Review

The Impact of Hypoglycemia on the Cardiovascular System: Physiology and Pathophysiology

Angiology 2016, Vol. 67(9) 802-809 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319715623400 ang.sagepub.com

Shi-Wei Yang, MD1, Kyoung-Ha Park, MD, PhD2, and Yu-Jie Zhou, MD, FACC, FSCAI, FHRS1

Abstract Intensive glycemic control may increase cardiovascular (CV) risk and mortality due to hypoglycemia. The pathophysiology of glucose counter-regulation in patients with type 1 or type 2 diabetes for over 15 years is characterized by impairment of the defense mechanisms against hypoglycemia. Hypoglycemia causes pronounced physiological and pathophysiological effects on the CV system as consequences of autonomic system activation and counter regulatory hormones release. These effects provoke a series of hemodynamic changes that include an increase in heart rate and peripheral systolic blood pressure, a decrease in central blood pressure, reduced peripheral arterial resistance, and increased myocardial contractility and cardiac output. Cardiac electrophysiological changes including flattening or inversion of T waves, QT prolongation, and ST segment depression were observed in both insulin-induced and spontaneous hypoglycemia. Sympathoadrenal activation is the main cause of these changes through mechanisms that involve, but are not limited to, catecholamine-mediated hypokalemia. Hypoglycemia is also involved in platelet activation. There is growing concern about the long-term effects of hypoglycemia, especially as related to inflammation and atherogenesis. Keywords hypoglycemia, cardiovascular risk, physiological and pathophysiological effects, diabetes

Introduction Hypoglycemia often occurs as a side effect of diabetic medications, including insulin and some oral antidiabetic agents, especially sulphonylureas. Strict glycemic control using intensive insulin therapy increases the risk of severe hypoglycemia 3-fold.1 Nondiabetic individuals can also experience reactive hypoglycemia or secondary to insulinoma, glycogen storage disease, and so on.2-5 For a long time, due to excessive emphasis on the benefits of strict glycemic control in patients with diabetes mellitus (DM), the potentially life-threatening adverse effects of hypoglycemia have been overlooked or dismissed.2-5 This scenario may be a misperception based on inadequate information. The burden of covert hypoglycemia associated with diabetic medications may be underestimated. And the misperception has been corrected by the findings of a series of epidemiological or cohort investigations, which revealed that severe hypoglycemia events are not rare in insulintreated as well as sulfonylurea-treated type 2 DM.6-10

Cardiovascular Morbidity and Mortality Associated With Hypoglycemia The possibility of hypoglycemia as a risk factor for cardiovascular (CV) events is now gradually emerging with evidence

from clinical trials. Although these trials defined hypoglycemia in different ways, they all provided some insight into the nature of the relationship between hypoglycemia and CV events. The large scale trials11-22 tend to suggest that intensive glycemic control may in fact increase CV risk and mortality due to hypoglycemia. In one of the largest clinical trials on the effects of intensive glucose control on CV outcomes, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial,11 11 140 patients with type 2 DM were randomly assigned to intensive therapy targeting a glycated hemoglobin A1C < 6.5% or conventional

1

Department of Cardiology, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, The Key Laboratory of Remodeling-related Cardiovascular Disease, Ministry of Education, Beijing, China 2 Division of Cardiology, Department of Internal Medicine, Hallym University Medical Center, Anyang, Korea Corresponding Author: Yu-Jie Zhou, 12th Ward, Department of Cardiology, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, The Key Laboratory of Remodeling-related Cardiovascular Disease, Ministry of Education, Chao Yang District, Beijing 100029, China. Email: [email protected]

Yang et al

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Figure 1. Systemic physiological and pathophysiological responses to hypoglycemia. BGL indicates blood glucose level.

therapy. After a median of 5 years of follow-up, there were no significant effects of the type of glucose control on major macrovascular events, death from CV causes, or death from any cause. Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7% vs 1.5% in the standard-control group; P < .001). In another large scale clinical trial, the Action to Control Cardiovascular Risk in Diabetes (ACCORD),17,18 10 251 patients with type 2 DM were assigned to receive intensive therapy (targeting a glycated hemoglobin A1c level