In this large cohort study, we found that about 11.6% of the patients with CAS developed diabetes during a mean follow-up of 6.2 years. During the entire follow-up period, the respective annual incidence of diabetes was 2.22% in the CAS group and 1.39% in the control group. The median time to incident diabetes, which did not vary by sex, was 2.9 and 3.5 years in the CAS and the control groups, respectively. CAS was a risk factor for incident diabetes regardless of sex and the length of follow-up. Although age did not affect the risk of incident diabetes associated with CAS, the risk was less apparent in the subgroups of males and patients with dyslipidemia, COPD, stroke, gout, and medicated hypertension. CAS patients aged <50 years compared with patients ≥50 years had a greater risk of incident diabetes in females, but not in males. On the other hand, older male CAS patients compared with their younger counterparts developed diabetes in a shorter length of time. In contrast, this age phenomenon was not observed in the female CAS patients <50 years.
The sex-specific annual incidences of diabetes in CAS patients was 2.16% in males and 2.26% in females, which has not been reported previously. The annual risk of developing diabetes in people with normal glucose level is 0.7%, whereas patients with prediabetes have a yearly risk of up to 10% . While the prevalence of fasting post-stroke hyperglycemia is 14.6% in non-diabetic stroke patients , about 8% of non-diabetic stroke survivors develop diabetes during a mean follow-up of 10 years , which is more than 2 times higher than expected compared with people from a Dutch general practitioner registry with similar age and sex . Taken together, patients with cardiovascular events have an increased risk of incident diabetes. Furthermore, insulin resistance is the earliest metabolic abnormality detected in subjects destined to develop diabetes , and precipitously increased with HbA1c levels >5.5%. Although the higher short-term risk of developing diabetes among CAS patients than controls may be attributed to earlier medical attention, the CAS patients in our single hospital study had an average glycated hemoglobin level 5.8%, which are considered high-risk for diabetes by the American Diabetes Association . On the other hand, insulin resistance and atherosclerosis could represent independent responses to the disruption of cellular homeostasis . Inactivation of the insulin receptor decreases mouse atherosclerosis lesions [30, 31], which become more complex at later time points [30, 31], suggesting that insulin resistance could have differential adaptive effects on CAS and atherosclerotic obstructive coronary artery disease.
The age-associated incidence of CAS-related diabetes was similar to previous studies in patients after stroke  and the general population . However, age did not affect the risk of CAS-related incident diabetes, suggesting that CAS may be a stronger modulating factor than age for incident diabetes. Sex differences in risk of incident diabetes arise from sociocultural processes, such as stress , which has a greater impact on incident diabetes in females than males . Therefore, the sex differences in CAS-related diabetes result from the effects other than hormones. Furthermore, when glucose tolerance deteriorates, insulin sensitivity in women is reduced more dramatically than in men , contributing to the higher risk of incident diabetes in females than males with CAS, which may partly explain why women show better insulin sensitivity if they are normoglycemic . Although dyslipidemia contributes to acquired insulin resistance , dyslipidemia did not increase the risk of diabetes in CAS patients, which may be due to the more important role of the reciprocal relationships between impaired insulin-stimulated blood flow and glucose uptake  than dyslipidemia in CAS. While COPD with associated insulin resistance has been demonstrated to be a risk factor for incident diabetes , CAS had a higher risk of incident diabetes in patients without COPD than with COPD, suggesting that impaired lung function in CAS does not increase the risk of diabetes. Previous studies showed that more than half of non-diabetic stroke patients have pre-diabetes 3 months after stroke . However, the risk of incident diabetes was higher in CAS patients without stroke than with stroke when impaired glucose metabolism in the acute stress period should have subsided, suggesting that it is a reflection of unrecognized incident diabetes and not caused by stress of the acute phase of cardiovascular events. Although gout contributes to insulin resistance and increased levels of CRP , gout did not increase the risk of CAS-related diabetes. Hence, CRP could be an epiphenomenon in the development of CAS-related diabetes. While hypertension is less closely associated with insulin resistance than are other metabolic abnormalities , the antihypertensive treatment improves both insulin sensitivity and endothelial function . Therefore, the risk of diabetes was more apparent in CAS patients without hypertension or with non-medicated hypertension than in CAS patients with medicated hypertension. Taken together, the increased risk of incident diabetes associated with CAS was more apparent in females aged <50 years and patients without dyslipidemia, COPD, stroke, gout or medicated hypertension. Prospective studies are needed to examine this hypothesis.
While the incidence of diabetes in the general population reaches the highest rates in the very old females , CAS patients aged <50 than ≥50 years have a greater risk of incident diabetes in females but not in males, which seems to be related to sex differences in pre-diabetes . Moreover, the essential interaction between estrogen receptor α and caveolin-1 for localization of estrogen receptor to the plasma membrane in endothelial cells  may be abrogated in CAS because increased Interleukin-6 levels inhibit endothelial nitric oxide synthase activation by increasing endothelial nitric oxide synthase binding to caveolin-1 in vascular endothelial cells . Although the complex interactions between insulin resistance, hyperglycemia and estrogen impairs the endothelial response in females more dramatically than in males , as age reduces the benefits of estrogen on insulin-mediated glucose disposal  in females, sex differences are reduced. Our data suggest that the sex-specific effects of CAS attenuate the protective effect of female sex, leading to a higher risk of incident diabetes in females than in males.
Consistent with a previous study showing that the rate of onset of diabetes was greater for men than for women , the median time to CAS-related incident diabetes was slightly earlier in males rather than females. Moreover, insulin resistance occurs with aging . Thus, older rather than younger males with CAS may be less sensitive to insulin, leading to a shorter length of time in developing diabetes. However, age did not reduce the time to incident diabetes in CAS females aged <50 years, suggesting a protective role for premenopausal estrogen against incident diabetes. Although we did not perform any analyses of lifestyle or dietary habits among CAS patients, these factors could be key variables that could affect the length of time before incident diabetes develops between males and females with CAS. Because the early onset of diabetes is associated with a more aggressive diabetic course, a better understanding of the potentially modifiable precursors to cardiometabolic disease, such as CAS, is essential.