Prognostic Effect of Glycemic Management In Acute First-Ever Ischemic Stroke On Stroke Recurrence And Mortality For Patients Without Previous Diabetes: A Longitudinal Cohort Study

Abstract

Objective This study aimed to investigate the short- and long-term prognostic effects of glycemic management on stroke recurrence and mortality in patients with acute first-ever ischemic stroke (FIS) without previous diabetes.

Methods In total, 484,952 patients aged ≥20 years with FIS and nonprevious diabetes were retrieved from the 2000 to 2015 Taiwan’s National Health Insurance Research Database. Patients were categorized into the following cohorts: FIS without hyperglycemia (FISw/oHG), FIS with hyperglycemia without glycemic treatment (FISHGw/oGT), and FIS with hyperglycemia with glycemic treatment (FISHGw/GT). The short-term (within 1 year) and long-term (at the endpoint of 9.3 ± 8.6 years) prognostic effects of glycemic treatment and blood glucose monitoring on stroke recurrence and mortality among the cohorts were tested through Cox regression analysis.

Results The mortality risk was lower in the FISHGw/GT cohort than in the FISHGw/oGT cohort at 3 months, 6 months, and 1 year (adjusted hazard ratio = 0.68, 0.62, 0.69, respectively, p < 0.001) as well as at the study endpoint, but no difference was observed in stroke recurrence at any time point (p > 0.05). Furthermore, compared with FISHGw/oGT without blood glucose monitoring, FISHGw/GT combined with blood glucose monitoring led to decreased risks of stroke recurrence within 1 year (p < 0.001) and mortality within 1 year and at the study endpoint (p < 0.001).

Conclusion For optimal glycemic management in the acute phase and improved prognoses for patients with FIS and nonprevious diabetes with hyperglycemia, intensive blood glucose monitoring combined with glycemic treatment is needed.

Introduction

Ischemic stroke, also known as central nervous system infarction, leads to the disruption of blood supply to the brain, which can cause brain cell death and brain damage ¹. As a result, patients with acute ischemic stroke (AIS) experience a sudden unexpected decline in cognition, autonomic nervous system function, and executive functions, leading to focal neurological deficit ^{1, 2}. In addition, stroke recurrence is frequent and cumulative, ranging from 5.4–10.4% at 1 year to 12.9–14.2% at 10 years after the first-ever stroke ^{3, 4}. Furthermore, mortality and functional disability are highly associated with stroke recurrence ⁵. Therefore, stroke recurrence and mortality rate are commonly regarded as indicators of the effectiveness of health care intervention in patients with AIS.

Hyperglycemia has been observed in 40–60% of patients with AIS; it is a response to the acute stress from brain damage and known as poststroke hyperglycemia ^{6, 7}. It is considered an essential survival response and usually disappears spontaneously after the acute phase of ischemic stroke ⁸. However, evidence indicates that poststroke hyperglycemia is an unfavorable occurrence associated with an increased risk of morbidity, poor prognosis, and mortality ^9–11.

Within 48 hours of an AIS attack, hyperglycemia has been determined to be an independent predictor for stroke recurrence ¹². According to an investigation of ischemic stroke recurrence within two years after the first-ever attack in a China cohort study, diabetes mellitus (DM) is a risk factor for stroke recurrence ¹³. A systematic review indicated that the relative risk of in-hospital or 30-day mortality was higher in patients with poststroke hyperglycemia (risk in patients with and without previously diagnosed diabetes was 1.30 and 3.07 times higher, respectively) than in those with normoglycemia ⁹. Studies have indicated that admission hyperglycemia and hyperglycemia in combination with high glycosylated hemoglobin (HbA1c) in patients with AIS are risk factors for short-term (from 3 months to 1 year after the stroke incidence) mortality, particularly in patients without a history of diabetes ^14–17.

Poststroke hyperglycemia is a modifiable risk factor for brain damage ². Glucose-lowering therapies reduce brain damage ¹⁸. However, tight glycemic control has no significant beneficial effect on functional outcomes or survival but might increase hypoglycemia risk ¹⁹. Researchers have postulated that tight glycemic control within the normal range in acute stroke might lead to brain glycopenia, which would hamper the body’s ability to meet the increased metabolic demand after acute brain damage and cause hypoglycemia and metabolic crisis ²⁰. According to the guidelines for ischemic stroke management, targeting a blood glucose level of 140–180 mg/dL and closely monitoring blood glucose are crucial for poststroke hyperglycemia management ². However, the guidelines do not indicate the glucose level threshold that requires intervention or specific insulin treatment regimens ². Furthermore, the guidelines have not recommended a particular frequency of blood glucose monitoring ²¹.

Glycemic management is implemented conservatively and varies across countries because of the risk of iatrogenic hypoglycemia and a lack of promising effects ²². The conservatove glycemic treatment in acute stroke might increase mortality, all-cause readmissions or emergency visits, recurrent stroke, infection morbidity, and psychological distress ¹⁵. In addition, hyperglycemia is frequently unmanaged has been reported, and the effect of glycemic control on AIS is controversial ²¹. However, major investigations into the prognostic longitudinal impact of glycemic management in patients with AIS are lacking. The purpose of this study was to use Taiwan’s National Health Insurance Research Database (NHIRD) to investigate the short- and long-term prognostic effects of glycemic management (combined glycemic treatment with blood glucose monitoring) on stroke recurrence and mortality in patients with acute first-ever ischemic stroke (FIS) without previous diabetes.

Methods

Results

Baseline Characteristics of the Study Population

In total, 484,952 patients with FIS met the inclusion criteria of this study, of whom 161,839 (33.4%) had FIS with hyperglycemia (FISHG). Among patients with FISHG, 69,018 (42.7%) had not received glycemic treatment and 92,821 (57.4%) had received glycemic treatment for acute stroke. After one-fold propensity matching, the 69,018 patients were categorized into one of the following three cohorts: FIS without hyperglycemia (FISw/oHG), FISHG without glycemic treatment (FISHGw/oGT), and FISHG with glycemic treatment (FISHGw/GT) (Fig. 1). This study included 207,054 patients with FIS aged 56.5 ± 10.3 years, and no significant differences were observed in age and sex distribution among the three cohorts (p = 0.78 and 1.00, respectively; Table 1). Blood glucose was monitored in 63,672 (92.25%) patients in the FISHGw/GT cohort and 6213 (9.00%) patients in the FISHGw/oGT cohort (p < 0.001).

Comparison of Stroke Recurrence and Mortality Among the FISw/oHG, FISHGw/oGT, and FISHGw/GT Cohorts

            After adjustment for covariates of sex, age, monthly income, seasons, geographical area of residence (location), urbanization level of the residence, and levels of care, both FISHGw/oGT and FISHGw/GT cohorts had significantly higher stroke recurrence than the FISw/oHG cohort (p < 0.05) within 1 year of tracking. However, at the 3-month follow-up, the FISHGw/GT cohort did not have a significantly higher stroke recurrence than the FISw/oHG cohort (p = 0.12; Table 1). The FISHGw/oGT and FISHGw/GT cohorts had a substantially higher mortality rate than the FISw/oHG cohort within 1 year of tracking (p < 0.05). At the study endpoint (9.3 ± 8.6 years), Cox regression analysis indicated that both the FISHGw/oGT and FISHGw/GT cohorts had a higher risk of stroke recurrence and mortality than the FISw/oHG cohort (adjusted hazard ratio [aHR] = 1.35 and 1.17, p < 0.001; 1.34 and 1.11, p < 0.001, respectively; Table 2). Kaplan–Meier analysis indicated that among the three cohorts, the FISw/oHG cohort had the lowest cumulative risks of stroke recurrence and mortality in the first year, which persisted until the end of the follow-up (log‐rank test; p < 0.001; Fig. 2).

Short- and Long-Term Prognostic Effects of Glycemic Treatment and Blood Glucose Monitoring on Stroke Recurrence in FISHG Patients

After adjustment for covariates, the FISHGw/GT cohort had a lower but nonsignificant aHR in stroke recurrence at 1-month, 3-month, 6-month, and 1-year follow-ups (p > 0.05) than FISHGw/oGT cohort. In addition, the FISHGw/GT cohort did not have a significantly lower stroke recurrence rate than the FISHGw/oGT cohort at the study endpoint (95% confidence interval [CI] = 0.92–1.01, p = 0.79).

Blood glucose monitoring in the FISHGw/GT cohort in the acute stroke phase led to a lower risk of stroke reoccurrence than that in the FISHGw/oGT cohort without blood glucose monitoring at 1-month, 3-month, 6-month, and 1-year follow-ups (aHR = 0.75, 0.84, 0.80, 0.82, respectively; p < 0.001). However, FISHGw/GT combined with blood glucose monitoring in the acute stroke phase had a lower but nonsignificant risk of stroke recurrence than did FISHGw/oGT without blood glucose monitoring at the study endpoint (p > 0.05; Table 3).

Short- and Long-Term Prognostic Effect of Glycemic Treatment and Blood Glucose Monitoring on Mortality in FISHG Patients

After adjustment for covariates, the FISHGw/GT cohort had a significantly lower risk of mortality than the FISHGw/oGT cohort at 3-month, 6-month, and 1-year follow-ups (aHR = 0.68, 0.62, 0.69, p < 0.001, respectively; Table 2) but not at 1-month follow-up (95% CI = 0.58–1.25, p = 0.45). The FISHGw/GT cohort had a significantly lower risk of mortality than the FISHGw/oGT cohort at the study endpoint (aHR = 0.83, 95% CI = 0.81–0.85, p < 0.001).

Patients with FISHGw/GT with blood glucose monitoring in the acute stroke phase had a significantly lower risk of mortality at 1-month, 3-month, 6-month, and 1-year follow-ups than did patients with FISHGw/oGT without blood glucose monitoring (aHR = 0.80, 0.67, 0.58, 0.66, respectively; p < 0.001; Table 3). Furthermore, at the study endpoint, a significantly lower risk of mortality was observed in patients with FISHGw/GT with blood glucose monitoring than in patients with FISHGw/oGT without blood glucose monitoring (aHR = 0.71, p < 0.001; Table 3).

Discussion

Using Taiwan’s NHIRD, we found that FISHG patients without previous diabetes had a higher risk of stroke recurrence and mortality in both short and long terms than FISw/oHG. This study confirmed the short- and long-term prognostic effects of individual glycemic treatment on the decreased risk of mortality, but not of stroke recurrence, in patients with FISHG in the acute stroke phase. The risk of stroke recurrence within 1 year and mortality in both short and long terms were lower in patients with FISHG who received glycemic management (combined glycemic treatment with blood glucose monitoring) in the acute phase than those who did not receive glycemic management.

In this study, nondiabetic patients with FIS with hyperglycemia were 33.4%, which is consistent with a systematic review, in which the prevalence of poststroke hyperglycemia ranged from 8–63% in nondiabetic patients with AIS ^{9, 17, 25}. Patients with FIS with hyperglycemia might present preexisting and unrecognized DM but mostly develop hyperglycemia as a stress reaction to brain damage ⁹. Stress hyperglycemia after stroke was related to an increased risk of stroke recurrence and all-cause death at the 12-month follow-up in nondiabetic patients with AIS ²⁶. A direct association of poststroke hyperglycemia with increased risk of stroke recurrence and 3-month mortality was found in patients with ischemic stroke without previously diagnosed diabetes ¹⁶. Patients with stroke with newly diagnosed DM based on glucose criteria (fasting plasma glucose ≥ 7.0 mmol/L or 2-hour oral glucose tolerance test ≥ 11.1 mmol/L with/without HbA1c ≥ 6.5%) were found to have a higher risk of stroke recurrence, poor functional outcomes, and mortality than nondiabetic patients at 1-year follow-up ¹⁷. A study compared the functional outcomes, severity, and mortality of stroke at 3-month follow-up among patients with AIS with diagnosed DM, and the results indicated that patients with newly diagnosed DM after stroke had poorer functional outcome, severer strokes, and increased mortality compared with those with previously diagnosed DM ²⁵. In line with previous study results, this study’s results indicated that patients with FISHG had a higher risk of stroke recurrence and mortality than those with FISw/oHG.

The mechanism underpinning the relation between poststroke hyperglycemia and poor prognoses of stroke is unclear. Poststroke hyperglycemia might be caused by neurohormonal dysfunction and the inflammatory response to ischemic brain damage ²⁷; furthermore, the complicated interaction of catecholamine, cortisol, and cytokine might induce an increase in the hepatic output of glucose ²⁸. Hyperglycemia exacerbates outcomes in patients with stroke through several possible pathophysiological mechanisms of neurotoxic effects, such as calcium imbalance, the accumulation of reactive oxygen species, increased lactic acidosis, decreased nitric oxide, and intensified inflammatory responses ²⁹. Insulin resistance and β-cell dysfunction cause relative insulin deficiency in hyperglycemia, which might increase the poor outcomes of nondiabetic patients with ischemic stroke ^{30, 31}. These pathophysiological mechanisms may result in the enhancement of lipid peroxidation, free radical formation, and the accumulation of intracellular calcium; furthermore, cell lysis in the umbra and penumbra regions promote and accelerate ischemic injury ^{15, 32–34}. A magnetic resonance imaging study reported that hyperglycemia is not only determined by the initial infarct volume but also by the infarct volume expansion ³⁵. Furthermore, prolonged poststroke hyperglycemia had been found to worsen neuronal damage and blood–brain dysfunction and increase the infarct volume growth in patients with ischemic stroke ^{15, 36}.

In light of the adverse outcome in patients with poststroke hyperglycemia, guidelines recommend early glucose management for survival after stroke in patients with hyperglycemia ². Guidelines for the early management of AIS in patients with hyperglycemia recommend glycemic treatment to achieve blood glucose levels in a range of 140–180 mg/dL and the necessity of intensive blood glucose monitoring for preventing hypoglycemia, which can lead to further brain damage and poor outcomes ². Using insulin for glycemic treatment not only controlled blood glucose level but also had a neuroprotective effect through the augmentation of astrocytic glycogen phosphorylase ³⁴. Brain reperfusion after ischemic stroke might cause extensive reperfusion-induced glycogen accumulation in the ischemic penumbra and is strongly associated with the development of ischemia/reperfusion (I/R) injury, which leads to aggravating glutamate excitotoxicity, calcium overload, free radical formation, and inflammation ³⁷. In the past decade, growing evidence has been discovered in support of the proposition that insulin plays a crucial role in neuroprotection through the maintenance of calcium homeostasis, inhibition of inflammation, downregulation of free radical released in the heart, and modulation of glucose metabolism, which further prevent I/R injury ^{38, 39}. Thus, glycemic treatment with insulin as a potential intervention for ischemic stroke focusing on glycogenolysis is promising. Nevertheless, the precise application of targeting strategies forglycemic treatment should be carefully considered depending on the timing of ischemia.

Although early glycemic management in acute stroke has a promising effect, previous studies have reported that intensive insulin therapy or glucose control in patients with acute stroke might not provide significant benefit in functional outcomes and survival and instead might cause hypoglycemic adverse effects ¹⁹. This line of argument suggests that brain injury during the acute stroke phase increases the need for glucose and is vulnerable to glucose deficit ^{40, 41}. Intensive glucose control within the normal range might lead to brain glycopenia, the metabolic crisis in the ischemic brain, and increased mortality ⁴². Thus, glycemic treatment during acute stroke is controversial. Another challenge, namely a lack of hyperglycemia management in the acute stroke phase, is emerging and is worth noting.

The guidelines recommend blood glucose monitoring during glycemic treatment for the avoidance of iatrogenic hypoglycemia from insulin treatment and the maintenance of a safe glucose level of in patients with ischemic stroke ². The risk of stroke recurrence is the highest immediately after an ischemic stroke and gradually decreases and reaches a steady state by 6 months to 1 year after stroke onset ^{43, 44}. This study’s results confirmed the benefit of glycemic treatment combined with blood glucose monitoring, particularly for the prevention of stroke recurrence within 1 year poststroke.

This study revealed that > 91% of FISHGw/GT patients had received blood glucose monitoring. Conversely, only 9% of the FISHGw/oGT cohort were prescribed blood glucose monitoring. A possible explanation is that the FISHGw/oGT cohort might present with a relatively stable blood glucose level in the acute phase, and blood glucose monitoring may be deemed unnecessary. The SHINE (Stroke Hyperglycemia Insulin Network Effort) multicenter randomized controlled trial proved that the optimal management of hyperglycemia at 80–130 mg/dL is safe and improves 3-month poststroke outcomes; however, researchers have emphasized the pivotal role of intensive and consistent blood glucose monitoring to avoid the onset of both hyperglycemia and hypoglycemia ^{45, 46}. In line with SHINE study, our study data revealed that short- and long-term mortality are lower in FISHGw/GT with blood glucose monitoring than in FISHGw/oGT without blood glucose monitoring.

Conclusions

Appropriate glycemic management, chiefly glycemic treatment accompanied by intensive blood glucose monitoring, may be dispensable for acute care of nondiabetic patients with FIS and hyperglycemia. This study did not explore the optimal glucose value at which corrective treatment should be initiated. Nonetheless, this study provides general knowledge regarding the beneficial effects of glycemic management on stroke recurrence and mortality in patients with acute stroke through short- and long-term follow-ups. The risk of hyperglycemia in acute stroke is not arguable, but the optimal glycemic treatment and insulin benefit effect are still debatable. Therefore, the implementation of blood glucose monitoring is essential to achieve optimal glycemic management in the acute stroke phase and improving prognoses for patients with FISHG without previous diabetes.

Declarations

Acknowledgements

The authors thank the National Health Research Institute in Taiwan for providing the insurance claims data. This study was supported by a research grant (CMNDMC10806) from the Chi-Mei Medical Center in Taiwan.

Author contributions 

H.H.Y. and Y.J.C. secured funding, conceptualized, designed, and performed the study, analyzed and interpreted the data, and wrote the manuscript. W.C.C., J.J.L., and C.C.Y. acquired, analyzed, and interpreted the data, review and edited the manuscript. C.H.C. and P.C.C acquired and analyzed the data.. T.T.L.advised on data collection and analysis, and edited the manuscript.

Competing interests

All authors declaire no competing interests. 

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Tables

Table 1. Characteristics of study participants at baseline. FISw/oHG = FIS without hyperglycemia; FISHGw/oGT = FIS with hyperglycemia without glycemic treatment; FISHGw/GT = FIS with hyperglycemia with glycemic treatment. p: chi-square/Fisher’s exact test on category variables and one-way analysis of variance.

Table 2. Cox regression analysis for the risks of stroke recurrence and mortality of the FISw/oHG, FISHGw/oGT, and FISHGw/GT cohorts within 1 year and at the endpoint. The covariates of sex, age, monthly income, seasons, geographical area of residence, urbanization level of the residence, and levels of care were included in the multivariable model for adjustment; FISw/oHG = FIS without hyperglycemia; FISHGw/oGT = FIS with hyperglycemia without glycemic treatment; FISHGw/GT = FIS with hyperglycemia with glycemic treatment; aHR = adjusted hazard ratio, CI = confidence interval; ^† = p < 0.001 as comparison of hazard ratio between FISHGw/oGT and FISHGw/GT cohorts; Endpoint = from the index date until death, withdrawal from the NHI program, or the end of 2015, whichever occurred first.

Table 3. Short- and long-term prognostic effect of the glycemic treatment and blood glucose monitoring on stroke recurrence and mortality in FISHG patients. The covariates of sex, age, monthly income, season, geographical area of residence, urbanization level of the residence, and level of care were included in the multivariable model for adjustment; FISHG = FIS patients with hyperglycemia; FISHGw/oGT = FIS with hyperglycemia without glycemic treatment; FISHGw/GT = FIS with hyperglycemia with glycemic treatment; BGM = blood glucose monitoring; aHR = adjusted hazard ratio; CI = confidence interval; Endpoint = from the index date until death, withdrawal from the NHI program, or the end of 2015, whichever occurred first.