Summary
Background and objectives Thiazolidinediones (pioglitazone and rosiglitazone) induce renal epithelial sodium channel (ENaC)–mediated sodium reabsorption, resulting in plasma volume (PV) expansion. Incidence and long-term management of fluid retention induced by thiazolidinediones remain unclear.
Design, setting, participants, & measurements In a 4-week run-in period, rosiglitazone, 4 mg twice daily, was added to a background anti-diabetic therapy in 260 South Indian patients with type 2 diabetes mellitus. Patients with PV expansion (absolute reduction in hematocrit in run-in, ≥1.5 percentage points) entered a randomized, placebo-controlled study to evaluate effects of amiloride and spironolactone on attenuating rosiglitazone-induced fluid retention. Primary endpoint was change in hematocrit in each diuretic group versus placebo (control group).
Results Of the 260 patients, 70% (n=180) had PV expansion. These 180 patients (70% male; mean age, 47.8 years [range, 30–80 years]) were randomly assigned to rosiglitazone, 4 mg twice daily, plus spironolactone, 50 mg once daily; rosiglitazone, 4 mg twice daily, plus amiloride, 10 mg once daily; or rosiglitazone, 4 mg twice daily, plus placebo for 24 weeks. Hematocrit continued to decrease significantly in control and spironolactone groups (mean absolute change, −1.2 [P=0.01] and −0.7 [P=0.02] percentage points, respectively), suggesting continued PV expansion. No change occurred with amiloride (mean change, 0.0 percentage points). Amiloride, but not spironolactone, was superior to control (mean hematocrit difference [95% confidence interval] relative to control, 1.27 [0.21–2.55] and 0.49 [−0.79–1.77] percentage points [P=0.04 and P=0.61], respectively).
Conclusions Prevalence of rosiglitazone-induced fluid retention in South Indian patients with type 2 diabetes is high. Amiloride, a direct ENaC blocker, but not spironolactone, prevented protracted fluid retention in these patients.
Introduction
Peroxisome proliferator–activated receptor-γ (PPARγ) agonists, such as rosiglitazone and pioglitazone, belong to the thiazolidinedione class of drugs. These insulin sensitizers are used as monotherapy or in combination with other oral agents or insulin for treating type 2 diabetes mellitus (T2DM) (1). Both rosiglitazone and pioglitazone induce fluid retention, which in some cases may precipitate or exacerbate pulmonary edema and congestive heart failure (2).
Rosiglitazone was recently withdrawn or has had its use limited in several countries because of concerns about adverse cardiac outcomes that may, at least in part, be related to plasma volume expansion (3,4). Dual PPARα/PPARγ agonists, which are in development for treatment of T2DM, can also cause fluid retention and edema and may precipitate congestive heart failure (5).
PPARγ is expressed in the human renal cortical collecting duct, a segment of the nephron that regulates sodium and water homeostasis via action of the epithelial sodium channel (ENaC) (6,7). The mechanisms underlying PPARγ agonist–induced plasma volume expansion and edema have become better understood in recent years; in vitro and animal data suggest that these drugs stimulate sodium reabsorption in the distal nephron by upregulating the expression and translocation of ENaC (6). In mice, treatment with amiloride, a specific blocker of ENaC, attenuated PPARγ agonist–induced fluid retention, hemodilution, and weight gain (8). However, another animal study suggested that PPARγ agonist–induced fluid retention may occur independently of collecting-duct ENaC activity (9).
We previously demonstrated that 7-day treatment with spironolactone, which inhibits aldosterone-induced activation of ENaC in the distal nephron, is an effective acute strategy to correct rosiglitazone-induced fluid retention in a group of predominantly white patients with T2DM (10). South Asian patients with T2DM, who have an earlier onset of T2DM than white patients, are characterized by greater insulin resistance before diagnosis and may be more susceptible to PPARγ agonist–induced fluid retention (11). The most appropriate long-term management strategy to address PPARγ agonist–associated fluid retention remains unclear (11). There are no human clinical data on the effect of amiloride on PPARγ agonist–induced fluid retention, and no controlled trial to date has addressed whether direct inhibition of ENaC (as with amiloride) or blockade of the effects of aldosterone (as with spironolactone) is more effective in patients with PPARγ agonist–induced fluid retention.
We therefore evaluated the effects of amiloride and spironolactone, two diuretics that affect ENaC differently, on the management of rosiglitazone-induced fluid retention.
Materials and Methods
Patients
This open-label, randomized, placebo-controlled, parallel-group study was conducted at two large diabetes research units in Chennai, South India. The three study medications (spironolactone, amiloride, and placebo) were distinguishable from each other, but patients were not informed about the drug administered to them. Patients with known T2DM (defined by American Diabetes Association criteria [12]) receiving stable background antidiabetic therapy were eligible for the study. The study was conducted between February 2007 and June 2010. Eligible patients were aged 30–80 years, and female patients had to be postmenopausal. All patients needed to have a fasting plasma glucose level of ≥126 mg/dl and ≤216 mg/dl, with a hemoglobin A1c (HbA1c) level >7%, while receiving stable doses of sulfonylurea or sulfonylurea plus metformin for at least 2 months or while being treated by diet only.
Exclusion criteria included the use of more than two concomitant oral antidiabetic agents or current use of insulin. Patients who were currently receiving any diuretic medication and patients who had started other drugs that could affect sodium balance (e.g., nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors, β-blockers, or calcium-channel antagonists) within the previous month were also excluded. Other exclusion criteria were a history of exposure to a PPARγ agonist, systolic BP >170 mmHg or diastolic BP >100 mmHg, a history of unstable or severe angina, coronary insufficiency, congestive heart failure (New York Heart Association class II–IV) or ejection fraction <40% on cardiac echocardiography, clinically significant anemia defined by hemoglobin concentration (<11 g/dl for men and <10 g/dl for women), and serum creatinine level >1.2 mg/dl.
See Figure 1 for the study flow diagram. In brief, 260 patients entered the 4-week run-in period. From this population, 180 patients were randomly assigned to one of three treatment groups and were eligible for inclusion in the intention-to-treat population for efficacy assessment in the final analysis (they all had postrandomization measurements). In total, 37 patients in the spironolactone group, 45 in the amiloride group, and 41 in the control group completed the study; 31 patients were lost to follow-up, and 25 withdrew consent before study completion, with no significant between-group differences. One patient in the spironolactone group had an anterior myocardial infarction and was withdrawn from the study. He went on to make an uneventful recovery from his cardiac event. No other serious adverse events occurred. Adherence to rosiglitazone treatment and study medications was >85%, with no differences between groups.
Flow chart of patients' disposition.
All study participants gave written informed consent. The study (clinical trial registration number CTRI/2012/05/002697; registered retroactively) was approved by the Madras Diabetes Research Foundation ethics committee and adhered to the Declaration of Helsinki.
Procedures
Hematocrit was used as a surrogate marker to assess plasma volume changes. The selection of the magnitude of hematocrit reduction as evidence of plasma volume expansion was derived from previous studies that compared directly measured plasma volume changes with hematocrit changes and validated the use of hematocrit as a surrogate for plasma volume changes (10,13).
Eligible patients continued to take their established antidiabetic treatment, and open-label rosiglitazone, 4 mg twice a day, was added for 4 weeks (run-in phase). Previous data indicated that hematocrit would decrease by 1.5 percentage points or more in patients susceptible to plasma volume expansion after 4 weeks’ treatment with rosiglitazone, 4 mg twice daily (10,14). Animal and in vitro data also demonstrate that significant effects of PPARγ on ENaC expression or activity and related renal sodium balance are observed 5–7 days after initiation of rosiglitazone or pioglitazone treatment (6,8).
On completion of 4 weeks of rosiglitazone treatment, patients who achieved an absolute hematocrit reduction of ≥1.5 percentage points from hematocrit value before rosiglitazone treatment were randomly assigned to one of three groups in the treatment phase of the study: rosiglitazone, 4 mg twice a day, plus spironolactone, 50 mg once a day; rosiglitazone, 4 mg twice a day, plus amiloride, 10 mg once a day; or rosiglitazone, 4 mg twice a day, plus placebo (control group) for 24 weeks. Patients who did not show a reduction in hematocrit of ≥1.5 percentage points after 4 weeks of rosiglitazone treatment in the run-in phase were withdrawn from the study. A reduction in hematocrit of ≥1.5 percentage points was used in view of our previous data that suggested that >50% of patients with evidence of plasma volume expansion with rosiglitazone had this degree of hematocrit change. Randomization was performed using a computer-generated system that automates the random assignment of treatment groups to randomization numbers. Randomization was stratified by sex and background antidiabetic medications to ensure minimal between-group differences.
We chose 50 mg of spironolactone daily because of our previous observations that a majority of patients responded to this dosage and that it was not associated with a significant risk of hyperkalemia (10). The equivalent dose of amiloride has been reported as 20 mg by some authors; however, because the local guidelines in Chennai, India, advocate the use of 10 mg, that dose was used (15,16).
The primary endpoint was the change in hematocrit from baseline at 24 weeks in each diuretic group versus the control group, with adjustment for significant baseline hematocrit differences, if any. Prespecified secondary outcomes included change from baseline in hemoglobin level, serum albumin level, foot and ankle volume, and plasma aldosterone level.
Patients were seen in the morning after an overnight fast before any medication was taken and after they had abstained from alcohol, nicotine, and caffeine for at least 10 hours. Weight was measured at every scheduled visit by digital weighing scales (ATMA Technologies, Chennai, India) with patients lightly dressed and after voiding urine. The same weighing equipment was used at every visit and was calibrated every 3 months for the duration of the study. Height was measured using a wall-mounted stadiometer.
Hematocrit was measured by the pulse height detection method (Sysmex XT 1800i, Tokyo, Japan) from an uncuffed venous blood sample at baseline and at 2, 4, 8, 12, and 24 weeks. Serum electrolytes, fasting plasma glucose, and plasma albumin were measured with a Beckman Coulter AU 2700 autoanalyzer (Olympus); full blood count (including hemoglobin) was obtained by an automated hematology analyzer (Sysmex XT 1800i, Tokyo, Japan) at baseline and 4, 8, 12, and 24 weeks. HbA1c was measured by HPLC using a Bio-Rad Variant II Turbo machine at baseline and 12 and 24 weeks. Plasma aldosterone levels were measured by radioimmunoassay using a Cobas e411 analyzer (Roche, Japan) at baseline and 24 weeks.
Foot and ankle volume was measured in the dominant leg with the patient in the seated position by an ankle volumeter (Sammons Preston, Bowlingbroke, IL) using the water displacement technique (17).
BP was measured in the seated position after a 5-minute rest at each visit using calibrated mercury sphygmomanometer. The average of three measurements was used for calculation. All patients received advice to follow a weight-maintaining diet with stable and controlled salt and fluid intake throughout the study.
During the study, antidiabetic agents other than rosiglitazone could be reduced or withdrawn if any severe hypoglycemic episodes occurred (defined as random capillary blood glucose level <3.9 mmol/L or a hypoglycemic event necessitating third-party assistance) (18). The use of any diuretic medication other than that allocated by randomization was not allowed during the study, nor was the use of drugs that could affect sodium balance. Adherence to rosiglitazone was monitored by tablet counting at each study visit.
Statistical Analyses
Sample size calculation was based on previous data in patients with T2DM (10). The assumption was that a total of 60 patients per group would provide 90% power to detect a significant hematocrit difference of 1.5 percentage points between each diuretic group and the control group at the 5% two-sided level.
Descriptive statistics were used for the analysis of demographic and clinical features of the participants. The primary analysis compared change in hematocrit in the group receiving rosiglitazone, 4 mg twice a day, plus spironolactone, 50 mg once a day, versus the group receiving rosiglitazone, 4 mg twice a day, plus placebo (control group) and between the group receiving rosiglitazone, 4 mg twice a day, plus amiloride, 10 mg once a day, versus the group receiving rosiglitazone, 4 mg twice a day, plus placebo (control group). The Dunnett pairwise multiple-comparison two-sided t test was used for these comparisons. The primary population used in this assessment was the intention-to-treat population. Additional comparisons were also performed to assess effects relative to the control group on prespecified secondary outcomes. Adjustments for significant baseline (at the end of the 4-week run-in) differences, if performed, are reported in the Results section. A paired t test was used to compare hematocrit, hemoglobin, plasma albumin, serum electrolyte levels, and body weight, change in each treatment group from baseline during the treatment phase. The Dunnett method was used to adjust for multiple comparisons with a control group (19).
All analyses were performed using SPSS software, version 17 (SPSS, Inc., Chicago, IL), by a statistician blinded to treatment allocations.
Results
After 4 weeks of rosiglitazone therapy, 70% of the 260 patients (n=180) showed a decrease in hematocrit of ≥1.5 percentage points. The comparison of patients who did not have volume expansion with those who did is the subject of a separate report (20). This report deals exclusively with the cohort of 180 patients who showed volume expansion and their response to diuretic treatment.
The baseline (at the end of the 4-week run-in period) demographic and clinical features of the patients in each of the three treatment groups are shown in Table 1. Background antidiabetic treatment was as follows: sulfonylurea only in 44% of patients, metformin only in 7%, metformin plus sulfonylurea in 35%, and diet only in 14%. The distribution of treatment modalities, number, doses, and class of antidiabetic medications were similar in all three groups. Approximately 14% of patients were treated by diet only, and these patients were similarly distributed in the three groups. In the cohort, 18% of the patients were receiving lipid-lowering therapy and 20% had known hypertension; of these, >90% were receiving treatment with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. The distribution, number, doses, and types of antihypertensive and lipid-lowering medications did not significantly differ between the three groups. Nearly 70% of patients were male, and no significant between-group differences were seen in sex distribution. The mean age, duration of diabetes, waist circumference, and body mass index were not significantly different between groups. At baseline, systolic BP and diastolic BP were well controlled, with no significant differences between the three groups (Table 1). No significant changes in systolic or diastolic BP were observed during the study, and at study end there were no significant BP differences between the three groups (spironolactone group: systolic BP, mean±SD, 118.6±13.7 mmHg, and diastolic BP, 75.8±9.0 mmHg; amiloride group: systolic BP, 117.6±12.3 mmHg, and diastolic BP, 74.3±8.4 mmHg; control group: systolic BP, 120.1±11.8 mmHg, and diastolic BP, 76.4 ±8.5 mmHg).
Baseline patient characteristics
Table 2 details the baseline and end-of-study values for selected clinical and biochemical variables. HbA1c improved similarly, by 0.8 to nearly 1 percentage point, in the three groups, with no significant differences between groups. Weight increased similarly and significantly, by 2.5–3.1 kg, from baseline to end of treatment in each group. There was no significant between-group differences in weight gained.
Baseline and end-of-treatment values of selected variables in the three treatment groups in 180 patients with type 2 diabetes mellitus and evidence of plasma volume expansion (hematocrit reduction ≥ 1.5 percentage points)
Hematocrit levels continued to decrease significantly in the control group by a mean absolute change (95% confidence interval [CI]) of −1.2 (−0.3 to −2.2) percentage points (P=0.01) and in the spironolactone group by −0.7 (−0.1 to −1.4) percentage points (P=0.02), suggesting continued plasma volume expansion. In contrast, no significant change occurred with amiloride (0.0 [−0.8 to 0.8] percentage points) (Table 2).
Figure 2 displays the primary endpoint of the study, the mean absolute hematocrit difference from the control group for each diuretic treatment group. Between-group analysis demonstrated that amiloride was superior to the control regimen in preventing further decrease in hematocrit, with a mean hematocrit difference (95% CI) of 1.27 (0.21–2.55) percentage points (P=0.04) (Figure 2). In contrast, spironolactone was not superior to the control regimen, with a mean hematocrit difference of 0.49 (−0.79 to 1.77) percentage points (P=0.61).
Mean difference in hematocrit, relative to values in control (placebo) group, in the amiloride and spironolactone treatment groups after 24 weeks of treatment with spironolactone, amiloride, or placebo. Values obtained in 180 patients receiving rosiglitazone, 4 mg twice daily, in addition to background antidiabetic therapy.
Changes in hemoglobin levels were concordant with changes in hematocrit, with total hemoglobin levels decreasing only in the placebo and spironolactone groups (Table 2).
Serum albumin levels decreased from 4.44±0.33 to 4.18±0.42 g/dl (P=0.05) in the placebo group; changes were nonsignificant in the amiloride (from 4.36±0.3 to 4.39±0.27 g/dl) and spironolactone (from 4.41±0.35 to 4.4±0.25 g/dl) groups.
Foot and ankle volume increased by 26–54 ml in all three groups. The increase of 54 ml in the placebo group (from 1149.7±163.7 to 1203.8 ±162.9 ml) was the only significant change (Table 2). Changes in serum albumin level and foot and ankle volume did not significantly differ between the diuretic groups and control group. During the trial period, as expected, plasma aldosterone levels increased significantly only in the diuretic groups (spironolactone group: 8.47±5.47–13.63 ±7.95 ng/dl, P=0.002; amiloride group: 7.37± 4.56–13.52±9.07 ng/dl, P=0.002; and control group: 7.29±5.4–8.99 ±5.39 ng/dl, P=0.10), given that both diuretics inhibit the actions and effects of aldosterone.
Serum sodium and potassium levels did not change significantly during the trial in the placebo or amiloride group. In the placebo group, sodium and potassium changes were 138.8±3.1–138.1± 4.1 mmol/L (P=0.22) and 4.28±0.29–4.31±0.36 mmol/L (P=0.73), respectively. In the amiloride group, sodium and potassium changes were 138.3±3.3–137.8 ±2.8 mmol/L (P=0.27) and 4.29±0.27–4.36±0.30 mmol/L (P=0.09), respectively. Serum sodium level decreased significantly but modestly in the spironolactone group (from 137.8±3.7 to 136.9±3.8 mmol/L; P=0.01), but there was no significant change in potassium levels (from 4.33± 0.37 to 4.33±0.30 mmol/L; P=0.97).
All patients had serum creatinine levels < 1.2 mg/dl, and serum creatinine did not change significantly during the trial. No patients developed significant hyperkalemia (defined as a serum potassium level ≥ 6.0 mmol/L) during the treatment phase.
Discussion
This study in a selected group of patients who exhibited rosiglitazone-induced plasma volume expansion (as indicated by the change in hematocrit, a surrogate indicator for plasma volume) demonstrated that amiloride and spironolactone, two diuretics with distinct modes of action on ENaC in the distal nephron, have different effects on PPARγ agonist–induced fluid retention at the doses used. Amiloride arrested the continued decrease in hematocrit levels that occurred in the placebo group during the 24 weeks of the study. In the group receiving spironolactone, 50 mg/d, the hematocrit decreased further by the end of the study. This finding is at variance with our previous work showing that treatment with spironolactone (50–100 mg/d) for 7 days significantly ameliorated rosiglitazone-induced fluid retention compared with frusemide or hydrochlorothiazide (10). The differences in drug dosage, ethnicity of the patients, and protocol design between the two studies may partly explain this discrepancy. The results with amiloride in the current study in humans confirm the animal data indicating that maneuvers that interfere with ENaC-mediated renal salt absorption attenuate protracted thiazolidinedione-induced fluid retention (8).
The reduction in hematocrit in the placebo group was accompanied by concomitant reductions in total hemoglobin and serum albumin concentrations, supporting the notion of persistent plasma volume expansion. These changes in hemoglobin and serum albumin levels were also blocked by amiloride. On a clinical level, foot and ankle volume increased significantly from baseline only in the placebo group, with no significant changes noted in the diuretic groups.
This study and data from our previous work strongly suggest that rosiglitazone has a persistent and protracted action on sodium retention in the distal nephron. Indeed, long-term thiazolidinedione treatment results in a decrease in plasma aldosterone concentrations and an increase in plasma atrial natriuretic peptide levels, changes that are physiologically consistent with increased sodium reabsorption and central venous volume expansion and resetting of salt and water balance (10).
It has been argued in one animal study that mechanisms other than activation of ENaC by PPARγ agonists may be involved in thiazolidinedione-induced fluid retention, but clinical data to support this are limited (9). In this respect, the effects of amiloride, a direct inhibitor of ENaC, are of interest. In healthy persons, amiloride is not a potent natriuretic drug, but upregulation of ENaC, as seen with long-term PPARγ agonist treatment, may lead to increased natriuretic potential; this situation is observed in patients with Liddle syndrome, in which this channel is overactivated (21).
We did not observe any significant baseline differences in HbA1c or BP, and indeed HbA1c improved similarly in all three groups with rosiglitazone treatment. Further, there were no significant differences between the three treatment groups in systolic or diastolic BP during the study. This finding suggests that the vasodilatory hemodynamic effects and improvement in glycemic control with rosiglitazone are unlikely to have significantly influenced the effect of amiloride on attenuating rosiglitazone-induced plasma volume expansion.
In our cohort of South Asian patients with T2DM, weight increased similarly in all three groups with rosiglitazone. In this ethnic group, fat accumulation is likely to be the predominant element in weight gain with thiazolidinedione treatment (22). Indeed, we found no significant effect of diuretic treatment on weight. This suggests only a modest contribution of fluid retention to the weight gain observed in South Asians and is at variance with our previous data in white patients with T2DM, in whom nearly 40% of weight gain was due to fluid accumulation. To be randomly assigned to one of the three treatment groups, patients needed to have a decrease in hematocrit of at least 1.5 percentage points after 4 weeks’ treatment with rosiglitazone. In the patients randomly assigned, the average reduction in hematocrit was 3 percentage points (20). From quantitative analyses of our previous work, a decrease in hematocrit of 3 percentage points would represent an increase in extracellular fluid volume of approximately 620 ml (10).
No significant differences in foot and ankle volume were noted between the amiloride and placebo groups. Our study was powered on the basis of hematocrit change (primary endpoint), and it is possible that detection of significant changes in foot and ankle volume, a measure with a lower degree of precision and thus sensitivity, would have required a larger volume shift with this sample size.
In white patients, weight decreased significantly with all diuretics and to the greatest extent with spironolactone (10). In Hispanic patients with T2DM, who display some of the clinical characteristics of increased insulin resistance observed in South Asian patients with T2DM, weight gain due to fluid accumulation with thiazolidinedione treatment has been reported to be about only 11% (23).
The extent of plasma volume expansion indicated by changes in hematocrit and hemoglobin may be moderate in our cohort of relatively uncomplicated patients with T2DM. However, it is reasonable to assume that in susceptible patients, chronic volume overload (which initially is compensated for by increased cardiac work and cardiac hypertrophy) would result, if not corrected, in the cardiomyopathy of overload, with the development of edema and heart failure (2,24).
This study has some limitations. Our protocol was not designed to formally test the primary prevention potential of spironolactone and amiloride; for utilitarian reasons, we only studied the effects of diuretics in patients with fluid retention. Nevertheless, our data do suggest that when faced with the need to start thiazolidinediones in patients who are potentially at risk of plasma volume expansion, amiloride may be useful as a primary preventive strategy.
This study cannot answer whether treatment with amiloride or spironolactone affects the onset of congestive heart failure in thiazolidinedione-treated patients. Indeed, the connection between thiazolidinedione-induced edema and congestive heart failure is in itself a problematic one and certainly not linear (2,11). However, thiazolidinedione-induced fluid retention is indeed part of the process that under certain circumstances may contribute to development or exacerbation of congestive heart failure (2,11,24). In our study, we used the maximum dosage of rosiglitazone (8 mg/d) licensed in India. Fluid retention with both rosiglitazone and pioglitazone is dose dependent (25); in North America, where rosiglitazone prescription is significantly restricted, a lower dosage of 4 mg/d is recommended for initiation of treatment (26). If fluid retention or edema persists and proves difficult to manage, alternative antidiabetic agents should be considered.
Our previous data suggest that withdrawal of thiazolidinediones for 1 week does not significantly reverse fluid retention because of the delayed and persistent actions of the drug (10). This indicates that in situations of need, withdrawal of therapy alone would not be a reliable means of rapid correction of thiazolidinedione induced volume expansion. The results from this study suggest that in such situations amiloride therapy should be considered.
All our patients had relatively preserved renal function and normal electrolyte levels at baseline. We cannot exclude the possible effects of amiloride or spironolactone treatment on the development of hyperkalemia in patients with impaired renal function, especially on the background of concomitant treatment with drugs such as angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Despite several new classes of agents, such as gliptins and incretin mimetics introduced for management of T2DM, pioglitazone remains widely used worldwide. The effect of thiazolidinediones on plasma volume expansion and increased risk of congestive heart failure is a class effect. Pioglitazone treatment displays changes in plasma volume markers and potential risk of congestive heart failure similar to those seen with rosiglitazone (27). Our data suggest that in South Asian patients with T2DM who demonstrate a decrease in hematocrit of ≥1.5 percentage points while receiving a thiazolidinedione, treatment with amiloride is a useful therapeutic strategy to minimize further plasma volume expansion and potentially limit adverse effects related to fluid retention. A recent meta-analysis suggested that pioglitazone is associated with a nearly 2.4-fold increased risk of edema (25). The results of our study are therefore likely to apply to the management of pioglitazone-induced fluid retention and edema. The concomitant use of amiloride may enable higher doses of pioglitazone to be tolerated and used clinically.
It is debatable whether amiloride treatment should be advocated at inception of thiazolidinedione therapy in T2DM, even though in the present study about 70% of the patients screened showed a degree of volume expansion. However, in clinical situations where incidence of thiazolidinedione-induced fluid expansion is likely to be high (e.g., when thiazolidinediones are used in combination with insulin), prompt initiation of amiloride therapy could be considered.
In conclusion, our study suggests that amiloride, a direct blocker of ENaC, is effective in arresting the protracted rosiglitazone-induced fluid retention in South Asian patients with T2DM. Our results underscore the role of ENaC upregulation in the pathophysiology of PPARγ agonist–induced fluid retention.
Disclosures
This study was supported by a research grant from GlaxoSmithKline, the makers of rosiglitazone. GlaxoSmithKline had no role in data collection, analysis, decision to publish, or preparation of the manuscript.
Acknowledgments
V.V., J.K., and G.V. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. We acknowledge the contribution of Dr. Murray Stewart and Dr. Swapneel Anouker, who advised on the clinical trial design and study protocol. We acknowledge the contribution and help of Ms. Priyanka Tilak, Dr. K. Satyavani, and Dr. Sareswar Agarwal, Department of Diabetes, M.V. Hospital for Diabetes and Prof M. Viswanathan Diabetes Research. We thank the patients who participated in this study.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
- Received June 26, 2012.
- Accepted October 26, 2012.
- Copyright © 2013 by the American Society of Nephrology
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