Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Hypoglycaemia and Cardiovascular Disease Risk in Patients with Diabetes

Author(s): Niki Katsiki*, Kalliopi Kotsa, Anca P. Stoian and Dimitri P. Mikhailidis

Volume 26, Issue 43, 2020

Page: [5637 - 5649] Pages: 13

DOI: 10.2174/1381612826666200909142658

Price: $65


Hypoglycaemia represents an important side effect of insulin therapy and insulin secretagogues. It can occur in both type 1 and type 2 diabetes mellitus patients. Also, some associations between hypoglycaemia and cardiovascular (CV) risk have been reported. Several mechanisms may be involved, including the sympathoadrenal system, hypokalaemia, endothelial dysfunction, coagulation, platelets, inflammation, atherothrombosis and impaired autonomic cardiac reflexes. This narrative review discusses the associations of hypoglycaemia with CV diseases, including coronary heart disease (CHD), cardiac arrhythmias, stroke, carotid disease and peripheral artery disease (PAD), as well as with dementia. Severe hypoglycaemia has been related to CHD, CV and all-cause mortality. Furthermore, there is evidence supporting an association between hypoglycaemia and cardiac arrhythmias, potentially predisposing to sudden death. The data linking hypoglycaemia with stroke, carotid disease and PAD is limited. Several factors may affect the hypoglycaemia-CV relationships, such as the definition of hypoglycaemia, patient characteristics, co-morbidities (including chronic kidney disease) and antidiabetic drug therapy. However, the association between hypoglycaemia and dementia is bilateral. Both the disorders are more common in the elderly; thus, glycaemic goals should be carefully selected in older patients. Further research is needed to elucidate the impact of hypoglycaemia on CV disease.

Keywords: Hypoglycaemia, cardiovascular risk, coronary heart disease, stroke, peripheral artery disease, dementia, carotid disease, cardiac arrhythmias, mortality.

International Hypoglycaemia Study Group. Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol 2019; 7(5): 385-96.
[] [PMID: 30926258]
Morales J, Schneider D. Hypoglycemia. Am J Med 2014; 127(10)(Suppl.): S17-24.
[] [PMID: 25282009]
Huang ES, Laiteerapong N, Liu JY, John PM, Moffet HH, Karter AJ. Rates of complications and mortality in older patients with diabetes mellitus: the diabetes and aging study. JAMA Intern Med 2014; 174(2): 251-8.
[] [PMID: 24322595]
de Decker L, Hanon O, Boureau AS, et al. Association Between Hypoglycemia and the Burden of Comorbidities in Hospitalized Vulnerable Older Diabetic Patients: A Cross-Sectional, Population-Based Study. Diabetes Ther 2017; 8(6): 1405-13.
[] [PMID: 29086351]
Luk AO, Ho TS, Lau ES, et al. Association of self-reported recurrent mild hypoglycemia with incident cardiovascular disease and all-cause mortality in patients with type 2 diabetes: Prospective analysis of the Joint Asia Diabetes Evaluation Registry. Medicine (Baltimore) 2016; 95(45): e5183.
[] [PMID: 27828844]
Wallis KA, Wells S, Selak V, Poppe K. Long-term follow up of older people on diabetes medications: observational study using linked health databases. Aust J Prim Health 2020; 26(4): 306-12.
[] [PMID: 32600527]
Martín-Timón I, Del Cañizo-Gómez FJ. Mechanisms of hypoglycemia unawareness and implications in diabetic patients. World J Diabetes 2015; 6(7): 912-26.
[] [PMID: 26185599]
Reno CM, Bayles J, Huang Y, et al. Severe Hypoglycemia-Induced Fatal Cardiac Arrhythmias Are Mediated by the Parasympathetic Nervous System in Rats. Diabetes 2019; 68(11): 2107-19.
[] [PMID: 31439645]
Kang MY. Blood electrolyte disturbances during severe hypoglycemia in Korean patients with type 2 diabetes. Korean J Intern Med (Korean Assoc Intern Med) 2015; 30(5): 648-56.
[] [PMID: 26354059]
Skogestad J, Aronsen JM. Hypokalemia-Induced Arrhythmias and Heart Failure: New Insights and Implications for Therapy. Front Physiol 2018; 9: 1500.
[] [PMID: 30464746]
Khan E, Spiers C, Khan M. The heart and potassium: a banana republic. Acute Card Care 2013; 15(1): 17-24.
[] [PMID: 23425010]
Davis IC, Ahmadizadeh I, Randell J, Younk L, Davis SN. Understanding the impact of hypoglycemia on the cardiovascular system. Expert Rev Endocrinol Metab 2017; 12(1): 21-33.
[] [PMID: 29109754]
Wright RJ, Frier BM. Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev 2008; 24(5): 353-63.
[] [PMID: 18461635]
Yang SW, Park KH, Zhou YJ. The Impact of Hypoglycemia on the Cardiovascular System: Physiology and Pathophysiology. Angiology 2016; 67(9): 802-9.
[] [PMID: 26685181]
Gogitidze Joy N, Hedrington MS, Briscoe VJ, Tate DB, Ertl AC, Davis SN. Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals. Diabetes Care 2010; 33(7): 1529-35.
[] [PMID: 20587723]
Wright RJ, Newby DE, Stirling D, Ludlam CA, Macdonald IA, Frier BM. Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes. Diabetes Care 2010; 33(7): 1591-7.
[] [PMID: 20587725]
Papazafiropoulou A, Papanas N, Pappas S, Maltezos E, Mikhailidis DP. Effects of oral hypoglycemic agents on platelet function. J Diabetes Complications 2015; 29(6): 846-51.
[] [PMID: 26026848]
Mikhailidis DP, Barradas MA, Hutton RA, Jeremy JY, Sabur M, Dandona P. The effect of non-specific beta-blockade on metabolic and haemostatic variables during hypoglycaemia. Diabetes Res 1985; 2(3): 127-34.
[PMID: 2866057]
Hutton RA, Mikhailidis D, Dormandy KM, Ginsburg J. Platelet aggregation studies during transient hypoglycaemia: a potential method for evaluating platelet function. J Clin Pathol 1979; 32(5): 434-8.
[] [PMID: 469000]
Mikhailidis DP, Barradas MA, Jeremy JY, Dandona P. Effect of alpha a-adrenoceptor antagonist on platelet activation during insulin-induced hypoglycaemia in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1989; 32(2): 147-9.
[] [PMID: 2566548]
Ceriello A, Novials A, Ortega E, et al. Hyperglycemia following recovery from hypoglycemia worsens endothelial damage and thrombosis activation in type 1 diabetes and in healthy controls. Nutr Metab Cardiovasc Dis 2014; 24(2): 116-23.
[] [PMID: 24094827]
Ceriello A, Novials A, Ortega E, et al. Evidence that hyperglycemia after recovery from hypoglycemia worsens endothelial function and increases oxidative stress and inflammation in healthy control subjects and subjects with type 1 diabetes. Diabetes 2012; 61(11): 2993-7.
[] [PMID: 22891214]
Sun B, He F, Gao Y, et al. Prognostic impact of visit-to-visit glycemic variability on the risks of major adverse cardiovascular outcomes and hypoglycemia in patients with different glycemic control and type 2 diabetes. Endocrine 2019; 64(3): 536-43.
[] [PMID: 30868413]
Zinman B, Marso SP, Poulter NR, et al. DEVOTE Study Group. Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2). Diabetologia 2018; 61(1): 48-57.
[] [PMID: 28913575]
Batnyam U, Ko Ko N, Javaid A. Hypoglycemia-associated In-stent Thrombosis: Are We Doing Too Much? Cureus 2017; 9(9): e1712.
[] [PMID: 29188156]
Mahajan VV, Dogra V, Pargal I, Singh N. Silent myocardial infarction during hypoglycemic coma. Indian J Endocrinol Metab 2012; 16(1): 139-40.
[] [PMID: 22276266]
Nishioka Y, Okada S, Noda T, et al. Absolute risk of acute coronary syndrome after severe hypoglycemia: A population-based 2-year cohort study using the National Database in Japan. J Diabetes Investig 2020; 11(2): 426-34.
[] [PMID: 31581351]
Zhang JW, Zhou YJ. Association of silent hypoglycemia with cardiac events in non-diabetic subjects with acute myocardial infarction undergoing primary percutaneous coronary interventions. BMC Cardiovasc Disord 2016; 16: 75.
[] [PMID: 27112137]
Avogaro A, Bonora E, Consoli A, Del Prato S, Genovese S, Giorgino F. Glucose-lowering therapy and cardiovascular outcomes in patients with type 2 diabetes mellitus and acute coronary syndrome. Diab Vasc Dis Res 2019; 16(5): 399-414.
[] [PMID: 31044622]
Tsujimoto T, Yamamoto-Honda R, Kajio H, et al. Vital signs, QT prolongation, and newly diagnosed cardiovascular disease during severe hypoglycemia in type 1 and type 2 diabetic patients. Diabetes Care 2014; 37(1): 217-25.
[] [PMID: 23939540]
Cooper MN, de Bock MI, Carter KW, de Klerk NH, Jones TW, Davis EA. Incidence of and risk factors for hospitalisations due to vascular complications: A population-based type 1 diabetes cohort (n=1316) followed into early adulthood. J Diabetes Complications 2017; 31(5): 843-9.
[] [PMID: 28242271]
Peña AS, Couper JJ, Harrington J, et al. Hypoglycemia, but not glucose variability, relates to vascular function in children with type 1 diabetes. Diabetes Technol Ther 2012; 14(6): 457-62.
[] [PMID: 22313018]
Rezende PC, Everett BM, Brooks MM, et al. Hypoglycemia and Elevated Troponin in Patients With Diabetes and Coronary Artery Disease. J Am Coll Cardiol 2018; 72(15): 1778-86.
[] [PMID: 30286920]
Tang O, Daya N, Matsushita K, et al. Performance of High-Sensitivity Cardiac Troponin Assays to Reflect Comorbidity Burden and Improve Mortality Risk Stratification in Older Adults With Diabetes. Diabetes Care 2020; 43(6): 1200-8.
[] [PMID: 32161049]
Fährmann ER, Adkins L, Loader CJ, et al. Severe hypoglycemia and coronary artery calcification during the diabetes control and complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) study. Diabetes Res Clin Pract 2015; 107(2): 280-9.
[] [PMID: 25467622]
Pistrosch F, Hanefeld M. Hypoglycemia and cardiovascular disease: lessons from outcome studies. Curr Diab Rep 2015; 15(12): 117.
[] [PMID: 26468155]
Lee AK, Warren B, Lee CJ, et al. The Association of Severe Hypoglycemia With Incident Cardiovascular Events and Mortality in Adults With Type 2 Diabetes. Diabetes Care 2018; 41(1): 104-11.
[] [PMID: 29127240]
Leong A, Berkowitz SA, Triant VA, et al. Hypoglycemia in Diabetes Mellitus as a Coronary Artery Disease Risk Factor in Patients at Elevated Vascular Risk. J Clin Endocrinol Metab 2016; 101(2): 659-68.
[] [PMID: 26672635]
Gitt AK, Bramlage P, Binz C, et al. DiaRegis Study Group. Hypoglycaemia is more frequent in type 2 diabetic patients with co-morbid vascular disease: an analysis of the DiaRegis registry. Eur J Prev Cardiol 2012; 19(4): 765-72.
[] [PMID: 21628353]
Mellbin LG, Rydén L, Riddle MC, et al. ORIGIN Trial Investigators. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J 2013; 34(40): 3137-44.
[] [PMID: 23999452]
Goto A, Goto M, Terauchi Y, Yamaguchi N, Noda M. Association between severe hypoglycemia and cardiovascular disease risk in Japanese patients with type 2 diabetes. J Am Heart Assoc 2016; 5(3): e002875.
[] [PMID: 26961698]
Davis SN, Duckworth W, Emanuele N, et al. Investigators of the Veterans Affairs Diabetes Trial. Effects of Severe Hypoglycemia on Cardiovascular Outcomes and Death in the Veterans Affairs Diabetes Trial. Diabetes Care 2019; 42(1): 157-63.
[] [PMID: 30455335]
Zoungas S, Patel A, Chalmers J, et al. ADVANCE Collaborative Group. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010; 363(15): 1410-8.
[] [PMID: 20925543]
Ohkuma T, Zoungas S, Jun M, et al. ADVANCE Collaborative Group. Intensive glucose-lowering and the risk of vascular events and premature death in patients with decreased kidney function: The ADVANCE trial. Diabetes Obes Metab 2020; 22(3): 452-7.
[] [PMID: 31486188]
Tian J, Ohkuma T, Cooper M, et al. Effects of Intensive Glycemic Control on Clinical Outcomes Among Patients With Type 2 Diabetes With Different Levels of Cardiovascular Risk and Hemoglobin A1c in the ADVANCE Trial. Diabetes Care 2020; 43(6): 1293-9.
[] [PMID: 32193249]
Khunti K, Davies M, Majeed A, Thorsted BL, Wolden ML, Paul SK. Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study. Diabetes Care 2015; 38(2): 316-22.
[] [PMID: 25492401]
Pieber TR, Marso SP, McGuire DK, et al. DEVOTE Study Group. DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality. Diabetologia 2018; 61(1): 58-65.
[] [PMID: 28913543]
Yeh JS, Sung SH, Huang HM, et al. Hypoglycemia and risk of vascular events and mortality: a systematic review and meta-analysis. Acta Diabetol 2016; 53(3): 377-92.
[] [PMID: 26299389]
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(9131): 837-53.
[] [PMID: 9742976]
Patel A, MacMahon S, Chalmers J, et al. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358(24): 2560-72.
[] [PMID: 18539916]
Duckworth W, Abraira C, Moritz T, et al. VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360(2): 129-39.
[] [PMID: 19092145]
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(15): 1577-89.
[] [PMID: 18784090]
Hayward RA, Reaven PD, Wiitala WL, et al. VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 372(23): 2197-206.
[] [PMID: 26039600]
Zoungas S, Chalmers J, Neal B, et al. ADVANCE-ON Collaborative Group. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med 2014; 371(15): 1392-406.
[] [PMID: 25234206]
Zhang X, Liu Y, Zhang F, Li J, Tong N. Legacy Effect of Intensive Blood Glucose Control on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Very High Risk or Secondary Prevention of Cardiovascular Disease: A Meta-analysis of Randomized Controlled Trials. Clin Ther 2018; 40(5): 776-788.e3.
[] [PMID: 29656857]
Gerstein HC, Miller ME, Byington RP, et al. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358(24): 2545-59.
[] [PMID: 18539917]
Miller ME, Williamson JD, Gerstein HC, et al. ACCORD Investigators. Effects of randomization to intensive glucose control on adverse events, cardiovascular disease, and mortality in older versus younger adults in the ACCORD Trial. Diabetes Care 2014; 37(3): 634-43.
[] [PMID: 24170759]
Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009; 373(9677): 1765-72.
[] [PMID: 19465231]
Fang HJ, Zhou YH, Tian YJ, Du HY, Sun YX, Zhong LY. Effects of intensive glucose lowering in treatment of type 2 diabetes mellitus on cardiovascular outcomes: A meta-analysis of data from 58,160 patients in 13 randomized controlled trials. Int J Cardiol 2016; 218: 50-8.
[] [PMID: 27236108]
Zhang CY, Sun AJ, Zhang SN, et al. Effects of intensive glucose control on incidence of cardiovascular events in patients with type 2 diabetes: a meta-analysis. Ann Med 2010; 42(4): 305-15.
[] [PMID: 20429797]
Sardar P, Udell JA, Chatterjee S, Bansilal S, Mukherjee D, Farkouh ME. Effect of Intensive Versus Standard Blood Glucose Control in Patients With Type 2 Diabetes Mellitus in Different Regions of the World: Systematic Review and Meta-analysis of Randomized Controlled Trials. J Am Heart Assoc 2015; 4(5): e001577.
[] [PMID: 25944874]
Fisman EZ, Motro M, Tenenbaum A, et al. Is hypoglycaemia a marker for increased long-term mortality risk in patients with coronary artery disease? An 8-year follow-up. Eur J Cardiovasc Prev Rehabil 2004; 11(2): 135-43.
[] [PMID: 15187817]
Upadhyay J, Polyzos SA, Perakakis N, et al. Pharmacotherapy of type 2 diabetes: An update. Metabolism 2018; 78: 13-42.
[] [PMID: 28920861]
Chaudhury A, Duvoor C, Reddy Dendi VS, et al. Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management. Front Endocrinol (Lausanne) 2017; 8: 6.
[] [PMID: 28167928]
Rosenstock J, Perkovic V, Johansen OE, et al. CARMELINA Investigators. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial. JAMA 2019; 321(1): 69-79.
[] [PMID: 30418475]
Perkovic V, Toto R, Cooper ME, et al. CARMELINA investigators. Effects of Linagliptin on Cardiovascular and Kidney Outcomes in People With Normal and Reduced Kidney Function: Secondary Analysis of the CARMELINA Randomized Trial. Diabetes Care 2020; 43(8): 1803-12.
[] [PMID: 32444457]
Kumar K, Kheiri B, Simpson TF, Osman M, Rahmouni H. Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure: A Meta-Analysis of Randomized Clinical Trials. Am J Med 2020; 133(11): e625-30.
Ishida Y, Murayama H, Shinfuku Y, Taniguchi T, Sasajima T, Oyama N. Cardiovascular safety and effectiveness of vildagliptin in patients with type 2 diabetes mellitus: a 3-year, large-scale post-marketing surveillance in Japan. Expert Opin Drug Saf 2020; 19(5): 625-31.
[] [PMID: 32228183]
Müller N, Lehmann T, Klöss A, Günster C, Kloos C, Müller UA. Changes in incidence of severe hypoglycaemia in people with type 2 diabetes from 2006 to 2016: analysis based on health insurance data in Germany considering the anti-hyperglycaemic medication. Diabet Med 2020; 37(8): 1326-32.
[] [PMID: 32145093]
Liu YS, Chen CN, Chen ZG, Peng Y, Lin XP, Xu LL. Vascular and metabolic effects of metformin added to insulin therapy in patients with type 1 diabetes: A systematic review and meta-analysis. Diabetes Metab Res Rev 2020; 36(6): e3334.
[PMID: 32390336]
Ninčević V, Omanović Kolarić T, Roguljić H, Kizivat T, Smolić M, Bilić Ćurčić I. Renal Benefits of SGLT 2 Inhibitors and GLP-1 Receptor Agonists: Evidence Supporting a Paradigm Shift in the Medical Management of Type 2 Diabetes. Int J Mol Sci 2019; 20(23): E5831.
[] [PMID: 31757028]
Varin EM, McLean BA, Lovshin JA. Glucagon-Like Peptide-1 Receptor Agonists in Adult Patients With Type 2 Diabetes: Review of Cardiovascular Outcome Trials. Can J Diabetes 2020; 44(1): 68-77.
[] [PMID: 31699625]
Nagahisa T, Saisho Y. Cardiorenal Protection: Potential of SGLT2 Inhibitors and GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes. Diabetes Ther 2019; 10(5): 1733-52.
[PMID: 31440988]
Yaribeygi H, Atkin SL, Katsiki N, Sahebkar A. Narrative review of the effects of antidiabetic drugs on albuminuria. J Cell Physiol 2019; 234(5): 5786-97.
[] [PMID: 30367464]
Katsiki N, Athyros VG, Mikhailidis DP. Cardiovascular effects of sodium-glucose cotransporter 2 inhibitors: multiple actions. Curr Med Res Opin 2016; 32(9): 1513-4.
[] [PMID: 27309977]
Katsiki N, Papanas N, Mikhailidis DP. Dapagliflozin: more than just another oral glucose-lowering agent? Expert Opin Investig Drugs 2010; 19(12): 1581-9.
[] [PMID: 21105857]
Katsiki N, Mikhailidis DP, Theodorakis MJ. Sodium-glucose Cotransporter 2 Inhibitors (SGLT2i): Their Role in Cardiometabolic Risk Management. Curr Pharm Des 2017; 23(10): 1522-32.
[] [PMID: 28088910]
Katsiki N, Dimitriadis G, Hahalis G, et al. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) use and risk of amputation: an expert panel overview of the evidence. Metabolism 2019; 96: 92-100.
[] [PMID: 30980838]
Katsiki N, Purrello F, Tsioufis C, Mikhailidis DP. Cardiovascular disease prevention strategies for type 2 diabetes mellitus. Expert Opin Pharmacother 2017; 18(12): 1243-60.
[] [PMID: 28685623]
Patti AM, Rizvi AA, Giglio RV, Stoian AP, Ligi D, Mannello F. Impact of Glucose-Lowering Medications on Cardiovascular and Metabolic Risk in Type 2 Diabetes. J Clin Med 2020; 9(4): 912.
[] [PMID: 32225082]
Zelniker TA, Braunwald E. Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review. J Am Coll Cardiol 2020; 75(4): 422-34.
[] [PMID: 32000955]
Sarafidis P, Ferro CJ, Morales E, et al. SGLT-2 inhibitors and GLP-1 receptor agonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease. A consensus statement by the EURECA-m and the DIABESITY working groups of the ERA-EDTA. Nephrol Dial Transplant 2019; 34(2): 208-30.
[] [PMID: 30753708]
Yaribeygi H, Katsiki N, Butler AE, Sahebkar A. Effects of antidiabetic drugs on NLRP3 inflammasome activity, with a focus on diabetic kidneys. Drug Discov Today 2019; 24(1): 256-62.
[] [PMID: 30086405]
Yaribeygi H, Butler AE, Atkin SL, Katsiki N, Sahebkar A. Sodium-glucose cotransporter 2 inhibitors and inflammation in chronic kidney disease: Possible molecular pathways. J Cell Physiol 2018; 234(1): 223-30.
[] [PMID: 30076706]
Khat DZ, Husain M. Molecular Mechanisms Underlying the Cardiovascular Benefits of SGLT2i and GLP-1RA. Curr Diab Rep 2018; 18(7): 45.
[] [PMID: 29886514]
Cotter DG, Schugar RC, Crawford PA. Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol 2013; 304(8): H1060-76.
[] [PMID: 23396451]
Rosenstock J, Kahn SE, Johansen OE, et al. CAROLINA Investigators. Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial. JAMA 2019; 322(12): 1155-66.
[] [PMID: 30844023]
Jensen MH, Kjolby M, Hejlesen O, Jakobsen PE, Vestergaard P. Risk of Major Adverse Cardiovascular Events, Severe Hypoglycemia, and All-Cause Mortality for Widely Used Antihyperglycemic Dual and Triple Therapies for Type 2 Diabetes Management: A Cohort Study of All Danish Users. Diabetes Care 2020; 43(6): 1209-18.
[] [PMID: 32238426]
Ratner RE, Gough SC, Mathieu C, et al. Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials. Diabetes Obes Metab 2013; 15(2): 175-84.
[] [PMID: 23130654]
Marso SP, McGuire DK, Zinman B, et al. DEVOTE Study Group. Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes. N Engl J Med 2017; 377(8): 723-32.
[] [PMID: 28605603]
Wysham C, Bhargava A, Chaykin L, et al. Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial. JAMA 2017; 318(1): 45-56.
[] [PMID: 28672317]
Pratley RE, Emerson SS, Franek E, et al. DEVOTE Study Group. Cardiovascular safety and lower severe hypoglycaemia of insulin degludec versus insulin glargine U100 in patients with type 2 diabetes aged 65 years or older: Results from DEVOTE (DEVOTE 7). Diabetes Obes Metab 2019; 21(7): 1625-33.
[] [PMID: 30850995]
Amod A, Buse JB, McGuire DK, et al. DEVOTE Study Group. Glomerular Filtration Rate and Associated Risks of Cardiovascular Events, Mortality, and Severe Hypoglycemia in Patients with Type 2 Diabetes: Secondary Analysis (DEVOTE 11). Diabetes Ther 2020; 11(1): 53-70.
[] [PMID: 31667706]
McCoy RG, Lipska KJ, Van Houten HK, Shah ND. Association of Cumulative Multimorbidity, Glycemic Control, and Medication Use With Hypoglycemia-Related Emergency Department Visits and Hospitalizations Among Adults With Diabetes. JAMA Netw Open 2020; 3(1): e1919099.
[] [PMID: 31922562]
Yakubovich N, Gerstein HC. Serious cardiovascular outcomes in diabetes: the role of hypoglycemia. Circulation 2011; 123(3): 342-8.
[] [PMID: 21263007]
Ko SH, Park YM, Yun JS, et al. Severe hypoglycemia is a risk factor for atrial fibrillation in type 2 diabetes mellitus: Nationwide population-based cohort study. J Diabetes Complications 2018; 32(2): 157-63.
[] [PMID: 29196120]
Christensen TF, Cichosz SL, Tarnow L, et al. Hypoglycaemia and QT interval prolongation in type 1 diabetes--bridging the gap between clamp studies and spontaneous episodes. J Diabetes Complications 2014; 28(5): 723-8.
[] [PMID: 24666922]
Kacheva S, Karges B, Göller K, Marx N, Mischke K, Karges W. QT prolongation caused by insulin-induced hypoglycaemia - An interventional study in 119 individuals. Diabetes Res Clin Pract 2017; 123: 165-72.
[] [PMID: 28024277]
Fitzpatrick C, Chatterjee S, Seidu S, et al. Association of hypoglycaemia and risk of cardiac arrhythmia in patients with diabetes mellitus: A systematic review and meta-analysis. Diabetes Obes Metab 2018; 20(9): 2169-78.
[] [PMID: 29740922]
Tsujimoto T, Yamamoto-Honda R, Kajio H, et al. High risk of abnormal QT prolongation in the early morning in diabetic and non-diabetic patients with severe hypoglycemia. Ann Med 2015; 47(3): 238-44.
[] [PMID: 25861830]
Giunti S, Gruden G, Fornengo P, et al. Increased QT interval dispersion predicts 15-year cardiovascular mortality in type 2 diabetic subjects: the population-based Casale Monferrato Study. Diabetes Care 2012; 35(3): 581-3.
[] [PMID: 22301117]
Novodvorsky P, Bernjak A, Chow E, et al. Diurnal Differences in Risk of Cardiac Arrhythmias During Spontaneous Hypoglycemia in Young People With Type 1 Diabetes. Diabetes Care 2017; 40(5): 655-62.
[] [PMID: 28213374]
Chow E, Bernjak A, Williams S, et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes 2014; 63(5): 1738-47.
[] [PMID: 24757202]
Allen KV, Frier BM. Nocturnal hypoglycemia: clinical manifestations and therapeutic strategies toward prevention. Endocr Pract 2003; 9(6): 530-43.
[] [PMID: 14715482]
Reno CM, Skinner A, Bayles J, Chen YS, Daphna-Iken D, Fisher SJ. Severe hypoglycemia-induced sudden death is mediated by both cardiac arrhythmias and seizures. Am J Physiol Endocrinol Metab 2018; 315(2): E240-9.
[] [PMID: 29486140]
Reno CM, Daphna-Iken D, Chen YS, VanderWeele J, Jethi K, Fisher SJ. Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation. Diabetes 2013; 62(10): 3570-81.
[] [PMID: 23835337]
Jauch-Chara K, Schultes B. Sleep and the response to hypoglycaemia. Best Pract Res Clin Endocrinol Metab 2010; 24(5): 801-15.
[] [PMID: 21112027]
Lainetti KR, Pimenta J, Vendramini MF. Can hypoglycemic episodes in type 1 diabetics trigger cardiac arrhythmias? Diabetes Res Clin Pract 2019; 158: 107878.
[] [PMID: 31669624]
Andersen A, Jørgensen PG, Knop FK, Vilsbøll T. Hypoglycaemia and cardiac arrhythmias in diabetes. Ther Adv Endocrinol Metab 2020; 11: 2042018820911803.
[] [PMID: 32489579]
Dewan N, Shukla V, Rehni AK, et al. Exposure to recurrent hypoglycemia alters hippocampal metabolism in treated streptozotocin-induced diabetic rats. CNS Neurosci Ther 2020; 26(1): 126-35.
[] [PMID: 31282100]
Shukla V, Fuchs P, Liu A, et al. Recurrent Hypoglycemia Exacerbates Cerebral Ischemic Damage in Diabetic Rats via Enhanced Post-Ischemic Mitochondrial Dysfunction. Transl Stroke Res 2019; 10(1): 78-90.
[] [PMID: 29569040]
Smith L, Chakraborty D, Bhattacharya P, Sarmah D, Koch S, Dave KR. Exposure to hypoglycemia and risk of stroke. Ann N Y Acad Sci 2018; 1431(1): 25-34.
[] [PMID: 29917249]
Nunes AP, Iglay K, Radican L, et al. Hypoglycaemia seriousness and weight gain as determinants of cardiovascular disease outcomes among sulfonylurea users. Diabetes Obes Metab 2017; 19(10): 1425-35.
[] [PMID: 28497592]
Rosso C, Corvol JC, Pires C, et al. Intensive versus subcutaneous insulin in patients with hyperacute stroke: results from the randomized INSULINFARCT trial. Stroke 2012; 43(9): 2343-9.
[] [PMID: 22700528]
Staszewski J, Brodacki B, Kotowicz J, Stepien A. Intravenous insulin therapy in the maintenance of strict glycemic control in nondiabetic acute stroke patients with mild hyperglycemia. J Stroke Cerebrovasc Dis 2011; 20(2): 150-4.
[] [PMID: 20621520]
McCormick M, Hadley D, McLean JR, Macfarlane JA, Condon B, Muir KW. Randomized, controlled trial of insulin for acute poststroke hyperglycemia. Ann Neurol 2010; 67(5): 570-8.
[PMID: 20437554]
Ntaios G, Papavasileiou V, Bargiota A, Makaritsis K, Michel P. Intravenous insulin treatment in acute stroke: a systematic review and meta-analysis of randomized controlled trials. Int J Stroke 2014; 9(4): 489-93.
[] [PMID: 24373425]
Turnbull FM, Abraira C, Anderson RJ, et al. Control Group. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009; 52(11): 2288-98.
[] [PMID: 19655124]
Robbins NM, Swanson RA. Opposing effects of glucose on stroke and reperfusion injury: acidosis, oxidative stress, and energy metabolism. Stroke 2014; 45(6): 1881-6.
[] [PMID: 24743441]
Klingbeil KD, Koch S, Dave KR. Potential link between post-acute ischemic stroke exposure to hypoglycemia and hemorrhagic transformation. Int J Stroke 2017; 15(5): 477-83.
[] [PMID: 29134928]
Radermecker RP, Scheen AJ. Management of blood glucose in patients with stroke. Diabetes Metab 2010; 36(Suppl. 3): S94-9.
[] [PMID: 21211743]
Joseph JI, Torjman MC, Strasma PJ. Vascular Glucose Sensor Symposium: Continuous Glucose Monitoring Systems (CGMS) for Hospitalized and Ambulatory Patients at Risk for Hyperglycemia, Hypoglycemia, and Glycemic Variability. J Diabetes Sci Technol 2015; 9(4): 725-38.
[] [PMID: 26078254]
Waeschle RM, Bräuer A, Hilgers R, et al. Hypoglycaemia and predisposing factors among clinical subgroups treated with intensive insulin therapy. Acta Anaesthesiol Scand 2014; 58(2): 223-34.
[] [PMID: 24372028]
Del Olmo-García MI, Hervás Marín D, Caudet Esteban J, et al. Glycemic variability in type 2 diabetes mellitus and acute coronary syndrome: liraglutide compared with insulin glargine: a pilot study. J Int Med Res 2020; 48(6): 300060520926063.
[] [PMID: 32567433]
Lee J, Kim TM, Kim H, et al. Differences in Clinical Outcomes between Patients with and without Hypoglycemia during Hospitalization: A Retrospective Study Using Real-World Evidence. Diabetes Metab J 2020; 44(4): 555-65.
[] [PMID: 32431110]
Shirakabe A, Hata N, Kobayashi N, et al. Decreased blood glucose at admission has a prognostic impact in patients with severely decompensated acute heart failure complicated with diabetes mellitus. Heart Vessels 2018; 33(9): 1008-21.
[] [PMID: 29569033]
Singh A, Adams A, Dudley B, Davison E, Jones L, Wales L. Making surgical wards safer for patients with diabetes: reducing hypoglycaemia and insulin errors. BMJ Open Qual 2018; 7(3): e000312.
[] [PMID: 30057957]
Dei Cas A, Aldigeri R, Ridolfi V, et al. A performance score of the quality of inpatient diabetes care is a marker of clinical outcomes and suggests a cause-effect relationship between hypoglycaemia and the risk of in-hospital mortality. Diabetes Metab Res Rev 2020; 36(8): e3347.
[] [PMID: 32445284]
American Diabetes Association. 15. Diabetes Care in the Hospital: Standards of Medical Care in Diabetes-2020. Diabetes Care 2020; 43(Suppl. 1): S193-202.
[] [PMID: 31862758]
Naidech AM, Levasseur K, Liebling S, et al. Moderate Hypoglycemia is associated with vasospasm, cerebral infarction, and 3-month disability after subarachnoid hemorrhage. Neurocrit Care 2010; 12(2): 181-7.
[] [PMID: 19967566]
Prinz N, Stingl J, Dapp A, et al. DPV initiative. High rate of hypoglycemia in 6770 type 2 diabetes patients with comorbid dementia: A multicenter cohort study on 215,932 patients from the German/Austrian diabetes registry. Diabetes Res Clin Pract 2016; 112: 73-81.
[] [PMID: 26563590]
Bruderer SG, Bodmer M, Jick SS, Bader G, Schlienger RG, Meier CR. Incidence of and risk factors for severe hypoglycaemia in treated type 2 diabetes mellitus patients in the UK--a nested case-control analysis. Diabetes Obes Metab 2014; 16(9): 801-11.
[] [PMID: 24612200]
de Galan BE, Zoungas S, Chalmers J, et al. ADVANCE Collaborative group. Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Diabetologia 2009; 52(11): 2328-36.
[] [PMID: 19688336]
Feinkohl I, Aung PP, Keller M, et al. Edinburgh Type 2 Diabetes Study (ET2DS) Investigators. Severe hypoglycemia and cognitive decline in older people with type 2 diabetes: the Edinburgh type 2 diabetes study. Diabetes Care 2014; 37(2): 507-15.
[] [PMID: 24103900]
Kim YG, Park DG, Moon SY, et al. Hypoglycemia and Dementia Risk in Older Patients with Type 2 Diabetes Mellitus: A Propensity-Score Matched Analysis of a Population-Based Cohort Study. Diabetes Metab J 2020; 44(1): 125-33.
[] [PMID: 31701690]
McMillan JM, Mele BS, Hogan DB, Leung AA. Impact of pharmacological treatment of diabetes mellitus on dementia risk: systematic review and meta-analysis. BMJ Open Diabetes Res Care 2018; 6(1): e000563.
[] [PMID: 30487973]
Freeman J. Management of hypoglycemia in older adults with type 2 diabetes. Postgrad Med 2019; 131(4): 241-50.
[] [PMID: 30724638]
Mitrakou A, Katsiki N, Lalic NM. Type 2 Diabetes Mellitus and the Elderly: An Update on Drugs Used to Treat Glycaemia. Curr Vasc Pharmacol 2017; 15(1): 19-29.
[] [PMID: 27550054]
Schütt M, Fach EM, Seufert J, et al. DPV Initiative and the German BMBF Competence Network Diabetes Mellitus. Multiple complications and frequent severe hypoglycaemia in ‘elderly’ and ‘old’ patients with Type 1 diabetes. Diabet Med 2012; 29(8): e176-9.
[] [PMID: 22506989]
Mattishent K, Richardson K, Dhatariya K, Savva GM, Fox C, Loke YK. The effects of hypoglycaemia and dementia on cardiovascular events, falls and fractures and all-cause mortality in older individuals: A retrospective cohort study. Diabetes Obes Metab 2019; 21(9): 2076-85.
[] [PMID: 31069922]
Thorpe CT, Gellad WF, Good CB, et al. Tight glycemic control and use of hypoglycemic medications in older veterans with type 2 diabetes and comorbid dementia. Diabetes Care 2015; 38(4): 588-95.
[] [PMID: 25592195]
Farrell B, Black C, Thompson W, et al. Deprescribing antihyperglycemic agents in older persons: Evidence-based clinical practice guideline. Can Fam Physician 2017; 63(11): 832-43.
[PMID: 29138153]
Chen Y, Wang J, Wang LJ, Lin H, Huang PJ. Effect of different blood glucose intervention plans on elderly people with type 2 diabetes mellitus combined with dementia. Eur Rev Med Pharmacol Sci 2017; 21(11): 2702-7.
[PMID: 28678332]
Haroon NN, Austin PC, Shah BR, Wu J, Gill SS, Booth GL. Risk of dementia in seniors with newly diagnosed diabetes: a population-based study. Diabetes Care 2015; 38(10): 1868-75.
[] [PMID: 26216873]
Chi MJ, Liang CK, Lee WJ, Peng LN, Chou MY, Chen LK. Association of New-Onset Diabetes Mellitus in Older People and Mortality in Taiwan: A 10-Year Nationwide Population-Based Study. J Nutr Health Aging 2017; 21(2): 227-32.
[] [PMID: 28112781]
Abbatecola AM, Bo M, Barbagallo M, et al. Italian Society of Gerontology and Geriatrics (SIGG), Florence, Italy. Severe hypoglycemia is associated with antidiabetic oral treatment compared with insulin analogs in nursing home patients with type 2 diabetes and dementia: results from the DIMORA study. J Am Med Dir Assoc 2015; 16(4): 349.e7-349.e12.
[] [PMID: 25669671]
Kostev K, Dippel FW, Rathmann W. Predictors of hypoglycaemia in insulin-treated type 2 diabetes patients in primary care: a retrospective database analysis. Prim Care Diabetes 2014; 8(2): 127-31.
[] [PMID: 24183472]
Mita T, Katakami N, Shiraiwa T, et al. Relationship between frequency of hypoglycemic episodes and changes in carotid atherosclerosis in insulin-treated patients with type 2 diabetes mellitus. Sci Rep 2017; 7: 39965.
[] [PMID: 28067320]
Giménez M, Gilabert R, Monteagudo J, et al. Repeated episodes of hypoglycemia as a potential aggravating factor for preclinical atherosclerosis in subjects with type 1 diabetes. Diabetes Care 2011; 34(1): 198-203.
[] [PMID: 20929996]
Castaldo E, Sabato D, Lauro D, Sesti G, Marini MA. Hypoglycemia assessed by continuous glucose monitoring is associated with preclinical atherosclerosis in individuals with impaired glucose tolerance. PLoS One 2011; 6(12): e28312.
[] [PMID: 22164268]
Irace C, Cutruzzolà A, Carbotti DF, Mastroianni S, Cavallo M, Gnasso A. Hypoglycemia does not affect the progression of preclinical atherosclerosis in subjects with type 2 diabetes. PLoS One 2019; 14(3): e0212871.
[] [PMID: 30835778]
Gao L, Ortega-Sáenz P, García-Fernández M, González-Rodríguez P, Caballero-Eraso C, López-Barneo J. Glucose sensing by carotid body glomus cells: potential implications in disease. Front Physiol 2014; 5: 398.
[] [PMID: 25360117]
Magri CJ, Mintoff D, Camilleri L, Xuereb RG, Galea J, Fava S. Relationship of Hyperglycaemia, Hypoglycaemia, and Glucose Variability to Atherosclerotic Disease in Type 2 Diabetes. J Diabetes Res 2018; 2018: 7464320.
[] [PMID: 30140707]
Li Y, Mu Y, Ji Q, et al. Hypoglycaemia, Abnormal Lipids, and Cardiovascular Disease among Chinese with Type 2 Diabetes. BioMed Res Int 2015; 2015: 862896.
[] [PMID: 26504840]
Tschöpe D, Bramlage P, Binz C, Krekler M, Deeg E, Gitt AK. Incidence and predictors of hypoglycaemia in type 2 diabetes - an analysis of the prospective DiaRegis registry. BMC Endocr Disord 2012; 12: 23.
[] [PMID: 23075070]
Peled S, Pollack R, Elishoov O, Haze A, Cahn A. Association of Inpatient Glucose Measurements With Amputations in Patients Hospitalized With Acute Diabetic Foot. J Clin Endocrinol Metab 2019; 104(11): 5445-52.
[] [PMID: 31246256]
Li CI, Lin CC, Cheng HM, et al. Derivation and validation of a clinical prediction model for assessing the risk of lower extremity amputation in patients with type 2 diabetes. Diabetes Res Clin Pract 2020; 165: 108231.
[] [PMID: 32446799]
Jensen MH, Cichosz SL, Hirsch IB, Vestergaard P, Hejlesen O, Seto E. Smoking is Associated With Increased Risk of Not Achieving Glycemic Target, Increased Glycemic Variability, and Increased Risk of Hypoglycemia for People With Type 1 Diabetes. J Diabetes Sci Technol 2020. In press.
[] [PMID: 32456531]
Szwarcbard N, Villani M, Earnest A, et al. The association of smoking status with glycemic control, metabolic profile and diabetic complications- Results of the Australian National Diabetes Audit (ANDA). J Diabetes Complications 2020; 34(9): 107626.
[] [PMID: 32527672]
Athyros VG, Katsiki N, Doumas M, Karagiannis A, Mikhailidis DP. Effect of tobacco smoking and smoking cessation on plasma lipoproteins and associated major cardiovascular risk factors: a narrative review. Curr Med Res Opin 2013; 29(10): 1263-74.
[] [PMID: 23879722]
Tsiara S, Elisaf M, Mikhailidis DP. Influence of smoking on predictors of vascular disease. Angiology 2003; 54(5): 507-30.
[] [PMID: 14565627]
Anstey KJ, von Sanden C, Salim A, O’Kearney R. Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies. Am J Epidemiol 2007; 166(4): 367-78.
[] [PMID: 17573335]
Wong CKH, Wu T, Wong SKH, et al. Effects of bariatric surgery on kidney diseases, cardiovascular diseases, mortality and severe hypoglycaemia among patients with Type 2 diabetes mellitus. Nephrol Dial Transplant 2020.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy