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Hypoglycemia, Diabetes, and
Cardiovascular Events
YRUS V. DESOUZA, MD
EREMIA B. BOLLI, MD
leading to an increase in severe hypogly- IVIAN FONSECA, MD
cemia with brain dysfunction (9,11). Theresponse of adrenaline (and norepineph-rine) in individuals with hypoglycemia Diabetesisatepidemicproportions Whilethereasonfortheincreasedmor- unawarenessislowerthaninawaresub-
tality is unclear and hypoglycemia has not jects (9), a finding that might be of car- been implicated as a cause of death, these of glycemic control in decreasing the risk the degree of glycemic control required to quite varied in the literature (supplemen- tary Table 1, available in an online appen- complications has been controversial.
with lack of standardization of definition Several large clinical trials looking at this DEFINITION, INCIDENCE
of hypoglycemia and its classification.
issue have either shown no benefit or even OF, AND RISK FACTORS
ASSOCIATED WITH
trials reviewed in this article depends on glycemia as a risk factor for cardiovascular HYPOGLYCEMIA — The modern
the definitions of mild, moderate, and se- events is a topic of much debate. In this definition of hypoglycemia is plasma glu- vere hypoglycemia. Most recent large tri- review article, we discuss the evidence for cose Ͻ70 mg/dl (7–9). At plasma glucose below this threshold (60 – 65 mg/dl), the sible mechanisms that might be involved.
motes secretion of counterregulatory hor- those that are self-treated (supplementary creased risk of cardiovascular disease.
nized as a major barrier to achieving nor- firmly established (1,2). However, the as- “rapid” responses), which have relevant cardiovascular effects (9 –11). This occurs has therefore been investigated in terms of its impact (particularly on cognitive func- tion) and physiological counterregulation sive glucose control has often failed to re- at lower plasma glucose (Ͻ60 mg/dl) (9).
glucose control invariably increases the risk cur often over time (e.g., once a day), the ity of hypoglycemia (2) Several epidemio- creased cardiovascular risk (3–5). Recent higher levels (i.e., it takes a lower plasma large randomized trials looking at inten- glucose to activate symptom responses) is group treated with insulin (1). In the 4-T no benefit (Action in Diabetes and Vascu- glucose decreases to Յ50 mg/dl. In turn, patient per year were lowest in the basal insulin group (1.7), higher in the biphasic mia in an early phase (hypoglycemia aspart insulin group (3.0), and highest in unawareness) increases the risk of pro- cular Risk in Diabetes [ACCORD]) (6).
tients reported that the duration of diabe-tes and the duration of insulin treatment ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● From the 1University of Nebraska Medical Center, Omaha, Nebraska; the 2Section of Internal Medicine and glycemic episodes (15). Thus, although in Oncology, University of Perugia, Italy; and the 3Tulane University Health Sciences Center, New Orleans,Louisiana.
general in type 2 diabetes there is less hy- Corresponding author: Cyrus Desouza, [email protected].
Received 11 November 2009 and accepted 9 March 2010.
with increased diabetes and insulin treat- 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
org/licenses/by-nc-nd/3.0/ for details.
DIABETES CARE, VOLUME 33, NUMBER 6, JUNE 2010 Hypoglycemia and cardiovascular events
(8), primarily because of loss of glucagon the forefront the question of the role of risk for cardiovascular events. There are after artificial ventilation. Nineteen others aged Ն65 years, who used insulin or sul- few studies looking at this question.
were sleeping alone at the time of death, Broadly, they can be divided into studies that look at the effect of hypoglycemia on (23). Gill et al. (24) demonstrated that, in (16). In this cohort, recent hospital dis- patients with type 1 diabetes, severe hy- charge was the strongest predictor of sub- MYOCARDIAL ISCHEMIA,
INFARCTION, AND
tive study of 267 patients with both type 1 ARRHYTHMIAS — The earliest
study in 1932 reported chest pain consis- glycemic events in 155 patients (17). Pa- CEREBRAL ISCHEMIA,
seven type 1 diabetic patients with known STROKE, AND
DEMENTIA — Severe hypoglycemia
these findings (3,5). More recently, in a with coronary artery disease, recruited for correction of blood glucose. However, the with type 2 diabetes. Predictors of diabe- tes in this group included previous hypo- glycemia and duration of insulin therapy.
A retrospective cross-sectional analysis in to assess the efficacy of bezafibrate in re- dysfunction and dementia. Whitmer et al.
symptoms in 12% of diet-treated patients, Israel) over an 8-year mean follow-up, hy- study of 16,667 patients with type 2 dia- 30% of patients on insulin (18). Risk fac- betes looking at the relationship between hazard ratio of 1.84, but not of increased coronary artery disease mortality (4). The found that the attributable risk of demen- after institution of intensive glycemic con- trol versus standard control (32 vs. 20%) cognitive dysfunction has been associated (20). However, this was not significantly risk of severe hypoglycemia (hazard ratio 2.1) in patients with type 2 diabetes (26).
Diabetes (BARI 2D) trial, although severe glycemia itself was not found to increase major cardiovascular events were not sig- the risk of getting dementia (27). In type 1 cise, alcohol, older age, renal dysfunction, infection, decreased intake of energy, and ations in regional cerebral blood flow in mental health issues, including dementia, depression, and psychiatric illnesses. In EPIDEMIOLOGICAL
EVIDENCE FOR THE
ASSOCIATION BETWEEN
cemia. Less studied is the “dead-in-bed” blood flow in patients with type 1 diabe- HYPOGLYCEMIA AND
CARDIOVASCULAR
nocturnal death in type 1 diabetes. In one these are temporary and reversible (28). It MORBIDITY — Recent studies such
is unclear whether this finding can be ex- DIABETES CARE, VOLUME 33, NUMBER 6, JUNE 2010 Desouza, Bolli, and Fonseca
intensive insulin protocols to control in- risk for dementia is still controversial.
increased risk of hypoglycemia in the in- tensive treatment arm, there was no asso- from these trials have increased the con- ROLE OF HYPOGLYCEMIA
troversy over the risks versus benefit of IN THE RESULTS OF RECENT
cardiovascular mortality (30). One expla- tight inpatient glycemic control. Van den CLINICAL TRIALS — Recently, sev-
eral large randomized trials evaluating the tensive insulin therapy in critically ill pa- effects of glycemic control on cardiovas- tients reduced morbidity and mortality.
cular events have published their results farction) study found that insulin-glucose 10,251 participants with a history of car- infusion followed by intensive subcutane- diovascular events or significant cardio- ous insulin in diabetic patients with acute trial had a 2- to 3-year shorter duration of halted because of a significant increase in ority of insulin versus conventional treat- study. The relative risk of death associ- account for the low level of hypoglycemia cose Insulin in Stroke Trial (GIST)-U.K.
looked at tight control of glucose in pa- for the intensive arm versus 2.87 for the tients with acute stroke using an intensive standard arm in spite of larger number of rolled type 1 diabetic patients on insulin tensive arm. This suggests that severe hy- treatment. In contrast to the UK Diabetes poglycemia in a certain subset of patients than the strategy of treatment used (inten- tional” treatment group (0.19 episodes/ data are based on post hoc analysis, and the tality rate of 34 versus 22% for those who true cause of the increased mortality in these risk in the “intensive” group (0.62 epi- subset of patients most prone to the detri- mental effects of hypoglycemia had several of the following characteristics: they were increased cardiovascular mortality (13) at likely to be women, African American, older later follow-up (1). This indirectly high- patients, or patients with a longer duration lights the different cardiovascular risk of volume and insulin therapy in severe sep- hypoglycemia in type 2 versus type 1 dia- betes. Thus, it is clear that these trials had different treatment strategies to achieve risk with type 2 diabetes to an intensive treat- study by Kosiborod et al. (40), looking at appreciate that the strategy used to achieve group (31). At the end of the study, there risk factor modification is important in how dial infarction, found that a J-shaped re- was no significant difference in cardiovas- it affects patient outcomes. Moreover, the particular strategy’s effect on a risk factor arms. As expected, there was an increased may not predict its effect on patient out- incidence of severe hypoglycemia in the in- tensive treatment group. Predictors for hy- poglycemia included increased duration of HYPOGLYCEMIA AND
diabetes, insulin treatment at baseline, low INPATIENT GLUCOSE
steeper in patients with diabetes, suggest- CONTROL — Hyperglycemia is com-
mon in acutely ill patients and is associ- creased mortality, especially in diabetic patients. In another study, a pooled anal- 11,140 participants to an intensive glyce- mortality (33). This has subsequently led to a large number of trials using various DIABETES CARE, VOLUME 33, NUMBER 6, JUNE 2010 Hypoglycemia and cardiovascular events
ies, death occurred in 4.6% of the patientswith hypoglycemia versus 1% of thosewho were considered euglycemic (81–199 mg/dl) (41). In contrast, a sub-analysis of the DIGAMI 2 data did notshow hypoglycemia to be an independentrisk factor for future morbidity or mortal-ity in patients with type 2 diabetes andmyocardial infarction (42).
diovascular mortality in the inpatient set-ting is still controversial. Much of thevariability in results is due to the differentprotocols used, differences in definitionof hypoglycemia, as well as methodologyof its detection and report, presence orabsence of safeguards against hypoglyce-mia in the protocols, local training level ofthe personnel administering the proto-cols, and selected patient population.
Hence, carefully constructed clinical trailsto research this question are required.
However, it is prudent to conclude fromthe available data that severe hypoglyce-mia should be avoided as much as possi- Figure 1—Mechanisms by which hypoglycemia may affect cardiovascular events. Hypoglycemic events may trigger inflammation by inducing the release of C-reactive protein (CRP), IL-6, andvascular endothelial growth factor (VEGF). Hypoglycemia also induces increased platelet andneutrophil activation. The sympathoadrenal response during hypoglycemia increases adrenaline MECHANISMS BY WHICH
secretion and may induce arrhythmias and increase cardiac workload. Underlying endothelialdysfunction leading to decreased vasodilation may also contribute to cardiovascular risk. HYPOGLYCEMIA MAY
AFFECT CARDIOVASCULAR
EVENTS — Hypoglycemia induces
rate variability have been associated with several counterregulatory responses.
␤-cell insulin secretion, an increase in glycemia is associated with a significant ies did not find any associations betweenpancreatic ␣-cell glucagon secretion, an heart rate variability, hypoglycemia, and (QTC) in subjects with and without diabetes increased catecholamine release (10,46).
(10,24). Other electrocardiographic abnor- and norepinephrine (in addition to its ele- malities observed during hypoglycemia in- INFLAMMATION,
vated tissue turnover), as well as an in- COAGULATION, AND
creased secretion of ACTH/glucocorticoids.
moderate ST segment depressions (10).
ENDOTHELIAL
Besides these classical responses, there are DYSFUNCTION DURING
several indirect changes induced by hypo- HYPOGLYCEMIA — Inflammation
glycemia that affect inflammatory cytokine secretion, endothelial function, coagula- in particular could lead to a high risk of tion, and fibrinolysis. All of these responses have potential adverse effects on cardiovas- cular morbidity and mortality and will be vented or reversed by ␤ blockade (43).
THE SYMPATHOADRENAL
result in endothelial injury and abnormal- RESPONSE — Hypoglycemia stimu-
cardiac repolarization abnormalities.
ities in coagulation, resulting in increased lates the release of catecholamines, which These effects can be reversed by ␤ block- risk for cardiovascular events (Fig. 1).
Certain growth factor levels such as vas- and blood vessels. Catecholamines increase myocardial contractility, myocardial work- increased locally and in circulation after ulation may contribute to the occurrence of disease (3). The greater oxygen demand is adverse cardiac events (44). Abnormalities of hypoglycemia, thus perpetuating a pos- not met because of the rigid vessels, but also in high-frequency and low-frequency heart DIABETES CARE, VOLUME 33, NUMBER 6, JUNE 2010 Desouza, Bolli, and Fonseca
tis, Novo Nordisk, Takeda, Pfizer, sanofi- glycemia in healthy subjects. Ann Noninva- in platelet function and activation of the aventis, Eli Lilly, and the American Diabetes Association. He has also received honoraria for 11. Sherwin RS. Bringing light to the dark side epinephrine levels lead to an increase in of insulin: a journey across the blood-brain Kline, Novartis, Novo Nordisk, Takeda, Pfizer, sanofi-aventis, Eli Lilly, and Daiichi Sankyo.
12. Cryer PE: Hypoglycemia in Diabetes: Patho- physiology, Prevalence and Prevention. Alex- of these changes can be reversed by ␣ or ␤ Nordisk and Takeda for consulting. No other andria, VA, American Diabetes Association, potential conflicts of interest relevant to this 13. Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control acute hypoglycemia. Vessel wall stiffness and Complications Trial Research Group.
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