shows the baseline characteristics of those study participants with available baseline sRAGE data who went on to become CVD cases compared with the control group selected who did not develop CVD. Those who developed CVD were older, were more likely be a current or ex-smoker, had albuminuria, were male, and had slightly higher LDL-C. Further analyses for CVD risk adjusted for these factors. Among the 167 CVD cases, there were 128 CHD and 44 stroke events (5 people having both). Similar differences in baseline characteristics were seen for CHD cases versus control subjects as for CVD cases versus control subjects.
Baseline characteristics of incident CVD cases and control subjects
summarizes the main relationships we found between other factors and sRAGE. A very similar pattern of relationships was found for esRAGE. Neither sRAGE nor esRAGE differed significantly with age or by sex. However, although the numbers of nonwhite participants was low (n = 20 African Caribbean; n = 25 South Asians), there were marked ethnic differences, with much lower sRAGE and esRAGE in those of African Caribbean origin compared with whites and South Asians having intermediate levels. Those with lower estimated glomerular filtration rate (eGFR) had higher sRAGE and esRAGE but there was no association with albuminuria (the prevalence of albuminuria in this study population was low, however [see ]). There was a slight inverse association between HbA1c and esRAGE (Spearman ρ = −10; P = 0.006) but not sRAGE (Spearman ρ = −0.06; P = 0.09). Those with lower BMI levels had higher levels of both sRAGE and esRAGE, and consistent with this, there was a positive correlation with adiponectin (Spearman ρ = 0.14; P = 0.006). In a linear regression model with the above variables considered simultaneously, sRAGE remained associated with BMI (P = 0.007) or adiponectin (P < 0.001), ethnicity (P = 0.002), and eGFR level (P = 0.004). esRAGE remained associated with BMI (P < 0.001) or adiponectin (P < 0.001), ethnicity (P < 0.001), HbA1c (P = 0.019), and eGFR (P = 0.05). However, together these factors explained no more than 6 and 10% of the variance in sRAGE and esRAGE, respectively. There was no significant association between esRAGE and smoking, lipids, blood pressure, antihypertensive agents, diabetes duration, insulin, or oral diabetes drugs (data not shown). Neither was there any association with high-sensitivity C-reactive protein (Spearman ρ = −0.02; P = 0.6).
Association of sRAGE with eGFR, BMI, and ethnicity. (A high-quality color representation of this figure is available in the online issue.)
We explored the relationship of sRAGE to esRAGE. sRAGE and esRAGE were strongly correlated (Spearman ρ = 0.88), with a median ratio of sRAGE to esRAGE levels of 4.2 (ranging from threefold at the bottom 5% to sixfold at the top 5%). When we explored whether associations of patient characteristics to the ratio of sRAGE:esRAGE existed, we found that a higher ratio was associated with younger age (P = 0.001), higher HbA1c (P = 0.01), being nonwhite (P = 0.003), and having a higher BMI (P = 0.002). (P values shown are for a model including these characteristics and sex simultaneously.)
We examined the relationship of sRAGE and esRAGE to cardiovascular events. As shown in , there was no apparent difference in esRAGE or sRAGE between cases and control subjects for CVD. This lack of association was confirmed in a Cox regression model adjusting for age, sex, and treatment (HR for sRAGE = 1.26; 95% CI 0.97–1.64; P = 0.08). However for CHD considered separately, both sRAGE and esRAGE were higher in cases than control subjects adjusted for age and sex. The median (interquartile range) sRAGE was 1,499 pg/mL (1,138–1,910) in cases and 1,395 pg/mL (1,046–1,777) in control subjects, and the median esRAGE was 340 pg/mL (250–460) in cases and 320 pg/mL (240–430) in control subjects. As shown in and this association of both sRAGE and esRAGE with CHD incidence was statistically significant, adjusted for age, sex, and treatment allocation (P = 0.003 for sRAGE and P = 0.023 for esRAGE; ). In a Cox regression model adjusting further for potential CHD risk factors associated with baseline sRAGE and/or esRAGE, the association was independent of other factors. As shown in , model 3 adjusted for eGFR and albuminuria status, but this had very little effect on the relationship of sRAGE or esRAGE with CHD. There was no significant association between ethnicity and CHD (HR for white vs. nonwhite = 0.6; P = 0.1), and adjusting for ethnicity did not alter the association of esRAGE or sRAGE with CHD (model 2). Restricting the analysis to whites only showed similar effects (for example for model 1, the HR of CHD for sRAGE restricted to whites was 1.58; P = 0.004). There were too few nonwhites (n = 50) to model CVD events in these participants separately. Adjusting for BMI slightly strengthened the association of both sRAGE and esRAGE with CHD (model 2). The relationship of esRAGE to CHD was slightly weaker than the association of sRAGE with CHD (P = 0.001; difference in log likelihood for the two models = −2). In these models, esRAGE and sRAGE were log2 transformed because of their skewed distribution. Thus the HRs show the effect of a doubling of the sRAGE or esRAGE level. The data were consistent with a linear relationship of sRAGE with CHD. The HR for the mid-tertile adjusted for age, BMI, and ethnicity was slightly elevated at 1.11 (0.7–1.75) and for the top tertile was 1.62 (1.06–2.5), with the P value for linear trend across tertiles being 0.025. Using a logistic regression model, the same conclusions were reached.
Association of sRAGE and esRAGE with CHD and stroke with adjustment for other factors
Also shown in , the HRs for the association of sRAGE or esRAGE with stroke were in the opposite direction to that for CHD but were not statistically significant, and the CIs are wide, consistent with the small number of stroke events (n = 44).
We examined the effect of atorvastatin on sRAGE. As shown in , sRAGE levels were very stable in both treatment arms between baseline and 1-year follow-up. Using samples from 469 people (n = 285 allocated placebo and 184 allocated atorvastatin) who had prerandomization and 1-year postrandomization samples available for sRAGE, there was no effect of atorvastatin (10 mg daily) on within-person change in sRAGE (β for treatment allocation = −3.5; 95% CI −87 to 81, P = 0.9) in a regression model of follow-up RAGE adjusted for baseline sRAGE, age, and sex. Given the lack of atorvastatin effect on sRAGE and the strong correlation between esRAGE and sRAGE at baseline, quantification of follow-up esRAGE was not considered worthwhile.
Median (interquartile range) sRAGE at baseline and 1 year postrandomization by treatment group. (A high-quality color representation of this figure is available in the online issue.)