Tapan Mehta, MBBS, MPH
Aneurysmal subarachnoid haemorrhage (aSAH) is a medical emergency with a grim epidemiological profile. In spite of advancement in its diagnosis and management, mortality remains as high as 50%, and half of the patients affected are under the age of 50 years. In attempting to identify risk factors, there has been an increasing interest in association between diabetes mellitus and aSAH. Several studies have stated that diabetes mellitus may have a protective effect on aSAH; however, owing to their methodological flaws and lack of a supportive biological plausibility, the association remains unclear. Also, in previous studies, there is inconsistency in diagnostic testing of diabetes mellitus and lack of reliability of blood glucose level measurements as a measure of long-term glucose control. To explore the association between chronic hyperglycemia and risk of aSAH, in their study, Can et al tested the hypothesis that regardless of the self-reported diagnosis of diabetes mellitus, higher HbA1c values increase the risk of rupture of intracranial aneurysms and that the use of antihyperglycemic agents is protective against rupture. This study contributes to existing literature through its strengths over previous studies, which include adjusting for confounding risk factors hypertension and smoking, use of a large sample size, and use of HbA1c instead of blood glucose measurement as an indicator of blood glucose control in the patient population.
The study analyzed data collected by medical chart review of 4701 patients who were diagnosed with an intracranial aneurysm between 1990 and 2016 at the Brigham and Women’s Hospital and Massachusetts General Hospital. Patients were identified both prospectively on clinical presentation (2007–2016) and retrospectively using natural language processing in conjunction with the Partners Healthcare Research Patients Data Registry covering the two hospitals. Based on imaging studies, patients with possible infundibulum or non-definitive diagnoses of aneurysms, feeding artery aneurysms associated with arteriovenous malformations, fusiform or dissecting aneurysms, those lacking clinical notes or radiographic images, and patients who received treatment of their aneurysm(s) before presentation were excluded. Cases in the ruptured aneurysm group were defined as those who presented with aSAH. The diagnosis of aSAH was confirmed with a computed tomographic scan, cerebrospinal fluid analysis, or intraoperatively by a neurosurgeon. Apart from demographic variables, data included presence of comorbidities (hypertension, myocardial infarction, and atrial fibrillation), number and maximum size of intracranial aneurysms, family history of aneurysms or family history of SAH, information on current tobacco and alcohol use, HbA1c values within 1 year of diagnosis, and use of antihyperglycemic agents. Using Stata, baseline characteristics were compared between the two groups, i.e. ruptured vs. unruptured aneurysm. Univariate and multivariate logistic regression models were implemented to test for effects because of antihyperglycemic agents and HbA1c values, with a backward elimination procedure to identify significant confounders.
A total of 4701 patients with 6411 aneurysms were included, of whom 1302 (27.7%) were ruptured. In general, patients on antihyperglycemic agents were significantly older, more frequently men, black or Hispanic, and less frequently white. In addition, patients on antihyperglycemic agents were significantly more frequently diagnosed with hypertension and myocardial infarction, whereas significantly less frequently current alcohol users. HbA1c values were significantly higher in patients on antihyperglycemic agents.
In weighted multivariate analysis, black race (OR, 2.56; 95% confidence interval [CI], 1.73–3.77), Hispanic race (OR, 1.32; 95% CI, 1.42–3.79), Asian race (OR, 3.82; 95% CI, 1.37–10.65), other race (OR, 2.47; 95% CI, 1.34–4.58), current alcohol use (OR, 1.22; 95% CI, 1.05–1.40), and current tobacco use (OR, 2.12; 95% CI, 1.57–2.86) were significantly associated with aneurysmal SAH. In contrast, female sex (OR, 0.76; 95% CI, 0.58–0.92), age at diagnosis (OR, 0.99; 95% CI, 0.98–1.00), family history of aneurysms (OR, 0.51; 95% CI, 0.39–0.66), and antihyperglycemic agent use (OR, 0.57; 95% CI, 0.34–0.96) were significantly associated with a lower rupture risk. HbA1c values were not significantly associated with rupture. In subgroup analysis using complete prospective cases only, antihyperglycemic agent use was not statistically significant, albeit the direction of effects was similar.
A major limitation includes lack of data on duration of antihyperglycemic medication use. Factors including aneurysm morphology and location, which are also proven to be important risk factors for rupture, were not included in the study.
Hyperglycemia can lead to vascular endothelial damage and dysfunction, as well as decrease in cerebral tight junction protein expression. Both of these processes have been implicated in intracranial aneurysm pathogenesis. Hyperglycemia has been associated with activation of proteolytic matrix metalloproteinase 9 (MMP9), which has proteolytic activity against connective tissue proteins and is involved in inflammation and tissue remodeling. Increased levels of MMP9 have been found in abdominal and intracranial aneurysms. Studies in mice models have shown that treatment with antihyperglycemic agents, such as metformin, insulin, and glibenclamide, results in MMP9 inhibition, suggesting that antihyperglycemic agents use may affect the risk of aneurysm rupture directly rather than solely via reduction of blood glucose. In congruence with these lab research findings, Can et al also found that modern antihyperglycemic agents were more frequently used by patients with unruptured aneurysms compared with patients with ruptured aneurysms. However, the difference in effects of class-specific antihyperglycemic medications based on their mechanism of action was beyond the scope of this study, and can be explored in future research.
Non-invasive treatment for prevention of aneurysm rupture could have paramount impact on reduction of morbidity and mortality burden related to aneurysmal subarachnoid hemorrhage. The Can et al article provides a strong argument for investigating the effect of antihyperglycemic medications on intracranial aneurysms in clinical trial settings.