In the present study, we observed a positive and independent association between ACR and poor prognosis at 3 months, this association not influenced by the presence of diabetes. When categorizing into 3 ACR tertiles, we observed that being in the 3rd ACR tertile was also associated with a poor prognosis.

Acute hyperglycemia is, as previously mentioned, a frequent condition in neurological patients both with and without diabetes, and is related to a worse clinical prognosis [14, 15]. In this respect, the acute dysregulation in glucose metabolism can be evaluated using diverse parameters, including fasting glucose, admission random glucose, maximum glucose during the acute stage or HbA1c [16, 17]. Following this line, Sung et al. [18], focused on neurological patients and compared admission glucose, FBG and HbA1c in predicting neurological outcomes in subjects with AIS diagnosis. They concluded that fasting glucose was an independent predictor of poor neurological outcomes and had greater predictive power than that of admission glucose and HbA1c, not differing between subjects with and without diabetes. On the contrary, Roquer et al. [19] in 2015 published a study based on similar population cohort as the present study and observed that baseline glucose correlated with stroke severity in nondiabetic and diabetic patients with good previous glucose control (HbA1c < 7%), but not in those with poor glucose control (HbA1c > 7%).

Recent indexes and ratios have been established to further evaluate stress hyperglycemia, thus taking into account both acute and chronic glucose control [9, 20]. These include the previously mentioned ACR, or others such as the stress hyperglycemia ratio (SHR) or FBG / HbA1c ratio [8]. It has been hypothesized that they could play a more relevant role as outcome-predictive factors than only glucose values or HbA1c separately.

Considering neurological patients, to the best of our knowledge, the present study is one of the first to evaluate ACR as an outcome predictor after AIS diagnosis, confirming its relationship with a poor outcome and mortality at 3-month follow-up. Moreover, baseline NIHSS was also one of the observed mortality predictive factors. In this same line, a recent study including a total of 335 subjects with diabetes and AIS diagnosis specifically focused on the correlation between ACR and illness severity [12]. Despite the limited number of patients included, interestingly, when stratifying patients according to admission NIHSS, no differences were found in fasting glucose, admission glucose or HbA1c levels, although ACR was significantly different, hence highlighting the possible superiority of ACR as an outcome predictive factor in comparison to the other glycemic variables for separate. Another recent publication also observed a correlation between increased ACR and poor outcomes. However, in this publication, only 18.1% percentage of the subjects included had a previous diabetes diagnosis [21], in comparison to almost 35% of subjects with previous diabetes diagnoses in the present study. Age was positively associated with a poor prognosis at 3 months while revascularization therapy was found to be a protective factor, in accordance with previous publications [18]. Moreover, it is worth highlighting that, in the present study, despite less than 40% of the included subjects having diabetes diagnosis before admission, the imbalance between acute and chronic glycemic control continued to be an outcome-predictive factor during follow-up. A very recent study [22], in this case evaluating the FBG/ HbA1c ratio and not ACR, observed this ratio to be associated with more severe AIS. Specifically, the glucose-to-HbA1c ratio was associated with functional outcomes in patients without diabetes but not in patients with diabetes. These results highlight the importance of stress hyperglycemia in subjects with AIS diagnosis, even in the absence of an alteration in glucose metabolism before hospital admission.

The present study also divided the included patients according to 3 different ACR tertiles. It was observed that being included in the 3rd ACR tertile (> 1.13), increased the risk of a poor outcome by 62% and mortality by 88%. Hence, these results emphasize the fact that presenting a glucose level at admission 13% higher than expected has a detrimental effect on AIS prognosis. Following this same line, several previous publications also observed an association between glucose / HbA1c ratios and clinical outcomes in both patients with and without diabetes diagnosis [16, 17, 23, 24] although most of them did not categorize into different tertiles.

Moreover, since those subjects included in the top tertile present an increased risk of poor prognosis, it seems plausible to think that this subgroup of patients could benefit from a more intensive insulin therapy. However, it must be considered that, as observed in previous publications focused on critical patients [25, 26], a more intensive glucose control can also be associated with an increased mortality risk, secondary to a higher hypoglycemia rate. Hence, if we want to normalize acute high glucose levels of the 3rd ACR tertile group without increasing the presence of hypoglycemia, a precise blood glucose monitoring system seems essential. In this regard, the use of continuous glucose monitoring (CGM), which can continuously and automatically provide instant blood glucose values together with pre-specified hyper and hypoglycemia alarms, could play an important role in glucose management in these patients, as has previously demonstrated in intensive-care unit (ICU) patients [27]. Thus, combining intensive insulin therapy with CGM to fight stress hyperglycemia in the 3rd ACR tertile group in clinical daily practice could presumably have a direct effect on the patient’s prognosis in the short-term after AIS diagnosis.

Finally, the present study went one-step further, analyzing the possible clinical relevance of ACR in this subgroup of neurological patients. In this respect, it must be acknowledged that, although several scores have been defined to evaluate global cardiovascular risk [28, 29], to date no risk score has been specifically defined for stroke patients. Owing to all this, we created a model which included classical risk factors for neurological patients such as age, gender, diabetes, dyslipidemia, revascularization treatment, history Rankin and baseline NIHSS. This classical model obtained an AUC of 0.781 in the ROC curve, without a significant increase in the AUC when baseline glucose or ACR were included in the model. Hence, although the results in the present study are encouraging as they observe a significant and independent association between ACR and poor prognosis in the short term after AIS, the clinical relevance of this ratio still needs to be further defined.

This study is not without limitations. The study was realized in a single center, and hence this may limit the extrapolation of the results. Moreover, a retrospective analysis was realized. The relative short period of follow-up must also be taken into account, together with the possible presence of other confounding factors that could have affected the final results. Finally, diabetes diagnosis was defined using different variables, including previous medical history or use of hypoglycemic medication, but laboratory results of glucose values or HbA1c to confirm diagnosis were not available for all the included subjects.