Increased risk of stroke in patients with chronic kidney disease after recurrent hypoglycemia Tung-Min Yu, Cheng-Li Lin, Shih-Ni Chang, et al. Neurology 2014;83;686-694 Published Online before print July 16, 2014 DOI 10.1212/WNL.0000000000000711 This information is current as of July 16, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/83/8/686.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Increased risk of stroke in patients with chronic kidney disease after recurrent hypoglycemia Tung-Min Yu, MD Cheng-Li Lin, MSc Shih-Ni Chang, MSc Fung-Chang Sung, PhD Chia-Hung Kao, MD
Correspondence to Prof. Kao: [email protected]
ABSTRACT
Objective: In this study, we aimed to investigate the effect of hypoglycemia on cardiovascular outcomes in a sample of patients with chronic kidney disease (CKD).
Methods: Information about study participants was extracted from the National Health Insurance Research Database of Taiwan for the years 1998 through 2008. We conducted this retrospective cohort study of patients with CKD, with and without hypoglycemia, to evaluate the risk of overall mortality and cardiovascular complications including stroke, coronary heart disease, and congestive heart failure in both groups.
Results: This study included 46,135 patients with CKD, of whom 2,117 (4.59%) were hospitalized and had hypoglycemia. Results of multivariate Cox proportional hazard regression analyses indicated that stroke (hazard ratio [HR] 5 1.62, 95% confidence interval [CI] 5 1.29–2.03), coronary heart disease (HR 5 1.25, 95% CI 5 1.00–1.57), congestive heart failure (HR 5 1.49, 95% CI 5 1.13–1.98), and death (HR 5 2.53, 95% CI 5 1.99–3.21) were associated with hypoglycemia in patients with CKD. Recurrent episodes of hypoglycemia were associated with a higher risk of death (HR 5 33.0, 95% CI 5 22.3–48.8 for .2 episodes, p for trend ,0.0001), and a similar trend was observed for other multiple cardiovascular events. We observed an increased risk of stroke and overall mortality in patients with hypoglycemia compared to those without hypoglycemia, regardless of whether the patient had diabetes. Conclusions: CKD was associated with a higher risk of stroke and mortality in patients with hypoglycemia. Recurrent hypoglycemia considerably increased the risk of stroke and overall mortality in patients with CKD regardless of whether they had diabetes. These results suggest that hypoglycemia has a crucial role in stroke and death in patients with CKD. Neurology® 2014;83:686–694 GLOSSARY ADM 5 antidiabetic medication; CHD 5 coronary heart disease; CHF 5 congestive heart failure; CI 5 confidence interval; CKD 5 chronic kidney disease; HR 5 hazard ratio; ICD-9-CM 5 International Classification of Diseases, ninth revision, Clinical Modification; NHIRD 5 National Health Insurance Research Database.
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,1 which may in turn lead to plaque rupture in atherosclerotic lesions and resultant permanent cardiac and brain damage.2,3 Old age, multiple drug interactions, use of insulin, and particularly impaired kidney function may predispose patients to hypoglycemia.4–6 Supplemental data at Neurology.org From the Graduate Institute of Clinical Medical Science (T.-M.Y., C.-H. K.) and Department of Public Health (C.-L.L., S.-N.C., F.-C. S.), China Medical University, Taichung; Division of Nephrology (T.-M.Y.), Taichung Veteran General Hospital; and Management Office for Health Data (C.-L.L., S.-N.C., F.-C.S.) and Department of Radiation Oncology and Nuclear Medicine and PET Center (C.-H.K.), China Medical University Hospital, Taichung, Taiwan. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 686
© 2014 American Academy of Neurology
Patients with chronic kidney disease (CKD) are at high risk of hypoglycemia3,6,7; several 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.8 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.9 Peripheral insulin degradation is attenuated in patients with CKD, resulting in a lower insulin requirement.10 Moreover, uremic toxins lead to appetite suppression, typically resulting in suboptimal nutrition, which, in turn, contributes to reductions in glucose reserves.11 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.12 Hypoglycemia is a risk factor associated with cardiovascular complications such as coronary artery diseases, congestive heart failure (CHF), stroke, and death.3,13–16 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 including demographic data, records of clinical visits, hospital admissions, 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-9CM 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) (ICD-9-CM 410–414, and 429.2), or CHF (ICD-9CM 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, age, status of diabetes mellitus, and index date. 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 Neurology 83
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Figure 1
Flowchart of selection process for the study cohort
From the National Health Insurance Research Database of Taiwan, we identified 2,117 patients with hypoglycemia from 46,135 patients with chronic kidney disease (CKD). We excluded patients with CKD who experienced cardiovascular events including stroke, coronary heart disease (CHD), and congestive heart failure (CHF) before the index date of hypoglycemia. Of 2,117 hypoglycemia patients with CKD, we enrolled 576 patients with hypoglycemia who had not experienced any cardiovascular event before the index date in the study. Based on the same exclusion criteria, we selected 2,141 patients with CKD without hypoglycemia as the matched control group.
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, 688
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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 (HR 5 2.53, 95% CI 5 1.99–3.21), 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).
Table 1
Characteristics of patients with chronic kidney disease (CKD) with hypoglycemia and matched patients with CKD without hypoglycemia Hypoglycemia (n 5 576) No hypoglycemia (n 5 2,141) p Value
Age, y £64
246 (42.7)
947 (44.2)
330 (57.3)
1,194 (55.8)
64.2 (13.4)
64.8 (14.1)
0.38
Female
298 (51.7)
1,088 (50.8)
0.70
Male
278 (48.3)
1,053 (49.2)
491 (85.2)
1,802 (84.2)
0.53
‡65 a
Mean (SD)
0.51
Sex
Comorbidity Diabetes Hypertension
427 (74.1)
1,379 (64.4)
,0.0001
Hyperlipidemia
254 (44.1)
1,036 (48.4)
0.07
Chronic liver disease
137 (23.8)
554 (25.9)
0.31
Mental illness
245 (42.5)
764 (35.7)
0.003
Antidiabetic drugs Insulin
388 (67.4)
762 (35.6)
,0.0001
Metformin
395 (68.6)
997 (46.6)
,0.0001
Sulfonylurea
369 (64.1)
940 (43.9)
,0.0001
Data are n (%) unless otherwise indicated. Chi-square test and a t test comparing subjects with and without hypoglycemia.
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 Neurology 83
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Table 2
Incidence, incidence rate ratio, and HR of stroke, coronary heart disease, congestive heart failure, and mortality comparing patients with CKD with and without hypoglycemia Hypoglycemia
No hypoglycemia
Outcome
Event
PY
Ratea
Event
PY
Ratea
IRR (95% CI)
Adjusted HRb (95% CI)
Stroke
112
2,160
5.19
305
12,446
2.45
2.12 (1.74, 2.57)c
1.62 (1.29, 2.03)c
Female
63
1,215
5.19
159
6,411
2.48
2.09 (1.60, 2.73)c
1.55 (1.14, 2.10)d
Male
49
945
5.19
146
6,034
2.42
2.14 (1.60, 2.87)c
1.68 (1.20, 2.35)d
£64
39
1,088
3.59
82
6,245
1.31
2.73 (2.03, 3.67)c
1.92 (1.27, 2.90)d
‡65
73
1,071
6.81
223
6,201
3.60
1.89 (1.47, 2.45)c
1.49 (1.13, 1.97)d
d
1.25 (1.00, 1.57)
Sex
e
Age, y
Coronary heart disease
104
1,971
5.28
420
11,255
3.73
1.41 (1.13, 1.76)
Female
59
1,076
5.48
205
5,828
3.52
1.56 (1.16, 2.09)d
1.35 (1.00, 1.84)
Male
45
894
5.03
215
5,427
3.96
1.27 (0.91, 1.77)
1.14 (0.82, 1.60)
£64
49
973
5.03
165
5,643
2.92
1.72 (1.25, 2.36)c
1.36 (0.96, 1.93)
‡65
55
997
5.52
255
5,611
4.54
1.21 (0.89, 1.65)
1.13 (0.84, 1.53)
Sex
Age, y
Congestive heart failure
c
1.49 (1.13, 1.98)d
71
2,173
3.27
224
12,495
1.79
1.82 (1.46, 2.27)
37
1,211
3.05
119
6,394
1.86
1.64 (1.21, 2.23)d c
1.77 (1.18, 2.65)d
1.88 (1.20, 2.97)d
Sex Female Male
1.30 (0.88, 1.93)
34
963
3.53
105
6,101
1.72
2.05 (1.50, 2.82)
32
1,073
2.98
69
6,189
1.11
2.68 (1.94, 3.70)c
2.46
1.44 (1.07, 1.95)
f
1.30 (0.90, 1.87)
c
2.53 (1.99, 3.21)c
Age, ye £64 ‡65 Mortality
39
1,101
3.54
155
6,306
115
2,423
4.74
245
13,318
1.84
2.58 (2.14, 3.12)
Female
43
1,353
3.18
113
6,858
1.65
1.93 (1.46, 2.56)c
1.87 (1.29, 2.72)c
Male
72
1,071
6.72
132
6,459
2.04
3.29 (2.54, 4.26)c
3.18 (2.32, 4.35)c
£64
61
1,200
5.09
118
6,489
1.82
2.80 (2.14, 3.65)c
2.64 (1.86, 3.73)c
‡65
54
1,224
4.41
127
6,829
1.86
2.37 (1.81, 3.11)c
2.30 (1.64, 3.22)c
Sexg
Age, y
Abbreviations: CI 5 confidence interval; CKD 5 chronic kidney disease; HR 5 hazard ratio; IRR 5 incidence rate ratio; PY 5 person-years. a Incidence rate per 100 PY. b Adjusted for age, sex, comorbidities, insulin, metformin, and sulfonylurea. c p , 0.001. d p , 0.01. e p Value for interaction ,0.01. f p , 0.05. g p Value for interaction ,0.05.
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 690
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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
Table 3
Risk of stroke, coronary heart disease, congestive heart failure, and mortality among frequency for medical visits of hypoglycemia in Cox proportional hazard regression
Frequency for medical visit, per 1 y
Event
PY
Ratea
IRR (95% CI)
305
12,446
2.45
1 (reference)
Adjusted HRb (95% CI)
Stroke No hypoglycemia £2 >2
82 30
2,086 74
3.93 40.6
1 (reference)
1.60 (1.29, 1.99)
c
1.25 (0.97, 1.61)
16.6 (11.9, 23.1)
c
11.6 (7.73, 17.5)c
p Value
,0.0001
Coronary heart disease No hypoglycemia £2 >2
420
11,255
3.73
1 (reference)
65
1,891
3.44
0.92 (0.71, 1.20)
39
80
48.7
13.1 (9.38, 18.2)
1 (reference) 0.84 (0.64, 1.10) c
p Value
9.40 (6.57, 13.5)c ,0.0001
Congestive heart failure No hypoglycemia
224
12,495
1.79
1 (reference)
1 (reference) d
£2
50
2,099
2.38
1.33 (1.04, 1.70)
>2
21
75
28.2
15.7 (10.9, 22.6)c
p Value
1.12 (0.81, 1.54) 11.2 (6.87, 18.2)c ,0.0001
Mortality No hypoglycemia
245
13,318
1.84
1 (reference)
1 (reference) c
1.80 (1.37, 2.36)c 33.0 (22.3, 48.8)c
£2
76
2,358
3.22
1.75 (1.42, 2.17)
>2
39
66
59.1
32.1 (24.3, 42.4)c
p Value
,0.0001
Abbreviations: CI 5 confidence interval; HR 5 hazard ratio; IRR 5 incidence rate ratio; PY 5 person-years. a Incidence rate per 100 PY. b Adjusted for age, sex, comorbidities, insulin, metformin, and sulfonylurea. c p , 0.001. d p , 0.05.
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 cardiovascular events and patient mortality in patients with CKD.26 Several conditions have been suggested to contribute to sympathetic overactivity in patients with Neurology 83
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692
Table 4
Cox proportional hazard regression analysis for the risk of hypoglycemia-associated events with joint effect of diabetes and antidiabetic drugs Stroke
Variable Hypoglycemia No
No.
No
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Yes
Yes
No
Hypoglycemia
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No No
Yes
Event, n
Adjusted HRa (95% CI)
Event, n
Mortality
Adjusted HRa (95% CI)
Event, n
Adjusted HRa (95% CI)
339
25
1 (reference)
48
1 (reference)
31
51
1 (reference)
372
1.49 (1.10, 2.01)
193
1.10 (0.75, 1.60)
194
10
1.22 (0.62, 2.41)
7
1.47 (0.65, 3.35)
16
1.88 (1.07, 3.29)c
1,802
280
85
8
2.01 (1.34, 3.03)
2.45 (1.11, 5.45)c
491
104
b
945
91
4.20 (2.71, 6.51)
94
c
1 (reference)
b
b
d
0.76 (0.56, 1.04)
2.00 (1.41, 2.84)
64
2.00 (1.30, 3.08)
99
2.27 (1.61, 3.20)b
1 (reference)
82
1 (reference)
82
1 (reference)
ADMs No Yes
Yes
No
Yes
Yes
Hypoglycemia
Adjusted HRa (95% CI)
Congestive heart failure
Diabetes
No
Yes
Event, n
Coronary heart disease
1,196
214
94
10
482
102
1 (reference)
163 b
2.12 (1.65, 2.71)
257
b
1.40 (1.15, 1.70)
142
d
142
d
1.49 (1.13, 1.96)
1.16 (0.90, 1.50)
c
2.07 (1.07, 3.97)
11
1.02 (0.55, 1.88)
11
2.33 (1.24, 4.39)
11
2.60 (1.60, 4.25)b
3.68 (2.76, 4.90)b
93
1.75 (1.35, 2.26)b
60
2.25 (1.61, 3.15)b
60
3.08 (2.33, 4.06)b
Insulin
No
No
1,379
151
1 (reference)
259
1 (reference)
124
1 (reference)
No
Yes
762
154
2.17 (1.73, 2.72)b
161
1.25 (1.03, 1.53)c
100
1.65 (1.26, 2.14)b
86
1.24 (0.95, 1.61)
Yes
No
188
28
2.05 (1.37, 308)b
32
1.31 (0.91, 1.90)
23
2.07 (1.33, 3.24)d
37
2.61 (1.82, 3.74)b
Yes
Yes
388
84
3.52 (2.68, 4.62)b
72
1.52 (1.17, 1.98)d
48
2.22 (1.59, 3.11)b
78
3.16 (2.40, 4.17)b
1,144
122
Hypoglycemia No
159
1 (reference)
Metformin No
1 (reference)
216 b
1 (reference)
108
1 (reference)
133 c
112
No
Yes
997
183
204
1.20 (0.99, 1.46)
116
Yes
No
181
28
2.62 (1.74, 3.96)b
25
1.10 (0.72, 1.66)
20
1.90 (1.18, 3.07)d
41
2.88 (2.02, 4.10)b
Yes
Yes
395
84
3.25 (2.45, 4.31)b
79
1.63 (1.26, 2.12)b
51
2.13 (1.52, 2.98)b
74
3.00 (2.24, 4.01)b
1,201
136
Hypoglycemia No No
1.96 (1.56, 2.47)
1.34 (1.03, 1.74)
1 (reference) 1.17 (0.91, 1.51)
Sulfonylurea No Yes
940
169
1 (reference)
226 b
1.85 (1.47, 2.32)
d
194
1 (reference)
116 c
1.23 (1.02, 1.50)
108
1 (reference)
145
1 (reference)
c
100
1.10 (0.85, 1.42)
d
1.33 (1.02, 1.73)
Yes
No
207
27
2.00 (1.32, 3.02)
28
1.16 (0.78, 1.72)
23
1.96 (1.25, 3.07)
50
3.20 (2.32, 4.43)b
Yes
Yes
369
85
3.39 (2.57, 4.46)b
76
1.63 (1.25, 2.12)b
48
2.06 (1.47, 2.90)b
65
2.64 (1.96, 3.56)b
Abbreviations: ADM 5 antidiabetic medication; CI 5 confidence interval; HR 5 hazard ratio. ADMs group: patients who ever used any one of the ADMs, such as insulin, metformin, and sulfonylurea. a Adjusted for age and sex. b p , 0.001. c p , 0.05. d p , 0.01.
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.
3.
4.
5.
6.
7.
8. 9.
10.
11. 12.
13. AUTHOR CONTRIBUTIONS Conception and design: Tung-Min Yu, Chia-Hung Kao. Administrative support: Cheng-Li Lin, Fung-Chang Sung. Collection and assembly of data: all authors. Data analysis and interpretation: Tung-Min Yu, Cheng-Li Lin, Chia-Hung Kao. Manuscript writing: all authors. Final approval of manuscript: all authors.
14.
STUDY FUNDING
15.
This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW103-TDU-B212-113002), China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM103010096), NRPB Stroke Clinical Trial Consortium (MOST 103-2325-B-039-006), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. The funders had no role in the study design, data collection or analysis, the decision to publish, or the preparation of the manuscript.
16.
17.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
18.
Received December 13, 2013. Accepted in final form May 12, 2014.
19.
REFERENCES 1. Wright RJ, Frier BM. Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev 2008;24:353–363. 2. Hilsted J, Bonde-Petersen F, Norgaard MB, et al. Haemodynamic changes in insulin-induced hypoglycaemia in normal man. Diabetologia 1984;26:328–332.
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Hsu PF, Sung SH, Cheng HM, et al. Association of clinical symptomatic hypoglycemia with cardiovascular events and total mortality in type 2 diabetes: a nationwide population-based study. Diabetes Care 2013;36:894–900. Donnelly LA, Morris AD, Frier BM, et al. Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population-based study. Diabet Med 2005;22:749–755. ter Braak EW, Appelman AM, van de Laak M, Stolk RP, van Haeften TW, Erkelens DW. Clinical characteristics of type 1 diabetic patients with and without severe hypoglycemia. Diabetes Care 2000;23:1467–1471. Moen MF, Zhan M, Hsu VD, et al. Frequency of hypoglycemia and its significance in chronic kidney disease. Clin J Am Soc Nephrol 2009;4:1121–1127. Lin CH, Sheu WH. Hypoglycaemic episodes and risk of dementia in diabetes mellitus: 7-year follow-up study. J Intern Med 2013;273:102–110. Meyer C, Dostou JM, Gerich JE. Role of the human kidney in glucose counterregulation. Diabetes 1999;48:943–948. Biesenbach G, Raml A, Schmekal B, Eichbauer-Sturm G. Decreased insulin requirement in relation to GFR in nephropathic type 1 and insulin-treated type 2 diabetic patients. Diabet Med 2003;20:642–645. Snyder RW, Berns JS. Use of insulin and oral hypoglycemic medications in patients with diabetes mellitus and advanced kidney disease. Semin Dial 2004;17:365–370. Horton ES, Johnson C, Lebovitz HE. Carbohydrate metabolism in uremia. Ann Intern Med 1968;68:63–74. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351: 1296–1305. Brodovicz KG, Mehta V, Zhang Q, et al. Association between hypoglycemia and inpatient mortality and length of hospital stay in hospitalized, insulin-treated patients. Curr Med Res Opin 2013;29:101–107. Zhao Y, Campbell CR, Fonseca V, Shi L. Impact of hypoglycemia associated with antihyperglycemic medications on vascular risks in veterans with type 2 diabetes. Diabetes Care 2012;35:1126–1132. Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010;363:1410–1418. McCoy RG, Van Houten HK, Ziegenfuss JY, Shah ND, Wermers RA, Smith SA. Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care 2012;35:1897–1901. Chung WS, Peng CL, Lin CL, et al. Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study. Ann Rheum Dis Epub 2013 Aug 13. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–2572. Yahalom G, Schwartz R, Schwammenthal Y, et al. Chronic kidney disease and clinical outcome in patients with acute stroke. Stroke 2009;40:1296–1303. Oksala NK, Salonen T, Strandberg T, et al. Cerebral small vessel disease and kidney function predict longterm survival in patients with acute stroke. Stroke 2010;41:1914–1920. Muntner P, Hamm LL, Kusek JW, Chen J, Whelton PK, He J. The prevalence of nontraditional risk factors for
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coronary heart disease in patients with chronic kidney disease. Ann Intern Med 2004;140:9–17. Raggi P, Boulay A, Chasan-Taber S, et al. Cardiac calcification in adult hemodialysis patients: a link between endstage renal disease and cardiovascular disease? J Am Coll Cardiol 2002;39:695–701. Shlipak MG, Fried LF, Crump C, et al. Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation 2003;107: 87–92. Levin A, Thompson CR, Ethier J, et al. Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis 1999;34:125–134.
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Koomans HA, Blankestijn PJ, Joles JA. Sympathetic hyperactivity in chronic renal failure: a wake-up call. J Am Soc Nephrol 2004;15:524–537. Schlaich MP, Socratous F, Hennebry S, et al. Sympathetic activation in chronic renal failure. J Am Soc Nephrol 2009;20:933–939. Vonend O, Rump LC, Ritz E. Sympathetic overactivity: the Cinderella of cardiovascular risk factors in dialysis patients. Semin Dial 2008;21:326–330. Chandra P, Sands RL, Gillespie BW, et al. Predictors of heart rate variability and its prognostic significance in chronic kidney disease. Nephrol Dial Transplant 2012; 27:700–709.
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Increased risk of stroke in patients with chronic kidney disease after recurrent hypoglycemia Tung-Min Yu, Cheng-Li Lin, Shih-Ni Chang, et al. Neurology 2014;83;686-694 Published Online before print July 16, 2014 DOI 10.1212/WNL.0000000000000711 This information is current as of July 16, 2014 Updated Information & Services
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Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/07/16/WNL.00000 00000000711.DC1.html
References
This article cites 27 articles, 12 of which you can access for free at: http://www.neurology.org/content/83/8/686.full.html##ref-list-1
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Increased risk of stroke in patients with chronic kidney disease after recurrent hypoglycemia Tung-Min Yu, MD Cheng-Li Lin, MSc Shih-Ni Chang, MSc Fung-Chang Sung, PhD Chia-Hung Kao, MD
Correspondence to Prof. Kao: [email protected]
ABSTRACT
Objective: In this study, we aimed to investigate the effect of hypoglycemia on cardiovascular outcomes in a sample of patients with chronic kidney disease (CKD).
Methods: Information about study participants was extracted from the National Health Insurance Research Database of Taiwan for the years 1998 through 2008. We conducted this retrospective cohort study of patients with CKD, with and without hypoglycemia, to evaluate the risk of overall mortality and cardiovascular complications including stroke, coronary heart disease, and congestive heart failure in both groups.
Results: This study included 46,135 patients with CKD, of whom 2,117 (4.59%) were hospitalized and had hypoglycemia. Results of multivariate Cox proportional hazard regression analyses indicated that stroke (hazard ratio [HR] 5 1.62, 95% confidence interval [CI] 5 1.29–2.03), coronary heart disease (HR 5 1.25, 95% CI 5 1.00–1.57), congestive heart failure (HR 5 1.49, 95% CI 5 1.13–1.98), and death (HR 5 2.53, 95% CI 5 1.99–3.21) were associated with hypoglycemia in patients with CKD. Recurrent episodes of hypoglycemia were associated with a higher risk of death (HR 5 33.0, 95% CI 5 22.3–48.8 for .2 episodes, p for trend ,0.0001), and a similar trend was observed for other multiple cardiovascular events. We observed an increased risk of stroke and overall mortality in patients with hypoglycemia compared to those without hypoglycemia, regardless of whether the patient had diabetes. Conclusions: CKD was associated with a higher risk of stroke and mortality in patients with hypoglycemia. Recurrent hypoglycemia considerably increased the risk of stroke and overall mortality in patients with CKD regardless of whether they had diabetes. These results suggest that hypoglycemia has a crucial role in stroke and death in patients with CKD. Neurology® 2014;83:686–694 GLOSSARY ADM 5 antidiabetic medication; CHD 5 coronary heart disease; CHF 5 congestive heart failure; CI 5 confidence interval; CKD 5 chronic kidney disease; HR 5 hazard ratio; ICD-9-CM 5 International Classification of Diseases, ninth revision, Clinical Modification; NHIRD 5 National Health Insurance Research Database.
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,1 which may in turn lead to plaque rupture in atherosclerotic lesions and resultant permanent cardiac and brain damage.2,3 Old age, multiple drug interactions, use of insulin, and particularly impaired kidney function may predispose patients to hypoglycemia.4–6 Supplemental data at Neurology.org From the Graduate Institute of Clinical Medical Science (T.-M.Y., C.-H. K.) and Department of Public Health (C.-L.L., S.-N.C., F.-C. S.), China Medical University, Taichung; Division of Nephrology (T.-M.Y.), Taichung Veteran General Hospital; and Management Office for Health Data (C.-L.L., S.-N.C., F.-C.S.) and Department of Radiation Oncology and Nuclear Medicine and PET Center (C.-H.K.), China Medical University Hospital, Taichung, Taiwan. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 686
© 2014 American Academy of Neurology
Patients with chronic kidney disease (CKD) are at high risk of hypoglycemia3,6,7; several 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.8 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.9 Peripheral insulin degradation is attenuated in patients with CKD, resulting in a lower insulin requirement.10 Moreover, uremic toxins lead to appetite suppression, typically resulting in suboptimal nutrition, which, in turn, contributes to reductions in glucose reserves.11 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.12 Hypoglycemia is a risk factor associated with cardiovascular complications such as coronary artery diseases, congestive heart failure (CHF), stroke, and death.3,13–16 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 including demographic data, records of clinical visits, hospital admissions, 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-9CM 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) (ICD-9-CM 410–414, and 429.2), or CHF (ICD-9CM 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, age, status of diabetes mellitus, and index date. 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 Neurology 83
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Figure 1
Flowchart of selection process for the study cohort
From the National Health Insurance Research Database of Taiwan, we identified 2,117 patients with hypoglycemia from 46,135 patients with chronic kidney disease (CKD). We excluded patients with CKD who experienced cardiovascular events including stroke, coronary heart disease (CHD), and congestive heart failure (CHF) before the index date of hypoglycemia. Of 2,117 hypoglycemia patients with CKD, we enrolled 576 patients with hypoglycemia who had not experienced any cardiovascular event before the index date in the study. Based on the same exclusion criteria, we selected 2,141 patients with CKD without hypoglycemia as the matched control group.
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, 688
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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 (HR 5 2.53, 95% CI 5 1.99–3.21), 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).
Table 1
Characteristics of patients with chronic kidney disease (CKD) with hypoglycemia and matched patients with CKD without hypoglycemia Hypoglycemia (n 5 576) No hypoglycemia (n 5 2,141) p Value
Age, y £64
246 (42.7)
947 (44.2)
330 (57.3)
1,194 (55.8)
64.2 (13.4)
64.8 (14.1)
0.38
Female
298 (51.7)
1,088 (50.8)
0.70
Male
278 (48.3)
1,053 (49.2)
491 (85.2)
1,802 (84.2)
0.53
‡65 a
Mean (SD)
0.51
Sex
Comorbidity Diabetes Hypertension
427 (74.1)
1,379 (64.4)
,0.0001
Hyperlipidemia
254 (44.1)
1,036 (48.4)
0.07
Chronic liver disease
137 (23.8)
554 (25.9)
0.31
Mental illness
245 (42.5)
764 (35.7)
0.003
Antidiabetic drugs Insulin
388 (67.4)
762 (35.6)
,0.0001
Metformin
395 (68.6)
997 (46.6)
,0.0001
Sulfonylurea
369 (64.1)
940 (43.9)
,0.0001
Data are n (%) unless otherwise indicated. Chi-square test and a t test comparing subjects with and without hypoglycemia.
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 Neurology 83
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Table 2
Incidence, incidence rate ratio, and HR of stroke, coronary heart disease, congestive heart failure, and mortality comparing patients with CKD with and without hypoglycemia Hypoglycemia
No hypoglycemia
Outcome
Event
PY
Ratea
Event
PY
Ratea
IRR (95% CI)
Adjusted HRb (95% CI)
Stroke
112
2,160
5.19
305
12,446
2.45
2.12 (1.74, 2.57)c
1.62 (1.29, 2.03)c
Female
63
1,215
5.19
159
6,411
2.48
2.09 (1.60, 2.73)c
1.55 (1.14, 2.10)d
Male
49
945
5.19
146
6,034
2.42
2.14 (1.60, 2.87)c
1.68 (1.20, 2.35)d
£64
39
1,088
3.59
82
6,245
1.31
2.73 (2.03, 3.67)c
1.92 (1.27, 2.90)d
‡65
73
1,071
6.81
223
6,201
3.60
1.89 (1.47, 2.45)c
1.49 (1.13, 1.97)d
d
1.25 (1.00, 1.57)
Sex
e
Age, y
Coronary heart disease
104
1,971
5.28
420
11,255
3.73
1.41 (1.13, 1.76)
Female
59
1,076
5.48
205
5,828
3.52
1.56 (1.16, 2.09)d
1.35 (1.00, 1.84)
Male
45
894
5.03
215
5,427
3.96
1.27 (0.91, 1.77)
1.14 (0.82, 1.60)
£64
49
973
5.03
165
5,643
2.92
1.72 (1.25, 2.36)c
1.36 (0.96, 1.93)
‡65
55
997
5.52
255
5,611
4.54
1.21 (0.89, 1.65)
1.13 (0.84, 1.53)
Sex
Age, y
Congestive heart failure
c
1.49 (1.13, 1.98)d
71
2,173
3.27
224
12,495
1.79
1.82 (1.46, 2.27)
37
1,211
3.05
119
6,394
1.86
1.64 (1.21, 2.23)d c
1.77 (1.18, 2.65)d
1.88 (1.20, 2.97)d
Sex Female Male
1.30 (0.88, 1.93)
34
963
3.53
105
6,101
1.72
2.05 (1.50, 2.82)
32
1,073
2.98
69
6,189
1.11
2.68 (1.94, 3.70)c
2.46
1.44 (1.07, 1.95)
f
1.30 (0.90, 1.87)
c
2.53 (1.99, 3.21)c
Age, ye £64 ‡65 Mortality
39
1,101
3.54
155
6,306
115
2,423
4.74
245
13,318
1.84
2.58 (2.14, 3.12)
Female
43
1,353
3.18
113
6,858
1.65
1.93 (1.46, 2.56)c
1.87 (1.29, 2.72)c
Male
72
1,071
6.72
132
6,459
2.04
3.29 (2.54, 4.26)c
3.18 (2.32, 4.35)c
£64
61
1,200
5.09
118
6,489
1.82
2.80 (2.14, 3.65)c
2.64 (1.86, 3.73)c
‡65
54
1,224
4.41
127
6,829
1.86
2.37 (1.81, 3.11)c
2.30 (1.64, 3.22)c
Sexg
Age, y
Abbreviations: CI 5 confidence interval; CKD 5 chronic kidney disease; HR 5 hazard ratio; IRR 5 incidence rate ratio; PY 5 person-years. a Incidence rate per 100 PY. b Adjusted for age, sex, comorbidities, insulin, metformin, and sulfonylurea. c p , 0.001. d p , 0.01. e p Value for interaction ,0.01. f p , 0.05. g p Value for interaction ,0.05.
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 690
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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
Table 3
Risk of stroke, coronary heart disease, congestive heart failure, and mortality among frequency for medical visits of hypoglycemia in Cox proportional hazard regression
Frequency for medical visit, per 1 y
Event
PY
Ratea
IRR (95% CI)
305
12,446
2.45
1 (reference)
Adjusted HRb (95% CI)
Stroke No hypoglycemia £2 >2
82 30
2,086 74
3.93 40.6
1 (reference)
1.60 (1.29, 1.99)
c
1.25 (0.97, 1.61)
16.6 (11.9, 23.1)
c
11.6 (7.73, 17.5)c
p Value
,0.0001
Coronary heart disease No hypoglycemia £2 >2
420
11,255
3.73
1 (reference)
65
1,891
3.44
0.92 (0.71, 1.20)
39
80
48.7
13.1 (9.38, 18.2)
1 (reference) 0.84 (0.64, 1.10) c
p Value
9.40 (6.57, 13.5)c ,0.0001
Congestive heart failure No hypoglycemia
224
12,495
1.79
1 (reference)
1 (reference) d
£2
50
2,099
2.38
1.33 (1.04, 1.70)
>2
21
75
28.2
15.7 (10.9, 22.6)c
p Value
1.12 (0.81, 1.54) 11.2 (6.87, 18.2)c ,0.0001
Mortality No hypoglycemia
245
13,318
1.84
1 (reference)
1 (reference) c
1.80 (1.37, 2.36)c 33.0 (22.3, 48.8)c
£2
76
2,358
3.22
1.75 (1.42, 2.17)
>2
39
66
59.1
32.1 (24.3, 42.4)c
p Value
,0.0001
Abbreviations: CI 5 confidence interval; HR 5 hazard ratio; IRR 5 incidence rate ratio; PY 5 person-years. a Incidence rate per 100 PY. b Adjusted for age, sex, comorbidities, insulin, metformin, and sulfonylurea. c p , 0.001. d p , 0.05.
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 cardiovascular events and patient mortality in patients with CKD.26 Several conditions have been suggested to contribute to sympathetic overactivity in patients with Neurology 83
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691
692
Table 4
Cox proportional hazard regression analysis for the risk of hypoglycemia-associated events with joint effect of diabetes and antidiabetic drugs Stroke
Variable Hypoglycemia No
No.
No
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Yes
Yes
No
Hypoglycemia
August 19, 2014
No No
Yes
Event, n
Adjusted HRa (95% CI)
Event, n
Mortality
Adjusted HRa (95% CI)
Event, n
Adjusted HRa (95% CI)
339
25
1 (reference)
48
1 (reference)
31
51
1 (reference)
372
1.49 (1.10, 2.01)
193
1.10 (0.75, 1.60)
194
10
1.22 (0.62, 2.41)
7
1.47 (0.65, 3.35)
16
1.88 (1.07, 3.29)c
1,802
280
85
8
2.01 (1.34, 3.03)
2.45 (1.11, 5.45)c
491
104
b
945
91
4.20 (2.71, 6.51)
94
c
1 (reference)
b
b
d
0.76 (0.56, 1.04)
2.00 (1.41, 2.84)
64
2.00 (1.30, 3.08)
99
2.27 (1.61, 3.20)b
1 (reference)
82
1 (reference)
82
1 (reference)
ADMs No Yes
Yes
No
Yes
Yes
Hypoglycemia
Adjusted HRa (95% CI)
Congestive heart failure
Diabetes
No
Yes
Event, n
Coronary heart disease
1,196
214
94
10
482
102
1 (reference)
163 b
2.12 (1.65, 2.71)
257
b
1.40 (1.15, 1.70)
142
d
142
d
1.49 (1.13, 1.96)
1.16 (0.90, 1.50)
c
2.07 (1.07, 3.97)
11
1.02 (0.55, 1.88)
11
2.33 (1.24, 4.39)
11
2.60 (1.60, 4.25)b
3.68 (2.76, 4.90)b
93
1.75 (1.35, 2.26)b
60
2.25 (1.61, 3.15)b
60
3.08 (2.33, 4.06)b
Insulin
No
No
1,379
151
1 (reference)
259
1 (reference)
124
1 (reference)
No
Yes
762
154
2.17 (1.73, 2.72)b
161
1.25 (1.03, 1.53)c
100
1.65 (1.26, 2.14)b
86
1.24 (0.95, 1.61)
Yes
No
188
28
2.05 (1.37, 308)b
32
1.31 (0.91, 1.90)
23
2.07 (1.33, 3.24)d
37
2.61 (1.82, 3.74)b
Yes
Yes
388
84
3.52 (2.68, 4.62)b
72
1.52 (1.17, 1.98)d
48
2.22 (1.59, 3.11)b
78
3.16 (2.40, 4.17)b
1,144
122
Hypoglycemia No
159
1 (reference)
Metformin No
1 (reference)
216 b
1 (reference)
108
1 (reference)
133 c
112
No
Yes
997
183
204
1.20 (0.99, 1.46)
116
Yes
No
181
28
2.62 (1.74, 3.96)b
25
1.10 (0.72, 1.66)
20
1.90 (1.18, 3.07)d
41
2.88 (2.02, 4.10)b
Yes
Yes
395
84
3.25 (2.45, 4.31)b
79
1.63 (1.26, 2.12)b
51
2.13 (1.52, 2.98)b
74
3.00 (2.24, 4.01)b
1,201
136
Hypoglycemia No No
1.96 (1.56, 2.47)
1.34 (1.03, 1.74)
1 (reference) 1.17 (0.91, 1.51)
Sulfonylurea No Yes
940
169
1 (reference)
226 b
1.85 (1.47, 2.32)
d
194
1 (reference)
116 c
1.23 (1.02, 1.50)
108
1 (reference)
145
1 (reference)
c
100
1.10 (0.85, 1.42)
d
1.33 (1.02, 1.73)
Yes
No
207
27
2.00 (1.32, 3.02)
28
1.16 (0.78, 1.72)
23
1.96 (1.25, 3.07)
50
3.20 (2.32, 4.43)b
Yes
Yes
369
85
3.39 (2.57, 4.46)b
76
1.63 (1.25, 2.12)b
48
2.06 (1.47, 2.90)b
65
2.64 (1.96, 3.56)b
Abbreviations: ADM 5 antidiabetic medication; CI 5 confidence interval; HR 5 hazard ratio. ADMs group: patients who ever used any one of the ADMs, such as insulin, metformin, and sulfonylurea. a Adjusted for age and sex. b p , 0.001. c p , 0.05. d p , 0.01.
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.
3.
4.
5.
6.
7.
8. 9.
10.
11. 12.
13. AUTHOR CONTRIBUTIONS Conception and design: Tung-Min Yu, Chia-Hung Kao. Administrative support: Cheng-Li Lin, Fung-Chang Sung. Collection and assembly of data: all authors. Data analysis and interpretation: Tung-Min Yu, Cheng-Li Lin, Chia-Hung Kao. Manuscript writing: all authors. Final approval of manuscript: all authors.
14.
STUDY FUNDING
15.
This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW103-TDU-B212-113002), China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM103010096), NRPB Stroke Clinical Trial Consortium (MOST 103-2325-B-039-006), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. The funders had no role in the study design, data collection or analysis, the decision to publish, or the preparation of the manuscript.
16.
17.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
18.
Received December 13, 2013. Accepted in final form May 12, 2014.
19.
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Increased risk of stroke in patients with chronic kidney disease after recurrent hypoglycemia Tung-Min Yu, Cheng-Li Lin, Shih-Ni Chang, et al. Neurology 2014;83;686-694 Published Online before print July 16, 2014 DOI 10.1212/WNL.0000000000000711 This information is current as of July 16, 2014 Updated Information & Services
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Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/07/16/WNL.00000 00000000711.DC1.html
References
This article cites 27 articles, 12 of which you can access for free at: http://www.neurology.org/content/83/8/686.full.html##ref-list-1
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