Repeated Episodes of Hypoglycemia as a Potential Aggravating Factor for Preclinical Atherosclerosis in Subjects With Type 1 Diabetes

Giménez, Marga; Gilabert, Rosa; Monteagudo, Joan; Alonso, A.; Casamitjana, Roser; Paré, Carles; Conget, Ignacio

doi:10.2337/dc10-1371

Cited by 81 publications

(88 citation statements)

References 25 publications

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“…Our findings are supported by two previous studies that investigated atherosclerosis risk in T1DM (13,14). The DCCT/EDIC project reported that the prevalence of coronary artery calcification, an established atherosclerosis marker, was linearly correlated with the incidence rate of hypoglycemia on the DCCT stage (14).…”

Section: Comparison With Previous Studiessupporting

confidence: 80%

“…The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study of T2DM found a weakly inverse association between the annualized number of hypoglycemic episodes and the risk of death (11,12). By contrast, some studies find that repeated hypoglycemia may be an aggravating factor to atherosclerosis in T1DM (13,14). Studies on the compromised sympatheticadrenal reaction in patients with repeated hypoglycemia have been inconclusive regarding whether such a reaction may further damage intravascular coagulation and thrombosis (15) or decrease the vulnerability of these patients to adverse health outcomes (12).…”

mentioning

confidence: 99%

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A Population-Based Study of All-Cause Mortality and Cardiovascular Disease in Association With Prior History of Hypoglycemia Among Patients With Type 1 Diabetes

Shen

et al. 2016

Diabetes Care

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OBJECTIVEThis study investigated the effects of severe hypoglycemia on risks of all-cause mortality and cardiovascular disease (CVD) incidence in patients with type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODSTwo nested case-control studies with age-and sex-matched control subjects and using the time-density sampling method were performed separately within a cohort of 10,411 patients with T1DM in Taiwan. The study enrolled 564 nonsurvivors and 1,615 control subjects as well as 743 CVD case subjects and 1,439 control subjects between 1997 and 2011. History of severe hypoglycemia was identified during 1 year, 1-3 years, and 3-5 years before the occurrence of the study outcomes. Conditional logistic regression analyses were performed to estimate the odds ratio (OR) and 95% CI of the study outcomes. RESULTSPrior severe hypoglycemic events within 1 year were associated with higher risks of all-cause mortality and CVD (adjusted OR 2.74 [95% CI 1.96-3.85] and 2.02 [1.35-3.01], respectively). Events occurring within 1-3 years and 3-5 years before death were also associated with adjusted ORs of 1.94 (95% CI 1.39-2.71) and 1.68 (1.15-2.44), respectively. Significant dose-gradient effects of severe hypoglycemia frequency on mortality and CVD were observed within 5 years. CONCLUSIONSAlthough the CVD incidence may be associated with severe hypoglycemic events occurring in the previous year, the risk of all-cause mortality was associated with severe hypoglycemic events occurring in the preceding 5 years. Exposure to repeated severe hypoglycemic events can lead to higher risks of mortality and CVD.Cardiovascular disease (CVD) is the major cause of death for patients with type 1 diabetes mellitus (T1DM) (1). Although intensive glycemic control reportedly has long-term beneficial effects on CVD onset in T1DM (2), hypoglycemic events often accompany such strategy and must be addressed simultaneously.

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Section: Comparison With Previous Studiessupporting

confidence: 80%

mentioning

confidence: 99%

A Population-Based Study of All-Cause Mortality and Cardiovascular Disease in Association With Prior History of Hypoglycemia Among Patients With Type 1 Diabetes

Shen

et al. 2016

Diabetes Care

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“…Our patients did not show a particular metabolic instability, and hypoglycemia was not severe or very frequent. However, metabolic instability may also worsen c-IMT, and for this reason, another study performed in Spain with such patients presented a higher c-IMT compared with our cohort (27).…”

Section: Discussionmentioning

confidence: 90%

Low Prevalence of Subclinical Atherosclerosis in Asymptomatic Patients With Type 1 Diabetes in a European Mediterranean Population

et al. 2014

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OBJECTIVETo evaluate the presence of early carotid and coronary atherosclerosis in asymptomatic patients with type 1 diabetes with no history of ischemic heart disease. RESEARCH DESIGN AND METHODSOne hundred and fifty patients with type 1 diabetes (58% males; 38.6 6 8.1 years, 20.4 6 8.1 years of evolution; HbA 1c 8.1 6 2.3%; 52% nonsmokers; 26% retinopathy; 9% microalbuminuria) and 50 nondiabetic control subjects age and sex matched were studied. Carotid ultrasonography to determine common carotid artery intima-media thickness (c-IMT) and the presence of atheroma plaques and cardiac computed tomography for calcium analysis and quantification (coronary artery calcium score [CACS]) were performed. RESULTSMost patients with type 1 diabetes and control subjects displayed a CACS of 0 (82 vs. 92%). Patients with type 1 diabetes with CACS ‡1 were older and had higher HbA 1c (44.5 6 5.1 vs. 36.7 6 8.1 years [P < 0.001] and 8.5 6 1.1 vs. 7.8 6 1.0% [P < 0.003], respectively) and longer evolution of diabetes (25.4 6 9.2 vs. 19.3 6 7.4 years, P < 0.005) and mean c-IMT (0.67 6 0.18 vs. 0.53 6 0.11 mm, P < 0.001) compared with patients with CACS of 0. Smoking (P < 0.02), nephropathy (P < 0.05), retinopathy (P < 0.05), and male sex (P < 0.03) were significantly and positively associated with CACS ‡1. Mean c-IMT was significantly higher in patients with type 1 diabetes (0.55 6 0.14 vs. 0.48 6 0.14 mm, P < 0.01), and 11% of them presented atheroma plaques (8% of control subjects). Multivariant logistic regression analysis showed that c-IMT was related to CACS (b = 6.87, P < 0.001). CONCLUSIONSA small percentage of patients with type 1 diabetes showed data suggestive of subclinical atherosclerosis. Universal screening of coronary disease in this population is not justified. Carotid ultrasonography may be useful for screening in the subset of patients with cardiovascular risk factors and long disease evolution.

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“…From the perspective of acute cardiovascular events, the net effect of tight glycemic control with insulin in diabetes in ORIGIN was harm. However, it is conceivable that ORIGIN was too short to demonstrate an effect of glycemic control to significantly interrupt the pathogenesis of atherosclerotic macrovascular disease (23). It remains to be seen if early and sustained glycemic control does so.…”

Section: Upside Of Glycemic Control: Reduced Microvascular Complicationsmentioning

confidence: 99%

Glycemic Goals in Diabetes: Trade-off Between Glycemic Control and Iatrogenic Hypoglycemia

2014

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The selection of a glycemic goal in a person with diabetes is a compromise between the documented upside of glycemic control-the partial prevention or delay of microvascular complications-and the documented downside of glycemic control-the recurrent morbidity and potential mortality of iatrogenic hypoglycemia. The latter is not an issue if glycemic control is accomplished with drugs that do not cause hypoglycemia or with substantial weight loss. However, hypoglycemia becomes an issue if glycemic control is accomplished with a sulfonylurea, a glinide, or insulin, particularly in the setting of absolute endogenous insulin deficiency with loss of the normal decrease in circulating insulin and increase in glucagon secretion and attenuation of the sympathoadrenal response as plasma glucose concentrations fall. Then the selection of a glycemic goal should be linked to the risk of hypoglycemia. A reasonable individualized glycemic goal is the lowest A1C that does not cause severe hypoglycemia and preserves awareness of hypoglycemia, preferably with little or no symptomatic or even asymptomatic hypoglycemia, at a given stage in the evolution of the individual's diabetes.Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes (1). It causes recurrent morbidity in most people with type 1 diabetes and many with advanced (absolutely endogenous insulin deficient) type 2 diabetes and is sometimes fatal. It generally precludes maintenance of euglycemia over a lifetime of diabetes and thus full realization of the benefits of glycemic control. It impairs defenses against subsequent falling plasma glucose concentrations and causes a vicious cycle of recurrent hypoglycemia. The problem of iatrogenic hypoglycemia will be solved by the prevention or cure of diabetes, or the provision of precise insulin replacement or secretion-the former by a closed-loop system or the latter by transplantation of insulin-secreting tissue or b-cell expansion (2). Pending those treatments, we need to better understand the pathophysiology of hypoglycemiaassociated autonomic failure (HAAF) in diabetes if we are to lower the barrier of hypoglycemia in diabetes (2).The concept of HAAF in diabetes posits that iatrogenic hypoglycemia is the result of the interplay of therapeutic hyperinsulinemia, caused by treatment with a sulfonylurea, a glinide, or insulin, and compromised physiologic and behavioral defenses against the resulting falling plasma glucose concentrations (1,2). HAAF includes both defective glucose counterregulation, caused by an attenuated adrenomedullary epinephrine response in the setting of loss of a decrement in circulating insulin and loss of an increment in glucagon secretion, and impaired awareness of hypoglycemia, caused by an attenuated sympathoadrenal, largely sympathetic neural, response. The attenuated adrenomedullary and sympathetic neural responses are most often caused by recent antecedent hypoglycemia (1,2).The practice of hypoglycemia risk reduction in people with diabetes at risk for iatrogenic ...

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Repeated Episodes of Hypoglycemia as a Potential Aggravating Factor for Preclinical Atherosclerosis in Subjects With Type 1 Diabetes

Cited by 81 publications

References 25 publications

A Population-Based Study of All-Cause Mortality and Cardiovascular Disease in Association With Prior History of Hypoglycemia Among Patients With Type 1 Diabetes

A Population-Based Study of All-Cause Mortality and Cardiovascular Disease in Association With Prior History of Hypoglycemia Among Patients With Type 1 Diabetes

Low Prevalence of Subclinical Atherosclerosis in Asymptomatic Patients With Type 1 Diabetes in a European Mediterranean Population

Glycemic Goals in Diabetes: Trade-off Between Glycemic Control and Iatrogenic Hypoglycemia

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