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Ann N Y Acad Sci. Author manuscript; available in PMC 2019 November 01.
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Published in final edited form as:

Ann N Y Acad Sci. 2018 November ; 1431(1): 25–34. doi:10.1111/nyas.13872.

Exposure to hypoglycemia and risk of stroke

Logan Smith1,2, Diya Chakraborty1,2, Pallab Bhattacharya4,5, Deepaneeta Sarmah4,
Sebastian Koch2, and Kunjan R. Dave1,2,3
1Cerebral Vascular Disease Research Laboratories
2Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida
3Neuroscience Program, University of Miami Miller School of Medicine, Miami, Florida
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4National Institute of Pharmaceutical Education & Research-Ahmedabad, Gujarat, India

5Boston Children’s Hospital, Harvard Medical School, Boston, USA

Abstract
In the treatment of both Type 1 and Type 2 diabetes mellitus, maintaining a euglycemic state
represents one of the key challenges. Improper dosing and administration of glucose-lowering
drugs is associated with an increased risk of recurrent hypoglycemia episodes. In addition, the risk
of adverse cardiovascular events in diabetic patients, particularly myocardial infarctions and
strokes, is well-established. Current research indicates a potential link between the baseline risk of
cardio/cerebrovascular events in diabetic patients and exposure to hypoglycemia. In this review of
the literature we aim to determine if a relationship exists between recurrent hypoglycemia and
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adverse neurovascular events.

Keywords
diabetes; hypoglycemia; cerebrovascular event; stroke

Introduction
Chronic hyperglycemia in diabetic patients can lead to a variety of long-term
complications1–5. Of particular importance is the increased risk of cardiovascular diseases,
which is reported as the leading cause of death in diabetic patients6, 7. Tight and aggressive
glucose management treatment with pharmacological agents has been shown to reduce the
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risk for some macrovascular and microvascular pathologies, but such treatments also put
patients at increased risk for subclinical and severe hypoglycemia8. During hypoglycemia,

Address for correspondence: Kunjan R. Dave, Ph.D, Department of Neurology (D4-5), University of Miami Miller School of
Medicine, 1420 NW 9th Ave, NRB/203E, Miami, FL 33136. KDave@med.miami.edu.
LS and DC contributed equally to this manuscript.
Author contributions
LS, DC, PB, DS, SK, and KD: contributed to the conception, design of the article, contributed in writing parts of the manuscript and
critically revising the manuscript.
Competing interests
The authors declare that they have no competing interests.
 Smith et al. Page 2

the autonomic nervous system acts to increase release of catecholamines in an attempt to

restore normal concentrations by increasing hepatic production of glucose9. These increased
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systemic catecholamine levels can lead to unintended consequences, such as increased

platelet aggregation, fatal arrhythmias and chronic cardiac inflammation10. Repeated
episodes of hypoglycemia can weaken the body’s neuroglycopenic response to low blood
glucose11. Preclinical studies indicate that hypoglycemia may activate procoagulant
pathways. However, not all clinical studies support the notion that exposure to hypoglycemia
increases the risk of cardiovascular complications. In this review, we aim to review the
existing literature to determine if hypoglycemia has any effect on cerebrovascular events in
diabetic patients.

Incidence of hypoglycemia in diabetes management

The American Diabetes Associated Workgroup on Hypoglycemia defines hypoglycemia as
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“all episodes of abnormally low plasma glucose concentration that expose the individual to
potential harm”12. Several categories of hypoglycemia exist, including severe hypoglycemia
(requiring another individual to assist with treatment), symptomatic and asymptomatic
hypoglycemia (both of which have blood glucose ≤70 mg/dL but with variable symptoms),
probable hypoglycemia (symptoms reported, but not confirmed by glucose measurement)
and relative hypoglycemia (symptoms present, but glucose is still >70 mg/dL)12.

Although hypoglycemia presents with similar symptoms in type 1 diabetes (T1D) and type 2
diabetes (T2D), the differing pathologies of the diseases cause subtle differences in the
course of these hypoglycemic episodes. Repeated episodes of hypoglycemia in a short
amount of time increase the risk of development of hypoglycemia-associated autonomic
failure (HAAF), in which the body’s neurogenic responses to low blood sugar are blunted,
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leading to defective glucose counter-regulation and hypoglycemia unawareness13. These

repeated hypoglycemic episodes shift the systemic thresholds needed to induce these
autonomic responses to lower blood glucose levels11. Owing to the onset of hypoglycemia
unawareness in HAAF as well as the inability to properly measure and control blood glucose
during sleep, it has been hypothesized that both T1D and T2D patients experience mild and
moderate hypoglycemic episodes much more frequently than previously thought. Macleod et
al.14 performed a retrospective clinical study on a randomly selected sample of diabetic
patients (both T1D and T2D) and showed evidence of severe hypoglycemia at an event rate
of 170 per 100 patient-years and 73 per 100 patient-years in insulin-treated T1D and T2D
patients, respectively14. Several other studies also made similar observations15, 16. Studies
involving continuous blood glucose monitoring have shown that as many as 68% of T1D (3
days of monitoring)17 and 49% of T2D (5 days of monitoring)18 recorded systemic glucose
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levels below 60 mg/dl.

Impaired autonomic responses in old age may increase older diabetic patients’ susceptibility
to experiencing recurrent hypoglycemia19. An earlier study to evaluate incidences of
hypoglycemia in sulfonylurea (SU)- or insulin-treated older diabetic patients observed that
elderly persons using multiple medications and those who are frequently hospitalized, are at
greater risk for hypoglycemia19,20. Although difficult to estimate, repeated exposure to

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hypoglycemia in older individuals may lead to deterioration of general heath, disability and
poor outcomes19,21.
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Despite recent advances in new regimens for blood glucose control, the fear of
hypoglycemia still looms large22. There have been a small number of clinical trials in recent
years showing that the incidence of hypoglycemia with the use of insulin analogs and oral
hypoglycemic agents is an undeniable reality23, 24. The landmark clinical trials, such as
Action to Control Cardiovascular Risk in Diabetes (ACCORD)25 and Diabetes Control and
Complications Trial (DCCT)26, mostly concentrated on the hypoglycemia incidence in
developed nations. However, it is as much of a reality in developing nations with huge
population of diabetic patients, including India and China. The treatment of diabetes and the
availability of appropriate clinical expertise to manage the condition varies slightly from
country to country. The under-reporting of self-treated hypoglycemia events only adds to the
seriousness of the issue as the risks and incidence of hypoglycemia can be underestimated.
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The Hypoglycemia Assessment Tool (HAT) study conducted recently in developing

countries on 27,585 insulin-treated diabetic patients showed an incidence rate of
hypoglycemia higher than previously reported27. There have been a few European studies
that have also demonstrated the presence of self-treated hypoglycemia28, 29. As pointed out
in a recent review on hypoglycemia in diabetic patients, the protocols of close glucose
monitoring followed rigorously in clinical trials may not be an accurate representation of the
real incidence of hypoglycemia in actual clinical practice30.

The effect of hypoglycemia on procoagulant mechanisms

In this section we discuss potential mechanisms by which exposure to hypoglycemia (single
or repeated) accelerate procoagulant mechanisms. Mechanisms described below are
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summarized in Figure 1.

The relation of hypoglycemia with thrombotic and hemostatic mechanisms

Disturbances in platelet activity can lead to bleeding disorders and thrombosis.
Hypoglycemia appears to be associated with platelet activation31, 32. Hypoglycemia
accelerates vascular complications in diabetes by increasing platelet aggregation as well as
fibrinogen formation. Studies have shown that acute hypoglycemia impairs fibrinolytic
balance, increases pro-inflammatory responses, platelet activation and coagulation
biomarkers as well as reduces NO-mediated endothelial function33. Further studies have also
shown that hypoglycemia induces an increase in circulating levels of vascular adhesion
molecules (markers of endothelial cell damage), interleukin (IL)-6, and P-selectin (markers
of platelet activation)34,35. Injury to endothelial cells and activation of platelets can result in
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a procoagulant state. Previous studies have confirmed that hypoglycemia has an inhibitory
effect on fibrinolytic mechanisms35. Hypoglycemia also has a detrimental effect on calcium
homeostasis and platelet mitochondrial integrity34. Altered mitochondrial calcium
homeostasis and mitochondrial dysfunction can result in platelet activation36. Hypoglycemia
decreases the activated partial thromboplastin time (aPTT) and increases levels of fibrinogen
and factor VIII37. With recurrent transient hypoglycemic episodes, repeated occurrences
may have additive effects that accentuate inflammation-based processes that include

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atherogenesis and other thrombotic complications. Other pro-inflammatory changes include

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an increase in the plasma concentration of IL-6, IL-8,IL-1β and other pro-inflammatory

mediators that includes leukocytosis, reactive oxygen species (ROS) generation, lipid
peroxidation, and increased levels of tumor necrosis factor-α (TNF-α)38. It is well
established that proinflammatory mediators can increase systemic thrombogenicity by
affecting multiple pathways39, 40.

Atherosclerosis is one of the determining factors associated with ischemic stroke. Platelets
have been reported as one of the key factors in developing atherothrombosis41, 42. Platelets
play a significant role in the pathology of cerebral ischemia through their participation in the
generation of thromboemboli that may initiate stroke symptoms. More often, activated
platelets particularly are a major contributor to the large-vessel subtype of ischemic stroke
that occurs following atherosclerotic plaque rupture43. These detrimental effects would add
to the previously demonstrated relationship between hypoglycemia on ischemic stroke.
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Collectively, therefore, hypoglycemia can trigger a sequence of events that may induce
stroke.

Hypoglycemia stimulates the autonomic nervous system and brings about sympathoadrenal
activation to facilitate the release of catecholamines44. This promotes secondary effects on
the circulatory system, including a decrease in plasma volume45; an increase in leukocyte
and erythrocyte counts46, 47, and platelet aggregation48. In addition to these changes in the
formed elements of blood, hypoglycemia has substantial hemorheological effects.
Hypoglycemia is shown to increase blood coagulation factor VIII activity via a β2
adrenoceptor-mediated process49. This was further confirmed and supported by other
relevant studies50,51. Hypoglycemia leads to a rise in Von Willebrand factor52 and
accelerates the rate of thrombin generation50.
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Endothelin-1 (ET-1) is one of the major endothelins that acts as a potent vasoconstrictor. In
an earlier clinical trial, Wright et al. investigated the effect of acute symptomatic
hypoglycemia in adult T1D patients on plasma ET-1 response53. The goal of the study was
to determine the mechanism by which acute insulin-induced hypoglycemia leads to
vasoconstriction and triggers microvascular and macrovascular events. Plasma ET-1 levels
were observed to increase substantially during hypoglycemia. Though these results
adequately help to implicate the role of ET-1 in altered vascular hemodynamics during
hypoglycemia, whether the observed effect is directly due to hypoglycemia, or secondary
due to hypoglycemia-induced hormonal response, or insulin administration remains to be
determined. In another study, Trovati et al. observed that insulin-induced hypoglycemia
results in an increased platelet sensitivity to aggregating agents like ADP and thrombin in
vitro potentially due to hypoglycemia-related alpha-adrenoceptor activation54.
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Another clinical study determined the difference that euglycemia and hypoglycemia had on
fibrinolytic balance and pro-inflammatory mechanisms35. This study included thirty five
healthy and twenty four T1D volunteers who previously never experienced any episode of
hypoglycemia and had intact autonomic function. Pro-inflammatory markers, such as
vascular cel adhesion molecular (VCAM), intercellular adhesion molecular (ICAM), E-
Selectin and vascular endothelial growth factor (VEGF), were increased during the

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hyperinsulinemic hypoglycemia episodes. These results suggest the possibility of

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hypoglycemia leading to atheroma formation, as these proteins are normally present on cell
surfaces and are expressed during inflammation to promote leukocyte adhesion which can
lead to plaque and atheroma formation. Another study observed increased CD40 expression
and platelet–monocyte aggregation during acute hypoglycemia in both non-diabetic and
T1D subjects55. A recent study on 45 healthy subjects compared inflammatory and pro-
atherosclerotic biomarkers released during euinsulinemic hyperglycemia observed an
increase in plasminogen activator inhibitor-1 (PAI-1) and TNF-α levels during
hypoglycemia56. PAI-1 is a protein that inhibits activators of plasminogen and fibrinolysis
like tissue plasminogen activator (tPA) while TNF-α has been shown to facilitate activation
of the coagulation cascade57. These studies demonstrate activation of hemostatic
mechanisms by exposure to hypoglycemia.

Hemostatic activation is a major contributor to the progression of ischemic stroke. Elevated

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levels of several inflammatory and rheological variables are reported to be associated with
ischemic stroke. Past studies have provided strong evidence of increased thrombin
generation and fibrin turnover with associated altered fibrinolytic activity and derailed
endothelial function in acute stroke58–63. Further studies have revealed an elevated
thrombin–antithrombin complex (TAT) and fibrin D-dimer levels in patients with
progressing stroke63. This literature supports the notion that exposure to hypoglycemia may
increase the risk of ischemic stroke via activation of hemostatic mechanisms.

Hypoglycemia and free radicals

Hypoglycemia plays a major role in enhancing diabetes-related vascular complications10.
There is evidence that indicates a deleterious impact of hypoglycemia on the blood-brain
barrier (BBB)64–66. Compromised BBB function during hypoglycemia has been reported to
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trigger the pathogenesis of secondary brain injuries. Importantly, lower glucose levels inhibit
the protective physiological effects of flow-induced shear stress on vasculature and
endothelial responses to flow by abundant accumulation of ROS67. Reduced glutathione
functions as a major anti-oxidant in the brain. In hypoglycemia, impaired synthesis of
glutathione subjects the brain to considerable oxidative stress53. Glucose reintroduction after
hypoglycemic coma has been reported to generate superoxide and nitrotyrosine
immunoreactivity and is suggested to be the main cause of stimulation of oxidative stress
through the activity of NADPH oxidase68,69. Selective increase in lipo-peroxidation due to
hypoglycemia leads to oxidative stress70 that has been confirmed in animal studies71.
Animal studies have also confirmed increased mitochondrial ROS production during both
hypoglycemia72 and in cultured neurons during glucose deprivation73. ROS are also known
to activate several intermediates of thrombosis, including platelets74. These studies suggest
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that the hypoglycemic condition promotes the production of ROS and reactive nitrogen
species (ROS/RNS) that might create a pro-thrombotic state.

Incidence and morbidity of stroke in diabetes

The importance of diabetes as a risk factor for the occurrence of stroke is well-known. There
have been several studies proving an association between hyperglycemia and an increased

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risk of stroke75,76. The Framingham study was the first to report an increased occurrence of
ischemic stroke in both men and women with diabetes77. The Copenhagen Stroke Study and
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the GCNKSS study provided epidemiological link between diabetes and stroke78,79. There
are other studies that also support this link80,81. The U.S. Nationwide Inpatient Sample has
shown an increase of about 27% in the absolute number of hospitalizations for acute
ischemic stroke in patients with co-morbid diabetes (T2D) when compared to an overall
17% decrease in acute ischemic stroke hospitalizations without diabetes from 1997 to
200682. The rate of stroke in diabetic patients has declined by about 53% between 1990 and
201083.

Incidence of hypoglycemia and the risk of cerebrovascular events

Preclinical studies provide strong evidence that hypoglycemia may accelerate procoagulant
mechanisms. In view of this, below we provide a summary of studies that support and
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oppose this premise.

Effect of prior hypoglycemia and cerebrovascular events

A study conducted by Rathmann et al. comparing a group of T2D patients receiving a
dipeptidyl peptidase-4 inhibitor (DPP4-I) and another group receiving a SU only for two
years observed a 5-fold decrease in frequency of recorded hypoglycemia in DPP4-I users
compared to those on SU84. The hazard ratio for stroke/transient ischemic attack (TIA) was
0.57 (p < 0.001) in DPP4-I users compared to SU users. Similarly, hazard ratios for
macrovascular disease, coronary heart disease, myocardial infarction, and peripheral
vascular disease in DPP4-I treated patients were 0.74 (p < 0.001), 0.74 (p < 0.001), 0.81 (p <
0.05), and 0.73 (p < 0.001) compared to SU-treated patients, respectively. This study
suggests that increased incidences of hypoglycemia may be linked to increased risk of
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stroke/TIA and other macrovascular diseases in SU-treated diabetic patients. Another

prospective study was conducted by Gitt et al. to confirm earlier studies that treatment with
DPP4-I resulted in decreased incidences of hypoglycemia. Patients received dual treatment
with either metformin and sulfonylureas (SUs) or metformin and DPP4 inhibitors85. These
two groups were followed for 12 months to study the frequency of hypoglycemia in these
patients. It was observed that the patients on metformin + SU had a greater frequency of
episodes of hypoglycemia than the patients on metformin + DPP4-I. The group on
metformin + SU showed a substantial increase in stroke/TIA incidences when compared to
patients on DPP4-I + metformin (2% vs 0.2%; p < 0.05). It is plausible that increased
incidences of stroke/TIA in the SU + metformin group may be due to higher incidences of
hypoglycemia observed in this group. It should be noted that these two studies were
observational ones that did not adequately explore if hypoglycemia was an independent
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predictor of stroke/TIA. Although basic experimental data suggest the association of

hypoglycemia and stroke, future clinical studies aimed to determine this association are
warranted. The Veterans Affairs Diabetes Trial (VADT) reported significantly more episodes
of hypoglycemia in the intensive-therapy group than in the standard-therapy group6. Patients
with BMI of ≥27 and <27 were treated with metformin plus rosiglitazone or glimepiride plus
rosiglitazone, respectively. However, this study did not find any significant effect of

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intensive therapy on the rates of major cardiovascular events when compared to standard
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therapy.

A prospective study of participants with diagnosed diabetes from the Atherosclerosis Risk in
Communities (ARIC) aimed to determine the link between severe hypoglycemia and
cardiovascular disease observed that prior sever hypoglycemia exposure increases the risk of
coronary heart disease, all-cause mortality and cardiovascular mortality86. However, no
association between prior exposure to severe hypoglycemia and stroke was observed86.
Recently published secondary analysis of the double-blind Trial Comparing Cardiovascular
Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk
of Cardiovascular Events (DEVOTE) trial also evaluated the association between exposure
to severe hypoglycemia and a major adverse cardiovascular event (MACE), defined as either
cardiovascular death, non-fatal myocardial infarction or non-fatal stroke87. This study
observed an association between exposure to severe hypoglycemia and all-cause mortality.
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However a non-significant difference was observed in the risk of MACE in individuals who
experienced severe hypoglycemia (hazard ratio 1.38, p = .080) vs. those who did not.
Similarly a non-significant increase in the risk for non-fatal stroke was observed in
individuals those who had (hazard ratio 1.81, p = .085) vs. those who had not experienced
severe hypoglycemia. However, a recently published study using data from the Examination
of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study
observed that the adjusted hazard ratio for MACE risk in patients who experienced serious
hypoglycemia events (hazard ratio 2.42, p = .007) was significantly higher than those
without serious hypoglycemia exposure88. However, this study did not report effects on non-
fatal stroke separately. Another recent study evaluated the association between
hypoglycemia and cardiovascular disease in SUs-treated T2D observed that an increasing
frequency of hypoglycemia exposure was associated with increased stroke risk89. The
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strongest association between exposure to hypoglycemia and stroke risk was observed when
patients were exposed to 3 or more hypoglycemic events (relative risk 1.57)89. It should be
noted that the effect of mild or moderate hypoglycemia was not evaluated in the ARIC,
DEVOTE, or EXAMINE populations. It is plausible that the risk of cardio- and
cerebrovascular events may be already higher in studied patients owing to their high risk for
exposure to mild or moderate hypoglycemia, and if so, this may also mask (i.e. lower the
hazard ratio) the effect of severe hypoglycemia on studied cardio- and cerebrovascular
events.

The effects of intensive glucose control, involving the use of gliclazide (modified release) as
compared to standard glucose control in T2D patients was undertaken with 11,140 patients
from over 200 medical centers spanning over 20 countries by the ADVANCE Collaborative
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group. After a follow-up period of 5 years, there was a significant decrease in the overall
HbA1C values in the intensive group (6.5%) than in the standard control group (7.3%).
Hypoglycemia was more common in the intensive control group (2.7%) than the standard
control group (1.5%) [Hazard ratio 1.86; 95% CI 1.4 to 2.4 and p < .001]. However, the
study showed no statistically significant difference in the outcome of nonfatal stroke in the
two groups90. In the ACCORD Trial, participants belonging to the intensive glucose control
group experienced more episodes of hypoglycemia (self-monitored blood glucose < 70
mg/dl) than the standard control group (1.06 and 0.29 episodes per week, respectively)91, 92.

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In both original and nine year follow-up studies, the odds ratio for nonfatal stroke was lower
in the intensive glucose control group91–93. However, this difference was not statistically
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significant. These effects may be explained as gliclazide has anti-oxidant properties and thus
may also lower the impact of procoagulant pathways activated by hypoglycemia exposure94.
Similarly, studies also reported that other SUs also improve platelet function95,96. For
example, glibenclamide and glimepiride was able to suppress thrombin-stimulated increase
in intracellular calcium and thrombin-induced arachidonic acid metabolism in platelets95.
However, gliclazide showed no effect on above-mentioned parameters95. Another study
reported that both gliclazide and glyburide treatment in noninsulin-dependent diabetic
subjects normalized ADP-induced platelet aggregation when compared to a diet alone group
of noninsulin-dependent diabetic subjects96. It should be noted that this study did not
observe any correlation between plasma glucose levels and platelet function suggesting that
these effects may be from the drug and not plasma glucose level96. It is possible that
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beneficial effects of glucose-lowering medications used to treat T2D patients may mask
some of the deleterious effects of hypoglycemia on cerebrovascular outcomes.

Effect of acute post-stroke hypoglycemia and cerebrovascular events

The UK Glucose Insulin in Stroke Trial (GIST-UK) that determined if intensive insulin
therapy (variable-dose-insulin by glucose-potassium insulin: GKI infusion) immediately
after acute ischemic stroke reduces death at 90 days observed that episodes of hypoglycemia
(<72 mg/dl over a period >30 min) occurred in 73 patients belonging to the GKI infusion
group97, 98. Plasma glucose of lower than 72 mg/dl was also observed in an additional 187
patients belonging to the GKI group; however, these patients did not meet the temporal
requirement. This study also noted that 7 patients receiving GKI had a recurrent stroke
within 72 h after the initiation of treatment compared to only 3 patients in the control arm.
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However, this difference was not statistically significant.

The Treatment of Hyperglycemia in Ischemic Stroke (THIS) trial: a randomized,

multicenter, blinded feasibility, and tolerability trial evaluating the effect of aggressive
hyperglycemia correction using intravenous insulin vs standard care during acute cerebral
infarction, noted that 35% of patients receiving aggressive treatment had at least one episode
of hypoglycemia (<60 mg/dL). Only 3% of these patients had neurologic symptoms, and
majority of them (64%) were asymptomatic99. This trial did not observe any correlation
between the hypoglycemic episodes and worsened clinical outcomes. The Glucose
Regulation in Acute Stroke Patients (GRASP) trial: a prospective, randomized, multicenter,
trial evaluated the feasibility and safety of two insulin infusion protocols (tight glucose
control (70–110 mg/dL) and loose glucose control (200 mg/dL)), and compared with usual
care (glucose levels 70–300 mg/dL)100. This trial reported hypoglycemic (<55 mg/dL)
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episodes in 30% of patients in the tight glucose control group. This trial also did not report
any significant differences in serious adverse events among study groups.

In summary, some clinical evidence suggests that exposure to hypoglycemia increases the
risk of cerebrovascular events in diabetic patients. It is also possible that hypoglycemia may
indirectly affect stroke risk, as increased incidences of hypoglycemia may also reflect
underlying poor health per se that predisposes to adverse vascular outcomes. A systematic

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review aimed to summarize literature on the effect of hypoglycemia on cardiovascular risk in

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diabetic patients found that several studies identified hypoglycemia, via increasing
thrombotic tendency and other mechanisms, as contributing to cardiovascular risk in diabetic
patients10. Another similar review by Moheet and Seaquist concluded that although acute
hypoglycemia may lead to a prothrombotic state, current knowledge based on large clinical
trials does not establish a link between hypoglycemia and adverse cardiovascular
outcomes101. A recent review indicated a potential link between hemorrhagic transformation
observed in stroke patients and exposure to hypoglycemia post-stroke102. Similarly, future
pre-clinical and clinical studies aimed to determine association between hypoglycemia and
the risk of stroke are warranted.

Conclusions
Diabetic patients compared to non-diabetic subjects have both a higher risk of stroke and
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poor stroke outcomes. Frequent exposure to hypoglycemia is observed in both T1D and T2D
patients. Pre-clinical studies suggest that hypoglycemia may increase the risk of stroke in
diabetic patients. This premise is not well-supported by clinical studies. The effects of
hypoglycemia in diabetic patients on normal and pathological hemostatic pathways warrant
further investigation. It would be also important to identify any sub-group of diabetic
patients that are more susceptible to a hypoglycemia-induced pro-hypercoagulable state.

Acknowledgments
The present study is supported by NIH Grant NS073779. We would like to thank Dr. Brant Watson for critical
reading of this manuscript.

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Figure 1.
Schematic diagram summarizing procoagulant mechanisms activated by hypoglycemia.
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Ann N Y Acad Sci. Author manuscript; available in PMC 2019 November 01.