In this nationwide cohort study, individuals with type 1 diabetes had a threefold increased risk of being diagnosed with stroke compared with their matched controls from the general population. The risk of stroke was raised in all HbA1c categories, ranging from a 75% increase in the lowest HbA1c category to almost an eightfold increase in risk in the highest category. An effect of HbA1c on the risk of stroke was observed in men and women, for type 1 diabetes patients with a short and long duration of disease and in all three categories of renal impairment. These findings indicate an independent effect of glycaemic control on the risk of stroke. Even type 1 diabetes patients maintaining HbA1c levels within the recommended target [≤6.9% (≤52 mmol mol-1)] and with normoalbuminuria had an increased risk of all strokes because of an increased risk of ischaemic stroke events in this group.

 

Several previous studies have estimated the risk of stroke in type 1 diabetes patients compared with the general population [2-4, 20]. In a study that included participants with a similar age range as in the present study, a comparable incidence rate was observed [3]. The risk of stroke for type 1 diabetes patients as a group has been estimated to be between twofold and fourfold higher than in the general population [3, 20]. To the best of our knowledge, no previous study has estimated the risk of stroke for type 1 diabetes patients at different HbA1c levels and compared this risk with that of the general population.

HbA1c is a well-established risk factor for microvascular complications in type 1 diabetes [9, 21]. In the last decade, an increasing number of studies have shown that HbA1c affects the risk of cardiovascular disease and stroke in type 1 diabetes patients, even though the number of stroke events were often limited [10-12, 22, 23]. The finding in our study of an increased risk of all strokes and ischaemic stroke in type 1 diabetes patients with higher HbA1c levels is consistent with these previous results. The association between glycaemic level and the risk of haemorrhagic stroke is less clear. Recently, Hagg et al. [11] found that HbA1c was not a risk factor for haemorrhagic stroke in type 1 diabetes patients, whereas Secrest et al. [5] reported that HbA1c predicted haemorrhagic but not ischaemic stroke. In present study, there was a 2.5-fold excess risk of haemorrhagic stroke for type 1 diabetes patients as a group compared with controls, and this risk was significantly higher in all but the lowest HbA1c category. Therefore, we found an increased risk of ischaemic and haemorrhagic stroke with higher HbA1c levels in type 1 diabetes patients.

 

Blood pressure is an important risk factor for stroke in type 1 diabetes patients [11], but the difference in average blood pressure between the highest and lowest HbA1c category was comparatively minor (2.4 mmHg for systolic and 3.0 mmHg for diastolic blood pressures). The proportion of type 1 diabetes patients receiving antihypertensive treatment was 15% in the lowest HbA1c category, but approximately the same (21–25%) in all higher HbA1c categories. Additionally, in the analysis within the type 1 diabetes group, we were able to adjust for systolic blood pressure and still found an effect of HbA1c level on the risk of stroke (Table 3, model 4). Therefore, we believe that blood pressure level might explain some, but not all, of the increased risk of stroke with higher HbA1c category.

 

Previous studies have demonstrated that diabetic nephropathy is a predictor of stroke [5, 6]. In the present study, the risk of all strokes, and stroke subtypes, within the same HbA1c category gradually increased with worse renal impairment category (Fig. S2 and Table S6), which is in line with previous findings [5, 6]. The effect of HbA1c on the risk of haemorrhagic stroke for type 1 diabetes patients with normoalbuminuria was weaker than that for ischaemic stroke. Only type 1 diabetes patients with normoalbuminuria and HbA1c in the highest category ≥9.7% (≥83 mmol mol-1) had a significantly increased risk of haemorrhagic stroke compared with control subjects. For ischaemic stroke, the risk was significantly increased in all HbA1c categories for type 1 diabetes patients with normoalbuminuria. Further studies are needed to elucidate the relationships between diabetes, glycaemic control and subtypes of stroke in individuals with type 1 diabetes.

The most important strengths of the present study are the large number of individuals with type 1 diabetes and the presence of a control group from the general population. The size of the study population provided a larger number of strokes, both haemorrhagic and ischaemic, than in any previous study. Additionally, repeated measurements of several important characteristics in individuals with type 1 diabetes were available, as well as information on comorbidities and educational level for both control subjects and diabetes patients. However, there are also limitations that need to be considered. First, only stroke events leading to hospitalization or death outside hospital were captured. A recent study in Sweden showed that stroke awareness did not differ between patients with diabetes and individuals without regular healthcare contacts [24]. Therefore, we believe that the proportion of potential missed cases due to not seeking medical care should be the same between control subjects and individuals with diabetes. Secondly, no risk factor data other than demographic characteristics and comorbidities were available for the controls. HbA1c values were not available for the control subjects but those with diabetes were excluded. Given the relatively young age of the population, the numbers of undiagnosed cases of type 2 diabetes and of individuals in the prediabetic state with higher HbA1c should be very small amongst the controls, and accordingly the HbA1c level of the controls should be close to normal. Blood pressure, smoking and AF are important risk factors for stroke. However, mean blood pressure was not raised in individuals with type 1 diabetes and the proportion of participants with AF was similar to that of controls. The proportion of smokers amongst individuals with type 1 diabetes might be slightly lower than that in the general population. Accordingly, information on these variables is unlikely to have altered our results decisively. Thirdly, the diagnoses of haemorrhagic and ischaemic stroke were not formally validated, but computed tomography scans are routinely used in suspected stroke cases in Sweden, which should minimize misdiagnosis. In our study 14% of the strokes amongst type 1 diabetes patients were haemorrhagic. This is somewhat lower than was found for example by Hägg et al. [11]. However, we have not included subarachnoid haemorrhage in our study due to a different and more specific pathology. Additionally, the proportion of haemorrhagic strokes relative to all strokes differs between countries [25]. A previous study on the subtypes of stroke in Sweden demonstrated that 12% of the strokes were haemorrhagic (excluding subarachnoid haemorrhage) [26]. Therefore we believe our figures reflect the true proportion of haemorrhagic strokes amongst type 1 diabetes patients in Sweden. Fourthly, during the first years of the study not all hospitals in Sweden reported to the NDR. The coverage rose to approximately 50% of all type 1 diabetes patients in 2003 and to approximately 90% in 2013. However, hospitals report all their diabetes patients, both well and poorly controlled, to the NDR. Furthermore, a small number of patients with diabetes not registered in the NDR could be included amongst the controls during the first years of the study, potentially attenuating the effect of HbA1c level. Taken together, even though the coverage of the NDR was not complete during the first years of the study this should only have a minor effect on our results. Finally, as in all observational studies, we cannot definitively eliminate the possibility of residual confounding.

 

Individuals with type 1 diabetes have an increased risk of ischaemic and haemorrhagic stroke compared with the general population even when HbA1c levels are within target, and the risks are markedly increased with worse glycaemic control. Accordingly, continuous efforts to improve glycaemic control in individuals with type 1 diabetes are of major importance to protect this group against a disease with potentially devastating effects on daily life.

 

No conflict of interest to declare.

 

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