Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment

Victoria A Serhiyenko, Alexandr A Serhiyenko, Victoria A Serhiyenko, Alexandr A Serhiyenko

Abstract

Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes mellitus (DM) that is strongly associated with approximately five-fold increased risk of cardiovascular mortality. CAN manifests in a spectrum of things, ranging from resting tachycardia and fixed heart rate (HR) to development of "silent" myocardial infarction. Clinical correlates or risk markers for CAN are age, DM duration, glycemic control, hypertension, and dyslipidemia (DLP), development of other microvascular complications. Established risk factors for CAN are poor glycemic control in type 1 DM and a combination of hypertension, DLP, obesity, and unsatisfactory glycemic control in type 2 DM. Symptomatic manifestations of CAN include sinus tachycardia, exercise intolerance, orthostatic hypotension (OH), abnormal blood pressure (BP) regulation, dizziness, presyncope and syncope, intraoperative cardiovascular instability, asymptomatic myocardial ischemia and infarction. Methods of CAN assessment in clinical practice include assessment of symptoms and signs, cardiovascular reflex tests based on HR and BP, short-term electrocardiography (ECG), QT interval prolongation, HR variability (24 h, classic 24 h Holter ECG), ambulatory BP monitoring, HR turbulence, baroreflex sensitivity, muscle sympathetic nerve activity, catecholamine assessment and cardiovascular sympathetic tests, heart sympathetic imaging. Although it is common complication, the significance of CAN has not been fully appreciated and there are no unified treatment algorithms for today. Treatment is based on early diagnosis, life style changes, optimization of glycemic control and management of cardiovascular risk factors. Pathogenetic treatment of CAN includes: Balanced diet and physical activity; optimization of glycemic control; treatment of DLP; antioxidants, first of all α-lipoic acid (ALA), aldose reductase inhibitors, acetyl-L-carnitine; vitamins, first of all fat-soluble vitamin B1; correction of vascular endothelial dysfunction; prevention and treatment of thrombosis; in severe cases-treatment of OH. The promising methods include prescription of prostacyclin analogues, thromboxane A2 blockers and drugs that contribute into strengthening and/or normalization of Na+, K+-ATPase (phosphodiesterase inhibitor), ALA, dihomo-γ-linolenic acid (DGLA), ω-3 polyunsaturated fatty acids (ω-3 PUFAs), and the simultaneous prescription of ALA, ω-3 PUFAs and DGLA, but the future investigations are needed. Development of OH is associated with severe or advanced CAN and prescription of nonpharmacological and pharmacological, in the foreground midodrine and fludrocortisone acetate, treatment methods are necessary.

Keywords: Cardiac autonomic neuropathy; Cardiovascular reflex tests; Diabetes mellitus; Heart rate variability; Orthostatic hypotension; Prophylaxis; Risk factors; Screening for cardiac autonomic neuropathy; Treatment.

Conflict of interest statement

Conflict-of-interest statement: All authors declare no conflict of interest.

References

    1. Ogurtsova K, da Rocha Fernandes JD, Huang Y, Linnenkamp U, Guariguata L, Cho NH, Cavan D, Shaw JE, Makaroff LE. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017;128:40–50.
    1. Marazzi G, Volterrani M, Rosano GM. Metabolic agents in the management of diabetic coronary patients: a new era. Int J Cardiol. 2008;127:124–125.
    1. Standards of Medical Care in Diabetes-2017: Summary of Revisions. Diabetes Care. 2017;40:S4–S5.
    1. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33:2285–2293.
    1. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011;27:639–653.
    1. Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes. 2014;5:17–39.
    1. Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacol Ther. 2008;120:1–34.
    1. Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007;115:387–397.
    1. Vinik AI, Erbas T. Diabetic autonomic neuropathy. Handb Clin Neurol. 2013;117:279–294.
    1. Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 2012;11:521–534.
    1. Cannon CP. Combination therapy in the management of mixed dyslipidaemia. J Intern Med. 2008;263:353–365.
    1. Bril V. Treatments for diabetic neuropathy. J Peripher Nerv Syst. 2012;17 Suppl 2:22–27.
    1. Tandon N, Ali MK, Narayan KM. Pharmacologic prevention of microvascular and macrovascular complications in diabetes mellitus: implications of the results of recent clinical trials in type 2 diabetes. Am J Cardiovasc Drugs. 2012;12:7–22.
    1. Soares-Miranda L, Sandercock G, Vale S, Santos R, Abreu S, Moreira C, Mota J. Metabolic syndrome, physical activity and cardiac autonomic function. Diabetes Metab Res Rev. 2012;28:363–369.
    1. Hosseini A, Abdollahi M. Diabetic neuropathy and oxidative stress: therapeutic perspectives. Oxid Med Cell Longev. 2013;2013:168039.
    1. Vinik AI, Nevoret ML, Casellini C, Parson H. Diabetic neuropathy. Endocrinol Metab Clin North Am. 2013;42:747–787.
    1. Isik A, Firat D. Bilateral intra-areolar polythelia. Breast J. 2017 Epub ahead of print.
    1. Isik A, Soyturk M, Süleyman S, Firat D, Peker K, Yilmaz İ, Celebi F. Correlation of Bowel Wall Thickening Seen Using Computerized Tomography With Colonoscopies: A Preliminary Study. Surg Laparosc Endosc Percutan Tech. 2017;27:154–157.
    1. Ziegler D. Cardiovascular autonomic neuropathy: clinical manifestations and measurement. Diabetes Rev. 1999;7:300–315.
    1. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003;26:1553–1579.
    1. Rolim LC, Sá JR, Chacra AR, Dib SA. Diabetic cardiovascular autonomic neuropathy: risk factors, clinical impact and early diagnosis. Arq Bras Cardiol. 2008;90:e24–e31.
    1. Valensi P, Pariès J, Attali JR; French Group for Research and Study of Diabetic Neuropathy. Cardiac autonomic neuropathy in diabetic patients: influence of diabetes duration, obesity, and microangiopathic complications--the French multicenter study. Metabolism. 2003;52:815–820.
    1. Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet. 1999;353:617–622.
    1. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383–393.
    1. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT) Diabetologia. 1998;41:416–423.
    1. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580–591.
    1. Kempler P, Tesfaye S, Chaturvedi N, Stevens LK, Webb DJ, Eaton S, Kerényi Z, Tamás G, Ward JD, Fuller JH; EURODIAB IDDM Complications Study Group. Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study. Diabet Med. 2002;19:900–909.
    1. Pop-Busui R, Evans GW, Gerstein HC, Fonseca V, Fleg JL, Hoogwerf BJ, Genuth S, Grimm RH, Corson MA, Prineas R; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care. 2010;33:1578–1584.
    1. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D; American Diabetes Association. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956–962.
    1. Low PA, Benrud-Larson LM, Sletten DM, Opfer-Gehrking TL, Weigand SD, O’Brien PC, Suarez GA, Dyck PJ. Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care. 2004;27:2942–2947.
    1. Witte DR, Tesfaye S, Chaturvedi N, Eaton SE, Kempler P, Fuller JH; EURODIAB Prospective Complications Study Group. Risk factors for cardiac autonomic neuropathy in type 1 diabetes mellitus. Diabetologia. 2005;48:164–171.
    1. Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig. 2013;4:4–18.
    1. Orchard TJ, LLoyd CE, Maser RE, Kuller LH. Why does diabetic autonomic neuropathy predict IDDM mortality? An analysis from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Res Clin Pract. 1996;34 Suppl:S165–S171.
    1. Ziegler D, Zentai CP, Perz S, Rathmann W, Haastert B, Döring A, Meisinger C; KORA Study Group. Prediction of mortality using measures of cardiac autonomic dysfunction in the diabetic and nondiabetic population: the MONICA/KORA Augsburg Cohort Study. Diabetes Care. 2008;31:556–561.
    1. Maser RE, Lenhard MJ. Cardiovascular autonomic neuropathy due to diabetes mellitus: clinical manifestations, consequences, and treatment. J Clin Endocrinol Metab. 2005;90:5896–5903.
    1. Vinik AI, Maser RE, Ziegler D. Autonomic imbalance: prophet of doom or scope for hope? Diabet Med. 2011;28:643–651.
    1. Wackers FJ, Young LH, Inzucchi SE, Chyun DA, Davey JA, Barrett EJ, Taillefer R, Wittlin SD, Heller GV, Filipchuk N, et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care. 2004;27:1954–1961.
    1. Veglio M, Chinaglia A, Cavallo-Perin P. QT interval, cardiovascular risk factors and risk of death in diabetes. J Endocrinol Invest. 2004;27:175–181.
    1. Pop-Busui R, Boulton AJ, Feldman EL, Bril V, Freeman R, Malik RA, Sosenko JM, Ziegler D. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017;40:136–154.
    1. Dyck PJ, Albers JW, Andersen H, Arezzo JC, Biessels GJ, Bril V, Feldman EL, Litchy WJ, O’Brien PC, Russell JW; Toronto Expert Panel on Diabetic Neuropathy. Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. Diabetes Metab Res Rev. 2011;27:620–628.
    1. Albers JW, Pop-Busui R. Diabetic neuropathy: mechanisms, emerging treatments, and subtypes. Curr Neurol Neurosci Rep. 2014;14:473.
    1. Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care. 1985;8:491–498.
    1. Low PA. Prevalence of orthostatic hypotension. Clin Auton Res. 2008;18 Suppl 1:8–13.
    1. Low PA, Walsh JC, Huang CY, McLeod JG. The sympathetic nervous system in diabetic neuropathy. A clinical and pathological study. Brain. 1975;98:341–356.
    1. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996;93:1043–1065.
    1. Pop-Busui R. Cardiac autonomic neuropathy in diabetes: a clinical perspective. Diabetes Care. 2010;33:434–441.
    1. Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr Diab Rep. 2014;14:528.
    1. Martin CL, Albers JW, Pop-Busui R; 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.
    1. Ziegler D, Keller J, Maier C, Pannek J; German Diabetes Association. Diabetic neuropathy. Exp Clin Endocrinol Diabetes. 2014;122:406–415.
    1. Bernardi L, Spallone V, Stevens M, Hilsted J, Frontoni S, Pop-Busui R, Ziegler D, Kempler P, Freeman R, Low P, et al. Methods of investigation for cardiac autonomic dysfunction in human research studies. Diabetes Metab Res Rev. 2011;27:654–664.
    1. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Neurology. 1996;46:1470.
    1. Spallone V, Bellavere F, Scionti L, Maule S, Quadri R, Bax G, Melga P, Viviani GL, Esposito K, Morganti R, et al. Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy. Nutr Metab Cardiovasc Dis. 2011;21:69–78.
    1. Hage FG, Iskandrian AE. Cardiovascular imaging in diabetes mellitus. J Nucl Cardiol. 2011;18:959–965.
    1. Valensi PE, Johnson NB, Maison-Blanche P, Extramania F, Motte G, Coumel P. Influence of cardiac autonomic neuropathy on heart rate dependence of ventricular repolarization in diabetic patients. Diabetes Care. 2002;25:918–923.
    1. Santini V, Ciampittiello G, Gigli F, Bracaglia D, Baroni A, Cicconetti E, Verri C, Gambardella S, Frontoni S. QTc and autonomic neuropathy in diabetes: effects of acute hyperglycaemia and n-3 PUFA. Nutr Metab Cardiovasc Dis. 2007;17:712–718.
    1. Prince CT, Secrest AM, Mackey RH, Arena VC, Kingsley LA, Orchard TJ. Cardiovascular autonomic neuropathy, HDL cholesterol, and smoking correlate with arterial stiffness markers determined 18 years later in type 1 diabetes. Diabetes Care. 2010;33:652–657.
    1. Desouza CV, Bolli GB, Fonseca V. Hypoglycemia, diabetes, and cardiovascular events. Diabetes Care. 2010;33:1389–1394.
    1. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) J Hypertens. 2007;25:1105–1187.
    1. Shakespeare CF, Katritsis D, Crowther A, Cooper IC, Coltart JD, Webb-Peploe MW. Differences in autonomic nerve function in patients with silent and symptomatic myocardial ischaemia. Br Heart J. 1994;71:22–29.
    1. Veglio M, Borra M, Stevens LK, Fuller JH, Perin PC. The relation between QTc interval prolongation and diabetic complications. The EURODIAB IDDM Complication Study Group. Diabetologia. 1999;42:68–75.
    1. Kahn JK, Sisson JC, Vinik AI. QT interval prolongation and sudden cardiac death in diabetic autonomic neuropathy. J Clin Endocrinol Metab. 1987;64:751–754.
    1. Stevens MJ, Dayanikli F, Raffel DM, Allman KC, Sandford T, Feldman EL, Wieland DM, Corbett J, Schwaiger M. Scintigraphic assessment of regionalized defects in myocardial sympathetic innervation and blood flow regulation in diabetic patients with autonomic neuropathy. J Am Coll Cardiol. 1998;31:1575–1584.
    1. Suarez GA, Clark VM, Norell JE, Kottke TE, Callahan MJ, O’Brien PC, Low PA, Dyck PJ. Sudden cardiac death in diabetes mellitus: risk factors in the Rochester diabetic neuropathy study. J Neurol Neurosurg Psychiatry. 2005;76:240–245.
    1. Burgos LG, Ebert TJ, Asiddao C, Turner LA, Pattison CZ, Wang-Cheng R, Kampine JP. Increased intraoperative cardiovascular morbidity in diabetics with autonomic neuropathy. Anesthesiology. 1989;70:591–597.
    1. Rolim LC, de Souza JS, Dib SA. Tests for early diagnosis of cardiovascular autonomic neuropathy: critical analysis and relevance. Front Endocrinol (Lausanne) 2013;4:173.
    1. Bernardi L. Clinical evaluation of arterial baroreflex activity in diabetes. Diabetes Nutr Metab. 2000;13:331–340.
    1. Freeman R, Saul JP, Roberts MS, Berger RD, Broadbridge C, Cohen RJ. Spectral analysis of heart rate in diabetic autonomic neuropathy. A comparison with standard tests of autonomic function. Arch Neurol. 1991;48:185–190.
    1. Mogensen UM, Jensen T, Køber L, Kelbæk H, Mathiesen AS, Dixen U, Rossing P, Hilsted J, Kofoed KF. Cardiovascular autonomic neuropathy and subclinical cardiovascular disease in normoalbuminuric type 1 diabetic patients. Diabetes. 2012;61:1822–1830.
    1. Sammito S, Böckelmann I. Reference values for time- and frequency-domain heart rate variability measures. Heart Rhythm. 2016;13:1309–1316.
    1. Bauer A, Malik M, Schmidt G, Barthel P, Bonnemeier H, Cygankiewicz I, Guzik P, Lombardi F, Müller A, Oto A, et al. Heart rate turbulence: standards of measurement, physiological interpretation, and clinical use: International Society for Holter and Noninvasive Electrophysiology Consensus. J Am Coll Cardiol. 2008;52:1353–1365.
    1. Balcıoğlu AS, Müderrisoğlu H. Diabetes and cardiac autonomic neuropathy: Clinical manifestations, cardiovascular consequences, diagnosis and treatment. World J Diabetes. 2015;6:80–91.
    1. La Rovere MT, Pinna GD, Maestri R, Robbi E, Caporotondi A, Guazzotti G, Sleight P, Febo O. Prognostic implications of baroreflex sensitivity in heart failure patients in the beta-blocking era. J Am Coll Cardiol. 2009;53:193–199.
    1. Rosengård-Bärlund M, Bernardi L, Fagerudd J, Mäntysaari M, Af Björkesten CG, Lindholm H, Forsblom C, Wadén J, Groop PH; FinnDiane Study Group. Early autonomic dysfunction in type 1 diabetes: a reversible disorder? Diabetologia. 2009;52:1164–1172.
    1. Hoffman RP, Sinkey CA, Anderson EA. Microneurographically determined muscle sympathetic nerve activity levels are reproducible in insulin-dependent diabetes mellitus. J Diabetes Complications. 1998;12:307–310.
    1. Hilsted J. Catecholamines and diabetic autonomic neuropathy. Diabet Med. 1995;12:296–297.
    1. Freeman MR, Newman D, Dorian P, Barr A, Langer A. Relation of direct assessment of cardiac autonomic function with metaiodobenzylguanidine imaging to heart rate variability in diabetes mellitus. Am J Cardiol. 1997;80:247–250.
    1. Schnell O, Muhr D, Weiss M, Dresel S, Haslbeck M, Standl E. Reduced myocardial 123I-metaiodobenzylguanidine uptake in newly diagnosed IDDM patients. Diabetes. 1996;45:801–805.
    1. Nagamachi S, Jinnouchi S, Kurose T, Ohnishi T, Flores LG 2nd, Nakahara H, Futami S, Tamura S, Matsukura S. 123I-MIBG myocardial scintigraphy in diabetic patients: relationship with 201Tl uptake and cardiac autonomic function. Ann Nucl Med. 1998;12:323–331.
    1. DeGrado TR, Hutchins GD, Toorongian SA, Wieland DM, Schwaiger M. Myocardial kinetics of carbon-11-meta-hydroxyephedrine: retention mechanisms and effects of norepinephrine. J Nucl Med. 1993;34:1287–1293.
    1. Allman KC, Stevens MJ, Wieland DM, Hutchins GD, Wolfe ER Jr, Greene DA, Schwaiger M. Noninvasive assessment of cardiac diabetic neuropathy by carbon-11 hydroxyephedrine and positron emission tomography. J Am Coll Cardiol. 1993;22:1425–1432.
    1. Freeman R. Clinical practice. Neurogenic orthostatic hypotension. N Engl J Med. 2008;358:615–624.
    1. Low PA, Denq JC, Opfer-Gehrking TL, Dyck PJ, O’Brien PC, Slezak JM. Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects. Muscle Nerve. 1997;20:1561–1568.
    1. Pop-Busui R, Stevens M. Alexandria, VA: American Diabetes Association; 2014. Autonomic neuropathy in diabetes. In Therapy for Diabetes Mellitus and Related Disorders. 6th ed. Umpierrez GE, Ed; pp. 834–863.
    1. Ziegler D, Voss A, Rathmann W, Strom A, Perz S, Roden M, Peters A, Meisinger C; KORA Study Group. Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: the KORA S4 survey. Diabetologia. 2015;58:1118–1128.
    1. Lykke JA, Tarnow L, Parving HH, Hilsted J. 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;68:654–659.
    1. Pop-Busui R. What do we know and we do not know about cardiovascular autonomic neuropathy in diabetes. J Cardiovasc Transl Res. 2012;5:463–478.
    1. Ziegler D, Gries FA, Mühlen H, Rathmann W, Spüler M, Lessmann F. Prevalence and clinical correlates of cardiovascular autonomic and peripheral diabetic neuropathy in patients attending diabetes centers. The Diacan Multicenter Study Group. Diabete Metab. 1993;19:143–151.
    1. Serhiyenko VA, Serhiyenko AA. Diabetic cardiac autonomic neuropathy: Do we have any treatment perspectives? World J Diabetes. 2015;6:245–258.
    1. Esposito K, Giugliano D. Mediterranean diet and type 2 diabetes. Diabetes Metab Res Rev. 2014;30 Suppl 1:34–40.
    1. Sleiman D, Al-Badri MR, Azar ST. Effect of mediterranean diet in diabetes control and cardiovascular risk modification: a systematic review. Front Public Health. 2015;3:69.
    1. Carnethon MR, Prineas RJ, Temprosa M, Zhang ZM, Uwaifo G, Molitch ME; Diabetes Prevention Program Research Group. The association among autonomic nervous system function, incident diabetes, and intervention arm in the Diabetes Prevention Program. Diabetes Care. 2006;29:914–919.
    1. Smith AG, Russell J, Feldman EL, Goldstein J, Peltier A, Smith S, Hamwi J, Pollari D, Bixby B, Howard J, et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care. 2006;29:1294–1299.
    1. Balducci S, Iacobellis G, Parisi L, Di Biase N, Calandriello E, Leonetti F, Fallucca F. Exercise training can modify the natural history of diabetic peripheral neuropathy. J Diabetes Complications. 2006;20:216–223.
    1. Singleton JR, Marcus RL, Jackson JE, K Lessard M, Graham TE, Smith AG. Exercise increases cutaneous nerve density in diabetic patients without neuropathy. Ann Clin Transl Neurol. 2014;1:844–849.
    1. Colberg SR, Sigal RJ, Fernhall B, Regensteiner JG, Blissmer BJ, Rubin RR, Chasan-Taber L, Albright AL, Braun B; American College of Sports Medicine; American Diabetes Association. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement executive summary. Diabetes Care. 2010;33:2692–2696.
    1. Colberg SR, Vinik AI. Exercising with peripheral or autonomic neuropathy: what health care providers and diabetic patients need to know. Phys Sportsmed. 2014;42:15–23.
    1. Pagkalos M, Koutlianos N, Kouidi E, Pagkalos E, Mandroukas K, Deligiannis A. Heart rate variability modifications following exercise training in type 2 diabetic patients with definite cardiac autonomic neuropathy. Br J Sports Med. 2008;42:47–54.
    1. Epidemiology of Diabetes Interventions and Complications (EDIC) Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort. Diabetes Care. 1999;22:99–111.
    1. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA. 2003;290:2159–2167.
    1. Cefalu WT, Ratner RE. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: the “gift” that keeps on giving! Diabetes Care. 2014;37:5–7.
    1. Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–986.
    1. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol. 1995;38:869–880.
    1. Pop-Busui R, Herman WH, Feldman EL, Low PA, Martin CL, Cleary PA, Waberski BH, Lachin JM, Albers JW; DCCT/EDIC Research Group. DCCT and EDIC studies in type 1 diabetes: lessons for diabetic neuropathy regarding metabolic memory and natural history. Curr Diab Rep. 2010;10:276–282.
    1. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643–2653.
    1. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103–117.
    1. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837–853.
    1. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–1589.
    1. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–139.
    1. Albers JW, Herman WH, Pop-Busui R, Feldman EL, Martin CL, Cleary PA, Waberski BH, Lachin JM; Diabetes Control and Complications Trial /Epidemiology of Diabetes Interventions and Complications Research Group. 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 Interventions and Complications (EDIC) Study. Diabetes Care. 2010;33:1090–1096.
    1. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, Cuddihy R, Cushman WC, Genuth S, Grimm RH Jr, Hamilton BP, Hoogwerf B, Karl D, Katz L, Krikorian A, O’Connor P, Pop-Busui R, Schubart U, Simmons D, Taylor H, Thomas A, Weiss D, Hramiak I; ACCORD trial group. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376:419–430.
    1. Charles M, Fleischer J, Witte DR, Ejskjaer N, Borch-Johnsen K, Lauritzen T, Sandbaek A. Impact of early detection and treatment of diabetes on the 6-year prevalence of cardiac autonomic neuropathy in people with screen-detected diabetes: ADDITION-Denmark, a cluster-randomised study. Diabetologia. 2013;56:101–108.
    1. Charles M, Ejskjaer N, Witte DR, Borch-Johnsen K, Lauritzen T, Sandbaek A. Prevalence of neuropathy and peripheral arterial disease and the impact of treatment in people with screen-detected type 2 diabetes: the ADDITION-Denmark study. Diabetes Care. 2011;34:2244–2249.
    1. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J. 2016;37:2999–3058.
    1. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH; CARDS investigators. 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.
    1. Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, Grunberger G, Guerin CK, Bell DSH, Mechanick JI, et al. American association of clinical endocrinologists and american college of endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 2017;23:1–87.
    1. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–156.
    1. Praluent (alirocumab) prescribing information. Bridgewater, NJ: Sanofi-Aventis US, 2015.
    1. Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, Langslet G, Scott R, Olsson AG, Sullivan D, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:331–340.
    1. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–1499.
    1. Stoekenbroek RM, Kastelein JJ, Huijgen R. PCSK9 inhibition: the way forward in the treatment of dyslipidemia. BMC Med. 2015;13:258.
    1. Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V, Diaz R, Goodman SG, Hanotin C, Harrington RA, Jukema JW, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J. 2014;168:682–689.
    1. Norata GD, Tibolla G, Catapano AL. Targeting PCSK9 for hypercholesterolemia. Annu Rev Pharmacol Toxicol. 2014;54:273–293.
    1. Chapman MJ, Redfern JS, McGovern ME, Giral P. Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol Ther. 2010;126:314–345.
    1. Thompson A, Danesh J. Associations between apolipoprotein B, apolipoprotein AI, the apolipoprotein B/AI ratio and coronary heart disease: a literature-based meta-analysis of prospective studies. J Intern Med. 2006;259:481–492.
    1. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–2267.
    1. HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, Armitage J. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203–212.
    1. Ooi CP, Loke SC. Colesevelam for Type 2 diabetes mellitus: an abridged Cochrane review. Diabet Med. 2014;31:2–14.
    1. Ahn CH, Choi SH. New drugs for treating dyslipidemia: beyond statins. Diabetes Metab J. 2015;39:87–94.
    1. Bell DA, Hooper AJ, Burnett JR. Mipomersen, an antisense apolipoprotein B synthesis inhibitor. Expert Opin Investig Drugs. 2011;20:265–272.
    1. Adiels M, Olofsson SO, Taskinen MR, Borén J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28:1225–1236.
    1. Scott R, O’Brien R, Fulcher G, Pardy C, D’Emden M, Tse D, Taskinen MR, Ehnholm C, Keech A; Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study Investigators. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care. 2009;32:493–498.
    1. Taskinen MR, Borén J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis. 2015;239:483–495.
    1. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–1681.
    1. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735–742.
    1. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–1861.
    1. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–1574.
    1. Saha SA, Arora RR. Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus--a pooled meta-analysis of randomized placebo-controlled clinical trials. Int J Cardiol. 2010;141:157–166.
    1. Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005–2016.
    1. Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, de Craen AJ, Knopp RH, Nakamura H, Ridker P, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ. 2009;338:b2376.
    1. Power RA, Hulver MW, Zhang JY, Dubois J, Marchand RM, Ilkayeva O, Muoio DM, Mynatt RL. Carnitine revisited: potential use as adjunctive treatment in diabetes. Diabetologia. 2007;50:824–832.
    1. Solfrizzi V, Capurso C, Colacicco AM, D’Introno A, Fontana C, Capurso SA, Torres F, Gadaleta AM, Koverech A, Capurso A, et al. Efficacy and tolerability of combined treatment with L-carnitine and simvastatin in lowering lipoprotein(a) serum levels in patients with type 2 diabetes mellitus. Atherosclerosis. 2006;188:455–461.
    1. Kasznicki J, Kosmalski M, Sliwinska A, Mrowicka M, Stanczyk M, Majsterek I, Drzewoski J. Evaluation of oxidative stress markers in pathogenesis of diabetic neuropathy. Mol Biol Rep. 2012;39:8669–8678.
    1. Oyenihi AB, Ayeleso AO, Mukwevho E, Masola B. Antioxidant strategies in the management of diabetic neuropathy. Biomed Res Int. 2015;2015:515042.
    1. de M Bandeira S, da Fonseca LJ, da S Guedes G, Rabelo LA, Goulart MO, Vasconcelos SM. Oxidative stress as an underlying contributor in the development of chronic complications in diabetes mellitus. Int J Mol Sci. 2013;14:3265–3284.
    1. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114:1752–1761.
    1. Vincent AM, Russell JW, Low P, Feldman EL. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev. 2004;25:612–628.
    1. Obrosova IG, Ilnytska O, Lyzogubov VV, Pavlov IA, Mashtalir N, Nadler JL, Drel VR. High-fat diet induced neuropathy of pre-diabetes and obesity: effects of “healthy” diet and aldose reductase inhibition. Diabetes. 2007;56:2598–2608.
    1. Negre-Salvayre A, Coatrieux C, Ingueneau C, Salvayre R. Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors. Br J Pharmacol. 2008;153:6–20.
    1. Mahmood D, Singh BK, Akhtar M. Diabetic neuropathy: therapies on the horizon. J Pharm Pharmacol. 2009;61:1137–1145.
    1. Kalousová M, Skrha J, Zima T. Advanced glycation end-products and advanced oxidation protein products in patients with diabetes mellitus. Physiol Res. 2002;51:597–604.
    1. King RH. The role of glycation in the pathogenesis of diabetic polyneuropathy. Mol Pathol. 2001;54:400–408.
    1. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84.
    1. Bajaj S, Khan A. Antioxidants and diabetes. Indian J Endocrinol Metab. 2012;16:S267–S271.
    1. Balarabe SA, Adamu MD, Watila MM, Jiya N. Neuromyelitis optica and myasthenia gravis in a young Nigerian girl. BMJ Case Rep. 2015;2015:pii: bcr2014207362.
    1. Hamilton SJ, Chew GT, Watts GF. Therapeutic regulation of endothelial dysfunction in type 2 diabetes mellitus. Diab Vasc Dis Res. 2007;4:89–102.
    1. Packer L, Kraemer K, Rimbach G. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition. 2001;17:888–895.
    1. Ziegler D, Schatz H, Conrad F, Gries FA, Ulrich H, Reichel G. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie. Diabetes Care. 1997;20:369–373.
    1. Bertolotto F, Massone A. Combination of alpha lipoic acid and superoxide dismutase leads to physiological and symptomatic improvements in diabetic neuropathy. Drugs R D. 2012;12:29–34.
    1. McNulty H, Jacob RF, Mason RP. Biologic activity of carotenoids related to distinct membrane physicochemical interactions. Am J Cardiol. 2008;101:20D–29D.
    1. Berrone E, Beltramo E, Solimine C, Ape AU, Porta M. Regulation of intracellular glucose and polyol pathway by thiamine and benfotiamine in vascular cells cultured in high glucose. J Biol Chem. 2006;281:9307–9313.
    1. Lazo de la Vega-Monroy ML, Larrieta E, German MS, Baez-Saldana A, Fernandez-Mejia C. Effects of biotin supplementation in the diet on insulin secretion, islet gene expression, glucose homeostasis and beta-cell proportion. J Nutr Biochem. 2013;24:169–177.
    1. Sheikh-Ali M, Chehade JM, Mooradian AD. The antioxidant paradox in diabetes mellitus. Am J Ther. 2011;18:266–278.
    1. Rahimi R, Nikfar S, Larijani B, Abdollahi M. A review on the role of antioxidants in the management of diabetes and its complications. Biomed Pharmacother. 2005;59:365–373.
    1. Hotta N, Akanuma Y, Kawamori R, Matsuoka K, Oka Y, Shichiri M, Toyota T, Nakashima M, Yoshimura I, Sakamoto N, et al. Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial. Diabetes Care. 2006;29:1538–1544.
    1. Haupt E, Ledermann H, Köpcke W. Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study) Int J Clin Pharmacol Ther. 2005;43:71–77.
    1. Stracke H, Gaus W, Achenbach U, Federlin K, Bretzel RG. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study. Exp Clin Endocrinol Diabetes. 2008;116:600–605.
    1. Balakumar P, Rohilla A, Krishan P, Solairaj P, Thangathirupathi A. The multifaceted therapeutic potential of benfotiamine. Pharmacol Res. 2010;61:482–488.
    1. Stracke H, Lindemann A, Federlin K. A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes. 1996;104:311–316.
    1. Yan H, Guo Y, Zhang J, Ding Z, Ha W, Harding JJ. Effect of carnosine, aminoguanidine, and aspirin drops on the prevention of cataracts in diabetic rats. Mol Vis. 2008;14:2282–2291.
    1. Urios P, Grigorova-Borsos AM, Sternberg M. Aspirin inhibits the formation of pentosidine, a cross-linking advanced glycation end product, in collagen. Diabetes Res Clin Pract. 2007;77:337–340.
    1. Shen Q, Pierce JD. Supplementation of Coenzyme Q10 among Patients with Type 2 Diabetes Mellitus. Healthcare (Basel) 2015;3:296–309.
    1. Burnier M. Telmisartan: a different angiotensin II receptor blocker protecting a different population? J Int Med Res. 2009;37:1662–1679.
    1. Ahmed MA, Muntingh GL, Rheeder P. Perspectives on Peripheral Neuropathy as a Consequence of Metformin-Induced Vitamin B12 Deficiency in T2DM. Int J Endocrinol. 2017;2017:2452853.
    1. Fragasso G, Palloshi A, Puccetti P, Silipigni C, Rossodivita A, Pala M, Calori G, Alfieri O, Margonato A. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll Cardiol. 2006;48:992–998.
    1. Lee WS, Kim J. Diabetic cardiomyopathy: where we are and where we are going. Korean J Intern Med. 2017;32:404–421.
    1. Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Williams L, Ashrafian H, Horowitz J, Fraser AG, Clarke K, et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation. 2005;112:3280–3288.
    1. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A, Varshavsky S, Wolff AA, Skene A, McCabe CH, Braunwald E; MERLIN-TIMI 36 Trial Investigators. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA. 2007;297:1775–1783.
    1. Witteles RM, Fowler MB. Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options. J Am Coll Cardiol. 2008;51:93–102.
    1. Nikolaidis LA, Poornima I, Parikh P, Magovern M, Shen YT, Shannon RP. The effects of combined versus selective adrenergic blockade on left ventricular and systemic hemodynamics, myocardial substrate preference, and regional perfusion in conscious dogs with dilated cardiomyopathy. J Am Coll Cardiol. 2006;47:1871–1881.
    1. Sytze Van Dam P, Cotter MA, Bravenboer B, Cameron NE. Pathogenesis of diabetic neuropathy: focus on neurovascular mechanisms. Eur J Pharmacol. 2013;719:180–186.
    1. Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study. Circulation. 2001;104:511–514.
    1. Zepeda RJ, Castillo R, Rodrigo R, Prieto JC, Aramburu I, Brugere S, Galdames K, Noriega V, Miranda HF. Effect of carvedilol and nebivolol on oxidative stress-related parameters and endothelial function in patients with essential hypertension. Basic Clin Pharmacol Toxicol. 2012;111:309–316.
    1. Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol. 2015;7:719–741.
    1. Kelly AS, Gonzalez-Campoy JM, Rudser KD, Katz H, Metzig AM, Thalin M, Bank AJ. Carvedilol-lisinopril combination therapy and endothelial function in obese individuals with hypertension. J Clin Hypertens (Greenwich) 2012;14:85–91.
    1. Mak IT, Boehme P, Weglicki WB. Antioxidant effects of calcium channel blockers against free radical injury in endothelial cells. Correlation of protection with preservation of glutathione levels. Circ Res. 1992;70:1099–1103.
    1. Matsubara M, Hasegawa K. Benidipine, a dihydropyridine-calcium channel blocker, prevents lysophosphatidylcholine-induced injury and reactive oxygen species production in human aortic endothelial cells. Atherosclerosis. 2005;178:57–66.
    1. Habib JB, Bossaller C, Wells S, Williams C, Morrisett JD, Henry PD. Preservation of endothelium-dependent vascular relaxation in cholesterol-fed rabbit by treatment with the calcium blocker PN 200110. Circ Res. 1986;58:305–309.
    1. Fukao K, Shimada K, Hiki M, Kiyanagi T, Hirose K, Kume A, Ohsaka H, Matsumori R, Kurata T, Miyazaki T, et al. Effects of calcium channel blockers on glucose tolerance, inflammatory state, and circulating progenitor cells in non-diabetic patients with essential hypertension: a comparative study between azelnidipine and amlodipine on glucose tolerance and endothelial function--a crossover trial (AGENT) Cardiovasc Diabetol. 2011;10:79.
    1. Celık T, Balta S, Karaman M, Ahmet Ay S, Demırkol S, Ozturk C, Dınc M, Unal HU, Yılmaz MI, Kılıc S, et al. Endocan, a novel marker of endothelial dysfunction in patients with essential hypertension: comparative effects of amlodipine and valsartan. Blood Press. 2015;24:55–60.
    1. Fukutomi M, Hoshide S, Mizuno H, Kario K. Differential effects of aliskiren/amlodipine combination and high-dose amlodipine monotherapy on endothelial function in elderly hypertensive patients. Am J Hypertens. 2014;27:14–20.
    1. Okamura T, Tawa M, Geddawy A, Shimosato T, Iwasaki H, Shintaku H, Yoshida Y, Masada M, Shinozaki K, Imamura T. Effects of atorvastatin, amlodipine, and their combination on vascular dysfunction in insulin-resistant rats. J Pharmacol Sci. 2014;124:76–85.
    1. Zhou MS, Tian R, Jaimes EA, Raij L. Combination therapy of amlodipine and atorvastatin has more beneficial vascular effects than monotherapy in salt-sensitive hypertension. Am J Hypertens. 2014;27:873–880.
    1. Jain NK, Patil CS, Singh A, Kulkarni SK. Sildenafil-induced peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway. Brain Res. 2001;909:170–178.
    1. Patil CS, Singh VP, Singh S, Kulkarni SK. Modulatory effect of the PDE-5 inhibitor sildenafil in diabetic neuropathy. Pharmacology. 2004;72:190–195.
    1. Wang L, Chopp M, Szalad A, Liu Z, Bolz M, Alvarez FM, Lu M, Zhang L, Cui Y, Zhang RL, et al. Phosphodiesterase-5 is a therapeutic target for peripheral neuropathy in diabetic mice. Neuroscience. 2011;193:399–410.
    1. Peixoto CA, Nunes AK, Garcia-Osta A. Phosphodiesterase-5 Inhibitors: Action on the Signaling Pathways of Neuroinflammation, Neurodegeneration, and Cognition. Mediators Inflamm. 2015;2015:940207.
    1. Schäfer A, Fraccarollo D, Pförtsch S, Flierl U, Vogt C, Pfrang J, Kobsar A, Renné T, Eigenthaler M, Ertl G, et al. Improvement of vascular function by acute and chronic treatment with the PDE-5 inhibitor sildenafil in experimental diabetes mellitus. Br J Pharmacol. 2008;153:886–893.
    1. Wang L, Chopp M, Szalad A, Lu X, Jia L, Lu M, Zhang RL, Zhang ZG. Tadalafil Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice. PLoS One. 2016;11:e0159665.
    1. Wang L, Chopp M, Zhang ZG. PDE5 inhibitors promote recovery of peripheral neuropathy in diabetic mice. Neural Regen Res. 2017;12:218–219.
    1. Tse S, Mazzola N. Ivabradine (Corlanor) for Heart Failure: The First Selective and Specific I f Inhibitor. PT. 2015;40:810–814.
    1. DiFrancesco D. The role of the funny current in pacemaker activity. Circ Res. 2010;106:434–446.
    1. Reil JC, Tardif JC, Ford I, Lloyd SM, O’Meara E, Komajda M, Borer JS, Tavazzi L, Swedberg K, Böhm M. Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients. J Am Coll Cardiol. 2013;62:1977–1985.
    1. Rienzo M, Melka J, Bizé A, Sambin L, Jozwiak M, Su JB, Hittinger L, Berdeaux A, Ghaleh B. Ivabradine improves left ventricular function during chronic hypertension in conscious pigs. Hypertension. 2015;65:122–129.
    1. Jochmann N, Schröter F, Knebel F, Hättasch R, Gericke C, Stangl K, Baumann G, Stangl V. Effect of ivabradine-induced heart rate reduction on flow-mediated dilation measured with high-sensitivity ultrasound in patients with stable coronary heart disease. Cardiovasc Ultrasound. 2014;12:5.
    1. Nerla R, Di Franco A, Milo M, Pitocco D, Zaccardi F, Tarzia P, Sarullo FM, Villano A, Russo G, Stazi A, et al. Differential effects of heart rate reduction by atenolol or ivabradine on peripheral endothelial function in type 2 diabetic patients. Heart. 2012;98:1812–1816.
    1. Fox K, Ford I, Ferrari R. Ivabradine in stable coronary artery disease. N Engl J Med. 2014;371:2435.
    1. Dhule SS, Gawali SR. Platelet aggregation and clotting time in type II diabetic males. Natl J Physiol Pharm Pharmacol. 2014;4:121–123.
    1. Güven F, Yilmaz A, Aydin H, Korkmaz I. Platelet aggregation responses in type 2 diabetic patients. Health. 2010;2:708–712.
    1. Vinik AI. Diabetic neuropathy: pathogenesis and therapy. Am J Med. 1999;107:17S–26S.
    1. Jordan J, Shannon JR, Black BK, Ali Y, Farley M, Costa F, Diedrich A, Robertson RM, Biaggioni I, Robertson D. The pressor response to water drinking in humans : a sympathetic reflex? Circulation. 2000;101:504–509.
    1. Singer W, Opfer-Gehrking TL, McPhee BR, Hilz MJ, Bharucha AE, Low PA. Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension. J Neurol Neurosurg Psychiatry. 2003;74:1294–1298.
    1. Nóbrega AC, dos Reis AF, Moraes RS, Bastos BG, Ferlin EL, Ribeiro JP. Enhancement of heart rate variability by cholinergic stimulation with pyridostigmine in healthy subjects. Clin Auton Res. 2001;11:11–17.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera