Age, gender, insulin and blood glucose control status alter the risk of ischemic heart disease and stroke among elderly diabetic patients

Patients

We recruited diabetic individuals examined at 40 institutions throughout Japan between September 2004 and March 2005. Patients who had experienced previous myocardial infarctions or cerebrovascular accidents requiring hospitalization were excluded from the study. Other exclusion criteria included the following: a history of or complications related to serious heart disease (such as acute heart failure); serious hepatic or renal disease, such as non-compensated liver cirrhosis and chronic renal failure requiring hemodialysis; malignancy; intention to undergo surgery; any illness with a poor prognosis; and the recruiting physician's judgment that a patient was inappropriate for inclusion in the study.

Study design

This multicenter prospective longitudinal cohort study included 4,014 diabetic individuals examined on a consecutive outpatient basis (1,936 women and 2,078 men; mean age = 67.4 ± 9.5 years, range = 35-83 years, median = 70.4 years). The one-year and two-year follow-up rates were 98.2% and 92.3%, respectively (Figure 1). Primary endpoints were the onset of IHD (comprising fatal or nonfatal myocardial infarction; development of unstable angina; or the need for coronary revascularization procedures, either coronary artery bypass grafting or percutaneous coronary intervention because of angina or an acute coronary syndrome) or CVA (stroke with neurological deficit, except transient ischemic attack). Secondary endpoints were sudden cardiac death due to causes other than myocardial infarction, transient ischemic attack, subarachnoid hemorrhage and all-cause mortality. We collected blood samples from the patients to evaluate their plasma lipid levels, blood glucose levels and HbA1C levels during the same month each year. Informed consent was obtained from all subjects participating in the study. The study was approved by the Institutional Review Boards of the participating hospitals and the relevant safety monitoring boards [10]. The guidelines of the Japan Atherosclerosis Society, which state that LDL values should be less than 120 mg/dL and HDL values should be higher than 40 mg/dL in diabetic individuals, and the diagnostic criteria for T2DM of the American Diabetes Association were used [11, 12]. All reported events were confirmed by the organizing committee.

Group allocation by age and glycemic control

We investigated the relationships between age, diabetic control, IHD, and CVA. Because the median age and hemoglobin A1C values of the patients in this study were 70.4 years and 7.0%, respectively, we divided the patients into four groups based on age (≤ 70 and > 70) and hemoglobin A1C levels (≤ 7.0 and > 7.0%). The four groups were as follows: 1) NF: under 70 years of age with fair glycemic control (n = 870); 2) NP: under 70 years of age with poor glycemic control (n = 1,072); 3) OF: over 70 years of age with fair glycemic control (n = 923); and 4) OP: over 70 years of age with poor glycemic control (n = 1,149).

Group allocation by gender and glycemic control

We investigated the relationships between gender, diabetic control, IHD, and CVA. We divided the patients into four groups based on gender and hemoglobin A1C levels (≤ 7.0 and > 7.0%). The four groups were as follows: 1) MF: males with fair glycemic control (n = 1063); 2) MP: males with poor glycemic control (n = 950); 3) FF: females with fair glycemic control (n = 859); and 4) FP: females with poor glycemic control (n = 1,142).

Statistics

Results are presented as means ± SD (standard deviation) of the data analyzed. All statistical analyses were performed using JMP (version 7, SAS Institute Inc., Cary, NC). The incidence of IHD and CVA were analyzed according to age, which was stratified as 70 years or younger vs. older than 70 years. We used the chi-square test and Fisher's exact test for categorical comparisons of the data. Differences in the means of continuous measurements were tested using the Mann-Whitney U test. We selected possible significant predictors by conducting a univariate logistic regression analysis (P < 0.10) and performed multiple logistic regression analysis to identify important risk factors for IHD and CVA. Additionally, stepwise regression analysis was used to confirm the relationships between IHD, CVA, and clinical variables. P-values less than 0.05 were considered to be statistically significant.

Multiple regression analysis examining the relationship between the risk of IHD and clinical variables for each group divided by age and glucose control

Patients 70 years of age or younger: Univariate analysis revealed that higher systolic blood pressure, higher LDL-C and lower HDL-C were associated with IHD risk among patients in the NF group. However, only systolic blood pressure (OR = 1.81, 95% CI = 1.19-2.93; p = 0.009) and HDL-C level (OR = 0.46, 95% CI = 0.26-0.85; p = 0.006) were confirmed to be significantly associated with IHD risk by the multiple regression analysis.

Patients over 70 years of age: Lower diastolic blood pressure was associated with IHD risk among patients in the OF group (OR = 0.65, 95% CI = 0.48-0.96; p = 0.016). Insulin use was significantly associated with IHD risk in the OP group (OR = 2.27, 95% CI = 1.11-5.89; p = 0.026) (Table 2). The duration of diabetes did not affect IHD risk in either group.

Multiple regression analysis examining the relationship between clinical variables and the risk of CVA for each group divided by age and glucose control

Patients 70 years of age or younger: CVA tended to occur more frequently among patients with higher HbA1C levels than in those with lower HbA1C levels (OR = 4.11, 95% CI = 1.01-13.4; p = 0.067) in the NF group. Lower HDL-C (OR = 0.43, 95% CI = 0.23-0.78; p = 0.006) and a longer duration of diabetes (OR = 1.06, 95% CI = 1.01-1.11; p = 0.018) were associated with CVA risk among patients in the NP group.

Patients over 70 years of age: Insulin use was associated with CVA risk in the OF group (OR = 2.09, 95% CI = 1.06-4.25; p = 0.028) (Table 2). Univariate analysis revealed a trend toward an association between lower HDL-C levels and CVA in the OF and OP groups, but this association was not statistically significant according to the results of the multiple regression analysis.

Stepwise regression analysis

Stepwise multiple regression analyses were also performed separately for IHD and CVA risks. The results were very similar to those of the multiple regression analyses described above, except that LDL-C was associated with IHD in the NF group (Table 3).

Regarding IHD risk, higher systolic blood pressure (p = 0.003), lower HDL-C (p = 0.017), and higher LDL-C (p = 0.035) were all associated with IHD risk in the NF group. Insulin use (p = 0.005) and age (p = 0.015) were significantly associated with IHD in the OP group.

Regarding CVA risk, higher levels of hemoglobin A1C were associated with CVA risk in the NF group (p = 0.03), and lower HDL-C (p = 0.004) and the duration of diabetes (p = 0.01) were associated with CVA risk in the NP group. Insulin use (p = 0.038) was associated with CVA risk among patients in the OF group. Lower HDL-C levels tended to be associated with CVA in the OF group (p = 0.056) and the OP group (p = 0.08), although these associations were not statistically significant.

Influence of insulin therapy on IHD and CVA risk

The results indicated that insulin therapy was associated with IHD risk in the OP group and with CVA risk in the OF group (Figure 2). Interestingly, patients 70 years of age or younger who used insulin tended to have slightly decreased incidences of IHD and CVA, whereas patients over 70 years of age using insulin tended to have an increased incidence of CVA (Figure 2a and 2b).

Interestingly, insulin use was associated with IHD in the MP group (OR = 4.11, 95% CI = 1.22-8.12; p = 0.018) and with CVA in the FP group (OR = 3.26, 95% CI = 1.12-6.24; p = 0.02).

Multiple regression analysis examining the relationship between clinical variables and the risk of IHD for each group divided by gender and glucose control

Male patients: IHD was associated with high systolic blood pressure in the male/fair glycemic control group, age in the male/poor control group. Interestingly, insulin use was associated with IHD in the male/poor group (OR = 4.11, 95% CI = 1.22-8.12; p = 0.018).

Female patients: IHD was associated with a short duration of diabetic history in the female/fair and female/poor groups.

Multiple regression analysis examining the relationship between clinical variables and the risk of CVA for each group divided by gender and glucose control

Multiple regression analysis was performed to evaluate the relationship between CVA and each clinical measurement and insulin treatment for each group divided by gender and glucose control levels (HbA1C) (Table 4).

Male patients: CVA was not significantly associated with any variables.

Female patients: CVA was associated with a short duration of diabetic history in the female/fair and female/poor groups. Insulin use was associated with CVA in the female/poor group (OR = 3.26, 95% CI = 1.12-6.24; p = 0.02).

IHD risk factors

American guidelines for diabetic control suggest that diabetic individuals under 70 years of age have a risk of developing IHD similar to that for non-diabetic individuals having a prior myocardial infarction [8], and the results from the present study support this concept (Figure 2). We found that the incidence of IHD among diabetic Japanese was relatively high and comparable with that of IHD in Western countries, such as the U.K. [3, 15]. The incidence of IHD in our study was approximately three times higher than the incidence rates previously reported in Japanese trials, such as Mega study investigating patients under 70 years of age, not all of whom had diabetes [16, 17].

In the present study, among diabetic individuals in the NF group, higher systolic blood pressure and lower HDL-C were associated with a risk of IHD. Systolic blood pressure, not diastolic pressure, was confirmed as a classical IHD risk factor from previous studies [18–20]. The age of diabetic patients in those reports was less than 70. Stepwise regression analysis confirmed the association of high LDL-C and low HDL-C with a risk of IHD in the NF group; however, the significance of the LDL-C association was not confirmed by multiple regression analysis [21]. The use of anti-dyslipidemia agents, such as statins, with their pleiotropic effect may affect this difference [21]. Insulin use tended to decrease the incidence of IHD in patients in the NF group (Table 2).

Among older diabetic individuals with fair glycemic control (the OF group), lower diastolic blood pressure was associated with IHD. Insulin use was associated with IHD in the OP group. Coronary circulation depends on diastolic blood flow, and the isolated systolic hypertension (with lower diastolic blood pressure) values may reflect aortic atherosclerosis, which is common among the elderly.

Interestingly, insulin therapy was associated with IHD in the OP group. The duration of diabetes was longer among insulin users than among non-users in the NF and NP groups; however, there was no difference in diabetes duration between the OF compared to the OP group. Overall, the combination of higher plasma glucose and insulin use may progress atherosclerosis and subsequently increase the risk of IHD among elderly diabetic individuals. However, maintaining good glycemic control via insulin use could help prevent IHD. Because patients with a history of IHD and/or CVA were excluded from the study, few patients in our cohort used antiplatelet agents (< 10% of patients).

Conversely, IHD was associated with high systolic blood pressure in the MF group, age in the MP control, and short duration of diabetic history in the FF and FP groups. Insulin use was associated with IHD in the male/poor group. Females usually develop complications of atherosclerotic diseases, such as IHD or CVA, 10-15 years later than males [22], which may partially be due to the prevention of atherosclerosis progression by estrogen. However, previous reports have indicated that gender does not affect the age of onset of atherosclerotic disease in individuals with diabetes [23, 24]. Our observation that a short duration of diabetic history is associated with IHD and CVA in females may reflect these phenomena. A detailed mechanism was not obvious in the present study and should be evaluated in future research. Regarding gender differences and laboratory findings in Japanese populations, it was recently suggested that hsCRP levels increase continuously across the fasting plasma glucose (FPG) spectrum, starting from the lowest FPG in both men and women, but the increase in hsCRP levels is greater in women than men. Moreover, higher CRP gamma-glutamyl transferase (GGT) levels are synergistically associated with the metabolic syndrome and insulin resistance, independently of other confounding factors in the general population [25, 26].

CVA risk factors

The incidence of CVA is higher in East Asian individuals, such as the Japanese, than in Caucasians. Thus, the incidence of CVA was higher in the present study than those reported in previous Western studies, but it was comparable to that observed in prior Japanese studies, such as JDCS [27]. The differences in eating habits, diabetic complications, and older average age observed in the present study may have led to these differences.

Among patients in the NP group, low HDL-C was associated with CVA. This result is consistent with previous reports; however, the relationship between the HDL-C level and CVA has been described recently [9, 28].

Among patients in the OF group, insulin use was associated with CVA (OR = 2.09). Although the underlying mechanism is still unknown and the higher frequency of CVA in Japan may affect the data, our preliminary findings show that hypoglycemia occurred more frequently among individuals in the OF group than those in the OP group. Hypoglycemia increases stroke risk [5, 29]. In the strict glucose control group of the ACCORD study, morbidity rates increased in the form of severe hypoglycemia and weight gain.

In the OP group, glycemic control was worse among insulin users than among non-users. The duration of diabetes did not differ between the OF and OP groups. There has been a drastic increase in the elderly population in the last several decades. Therefore, understanding the characteristics of lifestyle-related diseases in the elderly is important to maintain their good health. Postprandial hyperglycemia is common in the elderly, and hyperosmolar nonketotic hyperglycemia often complicates the course of diabetes in the elderly. Insulin therapy reduces glucose toxicity and is necessary in some elderly diabetic patients. Strict blood glucose control including insulin therapy is necessary to prevent the progression of diabetic microangiopathies. However, insulin induces smooth muscle cell proliferation and may lead to the progression of atherosclerosis [30]. Muis et al. focused on type 1 diabetes patients (instead of type 2) to minimize the effects of insulin resistance [31]. They found that the cumulative dose of regular insulin was significantly related to carotid intima-media thickness. They observed a similar relationship between the use of intermediate-acting insulin with carotid intima-media thickness and concluded that the cumulative dose of insulin was a risk factor for atherosclerosis. Insulin contributes to cellular senescence and causes aging in organisms, such as mice [32, 33]. The detrimental effects of insulin therapy, such as hypoglycemia leading to stroke, was more evident in the elderly in the present study. Unfortunately, a detailed analysis was not possible because of the fact that patients' insulin regimens (dose and type of insulin) change frequently. Future studies should examine the effects of insulin. CVA was associated with short duration of diabetes in the FF and FP groups, and insulin use was associated in the FP group. The results that short duration of diabetic history is associated with CVA in the female may be explained similarly as to IHD, as drastic effect of menopause [34].

Limitations

Treatment for diabetes was based on data recorded at the time of enrollment. Patients were followed for 2 years, and we could not analyze the detailed mechanisms underlying insulin therapy on the risk of IHD and CVA.