Q J Med 2001; 94: 89-94
© 2001 Association of Physicians
Randomized placebo-controlled trial of perindopril in normotensive, normoalbuminuric patients with type 1 diabetes mellitus
From the Section of Endocrinology and Nephrology, Department of Internal Medicine, Esbjerg County Hospital, Esbjerg, Denmark
Received 14 January 2000 and in revised form 4 December 2000
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Diabetic nephropathy is one of the leading causes of end-stage renal disease. We examined whether ACE inhibitor treatment may have a nephroprotective effect in normotensive insulin-dependent diabetic patients without microalbuminuria and with normal glomerular filtration rate (GFR), and whether any effect was associated with the ACE genotype. In a prospective double-blind randomized study, normotensive patients with type 1 diabetes mellitus with normal serum creatinine and no microalbuminuria were treated with either placebo or perindopril, an ACE inhibitor. Urine albumine/creatinine ratio (ACR), mean blood pressure (MBP) and index of glomerular filtration rate (GFR) based on S-creatinine were determined. ACE genotype was determined by electrophoresis. ACR was higher in the placebo group than in the perindopril group after 4 months, and continued to increase during the study period. After 36 months of observation, ACR in the placebo group was 1.7±1.1 mg/mmol, and 0.6±0.2 mg/mmol in the ACE-inhibitor-treated group (p<0.001, Mann–Whitney test). During treatment, a significant increase in ACR in the placebo group (p=0.007), Wilcoxon matched paired test) was observed. There were no differences between the groups regarding MBP or GFR. The nephroprotective effects of ACE inhibitor treatment was not associated with the ACE genotype (II, ID, DD).
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Introduction |
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Diabetic nephropathy is one of the leading causes of end-stage renal disease in developed countries, and microalbuminuria is the hallmark of its early onset. In patients with diabetes and microalbuminuria, angiotensin-converting-enzyme (ACE) inhibitors seem particularly effective in reducing the risk of progression to clinical albuminuria, and this beneficial effect appears to be long-lasting.1,2 It has also recently been discussed whether an insertion/deletion polymorphism in the ACE gene might affect the beneficial effects of ACE inhibition on the progression of diabetic nephropathy.3,4 However it has been questioned whether these studies provide support for the use of ACE inhibitor as first-line therapy in diabetics without renal disease.5 The aim of this study was to examine whether ACE inhibitor treatment has a nephroprotective effect in normotensive insulin-dependent diabetic patients with normoalbuminuria and with normal glomerular filtration rate (GFR) early in the disease process, and to examine if such an effect was affected by the ACE genotype.
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Methods |
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We conducted a prospective double-blind randomized study. The protocol was approved by the local ethical committee, and all participants gave written consent.
Men and women with type 1 diabetes mellitus were eligible for the study if they met the following criteria: duration of diabetes >5 years (age 18–65 years), no microalbuminuria present (<20 µg/min or ratio albumine/creatinine (ACR)<2.5 mg/mmol at three consecutive examinations),6 normal serum creatinine and urine sediment, no hypertension (BP <140/90 mmHg or MBP (mean blood pressure) <108 mmHg).
The exclusion criteria were: ongoing treatment with ACE inhibitor, known side-effects of ACE inhibitor, pregnancy or intended pregnancy, known renal disease, systolic blood pressure <100 mmHg or diastolic blood pressure <50 mmHg.
Urinary albumin (µmol/l) was analysed using a immunological method by means of a Behring Nephelometer Analyser (BNA, Behringwerke AG). Urinary creatinine (mmol/l) was measured kinetically.7 The index of glomerular filtration rate was determined from adjusted serum creatinine.8 The ACE intron16ins287 polymorphism was analysed as described by Evans et al. with the following modified amplification conditions: 1 cycle at 95 °C for 5 min and 32 cycles of 95 °C for 1 min, 50 °C for 1 min, and 72 °C for 3 min. Amplification products were visualized after electrophoresis in a 3% agarose gel with ethidium bromide staining.9
Study design
All eligible patients were screened to determine if their ACR was stable below 2.5 mg/mmol (male) or 2.0 mg/mmol (female), and then received 4 mg perindopril daily for one week to check if perindopril was tolerated. After 4 weeks washout, patients were randomly assigned to receive 2 mg perindopril or placebo twice daily. The patients were examined every 4 months. The ethics committee required that the ACE polymorphism study was carried out separately. All patients were asked to participate in this additional study, and 57 agreed.
Outcome measures
The total study period was planned to last 5 years, including 1 year for entry, but due to technical problems, the entry period was extended to 2 years. Results are given as means±SD. Analysis of normality of the distribution revealed that both kurtosis and skewness differed from 0. Therefore, the Mann–Whitney test was used for comparison between groups, and the Wilcoxon matched-pair test for comparisons within the group. All data processing was done with the Statistica software (StatSoft).
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Results |
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Eighty-nine patients were randomly assigned to receive perindopril or placebo. All patients completed the test period without side-effects. Fourteen patients dropped out during the study (eight in the perindopril group and six in the placebo group), one because of cough, two because of pregnancy and 11 because of non-compliance. The difference between groups was not statistically significant.
ACE gene polymorphism was examined in 57 patients: 27 in the ACE-treated group. (II, n=8; ID, n=11; DD, n=8) and 30 in the placebo group (II, n=8; ID, n=13; DD, n=9).
Baseline values, including gender, age, GFR index, ACR ratio, MBP, level of HbAlc, duration of diabetes and the distribution of ACE genotype are given in Table 1
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At termination of the study, 52% of the initial 89 patients had been treated for >36 months.
ACR after 4 months of therapy was significantly higher in the placebo group compared to the ACE inhibitor treated group, a difference which persisted throughout the study period (Figure 1).
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During treatment, a significant increase in ACR occurred in the placebo group (p=0.007, Wilcoxon matched-pair test, ACR 0 months vs. ACR 36 months), and although Figure 1
indicates a decrease in ACR in the ACE treatment group, the difference was not statistically significant (p=0.11). No differences between the groups regarding MBP or creatinine clearance were observed (Figures 2 and 3).
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The effect of ACE inhibition was not associated with ACE genotype (Figure 4
) and there was no statistical difference between the ACR increase in the placebo-treated group in respect of ACE genotype (Figure 5).
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Discussion |
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Although all patients tolerated perindopril during the test period prior to the study, a number of patients dropped out of the study, but there was no statistical difference between the number of persons who dropped out in the perindropil group and the placebo group. Only one patient had a definite adverse effect (cough). It is unlikely that the ACE gene study would be biased by the fact that not all the patients participating in the original study agreed to be tested for ACE genotype polymorphism. All patients were asked to participate, and negligence was the reason given by the non-participants. As the study was blinded, treatment regimen was unlikely to influence the distribution of patients participating in this part of the study.
We found that the ACE inhibitor perindopril inhibited increase in ACR in a population of normoalbuminuric normotensive diabetic patients, without affecting GFR and MBP. After only 4 months, the ACR was significantly higher in the placebo group than in the ACE-inhibitor-treated group. The initial ACR ratio was lower, although not statistically different, in the placebo group compared to the ACE-I-treated group. We have no explanation of this observation, as the computer made the randomization, and patients entered the study concomitantly. The values of HbA1c are low compared to values reported from other centres. However in 1998, after termination of the study, the method for determination of HbA1c was changed at the laboratory, resulting in 10% higher values.
Our results agree with a recently published study reported by the EUCLID study group that ACE inhibitor (lisinopril) treatment slows the progression of renal disease as measured by albumine excretion rate (AER) in normotensive patients with little or no albuminuria.2 However, the EUCLID study group, in contrast to the present study, in which the effect of ACE inhibitor treatment was found after only 4 months and the difference between ACR in the treated and non-treated group continued to increase during the study period, reported that in the group treated for a full 2 years, the difference in the normoalbuminaemic group between baseline and 2 years was not significant (p=0.6). Furthermore, whereas an effect on blood pressure after ACE inhibitor treatment was reported in the EUCLID study, no diminishing effect on MBP was demonstrated in the present study. Another study including a small group of IDDM patients, with and without AER >20 µg/min but with normal blood pressure, showed that ACE treatment (captopril) for 3 months reduced albuminuria and GFR without a significant reduction of blood pressure in the ACE-treated group.10 It is difficult to explain the differences in effect on the blood pressure, as the patient population in the EUCLID study and in the present study seem comparable as regards duration of diabetes and initial blood pressure. The major difference between the present study and the EUCLID study is the duration of treatment and the type of ACE inhibitor used, and that no patients with albuminuria were included in the present study.
The observation of the present study of a tendency towards a decrease in ACR in the ACE-treated group agrees, however, with a prior study in which enalapril was given during 3 months to normoalbuminuric normotensive IDDM patients and a decline in AER was found, independent of an antihypertensive effects,11 and with a recent study of the effect of enalapril in patients with type 2 diabetes, in whom the level of albuminuria was reduced, whereas MBP remained normal.12 It is noteworthy that the difference between ACR in the placebo group and the perindopril-treated group was present after only 4 months. This observation suggests that renal function probably deteriorates from the onset of diabetes mellitus, although urine albumin excretion was considered normal in our study population.
In the present study, we were unable to observe an ACE-genotype-specific effect of ACE inhibition as described in previous studies. These studies demonstrated that in patients with diabetes and nephropathy, the deletion polymorphism in the ACE enzyme gene reduces the long-term beneficial effects of ACE inhibition on the progression of diabetic nephropathy, and that there was a significant renoprotective effect of ACE treatment in hypertensive albuminuric IDDM patients with the II genotype.3,4 However, the distribution of the genotypes differed between our study and the two previous studies. In the present study, D/D genotype was present in 30% compared to 31%/35%, I/I genotype in 28% compared to 40%/22% and I/D genotype in 42% compared to 29%/42%. An explanation could be that the patients in these other studies had nephropathy, in contrast to the present study in which the patients were normoalbuminuric. Another explanation might be that ACE genotype might be important for the progression of renal disease once nephropathy is present, but not relevant to the transmission from normal to the early stages of renal disease (microalbuminuria).
It has been suggested that sodium intake may influence the efficacy of ACE inhibition between the various genotypes, but as all patients had free sodium intake, it is unlikely that the sodium intake differed between the different ACE genotypes.
We conclude that perindopril exerts a potential renoprotective effect in normotensive, normoalbuminuric IDDM patients, and suggest that ACE inhibitor treatment may be considered as a prophylactic treatment in this patient group, but long-term studies are warranted.
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Acknowledgments |
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The authors thank technician Gunhild Andreasen for performing the ACE polymorphism studies. Perindopril was kindly supplied by Servier, France.
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Notes |
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Address correspondence to Dr J. Kvetny, Section of Endocrinology, Department of Internal Medicine, Esbjerg Centralsygehus, DK-6700 Esbjerg, Denmark. e-mail: jkv{at}ribeamt.dk
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References |
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1. Viberti G, Chaturvedi N. Angiotensin converting enzyme inhibitors in diabetic patients with microalbuminuria or normoalbuminuria. Kidney Int1997; 63:32–5.
2. The EUCLID Study Group. Randomised placebocontrolled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet1997; 21:1787–92.
3.
Parving HH, Jacobseb P, Tarnow L, et al. Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: observational follow up study. Br Med J1996; 313:591–4.
4. Jacobsen P, Rossing K, Rossing P, et al. Angiotensin converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy. Kidney Int1998; 53:1002–6.[Web of Science][Medline]
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Evans AE, Poirier O, Kee F, et al. Polymorphisms of the angiotensin converting enzyme gene in subjects who die from coronary heart disease. Q J Med1994; 87:211–14.
10. Wegmann TB, Herron KG, Chonko AM, MacDougall ML, Moore WV. Effect of angiotensin converting enzyme inhibition on renal function and albuminuria in normotensive type 1 diabetic patients. Diabetes1992; 41:62–7.[Abstract]
11. Mau Pedersen M, Schmitz A, Bjerregaard Pedersen E, Danielsen H, Sandahl Christiansen J. Acute and longterm renal effects of angiotensin converting enzyme inhibition in normotensive, normoalbuminuric insulindependent diabetic patients. Diabetic Med1988; 5:562–9.[Web of Science][Medline]
12. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. Ann Intern Med1998; 128:982–8.
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