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Effects of the Peroxisomal Proliferator-Activated Receptor- Agonist Pioglitazone on Renal and Hormonal Responses to Salt in Healthy Men

Division of Hypertension and Vascular Medicine, Department of Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland

Address all correspondence and requests for reprints to: Dr. Anne Zanchi, Division of Hypertension and Vascular Medicine, Avenue P. Decker, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland. E-mail: azanchidel{at}hotmail.com.

	Abstract

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Glitazones are used in the treatment of type 2 diabetes as efficient insulin sensitizers. They can, however, induce peripheral edema through an unknown mechanism in up to 18% of cases. In this double-blind, randomized, placebo-controlled, four-way, cross-over study, we examined the effects of a 6-wk administration of pioglitazone (45 mg daily) or placebo on the blood pressure, hormonal, and renal hemodynamic and tubular responses to a low (LS) and a high (HS) sodium diet in healthy volunteers. Pioglitazone had no effect on the systemic and renal hemodynamic responses to salt, except for an increase in daytime heart rate. Urinary sodium excretion and lithium clearance were lower with pioglitazone, particularly with the LS diet (P < 0.05), suggesting increased sodium reabsorption at the proximal tubule. Pioglitazone significantly increased plasma renin activity with the LS (P = 0.02) and HS (P = 0.03) diets. Similar trends were observed with aldosterone. Atrial natriuretic levels did not change with pioglitazone. Body weight increased with pioglitazone in most subjects. Pioglitazone stimulates plasma renin activity and favors sodium retention and weight gain in healthy volunteers. These effects could contribute to the development of edema in some subjects treated with glitazones.

	Introduction

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GLITAZONES, SYNTHETIC LIGANDS of peroxisomal proliferator-activated receptor (PPAR) are currently used in the treatment of type 2 diabetes, as efficient insulin sensitizers alone or in combination with metformin, sulfonylureas, or insulin. PPAR agonists have been found to induce peripheral edema. According to the manufacturer’s data, the incidence of peripheral edema with pioglitazone and rosiglitazone administered as monotherapy is approximately 5% and 4.8%, respectively, and these figures can increase up to 15.3% and 14.7% when glitazones are combined with insulin (1, 2, 3). Glitazone-induced edema is often mild in nature and does not require discontinuation of the drug. However, in one recent study in which 116 patients receiving a PPAR agonist were followed for 4–5 months, 18.1% of the patients developed edema, among whom 53% needed discontinuation of therapy because they were unresponsive to diuretics (furosemide and/or thiazide) (4). Also, there are case reports of pulmonary edema occurring in patients receiving glitazones (5, 6, 7). Based on these clinical observations, it has been recommended to restrict the use of glitazones to individuals without congestive heart failure New York Heart Association class III or IV because of the risk of aggravation of heart failure, particularly in insulin-treated individuals (4).

The mechanism(s) of glitazone-induced edema is not well understood. Hence, several hypothesis have been proposed. One of them is that glitazones increase the sensitivity to insulin at the renal level, leading to sodium retention. This hypothesis, however, has never been clearly demonstrated in humans. Alternatively, renal sodium retention could occur as a secondary response to peripheral vasodilatation consecutive to vascular effects of glitazones (8). Finally, PPAR agonists could have a direct renal tubular effect, as PPAR receptors have been identified in renal tubular cells, in particular in the ascending limb, distal tubules, and collecting duct (9).

The goal of this placebo-controlled, randomized, cross-over study was to examine the effects of pioglitazone (45 mg daily for 6 wk) on the renal and hormonal responses to changes in sodium intake in noninsulin-resistant, healthy, male volunteers.

	Subjects and Methods

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Ten healthy male subjects, aged 22–28 yr, were included in this study. Their body weight was 70.6 ± 2.3 kg (mean ± SEM; range, 58.5–80), and their body mass index was 21.6 ± 0.5 kg/m² (mean ± SEM; range, 19.1–24.3). A full medical history was obtained, and a complete physical examination was realized before inclusion. Subjects receiving drug therapy were excluded. An oral glucose tolerance test with 75 g glucose was performed before inclusion to guarantee that none of the subjects was glucose intolerant or diabetic. The protocol was approved by the local hospital ethical committee, and written informed consent was obtained from each subject.

Procedure

The study had a double-blind, randomized, placebo-controlled, 2-fold cross-over design as described in Fig. 1. A total of 36 ambulatory blood pressure measurements and hormonal and renal function studies were obtained. Each subject was randomized to receive either pioglitazone (45 mg daily) or placebo daily for 6 wk, with a 2-wk washout period between the two treatment phases. Drug compliance was measured using an electronic monitor, recording the date and time of each pillbox opening (MEMS, Aardex, Switzerland) (10). Once a week, the activity of -glutamyl transferase (GT), aspartate aminotransferase (ASAT), or alanine aminotransferase (ALAT) was measured to monitor drug tolerance. If any increase was observed, the subject was dropped from the study. From wk 1–4, subjects received their usual diet. During wk 5 and 6 of each treatment phase (placebo or pioglitazone), subjects received a low sodium (LS) and a high sodium (HS) diet for 1 wk. The sequence of the diets was randomized, but each volunteer received the same sequence while on placebo and on pioglitazone. The LS diet was provided in the hospital, all meals being composed by a dietitian to reach a sodium intake of approximately 20 mmol/24 h. The HS diet was obtained by adding 6 g salt to the subject’s regular diet (sodium intake, >200 mmol/24 h). On the sixth day of each dietary period, 24-h ambulatory blood pressure was recorded, with measurements performed at 20-min intervals from 0800–2200 h and at 30 min from 2200–0800 h (Profilomat, Disetronic, Switzerland). Simultaneously, 24-h urine samples were collected to measure sodium, potassium, and endogenous trace lithium excretions. Participants were instructed not to smoke or drink alcohol or any caffeine-containing beverages during that day. On the following day, the participants were investigated in the research unit after an overnight fast and underwent clearance studies as reported previously (11). In brief, two iv catheters were inserted into antecubital veins, one for the infusion of inulin and p-aminohippurate (PAH) and a second into the contralateral forearm for drawing blood. After an oral water load of 8 ml/kg and a 2-h equilibration period, two 1-h inulin and PAH clearances were obtained to measure the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Renal blood flow was calculated by dividing the ERPF by the hematocrit. Blood was also drawn to measure serum electrolytes, including endogenous trace lithium, as well as plasma renin activity (PRA), plasma aldosterone, atrial natriuretic factors, and hematocrit. Blood sampling for hormonal measurements was performed while subjects were supine after a 1-h rest and before the water load.

View larger version (12K): [in this window] [in a new window]   FIG. 1. Four weeks of pioglitazone/placebo treatment during a normal diet, followed by 1 wk (wk 5) on diet 1, followed by 1 wk (wk 6) on diet 2, followed by a 2-wk washout period. Diets were either HS or LS and were randomized, but each sequence was the same for a given volunteer. ABPM, Ambulatory blood pressure measurement; U24, 24-h urine collection.

Insulin sensitivity indexes were assessed by homeostasis model assessment for insulin resistance (HOMA-IR), log HOMA-IR, or quantitative insulin sensitivity check index (QUICKI) (12). Urinary and plasma sodium and potassium were measured by flame photometry (IL-943, Instrumentation Laboratory, Milan, Italy), and creatinine was determined by the picric acid method (Cobas-Mira, Roche, Basel, Switzerland). The hematocrit was determined using microhematocrit tubes. Plasma and urinary inulin and PAH were determined by photometry (Autoanalyzer II-Technicon, Bran & Luebbe, Norderstedt, Germany). Endogenous trace lithium was measured by atomic absorption spectrophotometry as described previously (13). PRA (14), plasma aldosterone (15), and atrial natriuretic peptide (16), were determined as described previously (17). Plasma insulin was determined by RIA (Insulin-RIA, Pharmacia Biotech, Dubendorf, Switzerland).

The urinary electrolyte excretion rate was calculated as U_x x V (micromoles per minute), and clearances (milliliters per minute) were calculated using the standard formula C_x = U_x x V/P_x, where U_x and P_x are the urinary and plasma concentrations of x, and V is the urine flow rate in milliliters per minute. The filtration fraction was calculated by dividing the GFR by the ERPF.

Statistical analysis

Data are expressed as the mean ± SEM. The statistical differences between the two periods of treatment (placebo and pioglitazone) and the two diets were evaluated by ANOVA, followed by paired t test. To examine the specific effects of pioglitazone in the same individual, the values obtained with placebo were subtracted from the values obtained with pioglitazone. The significance was examined by a one-sample t test for a significant difference from 0, with the zero value indicating no change. P < 0.05 was considered statistically significant.

	Results

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Baseline characteristics of the subjects and tolerability profile

One subject dropped out of the study due to intense low back pain and ingestion of nonsteroidal antiinflammatory drugs. At baseline, the mean body mass index of the nine subjects who completed the entire study was 21.5 ± 0.5 kg/m² (mean ± SEM), baseline systolic and diastolic blood pressures were 116.8 ± 2.8 and 71.6 ± 2.2 mm Hg, and pulse rate was 64 ± 2 beats/min. Blood sugar levels determined during the glucose tolerance test were 4.7 ± 0.1 mmol/liter at 0 min and 5.2 ± 0.4 mmol/liter 2 h after administration of 75 g glucose. The serum cholesterol level was 4.1 ± 0.3 mmol/liter, the high density lipoprotein cholesterol level was 1.2 ± 0.1 mmol/liter, and the triglycerides level was 0.9 ± 0.1 mmol/liter. Serum levels of GT, ASAT, and ALAT were all in the normal range. Microalbuminuria was less than 20 mg/liter in all volunteers. No increase in ASAT, ALAT, or GT was observed in any subject. One subject complained of headache during pioglitazone treatment. No subject developed edema, and the hematocrit remained unchanged with both treatments.

Compliance with drug therapy was excellent, with an average taking compliance of 99.7 ± 1% (mean ± SEM). There was no difference in compliance between placebo and pioglitazone.

Metabolic effects of pioglitazone

Insulin sensitivity indexes, as assessed by HOMA-IR, log HOMA-IR, or QUICKI (12), did not change significantly with pioglitazone treatment (Table 1). Similarly, the lipid profile (Table 1) and hematocrit did not change with pioglitazone or placebo administration. When receiving the placebo, subjects lost 1.46 kg under the LS diet (P = 0.025 vs. baseline), whereas weight loss was only 0.756 kg with pioglitazone (P = NS). On a HS diet, body weight change from baseline was comparable with both treatments (70.8 ± 2.4 kg in the placebo and 71.4 ± 2.5 kg in the pioglitazone phase; P = NS). Some individuals gained substantially more weight on pioglitazone compared with placebo than others. The maximum weight gain was 2.9 kg on a LS diet (range, -1 to +2.9 kg) and 3.4 kg on a HS diet (range, -1.5 to +3.4).

The changes in daytime and nighttime blood pressure are shown in Table 2. The salt diet had no effect on 24-h and daytime blood pressures. However, a significant increase in nighttime systolic blood pressure was found on a high sodium intake. This increase was comparable with placebo and pioglitazone. Overall, pioglitazone had no effect on daytime and nighttime blood pressures. The only significant effect of pioglitazone was an increased heart rate during the day, which reached statistical significance only on a LS diet.

The diet-induced changes in urinary sodium excretion with pioglitazone and placebo are presented in Table 3. Overall, urinary sodium excretion and lithium clearances were lower with pioglitazone than with placebo. When examining the pioglitazone-induced changes from values measured during placebo in each subject, urinary sodium excretion was lower during the pioglitazone phase than during the placebo phase on the LS diet (median, -12.2 mmol/24 h; range, -21 to +8.7 mmol/24 h; P = 0.05) and on the HS diet (median, -30 mmol/24 h; range, -344 to +69 mmol/24 h; P = NS). Likewise, the clearance of sodium at the proximal level as estimated by lithium clearance was lower during the pioglitazone phase on the LS diet (median, -4.9 ml/min; range, -14.4 to +1.5 ml/min; P = 0.01) and on the HS diet (median, -2 ml/min; range, -43 to +8.5 ml/min; Fig. 2). Statistical significance, however, was only reached with the LS diet.

View larger version (12K): [in this window] [in a new window]   FIG. 2. Pioglitazone-induced changes in lithium clearance from values obtained with placebo on the LS or HS diet. , Mean values with SEM.

The salt-induced changes in PRA, plasma aldosterone, and atrial natriuretic peptide (ANP) levels are presented in Table 4. As expected, PRA and plasma aldosterone decreased significantly on a high salt intake, whereas plasma ANP levels increased significantly. Comparing the pioglitazone and placebo phases in the same subjects, PRA was significantly higher with pioglitazone and the LS diet (median, 0.16 ng/ml·h; range, -0.07 to +0.8; P = 0.02) or the HS diet (median, 0.09 ng/ml·h; range, -0.1 to 0.21; P = 0.03; Fig. 3). Plasma aldosterone was higher with pioglitazone during the LS and HS diets, but the difference did not reach statistical significance. The ANP levels were similar during placebo and pioglitazone administration whatever the sodium intake.

View larger version (12K): [in this window] [in a new window]   FIG. 3. Pioglitazone-induced changes in PRA from values obtained with placebo on the LS or HS diet. , Mean values with SEM.

	Discussion

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Pioglitazone decreases blood pressure in animal models of hypertension as well as in diabetic and nondiabetic hypertensive subjects (18, 19). In the present study blood pressure was monitored over 24 h using a validated ambulatory blood pressure-measuring device to obtain the most reliable data outside the physician’s office. We found no significant effect of pioglitazone on blood pressure or on the blood pressure response to salt. The absence of effect may be due to the fact that we investigated healthy normotensive subjects with normal insulin sensitivity and that the glitazone-induced decrease in blood pressure occurs primarily when baseline blood pressure is elevated and/or when there is a glitazone-induced change in insulin sensitivity. Alternatively, as blood pressure was measured only after 6 wk of administration, we cannot exclude that pioglitazone induced a transient decrease in blood pressure counterbalanced by an activation of the renin-angiotensin and the sympathetic nervous systems leading to sodium retention and weight gain. In this respect, it is interesting to note the significant increase in daytime heart rate in our subjects when they were receiving pioglitazone. The increase in heart rate was present on both diets, but was statistically significant only on a low sodium diet, i.e. when the ability to compensate with sodium retention was the least effective. In the supine position during the night, the effect of pioglitazone on heart rate was not observed. Thus, one could postulate that pioglitazone induces peripheral vasodilatation in normotensive subjects that is compensated by the hormonal and renal responses. It is generally assumed that the blood pressure-lowering effect of glitazones is due to the improvement in insulin sensitivity and endothelial function leading to increased nitric oxide production. In addition to these chronic effects, there may be more acute effects, as experimental studies showed that PPAR agonists have a direct vascular effect by inhibiting vascular smooth muscle cell calcium currents (20, 21), reducing endothelin-1 secretion in endothelial cells (22), or modulating the endogenous production of ET-1 in endothelin-dependent hypertension (23). Fujishima et al. (24) reported that a single oral dose of troglitazone increased forearm vasodilation in healthy volunteers independently of any change in glucose, insulin, or nitrate ion levels.

In the kidney, pioglitazone had no significant effect on renal hemodynamics and did not affect the renal hemodynamic response to salt. Indeed, as observed previously in men, the HS diet induced an increase in the GFR with no change in renal plasma flow (25). The change in GFR was not modulated by pioglitazone. These results therefore contrast with the recent experimental data showing that troglitazone has a dual effect on isolated afferent and efferent renal arterioles independently of its influence on insulin sensitivity (26). Yet, the administration of pioglitazone had a significant impact on two other functions of the kidney, i.e. renin secretion and renal sodium handling.

As expected, PRA and plasma aldosterone levels were significantly higher with the LS diet than with the HS intake (25). However, whatever the sodium intake, PRA was significantly higher with pioglitazone than with placebo, suggesting that pioglitazone stimulates renin independently from the level of sodium intake. A similar pattern was observed with plasma aldosterone, but the pioglitazone-induced changes in aldosterone did not reach statistical significance. This is the first report of an activation of the renin-angiotensin system by glitazones in humans. Of note, the effect of pioglitazone on renin activity is not only independent of the sodium intake, but it occurs in subjects who gained weight, probably through sodium retention. Considering the changes in heart rate described above, the increase in PRA could represent a compensatory mechanism to the glitazone-induced peripheral vasodilatation (27). However, we cannot exclude other direct or indirect effects of pioglitazone on PRA. PPAR activation with troglitazone has been found to reduce angiotensin II AT₁ receptor expression and the calcium response to angiotensin II in vascular smooth muscle cells (28). The same effects were observed in vivo in angiotensin II-infused rats (29). In this model, pioglitazone attenuated the development of hypertension and endothelial dysfunction, and prevented the up-regulation of angiotensin II type 1 receptors in mesenteric arteries of angiotensin II-infused rats. According to these experimental observations, one could hypothesize that pioglitazone blunts the angiotensin II-mediated negative feedback on renin secretion. The PPAR agonist could also increase angiotensinogen expression in adipose tissue, leading to an increase in the substrate of renin, but the effects of glitazones on angiotensinogen expression have been contradictory (30, 31).

Sodium retention by the kidney was recognized as one possible mechanism by which glitazones could produce peripheral edema and increase body weight. However, no clinical study has ever demonstrated in humans that glitazones affect the renal handling of sodium. In our study urinary sodium excretion was lower with pioglitazone than with placebo whatever the sodium diet. A steady state in sodium excretion is generally obtained 4–5 d after a change in sodium intake (32). The lower values of urinary sodium excretion with pioglitazone suggest a delay in reaching a steady state. Moreover, lithium clearance, an indirect measurement of renal proximal sodium reabsorption, was lower during the administration of pioglitazone, suggesting an increased reabsorption of sodium in the proximal tubule. The effect of pioglitazone on sodium excretion was particularly significant when the subjects were receiving the LS diet under well controlled conditions in the hospital. On a HS diet, the difference was also present, but due to the individual variability, it did not reach statistical significance. The ability of pioglitazone to increase sodium reabsorption by the proximal tubule, particularly on a low salt intake, is in accordance with the smaller weight loss during salt restriction observed when subjects were receiving pioglitazone.

Pioglitazone-induced sodium retention occurred in the absence of any significant variation in renal hemodynamics. Considering the effects of pioglitazone on PRA and plasma aldosterone, the ability of PPAR agonists to increase renal sodium reabsorption is most likely due to the activation of the renin-aldosterone system. Yet, one cannot exclude a direct tubular effect of pioglitazone or an indirect effect mediated by a change in insulin sensitivity at the renal level or an activation of the sympathetic nervous system. Of note, PPAR nuclear receptors have been identified in cultured glomerular mesangial cells, endothelial cells, and renal tubules (9, 33, 34).

As expected, the high sodium diet induced a significant increase in ANP due to volume expansion. However, despite sodium retention with pioglitazone, there was no increase in plasma ANP levels, suggesting a certain degree of peripheral vasodilation and volume redistribution.

Among each treatment-diet group, there was no correlation among the degree of sodium retention, PRA, weight gain, and blood pressure. However, because of the small number of subjects, this study did not have the power to examine correlations. It was designed to examine the variations in renal and hormonal responses to salt with pioglitazone in the same subject. When analyzing subjects according to their blood pressure response to salt (increase in blood pressure from LS to HS under placebo), subjects showing the greatest increase in blood pressure upon salt loading retained more salt with pioglitazone that those with a small blood pressure response to salt. However, because of the small number of subjects studied, we cannot conclude definitely whether the salt sensitivity of blood pressure increases the risk of sodium retention. A larger case-control study should address this issue.

To reconcile these findings and those of former studies, we hypothesize that renal sodium retention induced by glitazones is favored by an activation of the renin angiotensin system and possibly sympathetic nervous system due to peripheral vasodilation (27) (Fig. 4). In addition, glitazones may induce sodium retention through either an activation of PPAR receptors at the renal tubular level or the enhancement of insulin action on the kidney.

View larger version (22K): [in this window] [in a new window]   FIG. 4. Possible mechanisms involved in glitazone-induced edema.

	Footnotes

 
This work was supported by a grant from the Swiss National Fund (Grant 31-63947.00) (to M.B.) and a grant from the Faculty of Medicine (to A.Z.) to support the development of academic careers for women.

Abbreviations: ALAT, Alanine aminotransferase; ANP, atrial natriuretic peptide; ASAT, aspartate aminotransferase; ERPF, effective renal plasma flow; GFR, glomerular filtration rate; GT, -glutamyl transferase; HOMA-IR, homeostasis model assessment for insulin resistance; HS, high sodium; LS, low sodium; PAH, p-aminohippurate; PPAR, peroxisomal proliferator-activated receptor; PRA, plasma renin activity; QUICKI, quantitative insulin sensitivity check index.

Received September 3, 2003.

Accepted November 18, 2003.

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