Association Between Severe Hypoglycemia, Adverse Macrovascular Events, and Inflammation in the Edinburgh Type 2 Diabetes Study

Abstract

OBJECTIVETo determine whether a history of severe hypoglycemia was associated with an increased risk of subsequent macrovascular events in people with type 2 diabetes and to explore possible mediation of this association by inflammation. RESEARCH DESIGN AND METHODSA cohort of 1,066 adults aged 60-75 years with type 2 diabetes was evaluated prospectively. Baseline history of severe hypoglycemia and plasma levels of the inflammatory markers C-reactive protein, fibrinogen, interleukin-6, and tumor necrosis factor-a were recorded. Their association with incident macrovascular events after 4 years was explored. RESULTSAt baseline, 87 participants (8.2%) reported one or more episodes of severe hypoglycemia within the preceding year, and at follow-up 99 participants (9.3%) had suffered a new macrovascular event. Hypoglycemia was associated with increased odds of macrovascular events (odds ratio [OR] 2.11 [95% CI 1.06, 4.21], P = 0.035), including coronary heart events (OR 2.44 [95% CI 1.13, 5.26], P = 0.023), largely due to increased myocardial infarction (OR 4.02 [95% CI 1.54, 10.48], P = 0.004). Hypoglycemia was also associated with increased levels of inflammatory markers, including a general inflammation factor derived using principalcomponents analysis (P = 0.030, after adjustment for cardiometabolic risk factors). However, the significant association between hypoglycemia and macrovascular events persisted after adjustment for inflammatory markers. CONCLUSIONSThe odds of suffering a macrovascular event were higher in patients with type 2 diabetes who had a history of severe hypoglycemia. There was no evidence that a proinflammatory state had a major role in mediating this association.Macrovascular disease is the major cause of mortality in people with type 2 diabetes (1). Hypoglycemia is a potentially serious side effect of insulin and sulfonylureas when used to treat diabetes (2). It is associated with significant morbidity and mortality and can provoke acute cardiovascular and cerebrovascular events (2-4). Hypoglycemia may also have a role in aggravating other chronic complications (4)

Comparative effects of acute hypoglycemia and hyperglycemia on pro-atherothrombotic biomarkers and endothelial function in non-diabetic humans

“…Moreover, several studies have demonstrated or reported that acute hyperglycemia (5, 6, 9, 23, 27) or hypoglycemia (7, 25, 32, 41) can result in increased atherothrombotic mechanisms, reduced fibrinolytic balance, and impaired endothelial function in both nondiabetic and diabetic individuals (6, 10, 25, 32, 37). Despite recent data reporting the acute effects of hyperglycemia and hypoglycemia on pro-atherothrombotic responses, only one study has compared their relative effects in humans (9).…”

Glycaemia Self-Control Role in Prevention of Cardiovascular Diseases in Diabetes Mellitus Patients

“…Во время гипогликемии повышается уровень цирку-лирующих воспалительных маркеров, таких как CD40, CD40-лиганд, интерлейкин-6, С-реактивный белок, а также маркеров окислительного стресса, провоспали-тельных и атеротромботических биомаркеров (ICAM-1, VCAM-1, E-селектин, VEGF, ФНО-α) [21]. Эндотелиальная дисфункция является ранним предиктором субклиниче-ского атеросклероза.…”

“…Течение СД часто осложняется высоким риском воз-никновения гипогликемии, которая является значимым предиктором кардиоваскулярных событий, неблагопри-ятных клинических исходов и смертности у пациентов с СД 2-го типа [3][4][5][6]. По данным Connelly K.A.…”

Hypoglycemia in patients with insulin‑treated diabetes

“…57, 58 A recent systematic review and meta analysis, as well as cohort studies, have proved that severe hypoglycemia is associated with increased risk of cardiovascular disease and death among patients with type 2 diabetes. [59][60][61][62] Regarding patients with type 1 diabetes, it is suggested that repeated hy poglycemia could be related to worse prognosis in terms of preclinical atherosclerosis, as well as considered an aggravating factor for it. [63][64][65] Only a few studies have examined whether hypoglyce mia may increase the risk of cardiovascular dis ease or death among patients with type 1 diabe tes, and the results were ambiguous.…”