rajbhandari J, Fernandez CJ, Agarwal M, et al. Diabetic heart disease: a clinical update. World J Diabetes 2021; 12: 383–406.
Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020; 41(2): 255–323. Erratum: Eur Heart J. 2020; 41(45): 4317.
Lau DH, Schotten U, Mahajan R, et al. Novel mechanisms in the pathogenesis of atrial fibrillation: practical applications. Eur Heart J. 2016; 37: 1573–1581.
Zaccardi F, Khan H, Laukkanen JA. Diabetes mellitus and risk of sudden cardiac death: a systematic review and meta-analysis. Int J Cardiol. 2014; 177: 535–537.
Ricci F, Fedorowski A, Radico F, et al. Cardiovascular morbidity and mortality related to orthostatic hypotension: a meta-analysis of prospective observational studies. Eur Heart J. 2015; 36: 1609–1617.
Fleg JL, Evans GW, Margolis KL, et al. Orthostatic hypotension in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) blood pressure trial: prevalence, incidence, and prognostic significance. Hypertension 2016; 68: 888–895.
Jermendy Gy, Hargittai S. Assessment of diabetic cardiac autonomic neuropathy with the use of personal computers. [A diabeteses cardialis autonom neuropathia vizsgálata számítógéppel.] Diabetol Hung. 1995; 3: 23–26. [Hungarian]
Körei AE, Kempler M, Istenes I, et al. Why not to use the handgrip test in the assessment of cardiovascular autonomic neuropathy among patients with diabetes mellitus? Curr Vasc Pharmacol. 2017; 15: 66–73.
Kempler M, Hajdú N, Putz Z, et al. Diabetic cardiovascular autonomic neuropathy, the handgrip test and ambulatory blood pressure monitoring parameters: are there any diagnostic implications? J Clin Med. 2020; 9: 3322.
Greco C, Di Gennaro F, D’Amato C, et al. Validation of the Composite Autonomic Symptom Score 31 [COMPASS 31] for the assessment of symptoms of autonomic neuropathy in people with diabetes. Diabet Med. 2017; 34: 834–838.
Menduni M, D’Amato C, Leoni M, et al. Clinical scoring systems for the risk of cardiovascular autonomic neuropathy in type 1 and type 2 diabetes: a simple tool. J Peripher Nerv Syst. 2022; 27: 259–270.
Tang ZH, Wang L, Zeng F, et al. Bayesian estimation of cardiovascular autonomic neuropathy diagnostic test based on short-term heart rate variability without a gold standard. BMJ Open 2014; 4: e005096.
Gulichsen E, Fleischer J, Ejskjaer N, et al. Screening for diabetic cardiac autonomic neuropathy using a new handheld device. J Diabetes Sci Technol. 2012; 6: 965–972.
Brock C, Jessen N, Brock B, et al. Cardiac vagal tone, a non-invasive measure of parasympathetic tone, is a clinically relevant tool in type 1 diabetes mellitus. Diabet Med. 2017; 34: 1428–1434.
Mirizzi G, Giannoni A, Bramanti F, et al. A simple method for measuring baroreflex sensitivity holds prognostic value in heart failure. Int J Cardiol. 2013; 169: e9–e11.
Petry D, de Godoy Marques CM, Marques JL. Baroreflex sensitivity with different lags and random forests for staging cardiovascular autonomic neuropathy in subjects with diabetes. Comput Biol Med. 2020:127: 104098.
White DW, Shoemaker JK, Raven PB. Methods and considerations for the analysis and standardization of assessing muscle sympathetic nerve activity in humans. Auton Neurosci. 2015: 193: 12–21.
Tavakoli M, Begum P, McLaughlin J, et al. Corneal confocal microscopy for the diagnosis of diabetic autonomic neuropathy. Muscle Nerve 2015; 52: 363–370.
Nathan DM; DCCT/EDIC Research Group. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care 2014; 37: 9–16.
Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359: 1577–1589.
Spallone V, Valensi P. SGLT2 inhibitors and the autonomic nervous system in diabetes: a promising challenge to better understand multiple target improvement. Diabetes Metab. 2021; 47: 101224.
Winkler G. GLP1 receptor agonists in the therapy of type 2 diabetes. [GLP1-receptor-agonisták a 2-es típusú diabetes vércukorcsökkentő kezelésében.] Orv Hetil. 2022; 163: 1144–1151. [Hungarian]
Winkler G, Kis JT, Arapovicsné Kiss K, et al. From GLP1 receptor agonists to triple hormone receptor activation supplemented with glucagon receptor agonism. New perspectives in the treatment of type 2 diabetes and obesity. [A GLP1-receptor-agonistáktól a glükagonreceptor-agonizmussal kiegészített hármas hormonreceptor-aktiválásig. Új távlatok a 2-es típusú diabetes és az elhízás kezelésében.] Orv Hetil. 2023; 164: 1656–1664. [Hungarian]
Goldney J, Sargeant JA, Davies MJ. Incretins and microvascular complications of diabetes: neuropathy, nephropathy, retinopathy and microangiopathy. Diabetologia 2023; 66: 1832–1845.
Gad H, Elgassim E, Mohammed I, et al. Cardiovascular autonomic neuropathy is associated with increased glycemic variability driven by hyperglycemia rather than hypoglycemia in patients with diabetes. Diab Res Clin Pract. 2023; 200: 110670.
Kempler P, Tesfaye S, Chaturvedi N, et al. Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM complications study. Diabet Med. 2002; 19: 900–909.
Gæde 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: 2298–2307.
Tang Y, Shah H, Bueno CR, et al. Intensive risk factor management and cardiovascular autonomic neuropathy in type 2 diabetes: the ACCORD trial. Diabetes Care 2021; 44: 164–173.
Ziegler D, Low PA, Freeman R, et al. Predictors of improvement and progression of diabetic polyneuropathy following treatment with α-lipoic acid for 4 years in the NATHAN 1 trial. J Diab Compl. 2016; 30: 350–356.
Jermendy G, Rokszin G, Fábián I, et al. Morbidity and mortality of patients with diabetic neuropathy treated with pathogenetically oriented alpha-lipoic acid versus symptomatic pharmacotherapies – a nationwide database analysis from Hungary. Diabetes Res Clin Pract. 2023; 201: 110734.
Bhati P, Shenoy S, Hussain ME. Exercise training and cardiac autonomic function in type 2 diabetes mellitus: a systematic review. Diabetes Metab Syndr. 2018; 12: 69–78.
Guarino D, Nannipieri M, Iervasi G, et al. The role of the autonomic nervous system in the pathophysiology of obesity. Front Physiol. 2017; 8: 665.
Hermida RC, Ayala DE, Mojon A, et al. Influence of time of day of blood pressure-lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes. Diabetes Care 2011; 34: 1270–1276.