Background
Candesartan cilexetil is a selective angiotensin II type I receptor blocker (ARB). It is known that some ARBs improve insulin resistance [
1], and we reported that monotherapy with ARBs including candesartan had a favorable effect on glucose metabolism [
2]. Previous clinical trials showed that candesartan-based treatment reduced non-fatal strokes in elderly hypertensive patients [
3], and that a 7-day course of candesartan after an acute ischaemic stroke significantly improved cardiovascular morbidity and mortality [
4]. Pfeffer
et al. reported that administration of candesartan to patients with chronic heart failure improved cardiovascular morbidity and mortality [
5]. These large-scale clinical trials suggested the possibility that candesartan has an add-on effect to reduce cardiovascular risk. Meanwhile, an animal study showed that candesartan increased peroxisome proliferator-activated receptor-γ (PPAR-γ) mRNA expression and serum adiponectin level [
6]. Therefore, it has been suggested that candesartan has a potential effect on lipid metabolism. A recent clinical study on the effect of candesartan on lipid metabolism showed that total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels were significantly decreased in hypertensive patients administered candesartan for at least 6 months [
7]. However, the effects of prolonged administration of candesartan on lipid metabolism in patients are unclear.
In this study, we carried out candesartan monotherapy in patients, examined the longitudinal changes in plasma lipid profile up to 12 months, and studied the correlation between the profile and the duration of administration.
Discussion
In this study, we examined the changes in laboratory data of lipid metabolism up to 12 months in patients receiving candesartan monotherapy. Because this survey was a longitudinal study, the study population represented its own time-related control group. In this retrospective longitudinal survey, we found a significant reduction in HDL-C level from the start to 6~9 months of candesartan administration (Tables
2 and
3). These results suggest that candesartan has an unfavorable effect on lipid metabolism, with a reduction in HDL-C level by administration of candesartan for 6~9 months in female subjects. However, the effect of candesartan to reduce HDL-C level was transient and limited to female subjects. Moreover, HDL-C level was within the normal range throughout the study period (Table
4). Therefore, this slightly unfavorable effect of candesartan monotherapy on HDL-C in female subjects may not be a problem in clinical practice. Regarding lipid metabolism, candesartan may be safely used for patients with hypertension in the long term up to 12 months. Bramlage et al. reported that ARBs provide substantial cost savings and may prevent cardiovascular morbidity and mortality based on more complete antihypertensive coverage, suggesting that ARBs are an attractive choice for long-term treatment of hypertension [
19]. Our findings on the safety of long-term use of candesartan with respect to lipid metabolism reinforce these benefits of ARBs.
Only a few studies have examined the effect of candesartan on lipid metabolism; however, some showed that administration of candesartan had no effect on lipid metabolism. When HDL-C, TC, and TG levels were compared between before administration and after 2 weeks of candesartan administration to patients with essential hypertension, no significant difference was found [
20]. Also, when HDL-C, LDL-C, TC, and TG levels were compared between before administration and after 8 weeks of candesartan administration to patients with mild hypertension and type 2 DM, no significant difference was found [
21]. When HDL-C, LDL-C, TC, and TG levels were compared between before administration and after 12 weeks of candesartan administration to patients with mild hypertension and type 2 DM, no significant difference was found [
22]. Furthermore, when HDL-C, LDL-C, TC, and TG levels were compared between before administration and after 12 months of candesartan administration to patients with mild hypertension and type 2 DM, no significant difference was found [
23]. Supporting these previous reports, no significant changes were observed with candesartan administration for less than 6 months and more than 9 months in our study.
A close relationship has been suggested between lipid and glucose metabolism, but there was no association between lipid metabolism and the covariate of DM in our study results (Table
2). The reason for this may be that only patients with well-controlled blood glucose were selected during the subject selection stage in this study, because patients with a very high HbA1c level (≥8.0%) were excluded. As a result, there was a smaller effect of glucose metabolism abnormality on lipid metabolism.
In our study, HDL-C level was significantly reduced in female subjects, but not in male subjects (Figure
2 and Table
4). The reason for this discrepancy may be as follows. First, the effect of candesartan on HDL-C may be stronger in patients with a high HDL-C level than in those with a low HDL-C level. It is well known that there is a sex-difference in plasma lipid profile; plasma HDL-C level is generally higher in female subjects than in male subjects [
24,
25]. Second, the effect of candesartan on HDL-C may reflect its effects on hormones. A previous report revealed that oestrogen increases HDL-cholesterol [
26]. However, the reason for this discrepancy between male and female subjects is still unclear.
This study was a retrospective database study, which can provide many benefits as follows: First, real-time data can be provided quickly and cost-effectively. Second, the sample sizes are relatively large. Third, the influences on the patients' risk are minimal. These strengths readily led to stimulating studies and promising outcomes [
27]. On the other hand, our study was a retrospective observational study, which has some limitations with respect to the potential for selection bias and confounding factors. However, these problems caused by non-randomized data could be solved by combination with robust statistics; for example, propensity score method [
9]. Our study, with appropriate application of statistical analysis techniques; i.e., the propensity score adjustment and weighted-linear mixed model, may yield findings with validity, and help physicians make decisions on drug selection.
Conclusions
In this study, we examined the effect of candesartan monotherapy on lipid metabolism. Our results revealed that HDL-C level in female subjects declined from 6 to 9 months after the initiation of candesartan monotherapy. However, the reduction of HDL-C level was transient and was observed only in female subjects. Moreover, the HDL-C level was within the normal range throughout the study period. In addition, TG, TC and LDL-C levels were not influenced by candesartan monotherapy. These results indicate a lack of obvious evidence showing an unfavorable influence of candesartan on lipid metabolism. Therefore, the influence of candesartan monotherapy on lipid metabolism may be small and may not be a clinical problem. In the field of lipid metabolism, candesartan may be safely used for patients with hypertension.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
SA and YN conceived the study and participated in its design. YT performed the statistical analyses. TN, NK and MS drafted the manuscript and interpreted the data. All authors have read and approved the final manuscript.