Background and discussion points of the study
The numbers of diabetic elderly and their associated net medical costs have drastically increased in recent decades. The mean life expectancy is now approximately an additional 12 and 16 years at age 75 for males and females in Japan, respectively, although the average life span is 78.9 and 85.6 years, respectively. Consequently, the number of late elderly (individuals older than 75) exceeds 13 million, or 10% of the total Japanese population. Diabetes can either develop in the elderly or continue through old age after an earlier onset, and the numbers of diabetic elderly are increasing. In Japan, 55% of diabetic individuals were elderly in 2007, and approximately 25% were late elderly. These trends are spreading across the world, mainly in developed countries; however, the risk factors for IHD or CVA in late elderly diabetic individuals have not been identified. In the late elderly, atherosclerotic diseases, such as IHD and CVA, are a more frequent cause of death than malignancy. In Canada, diabetic patients are reported to suffer myocardial infarction approximately 14 years earlier than patients without diabetes. However, there is little evidence on the risk and preventive factors for IHD or CVA in the diabetic elderly, and there are no reports on the late elderly[14, 15].
Therefore, we organized this study as one of the largest attempts to examine IHD and CVA in middle-aged to elderly diabetic individuals. We defined the age categories as follows: 1) non-elderly: younger than 65, 2) early elderly: from 65 to 74, and 3) late elderly: equal to or older than 75. Sixty-five is usually defined as the threshold for being elderly worldwide[13, 16], and 75 is the beginning of the late elderly age in Japan, as defined by health insurance and care insurance systems and the Japan Geriatric Society.
The effect of age on IHD and CVA risk factors
One hundred fifty-three cases of IHD and 104 CVAs occurred, which represents 7.8 and 5.7/1,000 people per year, respectively, over this 5.5-year study, although we defined stroke strictly and excluded cerebral and subarachnoid hemorrhages from this definition. IHD occurs 2 to 3 times more frequently in diabetic individuals compared to the normal Japanese population, and CVA also occurs more frequently in diabetic individuals. The prevalence of IHD and CVA is slightly higher than reported in previous Japanese diabetic studies because we targeted relatively older diabetic individuals[16, 17]. However, even in diabetic individuals, the combined frequency of IHD and stroke was slightly lower in the Japanese population than among Caucasians.
To look for the candidate metabolic markers that may predict IHD and CVA in various age groups, Cox regression analyses were performed. The analyses showed that higher HbA1C and LDL-C levels, SBP and non-HDL-C were significantly correlated with the occurrence of IHD in subjects <65 years old, which is similar to previous reports[14–16]. The ratio of males/females was not significantly different between patients < 65, patients between 65 and 74, and patients ≥75. A relation between diabetes and ischemic stroke was reported. Patients (59.8 ± 7.2 y.o.) having a history of coronary heart disease with diabetes mellitus exhibited a 2.29-fold increased risk for stroke or TIA during the 4.8- to 8.1-year follow-up period than patients without diabetes. Impaired fasting glucose and hypertension were predictors, while HDL-C was not. These results are fairly consistent with those of the younger patients group (< 65 y.o.) in the present study.
In patients ≥75 y.o., a lower HDL-C level was correlated with IHD and CVA. This is a novel finding of the present study. Few data are available on the relationship between elderly type 2 diabetic patients and CVA, particularly among the late elderly[16–18, 20]; therefore, the finding of the importance of HDL-C in CVA in the late diabetic elderly may be important. The Kaplan-Meier estimator curves, which are shown in Figure 1, support these findings.
Thus, a lower HDL-C level is an important risk factor for both IHD and CVA among the late elderly diabetic patients in this study. Although the protective effects of higher HDL-C on IHD in the non-elderly are known, the effects on IHD among late elderly diabetics are not known. The CVA and IHD incidences in the late elderly may decrease to the levels found in middle-aged cohorts if higher HDL-C has protective effects on late elderly diabetic individuals and if their levels are easily increased. There are few agents available to increase HDL-C levels, except exercise, and adequate exercise or bodily movement may be necessary even in the elderly. The low HDL-C level may be related to low levels of physical activity in the elderly, which could influence a CVA in many ways that are separate from the HDL-C level. Atherosclerosis is an inflammatory disorder, and HDL-C may preserve endothelial function by increasing endothelial NO.
For LDL-C, three large-scale clinical studies on dyslipidemia, which included participants who were up to 75 or 80 years of age, are available[23–25]. Although these studies reported that the reduction in LDL-C by statins decreases IHD (including in diabetic people), the effects were weak in the elderly compared with those in the non-elderly (e.g., Prosper reported that pravastatin, a water-soluble statin, induced a 16% decrease in IHD without any effect on CVA in elderly patients compared to a 21% decrease in non-elderly patients). These data suggest that simply controlling LDL-C may not prevent IHD or CVA in the elderly. There are also no large observational studies on the diabetic elderly older than 75[26, 27]. For example, the international FIELD study analyzed approximately 10,000 patients up to the age of 75 years, with a mean age 63 years, and the Swedish NDR-study analyzed 18,673 patients up to 70 years old, with a mean age of 60 years. These large observational studies, analyzing all patients, found LDL-C, non-HDL-C, HDL-C, triglycerides and ratios of LDL-C/HDL-C and total-cholesterol/HDL-C to be significant risk factors for IHD. These data are consistent with our data on participants younger than 65, although those observational studies did not include patients older than 75. To lower LDL-C levels, 57% of the patients in our study had already been prescribed anti-dyslipidemic agents, of which 83% were statins. The average LDL-C level was 120 mg/dl, which matches the guidelines of the Japan atherosclerosis society but not that of the American Heart Association or IDF (100 mg/dl). Although doses and types of anti-dyslipidemic agents were changed often during the study, their effects other than LDL reduction (pleiotropic effects) cannot be evaluated yet.
Our study shows the importance of the LDL-C/HDL-C ratio as well as HDL-C and LDL-C levels, although the strength of these effects is different based on age. The LDL-C/HDL-C ratio was associated with IHD, which may represent the effect of LDL-C levels in the non-elderly and HDL-C levels in the elderly. The non-HDL-C level and the total cholesterol/HDL-C ratio are also proposed markers of atherosclerotic diseases[29, 30]. The non-HDL-C level was associated with IHD only among those younger than 65, and the total cholesterol/HDL-C ratio was not significantly associated with IHD (data not shown). We believe that these data are consistent with previous data from non-elderly diabetic individuals because the non-HDL-C level is a reflection of the effect of triglyceride levels, and hyper-triglyceridemia, complicated with metabolic syndrome, occurs more often in non-elderly than in elderly people.
Emerging Risk Factors Collaboration analysis showed the association of non-HDL-C with IHD and CVA. However, in this study, it was associated with CVA only in those younger than 65. The two studies are different in that 1) our cohort consisted only of diabetic patients; 2) in the Collaboration analysis, the mean age was 56.6 y.o., compared to 67.4 y.o. in our study; and 3) in the Collaboration analysis, almost all of the patients were North American or European, whereas our study was Japanese patients only. In the elderly, triglycerides are usually lower than in younger individuals, and non-HDL-C represents triglyceride.
A 1-mg/dl change in HDL-C and/or a 2-mg/dl change in LDL-C reflect a 2% change in the risk for atherosclerotic diseases, and this may be partially consistent within our diabetic elderly study. The LDL-C/HDL-C ratio may reflect the direct effects of both LDL-C and HDL-C levels, which may affect or interact with the progression of atherosclerosis and thrombosis formation more than other lipids, such as chylomicrons and chylomicron remnants, which are represented by the non-HDL-C level or the TC/HDL-C ratio. The fact that elderly individuals have different risk factors than younger individuals could be associated with genetic protection from such events or an accumulation of personal habits that may provide the elderly with protection. For example, differences in single nucleotide polymorphisms (SNP) may be related to the severity of atherosclerosis and, subsequently, to the different effects of predictors by age and should be evaluated in the future.
Interestingly, impaired fasting glucose and hypertension were the strongest predictors of risk for ischemic stroke or TIA in metabolic syndrome, and HbA1c had positive associations with glycemia, TG, HDL-C, and TG/HDL-C but not LDL-C in the study of 118 older adults aged 65–95 years, of whom less than 6.5% had an HbA1c of 93%[19, 33]. These data is consistent with our data in diabetic patients younger than 65. Another study evaluated the predictors of stroke stratified by age (at symptom onset: young; <50 years, older; 51–75 years, and oldest; 75 < years) using data collected over a 4-year period from 3,053 subjects with stroke. The metabolic syndrome was the only predictor among the older patients (OR 1.58) but not in the others. Although most patients were not diabetic, these types of studies should be accumulated to evaluate the effect of age on atherosclerotic diseases.