Abstract
Objective: The comparative effect of telmisartan and valsartan upon insulin resistance and adipocytokines in nondiabetic patients with mild hypertension is unclear.
Methods: Fifty nondiabetic patients with untreated mild hypertension were randomly assigned to telmisartan (40 mg/day) and valsartan (80 mg/day) groups and were switched in a crossover manner at 3-month intervals. Serum leptin, adiponectin, hsCRP and the HOMA-R were measured before and at 3 months during each treatment period.
Results: The HOMA-R significantly improved over the 3 months in the high insulin resistance group (HOMA-R>/=2.5) during the telmisartan treatment period (p=0.042), but not during the valsartan period. Both telmisartan and valsartan significantly decreased serum leptin levels in each female group during each treatment period (p<0.001 and p<0.001, respectively), but not in the male groups. Serum adiponectin did not increase in either treatment group. Serum hsCRP levels also significantly decreased in the high hsCRP subjects (>/=0.1) of both treatment groups (p=0.044 and p=0.015, respectively).
Conclusions: Telmisartan significantly improved insulin resistance, possibly through the effect on PPAR-gamma, while both telmisartan and valsartan significantly decreased serum leptin levels in female groups and hsCRP in both genders, suggesting no significantly different effects on adipocytokines by either drug in nondiabetic patients with mild hypertension.
Keywords: telmisartan, valsartan, leptin, insulin resistance, adiponectin
Introduction
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) plays a pivotal role in progressing insulin resistance and cardiovascular diseases including hypertension1, 2). Activation of PPAR-gamma may become a new therapeutic target to prevent hypertensive vascular, renal and perhaps brain changes in hypertension3). A recent study by Bensen et al. demonstrated that telmisartan, a structurally unique angiotensin II type 1 receptor blocker (ARB), can function as a partial agonist of PPARgamma, while no other commercially available ARBs appeared to activate PPARgamma4). In that study, telmisartan activated the expression of the PPARgamma gene involved in carbohydrate and lipid metabolism and reduced glucose, insulin and triglyceride levels in rats fed a high-fat and high-carbohydrate diet. In humans, Pershadsingh et al. first reported that 80 mg/day of telmisartan improved insulin resistance and reduced plasma triglycerides in a male patient with hypertension, visceral obesity (BMI 34.4 kg/m2) and impaired glucose tolerance (prediabetes)5). When the patient was switched to valsartan, the improvement of metabolic changes reversed. Then, switching back to telmisartan improved insulin sensitivity again5). This suggested that telmisartan predominantly improved insulin resistance compared with valsartan.
In addition to the effects of telmisartan on insulin resistance, it has recently been reported that telmisartan also affected adipocytokines such as leptin and adiponectin. Leptin is a 167-amino-acid-containing peptide that is specifically produced and secreted by mature adipocyte6). This adipocyte-derived protein acts in the hypothalamus to control appetite, energy expenditure and sympathetic nervous system outflow. Previous studies showed the close relationship of leptin with obesity and insulin resistance7). A very recent study by Usui et al. demonstrated that 20–40 mg of telmisartan for 3 or 6 months significantly reduced the fasting insulin level and the insulin resistance index estimated using homeostasis model assessment (HOMA-R) and that serum leptin significantly increased within 3 months in outpatients with both hypertension and type 2 diabetes mellitus for 6 months8). However, whether telmisartan affects the leptin level in the common nondiabetic patient with hypertension is unclear.
Adiponectin is a 30-kDa protein that is also specifically produced and secreted by mature adipocytes. Telmisartan treatment is considered to beneficially increase serum adiponectin. A recent study by Clasen et al. indicated that telmisartan induced adiponectin in adipocytes, which was associated with an improvement of parameters of insulin sensitivity and was likely mediated via PPARgamma activation involving a post-transcriptional mechanism9). Telmisartan treatment also decreased the weight of visceral adipose tissue and improved hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in diet-induced obese mice while also increasing the serum adiponectin and uncoupling protein 1 levels and reducing the serum resistin level10). However, the effect of telmisartan on increasing the serum adiponectin level was not sufficiently investigated in the common nondiabetic patient with hypertension.
The aim of this randomized crossover study was to evaluate the effects of telmisartan on improving insulin resistance and adipocytokines compared with valsartan, another major commercialized ARB available worldwide, in common nondiabetic outpatients with mild hypertension.
Methods
Subjects of the study
The study was approved by the ethics committees of Gifu University and Tohno-Kousei Hospital, and all patients gave written informed consent. The clinical significance and purpose of the study and the possible disadvantages of participation associated with switching medications in a crossover manner were explained in detail to each patient. Before enrollment in the study, we excluded patients who met the following exclusion criteria: 1)previous usage of the ARBs, 2) taking any medication considered to affect the PPAR and insulin resistance such as pioglitazone and fibrates, 3) taking medication for chronic heart diseases, 4) severe hepatic, respiratory or renal disease, failure, hematologic diseases or other grave complications, 5) oral steroid use and 6) history of poor drug compliance.
The subjects enrolled in the study were 50 nondiabetic outpatients with untreated mild hypertension. According to the guideline of the Japanese Society of Hypertension, values for systolic blood pressure of 140–159 mmHg or diastolic blood pressure of 90–99 mmHg are diagnosed as mild hypertension. After obtaining full informed consent from each participant, the participants were randomly divided into two groups, the initial telmisartan group and the initial valsartan group. The study subjects in the initial telmisartan group were treated with 40 mg/day of telmisartan for the first 3 months and were switched to a therapeutically equivalent dose of valsartan (80 mg/day) for the next 3 months. In contrast, those in the initial valsartan group were treated with 80 mg/day of valsartan for the first 3 months and then 40 mg/day of telmisartan for the next 3 months. Other kinds of medications used before the study, were allowed as concurrently taken drugs during the study, with the doses of these drugs being kept constant throughout the study periods. This study was carried out in accordance with the principles embodied in the Helsinki Declaration of 1995 (as revised in Edinburgh 2000).
Study protocol (Figure 1A)
Figure 1.
(A) Study protocol and (B) Flow chart of study participants.
The protocol of the study is shown in Figure 1A. Blood pressure was measured twice after resting for more than 15 minutes, and the lesser value was chosen. Each subject was examined for serum leptin, adiponectin and high sensitive C reactive protein (hsCRP), together with ordinary blood laboratory examinations including hepatic function and cholesterols, before, at one and three months after the start of the study and at three months after switching to the other ARB. The HOMA-R was used as the index of insulin resistance (a value of more than 2.5 is considered to indicate existence of insulin resistance). A fasting venous blood sample was obtained to measure blood laboratory data such as the plasma levels of cholesterols and glucose. These assays were performed using an automated analyzer (TBA-120FR, Toshiba, Tokyo, Japan). Each patient’s serum was immediately frozen at –70ºC, and serum adipocytokines were measured within 24 hours. Serum levels of leptin, adiponectin and hsCRP were measured using a leptin RIA kit (Linco Research, Inc., St. Charles, MO, USA), adiponectin ELISA kit (Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan) and N-latex CRP II kit (Dade Behring, Deerfield, IL, USA), respectively. The heights (measured to the nearest 0.1 cm), weights (measured to the nearest 0.1 kg) and waist circumferences (measured to the nearest 0.1 cm) of the subjects were measured by the same trained staff. Waist circumference was measured horizontally at the level of the umbilicus.
Statistical analyses
The significance level was set at 5%. Values of blood pressure, major blood laboratory data, BMI and waist circumference are presented as means ± SD. Comparisons between the initial telmisartan and initial valsartan groups in Table 1 were analyzed using Fisher’s exact test or the Mann-Whitney U test. Values of serum leptin, adiponectin, hsCRP and the HOMA-R index are presented as median and 25–75 percentiles. Statistical differences of blood pressure were analyzed by repeated measures one-way ANOVA and the Scheffe method as a post hoc test. Time-course changes in leptin, adiponectin, hsCRP, HOMA-R index and major blood laboratory tests were analyzed by the Friedman test and Wilcoxon signed-rank test with Bonferroni’s correction. Correlation between changes in Δleptin levels and ΔHOMA-R indexes for 3 months was examined with Spearman rank correlation. Statistical analyses were carried out using JMP, version 5.1.2 (SAS Institute Inc., Cary, NC, USA).
Table 1. Patient characteristics.
Results
Subjects
Ultimately, 42 nondiabetic patients with mild hypertension completed the study (Figure 1B). Patient characteristics are shown in Table 1. There was no statistical significance concerning the major indexes between the initial telmisartan and initial valsartan groups at enrollment in the study. During the study, the 42 subjects did not complain of any side effects.
Comparison of blood pressure between the two groups (Figure 2)
Figure 2.
Time-course changes in systolic and diastolic blood pressures over the study period. Statistical significance: *p<0.05, **p<0.01 and ***p<0.001 compared with the values at the start of the study.
Time-course changes in systolic and diastolic blood pressure in both groups are shown in Figure 2. In the initial telmisartan group, both the systolic and diastolic blood pressures were significantly improved one month after administration. This significant improvement in both blood pressures remained at three months after switching to valsartan. On the other hand, the changes in the systolic blood pressure were significantly decreased beginning one month after administration of valsartan in the initial valsartan group, while the diastolic blood pressure was not improved during the study period. As shown in Table 2, there were significant decreases in systolic blood pressure during each 3-month treatment period for telmisartan and valsartan. However, there was no statistical difference in the ΔSBP (3 months changes in systolic blood pressure) between both ARBs in males and females (p=0.122 and p=0.874, respectively). On the other hand, there were also significant improvements in the ΔDBP in both males and females in the telmisartan treatment group (p=0.004 and p<0.001, respectively), but there was no significant improvement in the ΔDBP in the female valsartan group (p=0.232). Accordingly, there was a significant difference in the ΔDBP between the female telmisartan and valsartan treatment groups (p=0.018).
Table 2. Comparative effects of telmisartan and valsartan during each 3 months treatment period.
| duration of telmisartan
treatment |
duration of valsartan
treatment |
p value
(statistical significance between both groups) |
||||
|---|---|---|---|---|---|---|
| Δ | p value (statistical significance compared with 0 M) |
Δ | p value (statistical significance compared with 0 M) |
|||
| Δ SBP (mmHg) | ||||||
| female | –15.5 ± 9.7 | <0.001 (***) | –9.7 ± 15.3 | 0.005 (**) | 0.122 | |
| male | –17.5 ± 10.1 | <0.001 (***) | –18.1 ± 10.8 | <0.001 (***) | 0.874 | |
| Δ DBP (mmHg) | ||||||
| female | –7.5 ± 6.5 | <0.001 (***) | –2.1 ± 8.6 | 0.232 | 0.018 (*) | |
| male | –6.5 ± 8.3 | 0.004 (**) | –8.1 ± 6.2 | <0.001 (***) | 0.529 | |
| Δ HOMA-R | ||||||
| female | –0.4 (–0.5, 0.3) | 0.391 | –0.2 (–0.4, 0.4) | 0.346 | 0.853 | |
| male | 0.0 (–0.1, 0.3) | 0.632 | –0.0 (–0.4, 0.3) | 0.795 | 0.704 | |
| Δ HOMA-R | ||||||
| (initaial value >/=2.5) | –0.3 (–0.7, –0.1) | 0.042 (*) | –0.8 (–1.4, –0.0) | 0.05 | 0.529 | |
| Δ leptin (ng/dL) | ||||||
| female | –2.7 (–4.0, –0.7) | <0.001 (***) | –2.5 (–4.5, –0.5) | <0.001 (***) | 0.853 | |
| male | –0.6 (–2.4, –0.5) | 0.106 | –0.8 (–1.6, –0.0) | 0.356 | 0.558 | |
| Δ adiponectin (ng/dL) | ||||||
| female | –1.1 (–1.8, –0.69) | 0.004 (**) | –0.9 (–2.6, 0.5) | 0.004 (**) | 0.948 | |
| male | –0.18 (–1.1, –0.75) | 0.632 | –0.1 (–0.7, 0.7) | 0.948 | 0.987 | |
| Δ hsCRP (mg/dL) | ||||||
| female | –0.002 (–0.018, 0.010) | 0.346 | 0.002 (–0.036, 0.011) | 0.438 | 0.869 | |
| male | –0.004 (–0.123, 0.032) | 0.317 | 0.002 (–0.116, 0.040) | 0.557 | 0.728 | |
| Δ hsCRP (mg/dL) | ||||||
| (initial value >/= 0.1) | –0.100 (–0.150, 0.042) | 0.044 (*) | –0.107 (–0.153, –0.036) | 0.015 (*) | 0.763 | |
Changes in insulin resistance
During the treatment period with telmisartan, although the changes were not significant, the values of IRI decreased from 9.4 ± 8.6 to 8.1 ± 13.4 (IU/L). The changes in the IRI tended to be remarkable in the high insulin resistance group (HOMA-R >/= 2.5), from 17.2 ± 10.9 to 13.1 ± 12.6 (IU/L; p=0.412). On the other hand, we found no change in the IRI during valsartan treatment period, from 8.5 ± 3.9 to 8.6 ± 4.7 (IU/L). We found no significant changes in the FBS values in both the telmisartan and valsartan treatment periods. As shown in Figure 3 (A), telmisartan significantly improved the levels of HOMA-R in the high insulin resistance group (the HOMA-R >/= 2.5) at one month after administration, while valsartan did not. In the high insulin resistance group of the initial valsartan group, the HOMA-R tended to decrease 3 months after changing from valsartan to telmisartan. In contrast, there were no statistically significant differences in either lower insulin resistance group (HOMA-R < 2.5). Furthermore, when evaluating the changes in the HOMA-R together with the male and female groups in each ARB treatment group, telmisartan significantly improved the ΔHOMA-R during the 3-month treatment periods, but valsartan did not (Table 2).
Figure 3.
Time-course changes in (A) the HOMA-R indexes, (B) serum leptin levels, (C) serum adiponectin levels and (D) serum hsCRP levels over the study period. Statistical significance: *p/3<0.05 and **p/3<0.01 compared with the values at the start of the study.
Changes in serum adipocytokines and hsCRP levels
As shown in Figure 3 (B), the serum leptin levels significantly improved at 3 months of the treatment in both female ARB groups (p=0.004 and p=0.009 compared with those at the start of the study, respectively). The significant improvement of serum leptin was lost three months after switching to valsartan in the female initial telmisartan group. In contrast, the significant improvement of the serum leptin levels at three months in the female initial valsartan group remained three months after changing to telmisartan (p=0.011). On the other hand, there were no significant changes in both male groups. Table 2 shows that the Δleptin over 3 months significantly decreased in both female ARB treatment groups, while it did not in the male groups. There was no significant difference in the value of Δleptin between the telmisartan and valsartan treatments for each 3-months period (Table 2). Serum adiponectin did not increase in both treatment groups.
The changes in hsCRP levels significantly decreased over the study period in the initial telmisartan group (p=0.019), while they did not in the initial valsartan group (p=0.266; Figure 3 (C)). Serum hsCRP was significantly improved after three months of treatment with telmisartan and significantly worsened at 3 months after the switch to valsartan. When selecting the subjects according to an initial hsCRP level of at least 0.1 mg/dL, we found a significant decrease in the value of ΔhsCRP over 3 months in both ARB treatment groups (Table 2).
Correlation to each index
The initial leptin levels at the start of the study were significantly correlated to the initial values of HOMA-R in both the male (p=0.001, R2=0.490, n=18 in total for both ARB groups) and female groups (p=0.002, R2=0.355, n=24 in total for both ARBs groups), respectively. As shown in Figure 4, the ΔHOMA-R (3M-0M) was significantly correlated to the ΔLeptin (3 M-0 M) in the female initial telmisartan group (p=0.021, R2=0.308 ), while it was not in the male initial telmisartan group and both initial valsartan groups. Furthermore, in this study, although we investigated the correlation among HOMA-R, leptin, adiponectin, hsCRP and blood pressure, we found no significant relationship in either ARB group (data not shown).
Figure 4.
Correlation between change in leptin levels and the HOMA-R indexes for 3 months.
Changes in blood laboratory examinations (Table 3)
Table 3. Time-course changes in major blood laboratory indexes over the study.
| Initial Telmisartan group |
Initial Valsartan group |
Statistical significance between two groups (0 M-3 M) (p value) |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| cross | Statistical significance (p value) |
cross | Statistical significance (p value) |
||||||||
| 0 M | 1 M | 3 M | 3 M | 0 M | 1 M | 3 M | 3 M | ||||
| UA (IU/L) | 5.36 ± 1.51 | 5.42 ± 1.37 | 5.55 ± 1.43 | 5.32 ± 1.40 | 0.134 | 5.41 ± 1.17 | 5.38 ± 1.32 | 5.55 ± 1.20 | 5.39 ± 1.19 | 0.58 | 0.923 |
| AST (IU/L) | 25.4 ± 12.3 | 23.6 ± 9.8 (†) | 23.1 ± 7.5 | 25.8 ± 9.1 (*) | 0.004 | 26.3 ± 8.6 | 25.1 ± 6.6 | 26.9 ± 9.3 | 29.3 ± 18.5 | 0.671 | 0.301 |
| ALT (IU/L) | 22.7 ± 13.4 | 20.2 ± 10.6 | 21.0 ± 10.2 | 24.4 ± 14.2 | 0.185 | 24.6 ± 12.4 | 24.2 ± 12.2 | 26.4 ± 13.7 | 29.2 ± 25.6 | 0.367 | 0.321 |
| γ-GTP (IU/L) | 32.2 ± 21.0 | 31.8 ± 21.6 | 31.4 ± 20.6 | 34.7 ± 34.0 | 0.956 | 30.8 ± 22.3 | 29.0 ± 19.9 | 30.8 ± 24.5 | 31.8 ± 21.3 | 0.767 | 0.728 |
| LDH (IU/L) | 213.8 ± 37.7 | 221.6 ± 42.2 | 211.4 ± 39.9 | 213.2 ± 39.1 | 0.215 | 210.8 ± 32.7 | 210.2 ± 34.3 | 207.4 ± 34.9 | 209.9 ± 31.7 | 0.441 | 0.313 |
| CK (IU/L) | 117.5 ± 69.7 | 124.5 ± 70.0 | 113.2 ± 84.3 | 112.8 ± 53.3 | 0.091 | 124.2 ± 78.6 | 127.5 ± 61.0 | 113.0 ± 62.3 | 123.0 ± 84.9 | 0.802 | 0.747 |
| HbA1c (%) | 5.87 ± 0.95 | 5.88 ± 0.95 | 5.86 ± 1.00 | 5.89 ± 0.99 | 0.87 | 5.90 ± 1.16 | 6.07 ± 1.51 | 5.98 ± 1.46 | 6.08 ± 1.63 | 0.33 | 0.593 |
| Total Cho (mg/dL) | 219.4 ± 35.7 | 222.3 ± 41.6 | 216.6 ± 35.2 | 223.6 ± 41.6 | 0.257 | 207.6 ± 27.5 | 208.6 ± 30.4 | 203.6 ± 27.5 | 209.7 ± 30.7 | 0.6 | 0.958 |
| HDL-C (mg/dL) | 58.8 ± 12.2 | 57.1 ± 15.4 (†) | 54.7 ± 13.8 (††) | 55.4 ± 13.6 (††) | 0.003 | 57.8 ± 17.2 | 55.8 ± 15.2 | 52.1 ± 15.7 (††) | 53.9. ± 14.7 (†) | < 0.001 | 0.7 |
| LDL-C (mg/dL) | 126.6 ± 39.5 | 129.7 ± 43.5 | 123.6 ± 38.8 | 129.0 ± 43.2 | 0.528 | 117.7 ± 25.5 | 118.2 ± 26.7 | 113.2 ± 28.0 | 114.4 ± 31.4 | 0.692 | 0.693 |
| TG (mg/dL) | 143.4 ± 95.3 | 152.3 ± 119.0 | 155.9 ± 116.8 | 143.3 ± 91.3 | 0.303 | 127.5 ± 72.0 | 151.7 ± 93.0 | 160.0 ± 111.7 | 164.8 ± 132.7 | 0.377 | 0.921 |
*p/3<0.05 compared with the value at the three months after the start (the Wilcoxon signed-rank test with Bonferroni’s correction). †p/3<0.05 and ††p/3<0.01 compared with the value at the start of the study (the Wilcoxon signed-rank test with Bonferroni’s correction).
Table 3 shows time-course changes in major blood laboratory indexes over the study period. The serum levels of AST significantly decreased in the initial telmisartan treatment group. The levels of HDL-C also decreased in the both ARB groups.
Discussion
In this study, we evaluated the differences in the effects of telmisartan and valsartan upon the insulin resistance, adipocytokines and inflammation in common nondiabetic patients with mild hypertension. First, we showed that telmisartan significantly improved insulin resistance in the HOMA-R >/= 2.5 group at one month after administration in nondiabetic patients with mild hypertension, while valsartan did not (Figure 3 (A)). Furthermore, HOMA-R tended to worsen after switching to treatment with valsartan in this HOMA-R >/= 2.5 initial telmisartan group. These results are not inconsistent with the report by Pershadsingh et al.5). In addition, telmisartan beneficially had no influence on insulin resistance in the normal range group (the HOMA-R<2.5). These findings suggest that telmisartan can significantly and beneficially improve insulin resistance in common nondiabetic patients with mild hypertension. A recent study by Benndorf et al. showed that telmisartan improved insulin sensitivity in nondiabetic patients with essential hypertension11). Another very recent study by Ichikawa also showed that HOMA-R was significantly reduced by telmisartan compared with the baseline value, but not by valsartan, in hypertensive patients with metabolic syndrome12). Our findings are consistent with those of the above studies. Although there was no significant difference between the initial ARB groups in the present study, there may have been a tendency for subjects who had high insulin resistance to be chosen in the initial valsartan group through the first process of randomization. However, if valsartan has a sufficient effect upon the improvement of insulin resistance, the drug should improve the HOMA-R in a prominent situation compared with telmisartan.
As it is well-known that leptin is linked to insulin resistance7), we confirmed that the leptin levels were significantly correlated with the initial values of HOMA-R in both the male and female groups at the start of the study (p=0.001 and p=0.002, respectively). Furthermore, we found a significant gender difference in leptin levels between the initial male and female groups; those of the women were higher than those of the men in both the initial telmisartan and valsartan groups (p=0.003 and p=0.005, respectively; Table 1), which is consistent with the results of Takizawa et al.13). In the present study, we showed that both telmisartan and valsartan significantly decreased the serum leptin levels in both female groups, not but in the male groups (Table 2 and Figure 3 (B)). We also demonstrated that the changes in HOMA-R over 3 months (ΔHOMA-R) were significantly correlated with those of leptin over 3 months (Δleptin) in the female initial telmisartan group, but not in the male telmisartan group or either gender valsartan groups (Figure 4). The above results suggest that the reductive effect of both ARBs on leptin appeared to occur through a different mechanism from the improvement of insulin resistance in common nondiabetic patients with mild hypertension.
According to the results of in vivo and animal model experiments9, 10), we initially began the study with the anticipation that telmisartan would significantly increase the serum adiponectin levels during the treatment period. However, the results in this study showed that serum adiponectin did not increase in both ARB treatment groups (Table 2). This may be partly caused by the dose-dependent effects of telmisartan. Although previous studies used 80 mg of telmisartan5), we used only 40 mg/day of telmisartan for the common nondiabetic patients with hypertension in this study. However, we also showed the possibility that telmisartan may directly activate the PPAR-gamma receptor and improve insulin resistance with an independent mechanism through adiponectin elevation. A recent study by Usui et al. also demonstrated that 20–40 mg of telmisartan significantly reduced the HOMA-R for 3 or 6 months and significantly increased serum leptin within 3 months in outpatients with both hypertension and type 2 diabetes mellitus, and the authors reported that total and high molecular adiponectin, fasting plasma glucose, HbA1c, total and HDLcholesterol, triglyceride, body weight, BMI and waist length were unchanged14). Another study by Benndor et al. also showed that telmisartan did not affect serum adiponectin levels in nondiabetic patients with essential hypertension, in spite of improving insulin sensitivity11). In addition, they demonstrated that telmisartan significantly enhanced PPAR-gamma receptor activity in vitro using a PPAR-gamma reporter gene assay, suggesting that telmisartan improved insulin sensitivity by mechanisms apparently not involving adiponectin induction11). A randomized, placebo-controlled, double-blind and crossover study by Nagel et al. also showed that 40 mg of telmisartan did not significantly increase the adiponectin level in nondiabetic insulin-resistant subjects over 12 weeks compared with a placebo, instead of the reduction of the HOMA-R15). A very recent in vitro study by Moriuchi et al. indicated that the transcription of the human adiponectin gene by telmisartan may be regulated by the independent mechanism of PPAR-gamma16). Considering all the above studies, the result in this study that telmisartan significantly improved insulin resistance with no elevation of adiponectin may be consistent.
Both telmisartan and valsartan also significantly reduced the serum hsCRP levels in the hsCRP level >/= 0.1 groups (Table 2), but telmisartan decreased the levels more effectively compared with valsartan (Figure 3 (C)). Previous studies have shown the anti-inflammatory effect of telmisartan. A previous study by Koulouris et al. showed the same reductive effect of telmisartan on hsCRP in patients with type 2 diabetes mellitus17). Pathophysiological crosstalk between advanced glycation endproducts (AGEs) and their receptor (RAGE) plays a pivotal role in the pathogenesis of accelerated atherosclerosis in diabetes18). Telmisartan downregulated RAGE mRNA and inhibited superoxide generation in mesangial cells via PPAR-gamma activation, while Candesartan did not19). Another study demonstrated that telmisartan decreased the serum levels of RAGE in patients with essential hypertension20). A recent study by Yoshida et al. showed that telmisartan dose-dependently inhibited AGE-induced CRP expression in a human hepatoma cell line, which indicated that telmisartan may play an anti-inflammatory role via PPAR-gamma activation21). Although the exact reason for the reductive effect on hsCRP in this study is unclear, this reduction may be partly mediated by the inhibition of AGE via PPAR-gamma activation.
In conclusion, this open-label, randomized crossover study showed that telmisartan significantly and beneficially improved the high status of insulin resistance in common nondiabetic patients with hypertension compared with valsartan. Telmisartan and valsartan significantly decreased the serum leptin levels in the female group, but not in the male group. However, we found no increase in the serum adiponectin levels during both ARB treatment periods. Both telmisartan and valsartan also significantly reduced the high status of serum hsCRP levels. These results may possibly be reflected by the difference in potency of PPAR-gamma activation between telmisartan and valsartan.
References
- 1.Hsueh WA, Law R. The central role of fat and effect of peroxisome proliferator-activated receptor-gamma on progression of insulin resistance and cardiovascular disease. Am J Cardiol 2003. 92: 3J–9J. doi: 10.1016/S0002-9149(03)00610-6 [DOI] [PubMed] [Google Scholar]
- 2.Schiffrin EL, Amiri F, Benkirane K, Iglarz M, Diep QN. Peroxisome proliferator-activated receptors: vascular and cardiac effects in hypertension. Hypertension 2003. 42: 664–668. doi: 10.1161/01.HYP.0000084370.74777.B6 [DOI] [PubMed] [Google Scholar]
- 3.Leibovitz E, Schiffrin EL. PPAR activation: a new target for the treatment of hypertension. J Cardiovasc Pharmacol 2007. 50: 120–125. doi: 10.1097/FJC.0b013e318062153b [DOI] [PubMed] [Google Scholar]
- 4.Benson SC, Pershadsingh HA, Ho CI, et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 2004. 43: 993–1002. doi: 10.1161/01.HYP.0000123072.34629.57 [DOI] [PubMed] [Google Scholar]
- 5.Pershadsingh HA, Kurtz TW. Insulin-sensitizing effects of telmisartan: implications for treating insulin-resistant hypertension and cardiovascular disease. Diabetes Care 2004. 27: 1015. doi: 10.2337/diacare.27.4.1015 [DOI] [PubMed] [Google Scholar]
- 6.Meinders AE, Toornvliet AC, Pijl H. Leptin. Neth J Med 1996. 49: 247–252. doi: 10.1016/S0300-2977(96)00039-3 [DOI] [PubMed] [Google Scholar]
- 7.Girard J. Is leptin the link between obesity and insulin resistance? Diabetes Metab 1997. 23 (Suppl 3): 16–24. [PubMed] [Google Scholar]
- 8.Usui I, Fujisaka S, Yamazaki K, et al. Telmisartan reduced blood pressure and HOMA-IR with increasing plasma leptin level in hypertensive and type 2 diabetic patients. Diabetes Res Clin Pract 2007. 77: 210–214. doi: 10.1016/j.diabres.2006.11.014 [DOI] [PubMed] [Google Scholar]
- 9.Clasen R, Schupp M, Foryst-Ludwig A, et al. PPARgamma-activating angiotensin type-1 receptor blockers induce adiponectin. Hypertension 2005. 46: 137–143. doi: 10.1161/01.HYP.0000168046.19884.6a [DOI] [PubMed] [Google Scholar]
- 10.Araki K, Masaki T, Katsuragi I, et al. Telmisartan prevents obesity and increases the expression of uncoupling protein 1 in diet-induced obese mice. Hypertension 2006. 48: 51–57. doi: 10.1161/01.HYP.0000225402.69580.1d [DOI] [PubMed] [Google Scholar]
- 11.Benndorf RA, Rudolph T, Appel D, et al. Telmisartan improves insulin sensitivity in nondiabetic patients with essential hypertension. Metabolism 2006. 55: 1159–1164. doi: 10.1016/j.metabol.2006.04.013 [DOI] [PubMed] [Google Scholar]
- 12.Ichikawa Y. Comparative effects of telmisartan and valsartan on insulin resistance in hypertensive patients with metabolic syndrome. Intern Med 2007; 46: 1331–1336. doi: 10.2169/internalmedicine.46.7173 [DOI] [PubMed] [Google Scholar]
- 13.Takizawa H, Ura N, Saitoh S, et al. Gender difference in the relationships among hyperleptinemia, hyperinsulinemia, and hypertension. Clin Exp Hypertens 2001. 23: 357–368. doi: 10.1081/CEH-100102673 [DOI] [PubMed] [Google Scholar]
- 14.Usui I, Fujisaka S, Yamazaki K, et al. Telmisartan reduced blood pressure and HOMA-IR with increasing plasma leptin level in hypertensive and type 2 diabetic patients. Diabetes Res Clin Pract 2007. 77: 210–214. doi: 10.1016/j.diabres.2006.11.014 [DOI] [PubMed] [Google Scholar]
- 15.Nagel JM, Tietz AB, Göke B, et al. The effect of telmisartan on glucose and lipid metabolism in nondiabetic, insulin-resistant subjects. Metabolism 2006. 55: 1149–1154. doi: 10.1016/j.metabol.2006.04.011 [DOI] [PubMed] [Google Scholar]
- 16.Moriuchi A, Yamasaki H, Shimamura M, et al. Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-gamma activation. Biochem Biophys Res Commun 2007. 356: 1024–1030. doi: 10.1016/j.bbrc.2007.03.084 [DOI] [PubMed] [Google Scholar]
- 17.Koulouris S, Symeonides P, Triantafyllou K, et al. Comparison of the effects of ramipril versus telmisartan in reducing serum levels of high-sensitivity C-reactive protein and oxidized low-density lipoprotein cholesterol in patients with type 2 diabetes mellitus. Am J Cardiol 2005. 95: 1386–1388. doi: 10.1016/j.amjcard.2005.01.092 [DOI] [PubMed] [Google Scholar]
- 18.Yamagishi S, Nakamura K, Imaizumi T. Advanced glycation end products (AGEs) and diabetic vascular complications. Curr Diabetes Rev 2005. 1: 93–106. doi: 10.2174/1573399052952631 [DOI] [PubMed] [Google Scholar]
- 19.Matsui T, Yamagishi S, Ueda S, et al. Telmisartan, an angiotensin II type 1 receptor blocker, inhibits advanced glycation end-product (AGE)-induced monocyte chemoattractant protein-1 expression in mesangial cells through downregulation of receptor for AGEs via peroxisome proliferator-activated receptor-gamma activation. J Int Med Res 2007. 35: 482–489. doi: 10.1177/147323000703500407 [DOI] [PubMed] [Google Scholar]
- 20.Nakamura K, Yamagishi S, Nakamura Y, et al. Telmisartan inhibits expression of a receptor for advanced glycation end products (RAGE) in angiotensin-II-exposed endothelial cells and decreases serum levels of soluble RAGE in patients with essential hypertension. Microvasc Res 2005. 70: 137–141. doi: 10.1016/j.mvr.2005.10.002 [DOI] [PubMed] [Google Scholar]
- 21.Yoshida T, Yamagishi S, Nakamura K, et al. Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation. Diabetologia 2006. 49: 3094–3099. doi: 10.1007/s00125-006-0437-7 [DOI] [PubMed] [Google Scholar]