Increased risk of stroke in patients with chronic kidney disease after recurrent hypoglycemia.

Increased risk of stroke in patients

with

chronic kidney disease after

recurrent

hypoglycemia

Hypoglycemia is common in patients with abnormal glucose metabolism.

Although the prodromal

symptoms of hypoglycemia such as tachycardia, tremors, cold sweats, and

anxiety are nonspecific,

they may result in life-threatening conditions if unidentified.

There are various possible mechanisms that explain how hypoglycemia

may lead to cardiac

and brain ischemia. The overwhelming trigger of a sympathetic adrenal

surge in the setting

of hypoglycemia considerably accelerates preexisting and unstable

underlying disorders, including

abnormal cardiac depolarization as well as increased thrombosis,

vasoconstriction, and

inflammation,

which may in turn lead to plaque rupture in atherosclerotic

lesions and resultant

permanent cardiac and brain damage.

Old age, multiple drug interactions, use of insulin, and particularly

impaired kidney function

may predispose patients to hypoglycemia.

Patients with chronic kidney

disease (CKD)

factors are reported to contribute to hypoglycemia

in these patients.

Approximately 20% of endogenously produced

glucose is released by the kidneys,

accounting for approximately 40% of all gluconeogenesis

in the body.

Investigators observed

reduced renal gluconeogenesis in patients with

decreased renal mass. In addition, endogenous

insulin is exclusively excreted through renal

clearance; insulin retention in the presence of

renal disease prolongs its hypoglycemic effect.

Peripheral insulin degradation is attenuated in

patients with CKD, resulting in a lower insulin

requirement.

Moreover, uremic toxins lead to

appetite suppression, typically resulting in suboptimal

nutrition, which, in turn, contributes

to reductions in glucose reserves.

Collectively,

these abnormalities eventually result in higher

risk of hypoglycemia in patients with CKD.

Various vascular complications are prevalent

in patients with CKD, and the risk of death,

cardiovascular events, and hospitalization increases

as renal function declines.

Hypoglycemia

is a risk factor associated with cardiovascular

complications such as coronary artery diseases,

congestive heart failure (CHF), stroke, and

death.

Therefore, we hypothesized that hypoglycemia

may contribute to various vascular diseases

in patients with CKD. In this study,

we aimed to investigate the association

between hypoglycemia and vascular events in

patients with CKD.

METHODS Data sources. In the present retrospective cohort study, we used data obtained from the National Health Insurance Research Database (NHIRD) of Taiwan. The NHIRD contains all claims data from the National Health Insurance program

prescriptions, and disease status for more than 99% of the population of Taiwan. Data were anonymized, encrypted, and maintained by the National Health Research Institutes of Taiwan for research purposes. Diagnostic codes used in the database are based on the ICD-9-CM. Details of the NHIRD have

been described in previous studies.17

For this study, we analyzed 1 million patients randomly selected from all patients in the database for the years 1998 through 2008, who were representative of the entire population. Standard protocol approvals, registrations, and patient consents. Because we used encrypted anonymized data, this study was exempt from approval requirements by the Institutional Review Board of China Medical University in Central

Taiwan (CMU-REC-101-012).

Study patients. We identified study patients from the NHIRD as those with CKD (ICD-9-CM 580–589) who were newly diagnosed during the period from January 1998 to December 2008. From those patients with CKD, we subsequently identified those who also had hypoglycemia (ICD-9-CM 251.0, 251.1, and 251.2). The date of the first diagnosis of

hypoglycemia was used as the index date. We excluded patients younger than 20 years, and those with records of stroke (ICD-9-CM 430–438). We also excluded patients with CKD if they had ever experienced cardiovascular events before the index date. These exclusions include those with coronary heart disease (CHD) CM 410–414, and 429.2), or CHF (ICD-9-CM 428, 398.91, and 402.x1) predating the index date. In addition, we excluded those with the following diagnosis codes: 250.3 (diabetes mellitus with coma), 250.8 (diabetes mellitus with other specified manifestations), 270.3 (leucine-induced hypoglycemia), 775.6 (neonatal hypoglycemia), or 775.0 (hypoglycemia in an infant borne of a diabetic mother). For each of the remaining 576 patients with hypoglycemia, and CKD, we randomly selected 4 patients from the same period without hypoglycemia who comprised the nonhypoglycemia cohort; we used the same exclusion criteria and frequencymatched these patients with the hypoglycemia cohort for sex,

Outcome measures and comorbidities. We followed each of the study patients until they were diagnosed with stroke, CHD, or CHF, or until the patients were considered lost to follow-up, died, withdrew from the database, or to the end of 2010, whichever came first. In addition, we incorporated inpatient and outpatient diagnosis records to ascertain baseline comorbidities, including diabetes (ICD-9-CM 250), hypertension (ICD-9-CM 401–405), hyperlipidemia (ICD-9-CM 272), chronic liver disease (ICD-9-CM 571), and mental illness (ICD-9-CM 290–319). Statistical analysis. Using x2 tests, we compared distributions

of demographic characteristics including age, sex, comorbidities, and prescribed antidiabetic drugs for patients with CKD with and without hypoglycemia. We calculated the incidence density and rate ratio for each outcome based on age and sex using Poisson regression analysis. In addition, we used multivariate Cox proportional hazard regression analysis to determine the effects of

hypoglycemia on the risks of multiple cardiovascular events and mortality (we used hazard ratios [HRs] with 95% confidence intervals [CIs]). To estimate the overall survival of patients with and without hypoglycemia, we performed survival analysis using the Kaplan–Meier method and examined statistical significance using the log-rank test. We used SAS software (version 9.2; SAS Institute, Cary, NC) for all statistical analyses. Statistical significance (p value) was set at 0.05.

RESULTS Overall, we identified 2,117 (4.59%) patients

with CKD who presented with hypoglycemia from 46,135 patients with CKD. We observed a

higher rate of hypoglycemia in female patients compared with male patients (2.47% vs 2.12%, p ,

0.0001). Among the 2,117 patients with CKD and hypoglycemia, 576 patients did not experience any cardiovascular complications before the index date, and were therefore enrolled in the study; we included 2,141 matched patients without hypoglycemia as the control cohort (figure 1). In the hypoglycemia cohort, 57.3% of the patients were older than 65 years. There

were no differences in age and sex between the 2 groups. Comorbidities such as diabetes mellitus,

hyperlipidemia, and chronic liver disease were similar in both groups. Patients in the hypoglycemia cohort were more likely to use antidiabetic medication(s) (ADM) than those in the nonhypoglycemia cohort (67.4% vs 35.6%, p , 0.0001 for insulin; 68.6% vs 46.6%, p , 0.0001 for metformin; and 64.1% vs 43.9%, p , 0.0001 for sulfonylurea; table 1). We also analyzed incidence densities, rate ratios, and HRs of multiple cardiovascular events and mortality according to sex (table 2). Overall, patients with

hypoglycemia exhibited higher incidence of stroke (5.19 vs 2.45 per 100 person-years), CHD (5.28 vs 3.73 per 100 person-years), CHF (3.27 vs 1.79 per 100 person-years), and overall mortality (4.74 vs 1.84 per 100 person-years) compared to patients without nonhypoglycemia, with an incidence rate ratio of 2.12 (95% CI 5 1.74–2.51), 1.41 (95% CI 5 1.13–1.76), 1.82 (95% CI 5 1.46–2.27), and 2.58 (95% CI 5 2.14–3.12), respectively.

The results of multivariate Cox proportional hazard regression analysis for the risk of stroke revealed a higher risk in the hypoglycemia cohort (HR 5 1.62, 95% CI 5 1.29–2.03) than in the nonhypoglycemia cohort, particularly in male patients (HR 5 1.68, 95% CI 5 1.20–2.35) and those younger than 64 years (HR 5 1.92, 95% CI 5 1.27–2.90) (table 2). We found similar results for CHF, i.e., patients in the hypoglycemia cohort had a 1.49-fold higher risk (95% CI 5 1.13–1.98) of developing CHF compared with patients in the nonhypoglycemia cohort. Male patients (HR 5 1.77, 95% CI 5 1.18–2.65) and those younger than 64 years (HR 5 1.88, 95% CI 5 1.20–2.97) had the highest risk of CHF. Risk analysis for CHD in patients of the hypoglycemia cohort resulted in an adjusted overall HR of 1.25 (95% CI 5 1.00–1.57) (table 2).

Compared with the nonhypoglycemia cohort, the hypoglycemia cohort had an increased risk of mortality

(HR52.53, 95% CI51.99–3.21), especially for male patients (HR 5 3.18, 95% CI 5 2.32–4.35). Results of the log-rank test and Kaplan–Meier survival analysis indicated a difference in the risk of overall mortality between the nonhypoglycemia and hypoglycemia cohorts (p , 0.001) (figure e-1 on

the Neurology® _{Web site at Neurology.org). To explore the influence of recurrent}

hypoglycemia

on patients with CKD, we separated the hypoglycemia cohort into 2 groups according to the number

of episodes of hypoglycemia (#2 and .2 episodes; table 3). The adjusted HRs for cardiovascular events and mortality associated with episodes of hypoglycemia (HR 5 11.6, 95% CI 5 7.73–17.5 for .2

episodes, p for trend ,0.0001), CHD (HR 5 9.40, 95% CI 5 6.57–13.5 for .2 episodes, p for trend ,0.0001), CHF (HR 5 11.2, 95% CI 5 6.87–18.2 for .2 episodes, p for trend ,0.0001), and mortality (HR 5 33.0, 95% CI 5 22.3–48.8 for .2 episodes, p for trend ,0.0001) were higher in the

hypoglycemia cohort compared with the nonhypoglycemia cohort (table 3).

To clarify the confounding effect of diabetes mellitus on stroke in patients with CKD, we further compared the risk of stroke among 4 groups according to whether they had diabetes mellitus. Compared with the nonhypoglycemia groups, the hypoglycemia groups exhibited a graded risk of stroke regardless of whether the patients had diabetes (HR 5 1 was used as a reference for the nondiabetes group without hypoglycemia; HR 5 2.01, 95% CI 5 1.34–3.03,

p , 0.0001 for the diabetes group without hypoglycemia; HR 5 2.45, 95% CI 5 1.11–5.45, p , 0.05

for the nondiabetes group with hypoglycemia; and HR 5 4.20, 95% CI 5 2.71–6.51, p , 0.0001

for the diabetes group with hypoglycemia; table 4). Comparison of patients who took ADMs and those who did not take ADMs revealed a higher risk of

stroke in the hypoglycemia groups compared with that in the nonhypoglycemia groups (HR 5 1, used as a reference, for the nonhypoglycemia group that did not take ADMs; HR 5 2.12, 95% CI 5 1.65– 2.71, p , 0.0001 for the nonhypoglycemia group that took ADMs; HR 5 2.07, 95% CI 5 1.07–

3.97, p , 0.05 for the hypoglycemia group that did not take ADMs; and HR 5 3.68, 95% CI 5 2.76– 4.90, p , 0.0001 for the hypoglycemia group that took ADMs; table 4). In addition, we observed higher patient mortality in the hypoglycemia groups regardless of whether the patients had diabetes (HR 5 1.88,

95% CI 5 1.07–3.29 for the nondiabetes group; HR 5 2.27, 95% CI 5 1.61–3.20 for the diabetes group; p , 0.001; table 4).

DISCUSSION In the present study, the incidence

rate of hypoglycemia in patients with CKD was 4.5%, which is approximately twice the value noted in previous reports.3,7,15,18 Most previous studies were

limited by the relatively small number of patients with CKD included in the study by the exclusion of cases with CKD. Moen et al.6 reported a higher

incidence rate (3.6%) of hypoglycemia in patients with CKD compared to that of the general population, and explained the cause as attenuation of the

renal glucose reserve and renal excretory function in patients with CKD. Although the findings of previous studies vary depending on inclusion and exclusion criteria, the present findings suggest that patients with CKD are at a high risk of hypoglycemia, consistent with the findings of Moen et al.6

Hypoglycemia is a risk factor for multiple cardiovascular events and death caused by hypoglycemic

injury. Zoungas et al.15 reported that hypoglycemia

is associated with increased risk of multiple cardiovascular events, and that it contributes to a 3-fold

increase in the risk of death in diabetic patients. Moen et al.6 also demonstrated a high overall mortality

rate associated with hypoglycemia in patients with CKD with or without diabetes. They hypothesized

that, to a certain extent, excess cardiovascular morbidity and mortality frequently exhibited by patients

with CKD may be due to hypoglycemia. However, the effect of hypoglycemia on individual events

including stroke, CHD, and CHF has yet to be elucidated. Results of the present study were consistent

with the finding that hypoglycemia is associated with an increased risk of stroke, CHF, and overall mortality compared to patients with CKD without hypoglycemia. Moreover, multivariate analysis revealed a

2.53-fold increase in the risk of death for patients

with CKD with hypoglycemia after adjusting for related confounding factors, including hypertension,

hyperlipidemia, diabetes, and antidiabetic drugs. Furthermore, risks of stroke and mortality were higher in

male patients and in younger patients who presented with hypoglycemia.

Diabetes mellitus contributes to various cardiovascular events that occur in the general population, and patients with diabetes who take ADMs may have a higher risk of cardiovascular events. We separated the patients with hypoglycemia into groups to adjust for diabetes and ADMs as confounders, and compared the influence of hypoglycemia in these subgroups. We observed a clear relationship between

stroke and hypoglycemia regardless of whether the patients had diabetes. In addition, we observed a high

risk of stroke (adjusted HR 5 2.45) in the patients with hypoglycemia who did not have diabetes; to date, these patients have been generally considered as a relatively low-risk group for cardiovascular events.

We obtained similar results when examining the influence of ADMs: patients in the hypoglycemia

group who did not take ADMs were at high risk of stroke. Collectively, the results of this study clearly indicate the effect of hypoglycemia on stroke and

suggest that hypoglycemia may have a vital role in the occurrence of stroke and mortality in patients with CKD.

A growing body of evidence suggests that CKD is a strong risk factor for poor outcomes and mortality in patients with acute stroke.19,20 Researchers have

suggested that cerebral and glomerular small-vessel diseases share a common pathogenesis and are therefore linked. Precipitating factors that contribute to

stroke in patients with CKD are yet to be elucidated; based on the results of this study, we suggest that hypoglycemia is a crucial risk factor contributing to stroke in individuals with CKD.

We also examined the effect of recurrent hypoglycemia on individual adverse events and discovered an

11.6-fold higher risk of stroke and a 33.0-fold higher risk of mortality in patients with CKD who experienced more than 2 episodes of hypoglycemia. In

addition, we observed this trend for other cardiovascular events. In contrast to the indistinct association

between recurrent hypoglycemia and adverse events reported in the general population, the results of this study indicate a clear relationship, suggesting the highly potent effect of hypoglycemia in patients with CKD. There may be several reasons for these results. Patients with CKD have a high risk of concomitant cardiovascular disorders, meaning that these serious conditions may develop as renal function declines. For example, abnormally high levels of various inflammatory cytokines,21 plasma homocysteine,

and calcification can develop in patients with CKD, which in turn aggravates endothelial dysfunction as a result of increased arterial stiffness21–23 and left ventricle

hypertrophy.24 In addition, patients with CKD are

considered to exhibit greater hyperactive autonomic

dysfunction than the general population,25 which substantially

contributes to the exceedingly high rate of

with CKD.26 Several conditions have been suggested to

contribute to sympathetic overactivity in patients with CKD, including hyperactivity of the renin-angiotensin

system, increased plasma norepinephrine levels, peripheral denervation hypersensitivity, and decreased nitric oxide bioavailability.27,28

Assuming that recurrent hypoglycemia is associated with stroke in patients with CKD, such hypoglycemia may cause a deleterious increase in sympathetic activity. Therefore, the association between recurrent hypoglycemia and the risk of stroke determined in the current study may reflect a bidirectional effect. When encountering hypoglycemia in patients with CKD, physicians should maintain a high index of suspicion to prevent adverse outcomes.

This study involved several limitations. For

example, heart rate, blood pressure, and biochemistry results obtained at the time of the hypoglycemia episode were not available for further analysis in the NHIRD. However, physicians confirmed the diagnosis of hypoglycemia. Second, it is possible that

we underestimated the frequency of hypoglycemia

because the patients with mild or moderate hypoglycemic symptoms may have been overlooked. Finally,

data related to cardiovascular risk factors, including smoking habits, body mass index, and the extent of physical activity, could not be determined from the NHIRD. In conclusion, when encountering hypoglycemia in patients with CKD, physicians should remain aware of the risk of stroke to prevent the subsequent onset of stroke.