Indapamide Is as Effective as Captopril in the Control of Microalbuminuria in Diabetes

Summary: Microalbuminuria is a predictor of overt diabetic nephropathy and macrovascular disease. Thirty-one diabetic patients with persistent urinary albumin excretion rate (AER) of 20-200 μg min^-1 were randomised to receive indapamide 2.5 mg or captopril 37.5 mg daily for 12 weeks. After a 4-week washout, patients received the alternate agent for 12 weeks. Resting blood pressure (BP), AER, cholesterol, triglycerides, and HbA_1c were measured at baseline, after 6 and 12 weeks of each treatment, and after a 4-week washout period following each treatment arm. Results from patients who completed at least one treatment arm were analysed by repeated-measures analysis of variance (ANOVA). AER (median value and interquartile range) decreased significantly from baseline after treatment with indapamide and captopril [60(27-106) vs. 40(14-112) and 33(17-100); p < 0.005], but there was no difference between the effects of the two agents. Mean systolic BP (SBP) was also significantly reduced with treatment, and no difference was noted between the effects of the two agents. No correlation between changes in AER and SBP was noted with either agent. Diastolic blood pressure (DBP), cholesterol, triglycerides, and HbA_1c did not change during the study. These results suggest that indapamide is an effective alternative to angiotensin-converting enzyme (ACE) inhibitors in the treatment of diabetic patients with microalbuminuria.

The presence of microalbuminuria is well recognised as a prognostic marker in diabetes, both for renal function deterioration ^(1,2) and for increased risk of macrovascular disease ^(2-4). Consequently, researchers have shown much interest in evaluating various strategies to control this early indicator of chronic diabetic complications. Because patients with microalbuminuria, defined as a persistent urinary albumin excretion rate (AER) of 20-200 μg min^{-1 (5)}, are often mildly hypertensive, antihypertensive therapy has been a major focus of study in this group of patients.

In a recent study by Lewis and associates, the angiotensin-converting enzyme (ACE) inhibitor captopril was unequivocally shown to retard the rate of renal function deterioration in insulin-dependent diabetes mellitus (IDDM) patients with overt proteinuria ⁽⁶⁾. The protective effect of captopril on the glomerulus was additive to its influence on blood pressure, suggesting that ACE inhibitors should be the preferred drugs for treatment of overt diabetic nephropathy in IDDM. Similarly, many investigators have also cited ACE inhibitors as first-line therapy in the treatment of non-IDDM (NIDDM) patients with established nephropathy ^(7-10). In recent meta-analysis of 100 studies in patients with diabetic nephropathy, Kasiske and co-workers concluded that ACE inhibitors were capable of decreasing proteinuria and preserving glomerular function independent of changes in blood pressure or the type of diabetes ⁽¹¹⁾.

The evidence to substantiate the preferential use of ACE inhibitors in diabetic patients with microalbuminuria is not as clear-cut. Various antihypertensive agents with differing modes of action have been shown to reduce AER significantly and to prevent deterioration in renal function in both hypertensive and normotensive patients with microalbuminuria ^(11-16). Relatively few studies have been conducted to compare an ACE inhibitor directly with another type of antihypertensive agent. Therefore, we wished to compare the efficacy of indapamide with captopril on AER and blood pressure in diabetic patients with microalbuminuria. Indapamide was selected for this comparative study because it does not aggravate hyperglycemia and is commonly used in the treatment of mild to moderate hypertension, typical of that of many patients with microalbuminuria. Preliminary results of 12 patients were reported previously ⁽¹⁵⁾.

METHODS

Patients

Thirty-one patients with IDDM (n = 5; 3 males, 28 females) or NIDDM (n = 26; 21 males, 5 females), with an AER of 20-200 μg min^-1 on two separate occasions were recruited to participate in this 32-week, randomised, open-label, cross-over design study. The patients had a mean age of 51.6 ± 2.4 years (±SE) and a mean duration of diabetes of 8.8 ± 1.8 years. At baseline, their mean HbA_1c was 7.4 ± 0.3% (normal range 3.5-6.0%), with mean systolic blood pressure (SBP) of 138 ± 3 mm Hg, mean diastolic BP (DBP) of 84 ± 2 mm Hg, and median AER of 60 μg min^-1 (interquartile range 27-106 μg min^-1). Six patients were already receiving treatment with antihypertensive medications other than ACE inhibitors or diuretics, the dosage of which was not altered in the 4 weeks before recruitment or during the study period.

Protocol

All patients had two baseline measurements of AER, from urine collected under standard conditions (300 ml water followed by a 2.5-h collection at rest) to determine the presence of persistent microalbuminuria. BP was measured after patients had been lying down for 5 min. Each patient was then randomly assigned to receive either a constant dosage of indapamide 2.5 mg once daily or captopril 12.5 mg three times daily for 12 weeks. After a 4-week washout period, the patient was then treated with the alternate therapy, also for a 12-weeks period. The adherence of patients to the medication regimen was checked by pill counting, and occurrence of any adverse effects was noted at each visit.

Resting BP, AER, HbA_1c, total cholesterol, and triglycerides were measured at baseline, after 6 and 12 weeks of each treatment, and after a 4-week washout period following each treatment arm. Urinary albumin was measured by radioimmunoassay and expressed in micrograms per minute [Diagnostic Products, CA, U.S.A.: coefficient of variation (CV) <5%]. HbA_1c was measured by high-performance liquid chromatography (BioRad, CA, U.S.A.:CV <2%). Total cholesterol (normal range: <5.2 mM) was measured by enzymatic colorimetry (Boehringer Mannheim, Mannheim, Germany; CV <1%). Triglyceride level (normal range <2.3 mM) was measured by enzymatic colorimetry (Boehringer Mannheim: CV <3%).

Statistical analysis

All patients who were randomised to treatment and who completed at least one arm of the treatment (n = 26) were included in the analysis. The second baseline measurements were used for analysis purposes to allow spontaneous regression to the mean. All values are mean ± SE except AER, which is expressed as median values and interquartile ranges but was log transformed before analysis. Repeated-measures of analysis of variance (ANOVA) was used to determine effects of the order and type of treatment, and baseline BP status on AER, BP, and HbA_1c. Effects of antihypertensive treatment on cholesterol and triglyceride levels and in normotensive subjects were compared with baseline values by Wilcoxon signed-rank test. Multiple regression analysis was used to determine predictors for change in AER and BP.

RESULTS

Five patients withdrew from the study without completing either treatment arm for reasons that could not be directly attributable to drug therapy, including 2 who were lost to follow-up and 3 who chose not to continue participation. Three patients completed the indapamide arm but discontinued captopril; 1 due to skin rash, 1 due to cough, and 1 due to increased serum potassium. Two patients completed the captopril arm but discontinued indapamide; 1 had dizziness and 1 complained of a burning sensation. The remaining 21 patients completed both treatment arms.

The effects of antihypertensive therapy are shown in Table 1. AER decreased significantly with antihypertensive treatment (F_2,846.24; p < 0.005), but there was no significant difference between the effects of captopril or indapamide. There was a significant decrease in SBP overall (F_2,763.65; p < 0.05), again, no difference was noted between the effects of captopril or indapamide treatment. Order of treatment played no significant role in the decrease in AER or SBP. There was no significant correlation between change in AER and change in SBP in either treatment group. DBP, HbA_1c, cholesterol, and triglycerides did not change significantly during the study.

Table 1

DISCUSSION

The presence of albuminuria is the most important predictor of prognosis in patients with diabetes. Both overt proteinuria and microalbuminuria are well recognised not only as major predictors of renal function deterioration ^(1,2) but also as predictors for risk of macrovascular events ^(2-4). Reducing albuminuria with antihypertensive therapy has therefore been a therapeutic goal in such patients, with the hope that the reduction can be translated into lesser renal impairment in the longer term.

Captopril retarded the loss of renal function in proteinuric IDDM patients more effectively than other classes of antihypertensive agents ⁽⁶⁾. The use of ACE inhibitors has therefore been increasingly advocated as first-line therapy in diabetic patients with overt nephropathy. ACE inhibitors also reduced proteinuria in both normotensive and hypertensive NIDDM subjects with overt nephropathy ^(7-10).

Whether ACE inhibitors are superior to other antihypertensive agents in diabetic patients with microalbuminuria is less certain. Although many studies have compared the efficacy of an ACE inhibitor with that of placebo therapy in diabetic patients with microalbuminuria ^(12,16-21), fewer studies have directly compared effects of ACE inhibitors with those of other antihypertensive agents in such patients. Lacourcière and colleagues ⁽²²⁾ compared captopril with metoprolol and hydrochlorothiazide (either alone or in combination) in hypertensive NIDDM subjects with microalbuminuria. Even though both regimens reduced BP comparably, only the ACE inhibitor was capable of reducing albuminuria in the 3-year study period. On the other hand, the Melbourne Diabetic Nephropathy Study Group ⁽¹³⁾, who compared the ACE inhibitor perindopril with the calcium antagonist nifedipine for a 12-month period reported that both agents had like effects. AER did not increase in normotensive patients but did decrease in hypertensive patients, regardless of the agent used. The results of our study show beneficial effects of the ACE inhibitor captopril and indapamide to be of similar magnitude. The efficacy of indapamide was supported by the study of Gambardella and co-workers ⁽¹⁴⁾, who reported that long-term indapamide therapy (36 months) significantly reduced BP and AER in hypertensive patients with diabetes and microalbuminuria. Our findings suggest that with regard to reducing microalbuminuria, the type of antihypertensive agent used is not critical. Owing to the relatively normal BP of patients with microalbuminuria, we used a relatively low dose of ACE inhibitor in treatment. Nonetheless, the decrease in AER was of a magnitude similar to that obtained with use of a higher dosage ^(20,21).

Some patients cannot tolerate treatment with ACE inhibitors because of the development of a persistent dry cough, reported in ≈3-22% of patients, as well as rash and hyperkalaemia in others ⁽²³⁾. ACE inhibitors should also be used cautiously in women of childbearing age. For these reasons, ACE inhibitors cannot always be used in the treatment of diabetic patients with microalbuminuria even if they were shown to be superior to other antihypertensive agents. Indapamide is reported to have few adverse effects. In a study of 1,202 patients treated with indapamide, there was only a 1.3% dropout rate, with a low incidence of dizziness, headaches, and nausea reported ⁽²⁴⁾. Although some thiazide diuretics have been reported to reduce sensitivity to insulin, leading to deterioration in diabetic control ⁽²⁵⁾, long-term therapy with indapamide has been shown to have few deleterious consequences on glucose metabolism in patients with diabetes ^(26,27). It is therefore the thiazide more commonly used in the treatment of hypertension in diabetes. Similarly, indapamide has been shown not to alter serum lipid profiles significantly during short- and longer term administration ^(28,29). Because the presence of microalbuminuria is not only a marker for early renal dysfunction but also is associated with a greatly increased risk of macrovascular disease ^(2-4), the antihypertensive agent used must not exacerbate existing risk factors. The results of our study and those of others have shown that indapamide can reduce BP in hypertensive patients and reduce albumin excretion rate in both normotensive and hypertensive patients with microalbuminuria, without deterioration in glycaemic control or serum lipid profile.

Acknowledgment: This work was supported by grants from Servier Laboratories Australia and Diabetes Australia.