Effects of ARB Or ACE-Inhibitor Administration on Plasma Levels Of

Effects of ARB or ACE-Inhibitor Administration on Plasma Levels of Aldosterone and Adiponectin in Hypertension Tetsuya Nakamura,1 MD, Kenji Kawachi,3 MD, Yuichiro Saito,2 MD, Tomoko Saito,1 MD, Koujurou Morishita,3 MD, Jin Hoshino,3 MD, Tsutomu Hosoi,3 MD, Tsutomu Iwasaki,3 MD, Yoshio Ohyama,3 MD, and Masahiko Kurabayashi,2 MD

Summary Aldosterone production causes vascular injury and may occur despite the long-term administration of angiotensin converting enzyme-inhibitors (ACE-I) (ie, aldosterone breakthrough). The angiotensin II receptor blocker (ARB) telmisartan can function as a ligand for peroxisome proliferator-activated receptor (PPAR) γ. Stimulation of PPAR γ has been demonstrated to raise adiponectin production and suppress angiotensin II type 1 receptor expression. Thus, we investigated the effect of the ACE-I perindopril erbumin (perindopril) and the ARB telmisartan on plasma levels of aldosterone and adiponectin. Patients with essential hypertension were randomly assigned to receive 48 weeks of perindopril (2-8 mg/d) or telmisartan (20-80 mg/d). We measured adiponectin, aldosterone, angiotensin II, and renin at weeks 0, 8, 24, and 48. A total of 53 subjects were randomized. Data on 51 subjects (25 in the perindopril group and 26 in the telmisartan group; mean age, 65.1 years) were available for analyses. Plasma aldosterone decreased significantly in both the telmisartan (69.9 ± 5.6 to 58.1 ± 5.4 pg/mL) and perindopril (74.1 ± 4.7 to 64.7 ± 5.3 pg/mL) groups at 8 weeks, but returned toward the baseline in the perindopril group (67.9 ± 4.1 pg/mL) at 24 weeks. Plasma glycated hemoglobin levels or urine albumin did not change significantly after the treatment in either group. Telmisartan seemed to be more effective at suppressing aldosterone and raising adiponectin levels than perindopril; however, improvements in insulin sensitivity and albuminuria were not detected. These results are consistent with the idea that the use of an ARB with PPAR γ stimulating activity is equivalent to ACE-I for the treatment of hypertension. (Int Heart J 2009; 50: 501-512)

Key words: Leptin, Renin, Angiotensin, Peroxisome proliferator-activated receptor

From the 1 Clinical Investigation and Research Unit, Gunma University Hospital, 2 Department of Medicine and Biological Science, Gunma University Graduate School of Medicine and 3 Gunma Aldosterone Study Group, Gunma, Japan. Address for correspondence: Tetsuya Nakamura, MD, Clinical Investigation and Research Unit, Gunma University Hospi- tal, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511 Japan. Received for publication December 18, 2008. Revised and accepted March 16, 2009. 501 Int Heart J 502 NAKAMURA, ET AL July 2009

ALDOSTERONE has been proposed to play a direct role in vascular toxicity and fibrosis, independent of its effects on volume homeostasis and hemody- namics;1-3) however, aldosterone production may occur despite the long-term administration of an angiotensin-converting enzyme inhibitor (ACE-I).4-6) This phenomenon has been termed aldosterone breakthrough, and may reverse the beneficial effects of ACE inhibition on left ventricular hypertrophy in hypertension or on proteinuria in diabetic nephropathy.7) Breakthrough of aldosterone production despite ACE inhibition has been shown in patients with hypertension, chronic heart failure, and acute myocardial infarction8); however, the mechanisms of aldosterone breakthrough have not been fully elucidated.8,9) Moreover, it has not been clearly determined whether aldosterone breakthrough similarly occurs in the treatment of hypertension with angiotensin II type 1 receptor (AT1R) blockers (ARB).9,10) A subgroup of ARBs has recently been characterized as agonists of peroxisome proliferator-activated receptor γ (PPAR γ) independent of their AT1R blocking actions.11,12) Two ARBs, telmisartan and irbesartan, have been identified as new selective PPAR modulators (SPPARMs).11,12) Thiazolidinediones, origi- nally identified as PPAR γ ligands, are currently being used as insulin sensitizers in the treatment of type 2 diabetes, and have been shown to enhance the mRNA and plasma levels of adiponectin.13,14) Interestingly, Ichiki, et al15,16) and others17) demonstrated that PPAR γ activators, including both troglitazone and telmisartan, reduced the expression of AT1R at the mRNA and protein levels through PPAR γ activation in cultured vascular smooth muscle cells. Thus, telmisartan may additionally suppress aldosterone production through the inhibition of AT1R expression. We therefore investigated the effects of the ACE-I perindopril erbumin (perindopril) and the ARB telmisartan on plasma levels of aldosterone and adiponectin.

Methods Patients with essential hypertension were randomly assigned to receive 48 weeks of perindopril (2-8 mg/d) or telmisartan (20-80 mg/d) and followed for 48 weeks. Hypertension was defined as a systolic BP > 140 mmHg or diastolic BP > 90 mmHg, measured by sphygmomanometry. Patients with secondary hypertension, based on the results of standard laboratory and radiology tests, and patients treated with ACE-Is or ARBs in the past 6 months, were excluded from the study. Patients previously treated with calcium channel blockers, α- or β-adrenergic blockers, or diuretics, alone or in combination, were not excluded. Patients also were advised to continue their current medications and lifestyle for the duration of the study. Important baseline demographic and clinical and treat- Vol 50 No 4 ALDOSTERONE AND ADIPONECTIN IN HYPERTENSION 503

Table I. Baseline Characteristics and Drug Regimen Administered in the Study Population Perindopril group Telmisartan group Total number (n) 27 26 Men/women (n) 11/16 12/14 Age (years) 63.0 ± 2.5 (38-82) 66.6 ± 2.5 (33-84) Body mass index (kg/m2) 24.1 ± 1.0 (18.5-37.4) 24.3 ± 0.6 (21.0-29.9) History of diabetes 5 3 History of hypercholesterolemia 8 11

History of hyperuricemia 1 1 History of heart disease Myocardial infarction 1 0 Coronary artery disease 2 1 Atrial fibrillation 0 1 History of cerebral infarction 0 2 Smoking 3 4 Habitual alcohol consumption 11 8 Baseline drug regimen Calcium channel blocker 13 14 Diuretics 5 4 α-Adrenergic blocker 4 2 β-Adrenergic blocker 6 8 Aspirin 1 1 Statin 4 8 α-Glucosidase inhibitor 1 1 Sulfonylurea 1 1 None 6 4 Values are means ± SEM (range).

ment characteristics of the study population are shown in Table I. Blood pressure was measured every 4 weeks. After an overnight fast, ve- nous blood samples were collected in the morning following 30 minutes of rest with the subject in a supine position before and 8, 24, and 48 weeks after starting telmisartan or perindopril. We measured plasma levels of high-sensitivity C-reactive protein (hs-CRP), adiponectin, leptin, aldosterone, angiotensin II, B-type natriuretic peptide (BNP), renin, and cortisol at weeks 0, 8, 24, and 48. We also measured the concentrations of glucose and glycated hemoglobin (HbA1c) and lipid variables at weeks 0, 24, and 48. This study was performed with the approval of the ethics committee of our institution, and written in- formed consent was obtained from all of the subjects prior to their enrollment. Plasma adiponectin levels were assayed using a human adiponectin ELISA kit (Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan). Plasma leptin levels were measured with a human leptin RIA kit (Cosmic Corporation, Tokyo). The interassay variation of the assay systems was 3.3-3.6% for adiponectin and 3.7-7.5% for leptin. Plasma renin concentration and aldosterone and cortisol Int Heart J 504 NAKAMURA, ET AL July 2009 levels were measured by solid phase radioimmunoassay. Plasma BNP levels were measured by chemiluminescent enzyme immunoassay. Plasma angiotensin II levels were measured by a double-antibody radioimmunoassay. The hs-CRP levels were determined with a high-sensitivity immunonephelomeric assay on a ProSpec protein analyzer with a coefficient of variation below 5% (N Latex CRP; Dade Behring Ltd., Milton Keynes, UK). Serum total cholesterol, LDL and HDL cholesterol, triglyceride levels, serum creatinine, and uric acid, as well as other hematologic and biochemical assays, were performed in the clinical chemical laboratory by certified standard methods. Statistical analysis: Numeric variables are expressed as the mean ± SEM. One- way analysis of variance was used to analyze the data of longitudinal observa- tion combined with the Newman-Keuls post hoc test. Statistical analysis was also performed using the Student t test. A power calculation indicated the need for about 60 participants to have a 2-sided α level of 0.05 and 80% power to detect a standardized effect size of 0.7 for plasma aldosterone. The Bonferroni cor- rection was applied to the probability values to adjust for multiple comparisons. For discreet variables, group differences were assessed using the Chi-square test. All of the analyses were performed using SPSS 15.0 J software (SPSS Inc., Chicago, IL, USA). A 2-tailed P < 0.05 was considered statistically significant.

Results A total of 53 subjects were randomized. The demographic characteristics of the 53 subjects enrolled are presented in Table I. Four out of 8 and 8 out of 11 patients with hypercholesterolemia were treated with statin in the perindopril and telmisartan groups, respectively. The 2 groups were well matched, without any significant differences in any baseline clinical or demographic characteristics. Clinical follow-up was obtained in 51 patients. In the perindopril group, 2 patients suffered from dry cough and were lost to follow-up. Data on 51 subjects (25 in the perindopril and 26 in the telmisartan group; mean age, 65.1 years; 51.0% men) were available for analysis. After randomization, systolic and diastolic blood pressures were lowered significantly (P < 0.05) by the treatments with perindopril or telmisartan. The finally administered doses of perindopril and telmisartan were averaged at 4.2 ± 0.4 mg/day and 44.6 ± 2.3 mg/day, respectively. The systolic and diastolic blood pressures after 48 weeks of treatment did not differ significantly between the perindopril (137.2 ± 1.9/77.0 ± 1.9 mmHg) and telmisartan (136.8 ± 2.6/76.8 ± 2.3 mmHg) groups (Figure 1). Vol 50 No 4 ALDOSTERONE AND ADIPONECTIN IN HYPERTENSION 505

Figure 1. Changes in blood pressure in both the perindopril and telmisartan groups. Data are mean ± SEM. Open and closed circles represent the perindopril and telmisartan groups, respectively. * P < 0.05, compared with the value before starting the treatments.

Table II. Laboratory Values at Baseline and Follow-up Perindopril group Telmisartan group Baseline Hematocrit (%) 40.8 ± 0.9 39.0 ± 0.8 Serum uric acid (mg/dL) 5.5 ± 0.3 5.0 ± 0.3 Serum creatinine (mg/dL) 0.77 ± 0.03 0.73 ± 0.05 Serum sodium (mEq/L) 141.7 ± 0.5 142.0 ± 0.4 Serum potassium (mEq/L) 4.0 ± 0.1 4.2 ± 0.1 Urine albumin/creatinine (mg/g Cr) 23.8 ± 8.3 58.2 ± 34.1

24-week follow-up Hematocrit (%) 40.5 ± 0.7 38.5 ± 1.0 Serum uric acid (mg/dL) 5.7 ± 0.3 5.0 ± 0.3 Serum creatinine (mg/dL) 0.79 ± 0.04 0.79 ± 0.07 Serum sodium (mEq/L) 141.9 ± 0.5 141.9 ± 0.6 Serum potassium (mEq/L) 4.3 ± 0.1 4.3 ± 0.1 Urine albumin/creatinine (mg/g Cr) 40.8 ± 23.2 55.5 ± 34.2

48-week follow-up Hematocrit (%) 40.9 ± 0.8 38.2 ± 0.9 Serum uric acid (mg/dL) 5.8 ± 0.4 4.9 ± 0.3 Serum creatinine (mg/dL) 0.80 ± 0.04 0.75 ± 0.06 Serum sodium (mEq/L) 141.9 ± 0.3 141.8 ± 0.4 Serum potassium (mEq/L) 4.3 ± 0.1 4.3 ± 0.1 Urine albumin/creatinine (mg/g Cr) 41.5 ± 21.8 47.9 ± 28.5 Values are means ± SEM. Int Heart J 506 NAKAMURA, ET AL July 2009

Table III. Laboratory Values at Baseline and Follow-up Perindopril group Telmisartan group Baseline Plasma glucose (mg/dL) 110 ± 6 113 ± 4 Hemoglobin A1c (%) 5.5 ± 0.2 5.6 ± 0.3 Low-density lipoprotein (mg/dL) 119 ± 7 116 ± 5 High-density lipoprotein (mg/dL) 51.7 ± 2.5 52.5 ± 4.6 Serum triglycerides (mg/dL) 152.7 ± 17.7 163.0 ± 20.6

24-week follow-up Plasma glucose (mg/dL) 118 ± 7 113 ± 7 Hemoglobin A1c (%) 5.5 ± 0.1 5.6 ± 0.3 Low-density lipoprotein (mg/dL) 122 ± 6 117 ± 5 High-density lipoprotein (mg/dL) 52.1 ± 2.1 51.1 ± 4.3 Serum triglycerides (mg/dL) 141.1 ± 11.4 174.6 ± 22.9

48-week follow-up Plasma glucose (mg/dL) 104 ± 4 112 ± 7 Hemoglobin A1c (%) 5.6 ± 0.2 5.7 ± 0.3 Low-density lipoprotein (mg/dL) 122 ± 6 112 ± 8 High-density lipoprotein (mg/dL) 54.1 ± 2.5 50.6 ± 4.1 Serum triglycerides (mg/dL) 133.8 ± 11.8 153.5 ± 18.2 Values are means ± SEM.

Figure 2. Changes in plasma renin and angiotensin II concentrations in both the perindopril and telmisartan groups. Data are mean ± SEM. Open and closed circles represent the perindopril and telmisartan groups, respectively. *P < 0.05, compared with the value before starting the treatments. † P < 0.05, compared with the value of the perindopril group.

No significant changes in hematocrit or the serum levels of uric acid, creatinine, sodium, or potassium were observed after the treatments in either group (Table II). The urine albumin/creatinine ratio did not change significantly in either group. There was no significant difference in the urine albumin/creatinine ratio between the groups (Table II). The serum levels of HDL- and LDL-choles- Vol 50 No 4 ALDOSTERONE AND ADIPONECTIN IN HYPERTENSION 507

Figure 3. Changes in plasma aldosterone and cortisol concentrations in the perindopril and telmisartan groups. Data are mean ± SEM. Open and closed circles represent the perindopril and telmisartan groups, respectively. *P < 0.05, compared with the value before starting the treatments.

Figure 4. Changes in plasma B-type natriuretic peptide and high-sensitivity C-reactive protein concentrations in the perindopril and telmisartan groups. Data are mean ± SEM. Open and closed circles represent the perindopril and telmisartan groups, respectively. terol, or triglycerides and the plasma levels of glucose or HbA1c did not differ significantly between the groups and also did not change significantly after the treatments in either group (Table III). Plasma renin concentration increased significantly (P < 0.05) in both the telmisartan (9.0 ± 2.7 to 31.1 ± 8.2 pg/mL) and perindopril (12.9 ± 2.4 to 26.0 ± 5.3 pg/mL) groups. Plasma angiotensin II increased significantly (2-fold) in the telmisartan group (8.5 ± 1.2 to 19.6 ± 4.8 pg/mL), but did not change significantly in the perindopril group (Figure 2). Plasma aldosterone decreased significantly in both the telmisartan (69.9 ± 5.6 to 58.1 ± 5.4 pg/mL) and perindopril (74.1 ± 4.7 to 64.7 ± 5.3 pg/mL) groups at 8 weeks, but returned toward the baseline in the perindopril group (67.9 ± 4.1 pg/mL) at 24 weeks (Figure Int Heart J 508 NAKAMURA, ET AL July 2009

Figure 5. Changes in plasma adiponectin and leptin concentrations in the perindopril and telmisartan groups. Data are mean ± SEM. Open and closed circles represent the perindopril and telmisartan groups, respectively. *P < 0.05, compared with the value before starting the treatments.

3). Plasma aldosterone in the telmisartan group was still significantly (P < 0.05) suppressed at 24 weeks and also at 48 weeks (59.4 ± 6.1 pg/mL) (Figure 3). Neither treatment resulted in a significant change in plasma cortisol, leptin, BNP, or hs-CRP (Figures 4 and 5). Plasma adiponectin increased significantly (P < 0.05) only in the telmisartan group (8.6 ± 1.2 to 9.5 ± 1.4 pg/mL) at 8 weeks, but did not change significantly in the perindopril group (Figure 5).

Discussion In this study, we showed that long-term treatment with the ARB telmisartan, which also functions as a ligand for the PPAR γ, was slightly more effective at suppressing aldosterone and raising adiponectin production than ACE-I perindopril in patients with hypertension; however, we could not detect any accompa- nying improvement in plasma glucose, HbA1c, urine albumin, BNP, hs-CRP, or lipid profile. These results are consistent with the idea that using an ARB with PPAR γ stimulating activity is equivalent to an ACE-I for vascular events in the treatment of hypertension.18) It has not been clarified whether aldosterone breakthrough is also observed in the treatment of human hypertension with ARB. In the present study, plasma aldosterone tended to return to the baseline level at 24 weeks in the perindopril group, implying occurrence of aldosterone breakthrough; however, we did not observe recovery of aldosterone levels in the telmisartan group. Recent studies have described the effects of aldosterone on nonepithelial tissues such as the heart.1-3) Aldosterone facilitates cardiac fibrosis and cardiac hypertrophy without affecting blood pressure. With regard to ACE-I, Sato, et Vol 50 No 4 ALDOSTERONE AND ADIPONECTIN IN HYPERTENSION 509 al5,6) showed that plasma aldosterone tends to increase with the duration of ACE-I treatment and may reverse the beneficial effects of ACE-I on left ventricular hypertrophy and proteinuria. Moreover, they showed that adding a min- eralocorticoid receptor antagonist to ACE-I reduced urinary albumin excretion in diabetic nephropathy.5,6) In our study, however, we could not detect a difference in urine albumin or plasma BNP between the perindopril and telmisartan groups. A large clinical trial has also shown that using ARBs with PPAR γ stimulating activity is equivalent to ACE-I for vascular events in the treatment of hypertension.18) Therefore, it is still unconfirmed whether aldosterone plays a different role during the treatment with an ARB compared to with an ACE-I. Adipose tissue was once thought to be simply a depot for fuel storage in the form of triglycerides. It is now known that adipocytes secrete a variety of proteins, such as tumor necrosis factor (TNF)-α, plasminogen activator inhibitor-1, leptin, resistin, and adiponectin.19) These proteins are implicated in a wide range of biological effects. Adiponectin has been suggested to enhance insulin sensitivity and prevent atherosclerosis.20-22) Antihypertenisve drugs, such as ACE-I and ARB, have been reported to improve insulin sensitivity.23) Sharma, et al24) have hypothesized that RAS blockade promotes the recruitment and differentiation of preadipocytes and that increased formation of metabolically efficient adipocytes counteracts the ectopic deposition of lipids in muscle and liver, thereby improving insulin sensitivity. Increased formation of these adipocytes may also result in a greater net capacity for adiponectin production. The ARBs losartan and candesartan increase adiponectin plasma levels in patients with essential hypertension.23,24) In the present study, the treatment with telmisartan also increased adiponectin; however, ACE-I perindopril did not change adiponectin, despite an increase in plasma renin concentration similar to that of the telmisartan group. These results suggest that treatment with telmisartan could influence other mechanisms to regulate adiponectin production in addition to RAS blockade. One possible mechanism to raise adiponectin may be PPAR γ stimulation in the telmisartan group. Although designed to bind to the AT1R, a subset of ARBs that includes telmisartan has the potential to activate the insulin-sensi- tizing nuclear hormone receptor PPAR γ, completely independent from their AT1R blocking properties.25-27) Benson, et al27) showed that the potent PPAR γ -activating ARB telmisartan improved insulin sensitivity in rats fed a high-fat diet, whereas losartan had no effect. In addition, they showed that adiponectin expression in adipocytes and fat tissue was solely up-regulated by PPAR γ -activating ARBs, whereas non-PPAR-activating ARBs had no effect.27) The effect of telmisartan on adiponectin production in human hypertension is controversial. Some groups have indicated that telmisartan increases Int Heart J 510 NAKAMURA, ET AL July 2009 adiponectin,28,29) while others reported that telmisartan had no effect.30,31) In the present study, we observed a slight but significant rise in plasma adiponectin at 8 weeks after starting telmisartan; however, plasma glucose, HbA1c, hs-CRP, plasma LDL, and HDL were unchanged. Thus, we did not observe improvements in insulin sensitivity or lipid metabolism. Although it is reasonable to measure insulin sensitivity by more sensitive methods, such as the HOMA index, these observations suggest that the magnitude of telmisartan to stimulate PPAR γ may be modest compared with thiazolidinediones. PPAR γ has been demonstrated to repress the expression of the leptin ob gene in vitro;32) however, a number of studies indicate that the plasma leptin level did not change significantly after pioglitazone treatment in diabetic patients.13,33) The lack of effect of telmisartan on circulating leptin levels in our study is consistent with these clinical data. Angiotensin II did not decrease in the perindopril group; however, the blood pressure levels were comparable between the perindopril and telmisartan groups during the treatments. These data raise the possibility that angiotensin II may have still been produced by chymase34) despite the inhibition of ACE by perindopril, and that the degradation of bradykinin by kininase II35) may have been retarded by ACE-I and had a role in lowering blood pressure in the perindopril group. It has already been reported that plasma angiotensin II levels returned to baseline following the long-term administration of ACE-I in patients with hypertension36) or congestive heart failure.37) In conclusion, telmisartan was more effective at suppressing aldosterone and raising adiponectin levels than perindopril; however, we were unable to detect any evidence indicating an improvement in insulin sensitivity, albuminuria, or lipid metabolism. These results are consistent with the idea that the use of ARBs with PPAR γ stimulating activity is equivalent to ACE-I for the treatment of hypertension.

Acknowledgments This work was supported in part by a Grant-in-Aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 17590705).

Disclosure Statement Dr. Nakamura reports receiving grant support from Boehringer Ingelheim. Vol 50 No 4 ALDOSTERONE AND ADIPONECTIN IN HYPERTENSION 511

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