Abstract
Severe hypoglycemia in patients with diabetes is associated with increased risk of adverse cardiovascular events and death. Recent large randomized clinical trials in individuals with type 2 diabetes have shown that intensive glycemic control may result in increased mortality, and hypoglycemia has been investigated as a possible cause. Acute hypoglycemia is a proarrhythmic, proinflammatory, and prothrombotic state, and several mechanisms have been proposed to explain how hypoglycemia might increase cardiovascular morbidity and mortality. However, data from large clinical trials do not provide strong evidence to establish hypoglycemia as a cause of increased mortality. Severe hypoglycemia is also a marker of frailty and a predictor of adverse outcomes in patients with diabetes. Individualized therapy should be the goal in patients with diabetes to avoid severe hypoglycemia and any related adverse outcomes.
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Papers of particular interest, published recently, have been highlighted as: • Of importance
Riddle MC. Glycemic control and cardiovascular mortality. Curr Opin Endocrinol Diabetes Obes. 2011;18(2):104–9.
Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545–59.
Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–72.
Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129–39.
Finfer S, Blair D, Bellomo R, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283–97.
Riddle MC. Counterpoint: intensive glucose control and mortality in ACCORD-still looking for clues. Diabetes Care. 2010;33(12):2722–4.
• Gerstein HC, Miller ME, Genuth S, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364(9):818–28. This report describes the 5-year outcomes for mortality and cardiovascular events in participants in the ACCORD trial.
• Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. Br Med J. 2010;340:b4909. Post hoc analysis of the ACCORD study suggests that severe hypoglycemia was likely not the cause of the difference in mortality between the intensive treatment and control arms.
• Seaquist ER, Miller ME, Bonds DE, et al. The impact of frequent and unrecognized hypoglycemia on mortality in the ACCORD study. Diabetes Care. 2012;35(2):409–14. This post hoc analysis of the ACCORD study showed that subjects in the intensive control group who experienced more episodes of hypoglycemia had a lower risk of death. One explanation for this interesting finding is that individuals with diabetes who are exposed to frequent hypoglycemia can develop a blunted counterregulatory response to hypoglycemia which could reduce impact of hypoglycemia on cardiovascular function.
Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363(15):1410–8. This retrospective analysis of the ADVANCE study showed severe hypoglycemia was associated with increased risks of cardiovascular events and death.
Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association (vol 32, pg 187, 2009). Diabetes Care. 2009;32(4):754.
Johnston SS, Conner C, Aagren M, et al. Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes. Diabetes Care. 2011;34(5):1164–70.
McCoy RG, Van Houten HK, Ziegenfuss JY, et al. Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care. 2012;35(9):1897–901.
Hsu P, Sung S, Cheng H, et al. Association of clinical symptomatic hypoglycemia with cardiovascular events and total mortality in type 2 diabetes: a nationwide population-based study. Diabetes Care. 2013;36(4):894–900.
Zhao Y, Campbell CR, Fonseca V, Shi L. Impact of hypoglycemia associated with antihyperglycemic medications on vascular risks in veterans with type 2 diabetes. Diabetes Care. 2012;35(5):1126–32.
Gruden G, Barutta F, Chaturvedi N, et al. Severe hypoglycemia and cardiovascular disease incidence in type 1 diabetes the EURODIAB prospective complications study. Diabetes Care. 2012;35(7):1598–604.
Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359–67.
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449–61.
Soylemez Wiener R, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults—a meta-analysis. JAMA. 2008;300(8):933–44.
Svensson A, McGuire D, Abrahamsson P, Dellborg M. Association between hyper- and hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events. Eur Heart J. 2005;26(13):1255–61.
Kagansky N, Levy S, Rimon E, et al. Hypoglycemia as a predictor of mortality in hospitalized elderly patients. Arch Intern Med. 2003;163(15):1825–9.
Boucai L, Southern WN, Zonszein J. Hypoglycemia-associated mortality is not drug-associated but linked to comorbidities. Am J Med. 2011;124(11):1028–35.
Landstedt-Hallin L, Englund A, Adamson U, Lins P. Increased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus. J Intern Med. 1999;246(3):299–307.
• Frier BM, Schernthaner G, Heller SR. Hypoglycemia and cardiovascular risks. Diabetes Care. 2011;34:S132–7. This is a review article on the effects of hypoglycemia on the cardiovascular system.
Robinson R, Harris N, Ireland R, Lee S, Newman C, Heller S. Mechanisms of abnormal cardiac repolarization during insulin-induced hypoglycemia. Diabetes. 2003;52(6):1469–74.
Desouza C, Salazar H, Cheong B, et al. Association of hypoglycemia and cardiac ischemia—a study based on continuous monitoring. Diabetes Care. 2003;26(5):1485–9.
Gerritsen J, Dekker J, TenVoorde B, et al. Impaired autonomic function is associated with increased mortality, especially in subjects with diabetes, hypertension, or a history of cardiovascular disease—the Hoorn study. Diabetes Care. 2001;24(10):1793–8.
Maser R, Mitchell B, Vinik A, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes—a meta-analysis. Diabetes Care. 2003;26(6):1895–901.
Cryer P. Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes. 2005;54(12):3592–601.
Davis S, Galassetti P, Wasserman D, Tate D. Effects of antecedent hypoglycemia on subsequent counterregulatory responses to exercise. Diabetes. 2000;49(1):73–81.
Adler GK, Bonyhay I, Fainng H, et al. Antecedent hypoglycemia impairs autonomic cardiovascular function implications for rigorous glycemic control. Diabetes. 2009;58(2):360–6.
Wright RJ, Newby DE, Stirling D, et al. 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.
Joy NG, Hedrington MS, Briscoe VJ, et al. 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.
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A. Moheet declared no conflict of interest. E.R. Seaquist serves/has served as a consultant for AMG Medical, SkyePharma, Merck, and Sanofi-Aventis and is the PI on a grant from Lilly within the last three years.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
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This article is part of the Topical Collection on Clinical Trials and Their Interpretations
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Moheet, A., Seaquist, E.R. Hypoglycemia as a Driver of Cardiovascular Risk in Diabetes. Curr Atheroscler Rep 15, 351 (2013). https://doi.org/10.1007/s11883-013-0351-7
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DOI: https://doi.org/10.1007/s11883-013-0351-7