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INTRODUCTION
Diabetes mellitus is a well-established major risk factor for stroke. Type 2 diabetes is associated with a markedly increased risk of stroke relative to non-diabetic individuals. An elevated risk of stroke has also been reported among patients with type 1 diabetes. Stroke is a leading cause of mortality and disability in patients with diabetes mellitus, significantly reducing their quality of life. Furthermore, stroke patients with diabetes mellitus tend to have worse outcomes, including higher recurrence rates and slower recovery. Consequently, both primary and secondary stroke prevention are critical objectives in managing diabetes mellitus. This review explores the epidemiology of stroke in diabetes, the role of glycemic control, and antidiabetic medications in stroke prevention in patients with diabetes mellitus.
DIABETES AS AN INDEPENDENT RISK FACTOR FOR STROKE
Stroke is notably prevalent among patients with diabetes. According to the 2019 Diabetes Fact Sheet published by the Korean Diabetes Association, the incidence of stroke among patients with diabetes in Korea was 254 cases per 10,000 male patients and 258 cases per 10,000 female patients. Cerebrovascular diseases accounted for 8.9% of deaths in this population [1].
Cohort studies consistently report an elevated stroke risk in diabetes. In a UK study by Mulnier et al. [2], the age-adjusted hazard ratio (HR) for stroke in type 2 diabetes patients was 2.19 (95% confidence interval [CI], 2.09–2.32) over 7 years. Risk factors such as the duration of diabetes, smoking, obesity, atrial fibrillation, and hypertension were identified. Similarly, statistics from Korea’s National Health Insurance indicated a 2.2-fold higher stroke risk in diabetes patients (95% CI, 2.08–2.32) [3]. Type 1 diabetes was also associated with increased stroke risk in retrospective observational study (HR, 1.50; 95% CI, 1.23–1.83) [4].
A meta-analysis of 64 cohort studies found the HR for diabetes-related stroke to be 2.28 (95% CI, 1.93–2.69) in women and 1.83 (95% CI, 1.60–2.08) in men [5]. The increased risk was particularly pronounced in younger women, likely due to their relatively lower prevalence of other stroke risk factors, highlighting diabetes as a significant independent contributor to stroke occurrence.
There are differences in risk according to the stroke type. In a cohort observational study in Sweden with a mean follow-up of 7.9 years, HRs for ischemic and hemorrhagic strokes were 3.29 (95% CI, 2.96–3.66) and 2.49 (95% CI, 1.96–3.16), respectively [6].
A meta-analysis study also demonstrated that prediabetes—defined as fasting plasma glucose of 100 to 125 mg/dL, and/or 2-hour post-load plasma glucose levels of 140 to 199 mg/dL following a 75 g oral glucose tolerance test—was modestly associated with an increased risk of stroke compared to individuals with normoglycemia (HR, 1.20; 95% CI, 1.07–1.35) [7].
POST-STROKE OUTCOMES IN PATIENTS WITH DIABETES
Stroke outcomes are generally worse in patients with diabetes, marked by higher recurrence rates, delayed functional recovery, and diminished effectiveness of rehabilitation [3,8]. Patients with ischemic stroke and comorbid diabetes exhibit higher post-discharge mortality rates than those without diabetes [9–11].
Emerging evidence indicates that diabetes is associated with poorer cognitive outcomes following stroke compared to individuals without diabetes. Post-stroke cognitive impairment is common, with approximately 25% to 30% of ischemic stroke survivors developing either immediate or delayed vascular cognitive impairment [12]. Furthermore, studies have demonstrated that individuals with type 2 diabetes exhibit significantly worse cognitive performance 3 to 6 months after an ischemic stroke compared to those without type 2 diabetes [13].
EFFECTS OF STRICT GLYCEMIC CONTROL ON STROKE PREVENTION
Observational studies have indicated that uncontrolled hyperglycemia significantly increases the risk of stroke. For instance, a large Swedish observational study involving around 270,000 individuals with type 2 diabetes identified several predictors of stroke incidence, including smoking, physical activity, marital status, hemoglobin A1C (HbA1c) levels, and statin use. Notably, HbA1c levels emerged as the strongest predictor. The study revealed a linear increase in the HR for stroke as HbA1c levels rose above 7%, suggesting that maintaining HbA1c below this threshold could potentially reduce stroke risk [14]. Similarly, observational studies focusing on type 1 diabetes have shown that higher HbA1c levels are linked to an increased risk of stroke. Specifically, HbA1c levels exceeding 9.7% were associated with an HR of 7.94 (95% CI, 6.29–10.03) for ischemic stroke [6].
However, randomized controlled trials (RCTs) have not consistently demonstrated that strict glycemic control prevents strokes. The UKPDS (UK Prospective Diabetes Study), which involved newly diagnosed type 2 diabetes patients, showed that while intensive glycemic control significantly reduced the incidence of microvascular complications, it did not significantly lower the risk of stroke. The HRs were 1.07 (95% CI, 0.68–1.69) for nonfatal stroke and 1.17 (95% CI, 0.5–2.54) for fatal stroke [15]. Similarly, the DCCT (Diabetes Control and Complications Trial) for type 1 diabetes indicated a reduction in microvascular complications with intensive glycemic control, but it showed no significant decrease in macrovascular complications [16]. In a 10-year follow-up study after the completion of UKPDS, the group that underwent intensive glycemic control displayed significantly lower legacy effects on microvascular complications, myocardial infarction, and all-cause mortality, yet there was no difference in stroke occurrence [17].
Furthermore, subsequent RCTs including ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease—Preterax and Diamicron Modified Release Controlled Evaluation), and VADT (Veterans Affairs Diabetes Trial), explored whether maintaining near-normal, strict glycemic control could prevent macrovascular complications. These studies did not find significant differences in the incidence of major adverse cardiovascular events (MACE) and stroke between groups assigned to strict versus standard glycemic control [8–20]. The ACCORD, ADVANCE, and VADT trials specifically targeted type 2 diabetes patients at high cardiovascular risk, with an average disease duration of approximately 10 years.
However, an observational study spanning 10 years with patients newly diagnosed with diabetes indicated that an HbA1c level of ≥ 6.5% in the first-year post-diagnosis was associated with an increased incidence of macrovascular complications 10 years later [21]. This suggests that stricter glycemic control early in the course of diabetes might reduce the risk of such complications. Conducting long-term RCTs in patients with early-stage diabetes could provide more conclusive evidence.
In summary, maintaining strict glycemic control near-normal levels does not seem to prevent strokes in patients with diabetes. Therefore, the HbA1c target for stroke prevention should be consistent with general guidelines, though a higher target may be recommended for patients with macrovascular complications, including stroke [22]. This target should be tailored to individual factors such as risk of hypoglycemia, duration of diabetes, life expectancy, and existing comorbidities. Special consideration is required for patients with diabetes with a history of stroke, who are frequently older and more susceptible to hypoglycemia.
GLYCEMIC CONTROL DURING ACUTE STROKE
Hyperglycemia is commonly observed during the acute phase of a stroke and is associated with poorer clinical outcomes, regardless of a prior diabetes diagnosis. Several observational studies have linked acute hyperglycemia with larger infarcts, longer hospital stays, reduced functional recovery, and increased mortality [23]. However, there is no definitive evidence that strict glycemic control through continuous intravenous insulin infusion enhances outcomes. A meta-analysis of 11 RCTs revealed no significant differences in mortality or functional recovery between strict glycemic control (72–135 mg/dL) and standard glycemic control during acute ischemic stroke [24]. The recent SHINE (Stroke Hyperglycemia Insulin Network Effort) trial compared strict glycemic control (80–130 mg/dL) to standard glycemic control (80–179 mg/dL) during the acute phase of ischemic stroke. The trial found no significant differences in stroke severity scores, which assess disability at 90 days, or in mortality rates between the two groups. However, the group under strict control experienced higher rates of hypoglycemia [25]. Based on these results, it is recommended to maintain a blood glucose level of 140 to 180 mg/dL during the acute phase, within the first 24 hours post-stroke onset [26].
ANTIDIABETIC MEDICATIONS AND STROKE RISK
Numerous cardiovascular outcome trials have assessed the cardiovascular safety of antidiabetic medications, with a growing interest in those that are effective at preventing macrovascular complications. RCTs have evaluated the cardiovascular safety of thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and insulin analogues. Among these, thiazolidinediones and GLP-1 receptor agonists have shown efficacy in preventing strokes.
Thiazolidinediones
The PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) trial [27], an RCT evaluating the cardiovascular safety of pioglitazone in patients with type 2 diabetes and cardiovascular disease, used a composite primary endpoint comprising all-cause mortality, nonfatal myocardial infarction, ischemic stroke, acute coronary syndrome, revascularization of coronary or peripheral arteries, and above-ankle amputations. The primary endpoint revealed no significant differences between the treatment and control groups. However, a subgroup analysis of patients with a history of ischemic stroke showed a significant reduction in stroke recurrence in the pioglitazone group (HR, 0.53; 95% CI, 0.34–0.85). This effect was not seen in patients without a prior history of stroke [28]. The IRIS (Insulin Resistance Intervention after Stroke) trial investigated the use of pioglitazone in patients with insulin resistance but no diabetes who had experienced an ischemic stroke or transient ischemic attack. The findings indicated that the pioglitazone group had a lower risk of recurrent stroke or myocardial infarction (HR, 0.76; 95% CI, 0.62–0.93) than the control group [29]. These results suggest that pioglitazone may serve as an effective secondary prevention strategy for reducing the risk of recurrent stroke in patients with diabetes or insulin resistance who have had a previous stroke.
GLP-1 receptor agonists
Four GLP-1 receptor agonists—liraglutide, semaglutide, albiglutide, and dulaglutide—have been shown to reduce cardiovascular risk in RCTs. Notably, semaglutide and dulaglutide demonstrated significant reductions in the incidence of stroke in their respective studies.
The SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) trial demonstrated that semaglutide reduced MACE by 26% compared to the control group (HR, 0.74; 95% CI, 0.58–0.95), although mortality rates between the two groups were similar [30]. Notably, the semaglutide group also showed a significantly reduced risk of nonfatal stroke (HR, 0.61; 95% CI, 0.38–0.99). A study on the cardiovascular safety of dulaglutide, REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial, reported significant reductions in both MACE (HR, 0.88; 95% CI, 0.79–0.99) and nonfatal stroke (HR, 0.76; 95% CI, 0.61–0.95) compared to placebo [31]. In the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial [32], liraglutide reduced MACE by 13% (HR, 0.87; 95% CI, 0.78–0.97) and all-cause mortality by 15% (HR, 0.85; 95% CI, 0.74–0.97) compared to placebo. There was a trend toward stroke risk reduction, but this finding did not reach statistical significance (HR, 0.86; 95% CI, 0.71–1.06). The Harmony trial demonstrated that albiglutide significantly reduced MACE (HR, 0.78; 95% CI, 0.68–0.90), although no significant difference was observed in stroke incidence (HR, 0.86; 95% CI, 0.66–1.14) [33]. Similarly, subsequent studies evaluating oral semaglutide [34], lixisenatide (a short-acting GLP-1 receptor agonist) [35], and weekly exenatide [36] did not show significant differences in either MACE or stroke incidence compared to the control group. These findings suggest that long-acting GLP-1 receptor agonists may provide greater cardiovascular and stroke prevention benefits than short-acting agents.
Currently, there is no clinical trial that has specifically investigated the use of GLP-1 receptor agonists for the secondary prevention of stroke in patients with diabetes as a primary endpoint. In post hoc analyses of the LEADER and SUSTAIN 6 trials in subgroups with a history of stroke or myocardial infarction, no significant reduction in the risk of nonfatal stroke compared to placebo were shown.
CONCLUSIONS
Patients with diabetes face a significantly higher risk of stroke and generally experience worse outcomes than individuals who do not have diabetes. Although maintaining glycemic control is crucial, clinical trial data suggest that maintaining near-normal HbA1c levels (e.g., <6.5%) over the long term does not significantly reduce the incidence of stroke. Likewise, intensive glucose-lowering initiated during the acute phase of stroke—typically aiming for blood glucose levels below 130 mg/dL—has not demonstrated improvement in neurological outcomes. Therefore, it is necessary to manage modifiable risk factors to prevent strokes in patients with diabetes. Several glucose-lowering agents, including pioglitazone and certain GLP-1 receptor agonists (semaglutide and dulaglutide), may offer benefits in stroke prevention that are independent of their glycemic effects.
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