The renoprotective effects of structured care in a clinical trial setting in type 2 diabetic patients with nephropathy
Wilson Y. S. Leung1,
Wing-Yee So1,
Peter C. Y. Tong1,
Matthew K. W. Lo1,
Kar-Fai Lee1,
Gary T. C. Ko1,
Wing-Bun Chan1,
Clive S. Cockram1,
Barry M. Brenner2,
Shahnaz Shahinfar3,
Julian A. J. H. Critchley1,4 and
Juliana C. N. Chan1
1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, 2 Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA and 3 Merck Research Laboratory, Whitehouse, PA, USA 4 Professor J. A. J. H. Critchley, one of the senior investigators in this sub-study, unfortunately died after a road traffic accident on 13th July 2001 at the age of 50 years. During his 12 years of stay in Hong Kong, he had contributed significantly to the understanding of diabetes and metabolic syndrome in Hong Kong Chinese.
Correspondence and offprint requests to: Dr Juliana C. N. Chan, Divisions of Endocrinology and Clinical Pharmacology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, N.T., Hong Kong. Email: jchan{at}cuhk.edu.hk
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Abstract
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Background. The RENAAL Study has confirmed the renoprotective effects of Losartan in type 2 diabetes. In this subgroup analysis from the RENAAL Study, we hypothesized that the intensive care received by patients in a clinical trial setting also reduced the rate of decline in renal function through optimization of all risk factors.
Methods. We compared the rate of deterioration in renal function, expressed as the regression coefficient of the monthly serum creatinine (SeCr) reciprocal (beta-1/Cr) in 55 Chinese type 2 diabetic patients before and after entry into the RENAAL Study.
Results. Of the 55 patients, 44 had at least three out-patient SeCr measurements both before (2.9±2.4 years) and after (3.3±0.8 years) entry into the study for evaluation. In the Losartan group (n = 24), the median beta-1/Cr fell from 11.4 x 105 l µmol1 month1 before entry into the trial to 4.7 x 105 l µmol1 month1 following entry (P = 0.001). The respective figures were 9.1 x 105 and 5.0 x 105 l µmol1 month1 (P = 0.01) in the placebo group (n = 20). A decrease in beta-1/Cr was observed in 21 (87.5%) and 14 (70.0%) patients in the Losartan and placebo groups, respectively. Spot urinary albumin-to-creatinine ratio was reduced by 56% (P = 0.001) in the Losartan group but the change was not significant in the placebo group. At the end of the study, patients in both groups had lower blood pressure and better lipid control. The frequency of patient visits to doctors and nurses were doubled.
Conclusions. The rate of renal function decline was significantly reduced in the majority of patients allocated to either Losartan or placebo following entry into the RENAAL study. These results suggest that in patients with diabetic nephropathy, implementation of a structured care protocol in a clinical trial setting facilities intensive treatment of risk factors confering renoprotective effects in addition to those resulting from Losartan treatment.
Keywords: clinical trial; diabetic nephropathy; renoprotection; structured care
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Introduction
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Diabetes is the leading cause of renal failure worldwide [1,2] including Hong Kong. In an unselected population of Hong Kong Chinese with type 2 diabetes, the annual mortality rate was 3.5% with equal contribution from cardiovascular and renal events [3]. In a cohort of 102 type 2 diabetic patients in whom blood pressure (BP) was well controlled, 50% of patients with macroalbuminuria died or had one cardiovascular event (stroke, ischaemic heart disease or heart failure) or renal endpoint [dialysis or doubling of serum creatinine (SeCr)] within 5 years of follow-up [4].
Prospective studies have confirmed the beneficial effects of optimal control of BP in reducing the rate of renal function decline in both type 1 and type 2 diabetes [5,6]. Furthermore, epidemiological studies have shown that albuminuria, blood glucose and lipid indices were all independent predictors of cardiovascular and renal endpoints [3,7]. Optimal control of blood glucose [8,9] and lipids [10] have also been shown to reduce albuminuria although their effects on renal outcomes remain to be confirmed.
Despite these high quality data, translation of results from these clinical trials to daily clinical practice remains a major challenge. In the Steno type 2 diabetes study, it has been shown that intensive treatment using a multidisciplinary approach to optimize metabolic and BP control together with the use of aspirin and vitamin E reduced the rates of both macro- and microvascular complications by 5060% [11]. The Reduction in Endpoint Study in NIDDM with the AII Antagonist Losartan (RENAAL) Study was a 3.5 year, multinational, double-blind, randomized, placebo-controlled study which involved 1513 type 2 diabetic patients with nephropathy. The study confirmed that treatment with Losartan reduced the risk of reaching end-stage renal disease (ESRD) by 29% compared to conventional antihypertensive treatment [12]. We have hereby performed a post-hoc, subgroup analysis in patients recruited into the RENAAL study at our centre. We hypothesized that the intensive monitoring and treatment in a clinical trial setting per se might reduce the rate of deterioration of renal function in this group of high-risk patients.
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Methods
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Ninety-two Chinese patients were recruited from two hospital centres in Hong Kong into the RENAAL Study. Our study cohort comprised 55 Hong Kong Chinese subjects who were recruited and randomized at the Prince of Wales Hospital in 19971998. The patient population and study design has been previously described [12]. Briefly, patients were eligible for recruitment if they were male or female type 2 diabetic patients with an age range of 3170 years, had nephropathy [presence on two occasions of a ratio of urinary albumin-to-creatinine ratio (ACR) from a first morning specimen of
300 mg/g (
30 mg/mmol) or a rate of urinary protein excretion of at least 0.5 g/day] and renal impairment (SeCr 133265 µmol/l for males; 115265 µmol/l for females and males <60 kg), and had no stated exclusion criteria. The primary composite endpoint was death, ESRD, defined as the need for long-term dialysis or renal transplantation, or doubling of SeCr. The study was approved by the Clinical Research Ethics Committee at the Chinese University of Hong Kong. All 55 patients completed the study.
All patients gave written informed consent prior to recruitment into the RENAAL study. They underwent a 6 week washout/placebo period where medical history, body weight, BP, HbA1c, fasting plasma glucose, lipids and urinary albumin excretion were measured before they were randomized to receive either Losartan (50100 mg/day) or placebo treatment. All previous anti-hypertensive drugs were continued except for angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (AII) antagonists. Thereafter, all study patients received intensive care according to a structured protocol required by the clinical trial, with a BP goal of <140/90 mmHg [12]. This was compared to the usual care they received prior to entry into the study. Although all patients were attending a diabetes clinic at the time of recruitment, the frequencies of follow-up visits and treatment-to-target were less intense with usual care than in the clinical trial setting, and the decisions to order laboratory tests or intensify drug treatments were at individual doctors' discretion.
We compared the rate of decline of renal function, expressed as the slope of the regression line of reciprocal SeCr (1/Cr) vs time, before and after entry into the study [13]. To better approximate the rate of renal deterioration using the linear regression method, we only included patients who had at least three out-patient SeCr measurements over 6 months or longer for both the periods before and after entry into the RENAAL study. For the period before recruitment, the three or more SeCr measurements included for regression were taken after the patient had clinical proteinuria (urine protein
1+ on dipstick or an ACR
25 mg/mmol) or SeCr
120 µmol/l, confirmed by a second, consecutive measurement. Patients were excluded from this analysis if they withdrew from the RENAAL study, died within 6 months of randomization, had been followed up for <6 months at our medical out-patient clinic(s) or three out-patient SeCr measurements were not available before entry into the trial. SeCr measurements obtained during the 6 week washout, placebo run-in period when ACE inhibitors or AII antagonists had been withdrawn were not used for the 1/Cr regression analysis. Of the 55 patients randomized, 44 patients had data suitable for this analysis.
Statistical analyses
The main outcome measure was the change in the rate of decline of renal function following entry into the study. The rate of renal deterioration was analysed by applying regression analysis to the plot of 1/Cr (l µmol1) against time t (months) for each patient, and expressed as the regression coefficient (i.e. beta-1/Cr). Plasma triglycerides (TG) and spot urine ACR values were logarithmically transformed due to their skewed distributions. Each patient served as his/her own time control and paired t-tests,
2-tests, and non-parametric tests were used as appropriate. Data are shown as means±SD, geometric means x/÷ antilog SD, or median [inter-quartile range (IQR)] as appropriate. A P-value <0.05 was considered to be significant. All analyses were performed using the Statistical Package for Social Sciences (SPSS Version 9.0).
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Results
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Table 1 summarizes the baseline clinical and biochemical characteristics of all 55 patients at recruitment into the RENAAL study, and also the subgroup of 44 patients who met the criteria for inclusion in the comparison of the rate of renal decline before and after entry into the study, divided according to Losartan/placebo allocation. No significant differences were observed between the 44 and the remaining 11 patients (data not shown) or between the Losartan- and placebo-treated patients. Among the 44 patients, over 90% were taking antihypertensive medications at the first visit. The mean (SD) number of antihypertensive drugs was 1.6±0.8. Approximately 30% were previously taking ACE inhibitors and 30% were taking lipid-lowering agents. Table 2 shows the pattern of drug treatment in the Losartan and placebo groups at both the first and last study visits. More patients were taking lipid-lowering drugs (73 vs 36%, P<0.001) and using insulin therapy (82 vs 59%, P = 0.002) at the last visit when compared to the first visit and the number of antihypertensive medications (excluding Losartan or placebo) had increased from 1.6±0.8 at start of study to 2.5±1.0 (P<0.001). The increase in use of medications was not significantly different between the two treatment groups.
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Table 1. Baseline demographic and clinical characteristics of (1) all the 55 Type 2 diabetic patients recruited into the RENAAL study at the Prince of Wales Hospital Diabetes Center in Hong Kong, and (2) the subgroup of 44 patients included in the analysis of the change in rate of renal function decline according to Losartan/placebo allocation
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Table 2. Drug treatment at the start and the end of the RENAAL study for the subgroup of 44 patients included in the analysis of the change in rate of renal function decline according to Losartan/placebo allocation
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Among the 55 subjects, 38% had either died (18%) and/or reached ESRD (24%) during the 3.3±0.8 years of study. If doubling of SeCr was included, 51% had reached the primary composite endpoint. The direct causes of deaths were renal failure/uraemia (n = 3), pneumonia (n = 2), chest infection (n = 3) and hypertensive heart disease (n = 2).
Regression analyses were performed on the plots of 1/Cr (l µmol1) against time (months) for each of the 44 patients for the periods before (2.9±2.4 years) and after (3.3±0.8 years) entry. The average follow-up duration after entry was similar for the Losartan (3.4±0.7 years) and placebo groups (3.1±0.8 years). Taking all 44 patients as a group, the median beta-1/Cr before entry was 10.3 x 105 (IQR 12.7 x 105) l µmol1 month1, which was reduced to 4.8 x 105 (IQR 5.0 x 105) l µmol1 month1 after entry (P<0.001, Wilcoxin signed test). The absolute and percentage change in beta-1/Cr before and after the study was calculated for each of the 44 patients. The median reduction in beta-1/Cr was 4.6 x 105 (IQR 10.7 x 105) l µmol1 month1. In terms of percentage reduction, it was 61% (IQR 55%). In the Losartan-treated patients (n = 24), the median beta-1/Cr fell significantly from 11.4 x 105 (IQR 11.0 x 105) to 4.7 x 105 (IQR 4.5 x 105) l µmol1 month1 following entry into study (P = 0.001). In the placebo group (n = 20), the respective figures were 9.1 x 105 (IQR 16.3 x 105)(before entry) and 5.0 x 105 (IQR 6.5 x 105) l µmol1 month1 (after entry) (P = 0.01). For the whole group (n = 44), the magnitude of beta-1/Cr was reduced implying slowing of renal disease progression in 35 (79.5%) patients. In 22 (50%) patients, the decrease in beta-1/Cr was >50%. No significant difference in the change in beta-1/Cr values following entry into the study was found between the Losartan and placebo groups (P = 0.944, MannWhitney test). In terms of percentage responders, there was a trend that more patients in the Losartan than in the placebo groups experienced a decrease in beta-1/Cr after entry into study [87.5% (n = 21) vs 70.0% (n = 14), P = 0.151,
2-test].
Figure 1 is a hypothetical 1/Cr vs time plot in a study subject, using the median baseline SeCr value (170 µmol/l) and taking the median values of beta-1/Cr before (10.3 x 105 l µmol1 month1) and after (4.8 x 105 l µmol1 month1) entry as the slopes, to illustrate the reduction in rate of renal function decline following entry into the study. The after-entry line was extrapolated to intersect where SeCr was equal to 600 µmol/l, regarded as the threshold for ESRD, thus requiring renal replacement therapy. The dotted line was an extrapolation from the before-entry line also to a SeCr of 600 µmol/l.
t, which denotes the hypothetical delay in time-to-ESRD if patients had continued to receive intensive care since recruitment into the trial even after study completion, was computed to be 46.1 months. The values of beta-1/Cr and baseline SeCr were then varied by ±20% in multivariate sensitivity analysis and with all possible combinations,
t was found to range from 16.5 to 100.8 months.

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Fig. 1. The solid lines are the plots of reciprocal SeCr regressed against time before and after entry into the RENAAL study, using the median values of beta-1/Cr and baseline SeCr of all the 44 patients. The y-axis is drawn on the linear scale of the reciprocal SeCr, but the corresponding SeCr values that are clinically more readily understood are shown in parenthesis. Time 0 is the time of entry into the study. The long-dotted line represents the rate of renal function decline if the patient had not entered the study. The lines are extrapolated to intersect with the short-dotted, horizontal line (SeCr = 600 µmol/l) to denote the time-to-ESRD. t thus represents the delay in time-to-ESRD as a result of entry into the clinical trial.
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Table 3 compares the clinical and biochemical characteristics of the 44 patients at baseline and at the end of the study. In both treatment groups, patients had significantly lower systolic and diastolic BP, total cholesterol (TC) and LDL-C at the end of study as compared to baseline. In both groups, no differences in HbA1c and body mass index were observed at baseline and at the end of the study, although there was a trend towards an increase in body mass index in the Losartan group. In the latter group, spot urine ACR values were significantly reduced by 56% but the change was not significant with placebo. Comparing the follow-up periods before (2.9±2.4 years) and after (3.3±0.8 years) recruitment into the study, patients had a near doubling in the number of doctor (before, 4.7±2.3 times/year; after 8.8±2.3 times/year, P<0.001) and nurse visits (before, 5.2±3.3 times/year; after 9.4±2.6 times/year, P<0.001) after entry into the trial.
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Table 3. The clinical and biochemical characteristics at baseline and at the end of study for the subgroup of 44 patients included in the analysis of the change in rate of renal function decline according to Losartan/placebo allocation
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Discussion
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In this independent analysis involving a group of Chinese type 2 diabetic patients with advanced nephropathy and renal insufficiency, entry into the RENAAL trial, regardless of allocation to Losartan or placebo treatment, was associated with a significant reduction in the rate of decline of renal function compared to that before recruitment. Patients in the placebo group received intensive care as specified in the clinical trial protocol but received neither AII antagonists nor ACE inhibitors during the 3.3 year trial period. Nevertheless, slowing of renal function decline was evidenced in as many as 70% of the placebo recipients. This was compared to those who received Losartan in addition to intensive treatment where reduction in beta-1/Cr was noted in an additional 17.5% of patients. These findings suggest that the intensification of treatment made possible in a clinical trial setting has contributed to the stabilization or improvement in renal function. Although we did not observe a significant difference between the Losartan and placebo groups in the decrease in beta-1/Cr values following entry into the study, probably due to inadequate power, Losartan treatment has demonstrated an additional anti-proteinuric effect in line with the main RENAAL study [12].
Our analyses of the rate of renal function decline had inherent limitations. The first limitation related to the use of change in reciprocal SeCr concentrations (beta-1/Cr) to estimate the rate of renal deterioration. Nevertheless, our approach has been used in previous studies evaluating the effects of health care interventions on renal outcomes. In these studies, the number of subjects was also similar to ours [1416]. Therefore, in the absence of data on glomerular filtration rate in practice settings, we considered the use of SeCr measurements an appropriate method to determine the rate of renal disease progression. Secondly, we acknowledged that the SeCr measurements performed in clinical practice before entry into study were not the most ideal data for analyses. In this regard, only patients who had three or more measurements over a
6 month period prior to entry into study were included in the analyses.
Our findings corroborate those of other studies designed to examine the effects of intensive care in patients with diabetes. In an 8 year trial, 160 type 2 diabetic patients with microalbuminuria were randomized to receive either usual care or intensive care. Patients in the latter group received multifactorial interventions including education from a nurse and dietitian, and intensive treatment for hypertension, hyperglycaemia, dyslipidaemia and microalbuminuria. Patients allocated to intensive care had significantly lower risk for a cardiovascular event and for progression to nephropathy (risk reduction, 53 and 61%, respectively) [11]. However, patients with clinical diabetic nephropathy were not examined. In another study involving 76 patients with type 2 diabetic nephropathy, referral to a nephrology clinic was associated with a reduction in the rate of decline in renal function in 39% of patients which was attributed mainly to improvement in BP, HbA1c and serum cholesterol [14]. Nevertheless, the details of management protocol and treatment targets were not described in the report. In our study, all patients followed a standard treatment protocol which could be replicated in clinical practice [12]. Although we did not find a lowering of HbA1c, significant improvements in the control of BP and lipids were observed in both Losartan and placebo recipients following entry into the trial. Moreover, our results have indicated a doubling of the number of visits to doctors and nurse educators, and an increase in the number of antihypertensive medications during the study period. The need to use multiple drugs to control BP has been demonstrated repeatedly in randomized controlled trials where tight BP control was the treatment aim [12,17,18]. Similarly, 73% of our patients were receiving lipid-lowering drugs at the last visit compared to 37% at recruitment. Although the improvement in rate of renal decline cannot be attributed to any single component, our results have reinforced the need for close follow-up, patient education and aggressive pharmacological treatment in the routine management of patients with diabetic nephropathy.
The financial cost of providing structured care involving a team of specialist physicians and educators, frequent laboratory assessments and multiple pharmacological treatments is inevitably higher than that due to usual care. Nevertheless, these costs need to be viewed in the context of the high treatment costs of renal replacement therapy and the associated poor quality of life. In the main RENAAL study, it has been estimated that treatment with Losartan delayed the need for dialysis or transplantation by approximately 2 years as compared to placebo in the clinical trial setting. The number needed to treat to prevent one case of ESRD with Losartan treatment in 3.5 years was 16 [12]. Moreover, the renoprotective effects have translated into substantial cost savings [19]. In Hong Kong, the estimated annual costs related to peritoneal dialysis and haemodialysis are HK$100 000 (US$12 800) and HK$200 000 (US$25 600), respectively (Hong Kong Hospital Authority database). Using the median baseline SeCr at recruitment, we were able to postulate that the provision of intensified treatment delayed the need for dialysis by 46.1 months (range 16.5100.8 months using multivariate sensitivity analysis with all parameters varied by ±20%) which could translate into substantial cost savings. Given the tremendous costs of renal replacement therapy and the poor quality of life associated with dialysis [20], a care model which advocates treat-to-target and stay-on-therapy using a doctor/educator team approach emphasizing patient compliance is expected to be highly cost-effective, although more detailed pharmacoeconomic analyses are warranted.
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Acknowledgments
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We thank our research nurses, Margaret Y. F. Cheung, Germaine M. Y. Cheung, Ada W. Y. Chong and Yee-Mui Lee for their professionalism and dedication. The study was wholly sponsored by Merck Research Laboratory, Whitehouse, PA, USA.
Conflict of interest statement. The study was wholly sponsored by Merck Research Laboratory, Whitehouse, PA, USA.
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Received for publication: 9. 5.03
Accepted in revised form: 16. 6.04