Although the antihypertension drug candesartan has been reported to control inflammation [17, 18], there is little evidence about differences in effect by candesarton among each inflammatory parameter and what factors contribute to the differences. Moreover, there is the question of whether there are anti-inflammatory effects by candesartan in patients with advanced arteriosclerosis such as those with type 2 diabetes mellitus of long duration accompanied by hypertension. In this study, we analyzed the predictors showing which patients would receive the benefit of organ protection by candesartan.
HMW-ADN and PAI-1
Although both HMW-ADN and PAI-1 values had improved significantly at the end of the study period, there was no relationship between these parameters and SBP and DBP at baseline nor did changes in SPB and DBP have any relationship between changes in these parameters. These results might indicate that candesartan improved these parameters directly and not through changes in blood pressure.
HMW-ADN is secreted from adipose tissue and has a protective effect against cardiovascular disease . It was reported that HMW-ADN values change not only in the advanced stage of arteriosclerosis such with arteriosclerosis obliterans  but that HMW-AND is an independent prognostic factor .
PAI-1 is the primary physiological inhibitor of endogenous fibrinolysis that acts via inhibition of the tissue plasminogen activator (tPA) and the urokinase type activator (uPA), often leading to fibrin accumulation in basement membranes and interstitial tissues. Elevated plasma PAI-1 has been demonstrated in various subgroups as an important feature of type 2 diabetes and metabolic syndrome . Plasma levels of PAI-1 were reported to predict the occurrence of a first acute myocardial infarction and reinfarction . Recently, the BARI 2D Trial of subjects with a mean duration of diabetes mellitus of 10.4 years with stable coronary artery disease reported that for the older patients reducing the PAI-1 level in blood might offer an attractive strategy for decreasing cardiovascular risk . The results of our study appear to support these results.
Although the mean duration of diabetes mellitus in our study was over 15 years, HMW-ADN and PAI-1 values were reduced after patients received 12 mg candesartan o.d. for 6 months. This result might partially explain the protective effect of candesartan therapy against cardiovascular disease in hypertensive patients with type 2 diabetes mellitus.
On the other hand, there is evidence that pulse pressure is an index parameter of arteriosclerosis. Pulse pressure is a marker of arteriosclerosis that can be measured simply. It is correlated with IMT and PWV, and an increase in pulse pressure has been reported to be associated with risk of onset of coronary artery disease [25, 26]. It is a predictor of overall mortality in elderly persons . It was also reported that pulse pressure could be a predictive factor of a cardiovascular event in persons with diabetes mellitus . In healthy subjects, pulse pressure over 55 mmHg is associated with risk of a cardiovascular event . Another study showed that pulse pressure over 70 mmHg presented a risk in elderly persons . Among our study population, in those with type 2 diabetes mellitus of long duration, a correlation between pulse pressure and PWV was observed (CC=0.494,P=0.004). Multiple linear regression analysis suggested that pulse pressure had a relationship to PWV independent of age and BMI (Table 3).
We therefore focused attention on the relationship between changes in inflammatory parameters and changes in pulse pressure. Prior to the study, we divided patients into 2 groups, group A with high pulse pressure (66.0 mmHg ± 0.8) and group B with low pulse pressure (52.0 mmHg ± 0.8), and examined the rates of improvement in blood pressure, HMW-ADN, and PAI-1. In the total patient population, the median pulse pressure was 60.0 mmHg±1.4.
Interestingly, a significant improvement in HMW-ADN and PAI-1 was observed in the group with pulse pressure ≧60 mmHg (group A) compared with the group with pulse pressure <60 (group B). Findings were as follows: ⊿SBP: average =−9.20, P value=0.048; ⊿DBP: average =−6.61, P value=0.08; ⊿AND: average = group A 2.3 and group B 0.052 μg/ml, P value=0.005; PAI-1: average =group A −10.1 and group B −0.48 ng/ml, P value =0.012. These results suggest that diabetic patients with comparatively low pulse pressure indicating less advanced arteriosclerosis may receive benefits of improvement in inflammatory parameters such as HMW-ADN and PAI-1 by taking candesartan.
Hs-CRP, VCAM-1 and U-8-OHdG
Hs-CRP, VCAM-1 and U-8-OHdG values did not change during this study. Also, there were no relationships between blood pressure and pulse pressure changes and Hs-CRP, VCAM-1 and U-8-OHdG.
In this study, no improvement in Hs-CRP was observed because of the following reasons. It has been reported that Hs-CRP levels are increased in patients with arteriosclerosis and other diseases that cause blood flow disturbance, and that Hs-CRP can be used as a predictor of cardiovascular events. On the other hand, it has also been reported that Hs-CRP is increased in patients with obesity and diabetes, and could be decreased by certain antidiabetic drugs. The subjects of this study had a long history of diabetes, and drugs were used in most subjects. Indeed, the Hs-CRP levels were likely below detection level in almost half of the subjects before the commencement of the study, and this might contribute to the lack of improvement of Hs-CRP. The reason might be that VACM-1 reflects early vascular endothelial dysfunction, so it increases from the onset of hypertension or diabetes mellitus . The histories of diabetes and hypertension varied among the study population. Also, the study duration was too short to recognize changes in U-8-OHdG, as it could be expected to take longer for U-8-OHdG to change than the other factors evaluated. Moreover, although past clinical studies have suggested that ARB would have antioxidative and anti-inflammatory effects, most of the studies were performed in subjects that were not being treated with antihypertensive drugs. In this study, patients undergoing treatment with antihypertensive drugs, such as ARB, were included, and thus the study results might be affected by the fact that the levels of VCAM-1 and U-8-OHdG were already within a normal range prior to commencement of the study.
Alternatively, candesartan might be less effective in patients with advanced arteriosclerosis with regard to Hs-CRP, VACM-1 and U-8-OHdG. This may be why the ACCRD BP study did not find positive data for type 2 diabetic patients with hypertension from the point of view of inflammatory parameters.
It has been reported that ARB could increase adiponectin levels to a greater degree compared with calcium channel blockers and β blockers. By contrast, it has also been reported that ARB would have greater effects on VACM-1, U-8-OHdG, and PAI-1, while protecting organs, compared with calcium channel blockers in preclinical studies of diabetes. However, no difference in usefulness has been shown between the drugs in clinical studies, especially for patients with diabetes.
This study has limitations as single group pre-post study, small population, the unbalance between men and women. The results of larger clinical trials evaluating the cardiovascular protective effects including other ARBs are awaited.