Steno Diabetes Center, Gentofte, Copenhagen, Denmark
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Abstract |
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Methods. In a randomized, double-blind, crossover trial, 31 type 2 diabetic patients with elevated levels of AER (>30 mg/24 h) were, in random order, given ASA (150 mg/day) for 4 weeks followed by placebo for 4 weeks with a 2 week washout period or vice versa. At the end of each treatment period AER, glomerular filtration rate (GFR), blood pressure (BP), transcapillary escape rate (TERalb) of albumin and haemoglobin A1c (HbA1c) were measured.
Results. The following variables remained unchanged (mean (95% CI) unless otherwise noted) (ASA vs placebo, paired Student's t-test): AER (201 (119341) vs 205 (124340) mg/24 h (geometric mean, 95% CI); P=0.78), GFR (103 (94111) vs 102 (93110) ml/min; P=0.58), systolic BP (151 (146158) vs 152 (146158) mmHg; P=0.68), diastolic BP (87 (8391) vs 87 (8291) mmHg; P=0.88), TERalb (6.3 (5.76.9) vs 5.9 (5.16.7); P=0.45) and HbA1c (8.6 (8.19.0) vs 8.5 (8.19.0) %; P=0.60).
Conclusions. Low-dose treatment with 150 mg ASA daily does not have any impact on AER or GFR in type 2 diabetic patients with micro- or macroalbuminuria. Consequently, the widely recommended prescription of low-dose ASA as a primary and secondary prevention strategy against cardiovascular disease in these patients does not confound the diagnosis or monitoring of micro- or macroalbuminuria.
Keywords: acetylsalicylic acid; albuminuria; glomerular filtration rate; randomized trial; type 2 diabetes mellitus; urinary albumin excretion rate
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Introduction |
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In microalbuminuric type 1 diabetic patients, elevated renal synthesis of vasodilating prostaglandins has been reported [2] and high-dose treatment with the cyclooxygenase inhibitor indomethacin (150 mg daily) reduced albumin excretion rate (AER) by 58% in these patients [2]. Similar effects have been found using high-dose ASA in combination with dipyridamole (990 mg ASA and 225 mg dipyridamole daily) or indomethacin (150 mg daily) in type 1 diabetic patients with diabetic nephropathy [3,4]. We have previously reported a lack of impact of low-dose ASA on AER in microalbuminuric type 1 diabetic patients during treatment with ACE inhibitors [5]. A masking effect of ASA on albuminuria may have a major impact on the diagnosis and monitoring during treatment of micro- or macroalbuminuria, since most type 2 diabetic patients according to recommendations will start treatment with low-dose ASA while being in the normoalbuminuric range [1].
Therefore, the primary aim of the present study was to investigate whether the effect of short-term low-dose ASA on AER could cause misclassification of micro- and macroalbuminuria and, secondly, to examine the effect on glomerular filtration rate (GFR) and endothelial dysfunction, as measured by transcapillary escape rate, in type 2 diabetic patients with elevated levels of urinary AER.
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Subjects and methods |
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Crossover design
After the run-in period, patients entered a randomized, double-blind, crossover trial. The randomization was individual with concealed, computer-generated envelopes. The code was kept at the manufacturer of the tablets and not broken until all data were entered in a database. Patients were allocated to take one tablet of ASA 150 mg (Albyl; LEO A/S, Copenhagen) or one matching placebo tablet in the morning. After 4 weeks of treatment there was a 2 week washout period before patients crossed over to the opposite treatment for another 4 weeks [9]. Fifteen patients were given active treatment as the initial intervention and 16 were given placebo.
Measurements
Measurements were performed after a 12 h fast at the end of each treatment period of the double-blind crossover phase unless otherwise noted.
Transcapillary escape rate of albumin (TERalb) was determined as the rate constant of the mono-exponential decrease in plasma radioactivity over the first 60 min after injection of tracer albumin, as calculated by the least squares method described in detail elsewhere [10].
Glomerular filtration rate was measured after single intravenous injection of 3.7 MBq 51Cr-EDTA immediately after termination of the TERalb examination [11].
Urinary albumin excretion rate was measured by ELISA in three consecutive 24 h urine collections completed immediately before each visit.
Blood pressure. Supine blood pressure values were measured twice in both arms with a Hawksley random zero sphygmomanometer after at least 30 min rest and the average of these measurements was used.
Assays. Haemoglobin A1c (HbA1c) was measured from venous blood samples with high-performance liquid chromatography (Variant; Bio-Rad Laboratories, USA). Normal range of HbA1c in our laboratory is 4.16.4%. Serum total-cholesterol was measured by chromatography.
Statistical analysis
Results are expressed as means with SD or 95% confidence interval (CI), when appropriate. Urinary AER and fractional clearance of albumin are expressed as geometric mean (antilog 2.5% percentile to antilog 97.5% percentile for the average of the logged values) due to positive skewness of the distribution. Comparisons at baseline were performed using Student's t-test, MannWhitney U-test or 2-test when appropriate. We used paired Student's t-test to compare differences between the variables during the two phases of the crossover part of the study. The means of the logged values of urinary AER and fractional clearance of albumin have been used for comparison of these variables and the difference is expressed as percentage reduction with active treatment. Data were tested for a period effect and a treatment-period interaction with a two-sample t-test as described [12]. A sample-size calculation was performed giving that a minimum of 30 patients were needed to detect a 20% change in urinary AER with a two-sided
=0.05 and ß=0.8 [5].
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Results |
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Randomized, double-blind, crossover phase
Table 1 shows results after each of the two treatment periods. No patients had AER below 30 mg/24 h in either of the two treatment periods. We detected no significant order-of-treatment effect. No change in medication, except shift from active to placebo tablets and vice versa, was recorded in any patient during this period. The number of smokers remained unchanged throughout the crossover period.
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Compliance and side effects
Adherence was high with >99% of tablets taken using simple counting of the tablets during both treatment periods.
Two patients (6%) reported dyspepsia during placebo treatment compared with one patient during active treatment (3%). One patient who was treated with ASA during the first treatment period was admitted to hospital with a bleeding gastric ulcer 51 days after termination of the second treatment period.
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Discussion |
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In the kidney, the effect of blocking cyclooxygenase on glomerular function is an interaction between the production of vasodilating prostaglandins and vasoconstrictive thromboxanes [13]. Increased renal synthesis of prostaglandins occurs in both human and experimental diabetes [2]. High-dose treatment with indomethacin (150 mg/day), or ASA in combination with dipyridamole (990 mg/day and 225 mg/day, respectively) reduced renal prostaglandin synthesis and AER, while GFR remained unchanged [2,3]. These effects occurred shortly after start of treatment. Despite an increased renal production of vasodilating prostaglandins, the ratio between stable urinary metabolites of prostaglandins and thromboxane is decreased in type 2 diabetic patients with micro- or macroalbuminuria, suggesting an even further increase in intrarenal thromboxane production in these patients [14]. Our study showed no change in kidney function as measured by AER, fractional clearance of albumin and GFR during short-term treatment with low-dose ASA. We have, however, no direct information on intrarenal production or excretion of prostaglandins or thromboxanes.
The observed non-significant reduction in the primary outcome AER was 2.0% (95% CI, 1513%) in the present study. We had 80% power to detect a 20% change in AER and as a consequence the risk for a type 2 error is large given the observed reduction, unless numerous patients were included in the study. However, a reduction in AER of the observed size would not be large enough to justify changes in the definitions of micro- and macroalbuminuria. Patients in the present study did not receive treatment with ACE inhibitors during the study period in order to imitate the clinical situation, where a patient with type 2 diabetes would start treatment with low-dose ASA as a primary prevention strategy before micro- or macroalbuminuria had been diagnosed. In case of a marked reduction in AER, this effect could interfere with the diagnosis of micro- or macroalbuminuria, thus postponing recommended treatment against increased AER. It should be noted, however, that mean AER at randomization was 199 mg/24 h and thus substantially higher than the diagnostic level for microalbuminuria. As a consequence, we cannot be certain that a difference in AER during treatment with ASA does not exist at lower levels of AER, although this was not the case in a similar study in microalbuminuric type 1 diabetic patients [5]. Whether low-dose treatment with ASA in micro- or macroalbuminuric type 2 diabetic patients already treated with ACE inhibitors has any clinical impact on the monitoring effect of albuminuria lowering treatment also remains to be elucidated. However, in our previous study in type 1 diabetic patients with microalbuminuria, this was not the case [5].
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Notes |
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References |
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