Published online before print March 1, 2007, doi: 10.1161/01.STR.0000260100.71665.2f
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(Stroke. 2007;38:1154.)
© 2007 American Heart Association, Inc.
Original Contributions |
Incidence and Risk Factors for Stroke in Type 2 Diabetic Patients
The DAI Study
From Metabolism and Diabetes Unit (C.B.G.), ASL 8, Regione Piemonte, Chieri, Italy; Division of Metabolic Diseases (A.A.), University of Padova, Italy; National Institute of Health (M.M., F.L., S.S.A., R.R.), Rome, Italy; University of Florence and Azienda Ospedaliera Careggi (E.M.), Florence, Italy; Federico II University (S.T.), Naples, Italy; Casa di Cura Pineta del Carso (M.V.), Aurisina, Trieste, Italy; University of Pisa School of Medicine (E.F.), Pisa, Italy.
Correspondence to Dr Carlo Bruno Giorda, Metabolism and Diabetes Unit, ASL 8, Via De Maria, 1 10023 Chieri (TO), Italy. E-mail giordaca{at}tin.it
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Abstract |
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Background and Purpose— Type 2 diabetes mellitus is a strong predictor of cerebrovascular disease, yet few studies have assessed the incidence of stroke and the role of other risk factors in unselected type 2 diabetes mellitus populations.
Methods— We prospectively followed-up 14 432 type 2 diabetes mellitus patients, aged 40 to 97 years, with and without a history of cardiovascular disease at enrollment, and we estimated the incidence of stroke and the hazards ratios with respect to clinical variables.
Results— During a 4-year follow-up, 296 incident stroke events were recorded. In persons with no history of cardiovascular disease, the age-standardized incidence of stroke (per 1000 person-years) was 5.5 (95% confidence interval, 4.2 to 6.8) in men and 6.3 (95% confidence interval, 4.5 to 8.2) in women. In persons with a history of cardiovascular disease, it was 13.7 (95% confidence interval, 7.5 to 19.8) in men and 10.8 (95% confidence interval, 7.3 to 14.4) in women. The hazards ratios of stroke incidence varied according to age, sex, and history of cardiovascular disease. Among men with no history, HbA1c and smoking were predictors of stroke. Among patients with a history, the risk factors were, in men, therapy with insulin plus oral agents, treated high total cholesterol and low HDL cholesterol, whereas in women microvascular complications were a risk factor. Previous stroke was a strong predictor of stroke in both sexes.
Conclusions— Age and previous stroke are the main predictors of stroke in diabetes. The combined role of Hba1c, microvascular complications, low HDL cholesterol, and treatment with insulin plus oral agents highlights the importance of diabetic history and clinical background in the development of stroke.
Key Words: diabetes mellitus • epidemiology • risk factors
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Introduction |
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Comparisons of epidemiological data on diabetic and nondiabetic subjects in the general population have clearly demonstrated that type 2 diabetes mellitus (T2DM) is an independent risk factor for ischemic stroke.1–5 For example, in the Framingham Study, the incidence of nonhemorrhagic stroke has been found to be from 2.5- to 3.5-times higher among diabetic than among nondiabetic subjects.6 Furthermore, it has recently been proposed that, for women, diabetes be considered a cardiovascular disease risk equivalent for fatal stroke, in that the incidence of a first stroke is similar to the incidence of relapse among nondiabetic women.7 Although it can be hypothesized that there is an interaction of various atherogenic factors (eg, hypertension and coagulative, hemorheological, and lipidic alterations), which characterize T2DM and which could make the risk of stroke in these patients different from that in nondiabetic subjects, little is known about the incidence of stroke among diabetic patients.
The clinical history of diabetes and its systemic involvement could play an important role in the development of cerebrovascular complications. In the UKPDS study, stroke in diabetic subjects was prospectively evaluated with predictive formulas,8 yet the study population consisted of patients with newly diagnosed diabetes selected with criteria typical to clinical trials. Apart from analyses on middle-aged cohorts,5 relatively few prospective studies on cerebrovascular complications among diabetes patients older than 65 years of age have been published.
Compared with other European countries, Italy is unique in terms of diabetes care, in that there exists a network of 
700 public diabetes care units that provide care for up to 80% of known patients,9 performing such services as diagnostic confirmation, therapy, prevention, and the early diagnosis of acute and chronic complications through close follow-up of the patient by a team of specialists and the scheduling of regular check-ups. Most patients are referred to these care units by their general practitioner and care is free of charge.
The objective of the present study was to describe the incidence and the risk factors for stroke in T2DM patients, including elderly persons, who receive standard care on a regular basis at diabetes care units in Italy.
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Methods |
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The present analysis was conducted as part of the DAI Study, a multicenter cohort study on the prevalence and incidence of cardiovascular events among T2DM patients (myocardial infarction, ischemic heart disease, coronary artery bypass, coronary angioplasty, cerebral thromboembolism, and peripheral amputations). In the present work, we report the results of the incidence study. A detailed description of the DAI study methods has been reported elsewhere.10,11 A brief description is provided here.
The DAI study was begun in September 1998 by the Istituto Superiore di Sanità (the Italian National Institute of Health) together with the Italian Association of Clinical Diabetologists (AMD) and the Diabetes and Informatics Study Group (DIAINF). In 1998, 201 diabetes care units volunteered to participate. To encourage participation, data collection was limited to routine data. These care units are distributed throughout Italy and represent 29% of the existing units in Italy, comprising 19 570 patients. The DAI study population consisted of all patients with T2DM diagnosed after 39 years of age, according to the 1985 criteria of the World Health Organization,12 who visited the participating care units in the 2 enrollment periods (between September and December 1998, and from March to June 1999). In each unit, patients were chosen to create a sample representative of the diabetic population seen at the units. A systematic sampling technique, including in the cohort every fourth patient, was used.
A total of 201 care units voluntarily participated in the prevalence study. In the incidence study described herein, 157 of the 201 units participated, for a total of 14 432 diabetic patients (7214 men and 7218 women). At baseline, 2788 patients (1602 men and 1186 women) had a history of cardiovascular disease complications.
Data Collection and Definitions
The data used in this analysis was collected in 4 waves of follow-up in the period 2000 to 2003. All of the diabetes units participated at the first follow-up, 120 at the second, 97 at the third, and 77 at the fourth. During the baseline and follow-up visits, a standard questionnaire was used to collect the following information: personal data and life habits; anthropometric data; drug therapy; laboratory data (specified here); clinical history and data on complications (retinopathy, blindness, and foot ulcer); and data on cardiovascular complications. For patients who did not show up for the scheduled visits, information, including death, was obtained through telephone interviews with the patient, a relative, or the treating physician.
The following tests were performed at baseline and at each follow-up visit. Plasma glucose, HbA1c, and lipid profile were determined in fasting state. HbA1c was measured by each unit laboratory, and not by a centralized one. For this reason, for each patient the relative difference between the observed value and the upper limit of the normal range of the care unit was calculated. Urinary albumin excretion was obtained in a timed overnight collection: microalbuminuria was defined as urinary albumin excretion of 30 to 300 mg/L in at least 3 successive measurements, in the absence of other factors capable of causing proteinuria. A patient was defined as "hypertensive" if systolic blood pressure was 
140 mm Hg or diastolic blood pressure was 90 mm Hg, or if the patient was undergoing antihypertensive treatment. Retinopathy was assessed by a dilated and comprehensive eye examination and by the acquisition of high-quality stereoscopic photographs assessed by an ophthalmologist. Family history of cardiovascular disease was defined when the patient had a first-degree relative (parent, sibling, child) who had had a major cardiovascular event before 55 years of age. Alcohol consumption was calculated in equivalent mL of wine, taking into account the daily consumption of wine, hard alcohol (mL x4), liqueurs (mL x2), and beer (mL x0.5).
Cardiovascular Events
Stroke was defined according to WHO criteria for confirmed and possible stroke (ie, a clinical syndrome consisting of a rapid developing neurological deficit and persisting for >24 hours, or leading to death, in the absence of other diseases that could explain the symptoms). A hospital discharge record or a specialist visit was required to certify the event.
Other study events were myocardial infarction, coronary heart disease, coronary artery bypass, coronary angioplasty, and peripheral amputations.
The presence of coronary heart disease was assessed by documented clinical data and by ECG. Patients were classified as having coronary heart disease if they had one of the following: hospitalization for either fatal or nonfatal acute myocardial infarction or an episode of angina; positive 12-lead ECG for previous acute myocardial infarction or angina coded using the Minnesota coding system (criteria I, 1 to 3; IV, 1 to 3; V, 1 to 2; and VII, 1), history of coronary artery bypass graft, and percutaneous transluminal coronary angioplasty. Ninety-eight percent of patients had at least one ECG in the 12 months preceding enrollment to certify the absence of infarction.
Statistical Analysis
Based on the presence of cardiovascular disease at baseline, 2 cohorts were identified. Cohort A consisted of persons with no history of cardiovascular disease. Cohort B consisted of persons with previous cardiovascular disease. The analyses were performed separately for the 2 cohorts. The outcomes considered in the analysis were a first fatal or nonfatal stroke. All of the patients were followed-up from the baseline visit to the first of the following events: stroke (or any cardiovascular event in cohort A, because in this cohort the objective was to estimate the incidence of first stroke not preceded by any cardiovascular event), death, or the end of participation of the unit, or end of the study. Patients for whom no information was available at any of the follow-up waves (n=2062) were considered as lost to follow-up and were included in the cohort until the last available visit or proxy information.
Data are expressed as mean (±standard deviation) or median (and interquartile range) for continuous variables and as proportions for categorical variables. The incidence density of stroke was standardized based on the age distribution of the 1998 Italian population. Kaplan–Meier curves were used to construct the cumulative 4-year incidence of stroke. Univariate and multivariate Cox proportional hazard models were used to examine the risk factors for stroke. Preliminary data analysis was performed by univariate Cox proportional hazard models of all covariates, measured at the baseline visit (Table 1). Analyses were conducted separately for men and women, adjusting by age at baseline. The interaction between cholesterol level and anti-hyperlipidemic therapy and between blood pressure and anti-hypertensive therapy was tested. All covariates for men and women with P<0.1 (P
0.05 in cohort B, given the smaller sample size) were entered in the final multivariate models, performed separately for men and women (Table 2). The proportional hazards assumption was checked with Schoenfeld residuals; the results were checked using a stepwise technique. All variables were entered into the model without transformation, although the quadratic term for continuous covariates was first considered and assessed with the likelihood ratio test. All analyses were performed using the Stata 8.0 statistical package.
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Results |
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Table 1 summarizes the baseline characteristics for men and women, including a description of the cardiovascular disease in cohort B. The study population consisted of a high proportion of elderly patients with visceral adiposity. The most common cardiovascular risk factor was systolic hypertension, which was found in almost all patients. A high percentage of patients were undergoing treatment, especially those with a previous cardiovascular event (cohort B). These characteristics match those reported in a recently published survey of 140 000 diabetes patients in Italy.14
Compared with men, women, especially those with cardiovascular disease, had worse lipid profiles (ie, total cholesterol, high-density lipoprotein, triglycerides) and were less likely to be treated with lipid-lowering drugs. As expected, the average metabolic control was fair, confirming other reports of good average HbA1c levels in Italian T2DM patients receiving care at diabetes care units.14 The specific cardiovascular events were those typical to diabetes patients; specifically, the most common events were acute myocardial infarction and coronary heart disease (with acute myocardial infarction more frequent among men and coronary heart disease more frequent among women), followed by stroke, which was more frequent among women. The percentage of patients who smoked was 30% less than that for Italy’s general population.15
During the follow-up period, a total of 296 strokes were documented (188 in cohort A and 108 in cohort B). The crude cumulative risk for the 2 cohorts is shown in Figure 1. In cohort A, the age-standardized incidence rate per 1000 person-years was 5.5 (95% confidence interval, 4.2 to 6.8) in men and 6.3 (95% confidence interval, 4.5 to 8.2) in women; in cohort B, it was 13.7 (95% confidence interval, 7.5 to 19.8) in men and 10.8 (95% confidence interval, 7.3 to 14.4) in women.
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The multivariate analysis model for cohort A is shown in Table 3. In men, age, HbA1c, and smoking were independent predictors of first stroke. In women, independent predictors were age and microvascular complications.
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The multivariate analysis model for cohort B is shown in Table 4. In men, the predictors of stroke were age, insulin therapy in combination with oral agents, previous stroke, and treated high cholesterol levels. Because in this cohort it had already been demonstrated that individuals with high cholesterol had a greater likelihood of receiving aggressive lipid-lowering therapy as standard care,15 we determined the percentage of statin-treated patients (categorized into tertiles by total cholesterol) in the years after the baseline evaluation: the incidence of treatment was 11.9% in the lower tertile (189 mg/dL), 17.4% in the middle tertile (190 to 224 mg/dL); and 33.2% in the upper tertile (225 mg/dL; P<0.01). In women with previous cardiovascular disease, the predictors of stroke were age, low high-density lipoprotein cholesterol, microvascular complications, and previous stroke (hazard ratio, 3.1; 95% confidence interval, 1.7 to 5.5).
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Discussion |
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The age-adjusted incidence of stroke found for this large cohort of diabetic subjects confirms that stroke is an important complication among diabetic subjects. Compared with the nondiabetic population, the incidence is from 2- to 3-times greater.16 A particularly high incidence (approximately double) was found for patients with previous cardiovascular events, compared with patients with no history of cardiovascular disease, which, to the best of our knowledge, is the first such finding.
In our study, age was found to have played an important role in the occurrence of both a first stroke and relapse. Although this is not a new finding for the general population,17 this is the first time that it has been shown in a clear manner in a cohort of diabetic subjects not selected for age18,19 Among men with no history of cardiovascular disease, blood glucose control at enrollment was predictive of stroke. In other studies,4,5 the association was reported for high cut-off levels, exceeding 10% of Hba1c; in our study, each 20% increment above the normal glycohemoglobin levels, corresponding to 1% point of Hba1c, was significant. This finding is consistent with a previous report,20 and with regard to prevention it stresses the importance of strict metabolic control in the daily routine of these patients.
Microvascular complications, retinal lesions, microalbuminuria, and proteinuria, which were significantly associated with stroke among women, have been described as factors that are predictive of cardiovascular and cerebrovascular morbidity and mortality among diabetic subjects.21 Given that these complications are correlated with a history of poor blood glucose control, they may also be an indication of the effect of diabetes over time on the occurrence of stroke. The harmful affects could be explained not only by endothelial damage but also by factors such as hypertension, which is often triggered by kidney damage.
The significant increase in the hazard ratio for therapy with insulin plus oral agents in men with previous cardiovascular disease should be carefully considered. It is not rare that in observational studies, because of what can be defined as "indication bias," drug therapy,22,23 particularly insulin therapy,24,25 has been found to be associated with a worse cardiovascular prognosis. However, in clinical trials, intensive treatment has been observed to have an anti-atherogenic effect.26 In our study, it is more plausible that therapy with insulin plus oral agents was a proxy of severity and of the clinical course of the disease. In a recent national survey, patients undergoing this treatment showed the worst metabolic control.13
The significant hazard ratios for Hba1c in men, for microangiopathic vascular complications in women, and for therapy with insulin plus oral agents are difficult to explain, yet these combined factors as a whole highlight the role of diabetic history and clinical background in the development of stroke. Surprisingly, hypertension was not found to have been associated with stroke. Again, because the study population was not selected (with a very high proportion of hypertensive elderly persons), age and the weight of diabetes itself may have attenuated the emergence of other risk factors that were found for younger cohorts.5,28 Furthermore, it cannot be excluded that the high percentage of patients undergoing hypertensive treatment attenuated the role of hypertension.
In patients with a history of cardiovascular disease, the history of a previous stroke was a strong risk factor for relapse, confirming that arteriopathy, once established, tends to worsen and that relapses occur independently of other factors. To our knowledge this is the first time this relationship has been reported for diabetic subjects. With regard to lipids, the role of reverse cholesterol transport was highlighted by the consistently favorable effect of high-density lipoprotein cholesterol in women. The protective role of total cholesterol was unexpected, yet the interpretation of this finding warrants some caution. In the literature, the evidence demonstrating that cholesterol is a risk factor for cerebral vasculopathy is controversial.28 A possible and reasonable explanation for this lies in the fact that persons with high cholesterol received aggressive treatment in the 4 years of follow-up (the use of statins in these individuals was 3-fold that in persons with normal cholesterol). This explanation is consistent with a previous report that showed that, in this cohort, high cholesterol levels prompted aggressive treatment as standard care11 By contrast, the deleterious effects of high cholesterol levels, however treated, can be interpreted as the inability of therapy to counter severe dyslipidemia in this span of time. It should be noted that in subjects with previous cardiovascular disease, men, but not women, living in the south enjoyed a substantially lower hazard for stroke as compared with patients elsewhere in the country. This protective effect, which resisted all adjustments, may be the first trace of a lifestyle effect to ever have been detected in patients with diabetes. Adherence to a Mediterranean diet (which is higher in southern Italy) has been convincingly associated with a reduction in cardiovascular risk.29,30 Postmenopausal women may be inherently more resistant to diet-related risk reduction, as suggested by a recent study.31
A limitation of this study is that the lack of centralized laboratory data undoubtedly reduced the reliability of the information. Given that the observation period was relatively brief, there may not have been time for other potentially significant factors to emerge. Furthermore, although diabetes is predominantly ischemic,27 the possibility that a quota of events could be hemorrhagic cannot be ruled out. Finally, studying cerebral vasculopathy only by evaluating its most serious manifestation does not allow earlier stages of arteriopathy to be taken into consideration.
In addition to the large study population, the strengths of this study lie in the fact that it provides an accurate description of the daily reality of diabetes care. In particular, unlike other studies, we evaluated the incidence of stroke among advanced-age diabetic subjects, among whom the incidence of cerebral vasculopathy is greater. In Italy, the percentage of diabetic subjects who seek care at the diabetes care units is very high, reaching up to 80% of known cases;10 thus, our results most likely can be generalized to the entire T2DM population in Italy. What emerges from our results in practical terms is that a diabetes specialist with 2000 patients will probably have to face 15 new cases of stroke each year, consisting mostly of older patients and those with a more complex clinical history of diabetes.
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Acknowledgments |
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Disclosures
None.
Received July 25, 2006; accepted November 22, 2006.
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