Age and gender differences in risk factor burden, myocardial dysfunction and cardiovascular events in relation to glucose metabolism

Abstract: The risk of cardiovascular disease (CVD) and heart failure (HF) among individuals with diabetes is at least two times greater than in non-diabetic subjects. However, the excess risk of CVD in diabetic subjects seems to decrease with age. As the majority of patients with diabetes, CVD and HF are elderly it is important to establish the extent to which the associations between these conditions differ from those in younger populations. The overall aim of the work presented in this thesis was to study gender-related associations between glucose metabolism and myocardial dysfunction, risk factor burden and CVD events in middle-aged and elderly subjects. The hypothesis tested was that similar associations would be observed in elderly as in younger populations, although the associations would be weaker with advancing age. Data from two population-based cohort studies were used: MPP-RES (Sweden: n=18,238, mean age 69+/-6 years, range 57-86 years) and AGES-RS (Iceland: n=5,764, mean age 76+/-6 years, range 67-95). In Paper I the associations between echocardiographic indices of left ventricular diastolic dysfunction (LVDD), LV mass index (LVMI) and glucometabolic status were studied in echocardiography subcohorts from the two cohort studies (MPP-RES n=1,792; AGES-RS n=841). The MPP-RES cohort was divided into two age groups: middle-aged (57-69 years) and elderly subjects (70-80 years). All subjects were grouped according to fasting glucose level (FG, mmol/l): =<5.0; 5.1-5.5; 5.6-6.0 and 6.1-6.9 (pre-diabetic range) and >=7.0 (new-onset diabetes) and established diabetes, and trends between the groups were assessed. Few and inconsistent associations were observed in the AGES-RS cohort and in the elderly group in the MPP-RES cohort between increasing glucometabolic impairment and measures of LVDD. These observations are in contrast to previous findings in younger subjects as well as the present findings in the middle-aged group in the MPP-RES cohort, where a significant association was found between increasing LVDD and increasing glucometabolic impairment. It was concluded that changes in LV diastolic function may be more related to age than glucose metabolism in elderly subjects. In Paper II possible associations between N-terminal pro-B-type natriuretic peptide (Nt-proBNP) and FG as a continuous variable and in FG groups (as in Paper I) were assessed in the MPP-RES echocardiography subcohort. A positive correlation was found between Nt-proBNP and FG among middle-aged men. A positive correlation was also observed among elderly men, albeit non-significant. A non-significant negative correlation was observed among women in both age groups. The results indicate that caution should probably be exercised when interpreting Nt-proBNP values in subjects with impaired glucose metabolism. In Paper III the strength of the correlation between glucometabolic impairment, CVD risk factor burden and self-rated health (SRH), in middle-aged and elderly groups in the whole MPP-RES cohort (n=18,238) was compared. Correlations between increasing glucometabolic impairment and CVD risk factor burden and the proportion of subjects reporting poor SRH increased for both men and women in both age groups (p-trend <0.0001 for all). The slope of the trend curve with increasing CVD risk factor burden was significantly steeper for elderly women than for elderly men (p-interaction=0.002). The slope of the trend curve for poor SRH was significantly steeper for middle-aged than for elderly men (p-interaction=0.005), while no difference was observed between the age groups in the women. These results indicate lifelong CVD risk factor clustering and poorer SRH with increased glucometabolic impairment, being somewhat more pronounced in elderly women than in elderly men. Finally, in Paper IV we examined whether the previously observed age-related reduction in excess CVD risk for diabetic compared to non-diabetic subjects also applies to pre-diabetic conditions. The MPP-RES cohort was followed for 4.1+/-1.3 years during which 1,296 CVD events occurred. Subjects were grouped by FG, gender and age, as previously. The hazard ratios for CVD events increased with increasing FG among middle-aged men and women. No comparable increase was observed among elderly subjects, where men with FG =<5.0-6.9 and women with FG =<5.0-6.0 had HRs close to 1.0. The B-coefficients for interaction between age groups and intergroup trends were -0.17 (unadjusted p=0.01) and -0.15 (fully adjusted p=0.03) for men, and -0.13 (p=0.27) for women (irrespective of adjustment). It was concluded that FG values within the upper pre-diabetic range conveyed less excess risk of CVD events among elderly than middle-aged men and women.