Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical Trial

Abstract

Importance: Hyperglycemia during acute ischemic stroke is common and is associated with worse outcomes. The efficacy of intensive treatment of hyperglycemia in this setting remains unknown.

Objectives: To determine the efficacy of intensive treatment of hyperglycemia during acute ischemic stroke.

Design, setting, and participants: The Stroke Hyperglycemia Insulin Network Effort (SHINE) randomized clinical trial included adult patients with hyperglycemia (glucose concentration of >110 mg/dL if had diabetes or ≥150 mg/dL if did not have diabetes) and acute ischemic stroke who were enrolled within 12 hours from stroke onset at 63 US sites between April 2012 and August 2018; follow-up ended in November 2018. The trial included 1151 patients who met eligibility criteria.

Interventions: Patients were randomized to receive continuous intravenous insulin using a computerized decision support tool (target blood glucose concentration of 80-130 mg/dL [4.4-7.2 mmol/L]; intensive treatment group: n = 581) or insulin on a sliding scale that was administered subcutaneously (target blood glucose concentration of 80-179 mg/dL [4.4-9.9 mmol/L]; standard treatment group: n = 570) for up to 72 hours.

Main outcomes and measures: The primary efficacy outcome was the proportion of patients with a favorable outcome based on the 90-day modified Rankin Scale score (a global stroke disability scale ranging from 0 [no symptoms or completely recovered] to 6 [death]) that was adjusted for baseline stroke severity.

Results: Among 1151 patients who were randomized (mean age, 66 years [SD, 13.1 years]; 529 [46%] women, 920 [80%] with diabetes), 1118 (97%) completed the trial. Enrollment was stopped for futility based on prespecified interim analysis criteria. During treatment, the mean blood glucose level was 118 mg/dL (6.6 mmol/L) in the intensive treatment group and 179 mg/dL (9.9 mmol/L) in the standard treatment group. A favorable outcome occurred in 119 of 581 patients (20.5%) in the intensive treatment group and in 123 of 570 patients (21.6%) in the standard treatment group (adjusted relative risk, 0.97 [95% CI, 0.87 to 1.08], P = .55; unadjusted risk difference, -0.83% [95% CI, -5.72% to 4.06%]). Treatment was stopped early for hypoglycemia or other adverse events in 65 of 581 patients (11.2%) in the intensive treatment group and in 18 of 570 patients (3.2%) in the standard treatment group. Severe hypoglycemia occurred only among patients in the intensive treatment group (15/581 [2.6%]; risk difference, 2.58% [95% CI, 1.29% to 3.87%]).

Conclusions and relevance: Among patients with acute ischemic stroke and hyperglycemia, treatment with intensive vs standard glucose control for up to 72 hours did not result in a significant difference in favorable functional outcome at 90 days. These findings do not support using intensive glucose control in this setting.

Trial registration: ClinicalTrials.gov Identifier: NCT01369069.

Figure 1.. Enrollment, Randomization, and Follow-up of Patients

^aOne patient was randomized twice, 21 months apart. ^bThe collection window was predefined as 90 days (+30 days or −14 days) after randomization. ^cSome patients had multiple reasons for exclusion.

Figure 2.. Blood Glucose Concentrations in 3-Hour Intervals During the Treatment Period by Treatment Group

The box plots include observed data within a 3-hour interval. The box shows the interquartile range (IQR), with the bottom and top indicating the 25th and 75th percentiles. The line inside the box indicates the median. The dots inside the box indicate the means. The upper whisker extends from the top of the box to the largest value no farther than 1.5 × IQR, and the bottom whisker extends from the bottom of the box to the smallest value no farther than 1.5 × IQR. The trajectory line connects the medians at each 3-hour interval. The box plots have been offset to avoid superimposition. Each patient can contribute up to 3 glucose measurements during each 3-hour interval. The median number of measurements per patient within a 3-hour interval was 3 (IQR, 2-3) in the intensive treatment group and 1 (IQR, 1-1) in the standard treatment group.

Figure 3.. Distribution of 90-Day Modified Rankin Scale Score by Treatment Group and Baseline Stroke Severity

NIHSS indicates National Institutes of Health Stroke Scale. The modified Rankin Scale is a global stroke disability scale with scores ranging from 0 (no symptoms or completely recovered) to 6 (death). Each cell corresponds to a score on the modified Rankin Scale; the width of the cell indicates the proportion of patients with equivalent scores, and the percentage of patients is shown within the cell. The diagonal line between the 2 study groups indicates the dichotomization of favorable outcome in each severity stratum.