Rudy Bilous, MD; Nish Chaturvedi, MD; Anne Katrin Sjølie, MD; John Fuller, MD; Ronald Klein, MD; Trevor Orchard, MD; Massimo Porta, MD; Hans-Henrik Parving, MD
The results were presented at the 44th Annual Meeting of the European Association for the Study of Diabetes, Rome, Italy, 7–11 September 2008, and at the American Society of Nephrology Renal Week, Philadelphia, Pennsylvania, 4–9 November 2008.
Acknowledgment: The authors thank the HOPE Study investigators for supplying the unpublished data in Table 5.
Grant Support: By AstraZeneca and Takeda.
Potential Financial Conflicts of Interest:Consultancies: R. Bilous (AstraZeneca, Takeda, Roche, Johnson & Johnson, Novartis, GlaxoSmithKline, Bristol-Myers Squibb), N. Chaturvedi (AstraZeneca, Takeda), A.K. Sjølie (AstraZeneca, Takeda), J. Fuller (AstraZeneca, Takeda), T. Orchard (AstraZeneca, Takeda), M. Porta (AstraZeneca, Takeda), H.H. Parving (Novartis, Merck & Co., Pfizer, Sanofi-Aventis, AstraZeneca). Honoraria: R. Bilous (Bristol-Myers Squibb, GlaxoSmithKline, Roche, Takeda, AstraZeneca, Novartis, Johnson & Johnson), N. Chaturvedi (AstraZeneca, Takeda), A.K. Sjølie (AstraZeneca, Takeda), J. Fuller (Takeda, AstraZeneca), R. Klein (AstraZeneca, Lilly, Novartis, Pfizer), T. Orchard (AstraZeneca, Takeda), M. Porta (AstraZeneca, Takeda), H.H. Parving (Novartis, Merck & Co., Pfizer, Sanofi-Aventis, AstraZeneca). Stock ownership or options (other than mutual funds): T. Orchard (Bristol-Myers Squibb), H.H. Parving (Merck & Co., Novo Nordisk). Members of the steering committee received an annual honorarium/consultancy fee from the funding companies (AstraZeneca and Takeda).
Reproducible Research Statement:Study protocol: A description of the protocol has been published (10). The full version is available at http://www.clinicaltrials.gov. Statistical code: Not available. Data set: Main results (but not individual data) are available at http://www.direct-results.org.
Requests for Single Reprints: Rudy Bilous, MD, James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, United Kingdom; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Bilous: Newcastle University, South Tees Hospitals NHS Trust, Academic Centre, James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, United Kingdom.
Dr. Chaturvedi: International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College Healthcare NHS Trust, London W2 1PG, United Kingdom.
Dr. Sjølie: Department of Clinical Ophthalmology, Odense University Hospital, DK-5000 Odense C, Denmark.
Dr. Fuller: Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, United Kingdom.
Dr. Klein: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, University Avenue, Madison, WI 53726.
Dr. Orchard: Graduate School of Public Health, Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15213.
Dr. Porta: Department of Internal Medicine, University of Turin, Corso AM Dogliotti, I-10126 Turin, Italy.
Dr. Parving: Rigshospitalet, Department of Medical Endocrinology, University of Copenhagen, Blegdamsvej 9, DK 2100, Copenhagen, Denmark.
Author Contributions: Conception and design: R. Bilous, N. Chaturvedi, A.K. Sjølie, J. Fuller, T. Orchard, M. Porta, H.H. Parving.
Analysis and interpretation of the data: R. Bilous, N. Chaturvedi, A.K. Sjølie, J. Fuller, T. Orchard, M. Porta, H.H. Parving.
Drafting of the article: R. Bilous, N. Chaturvedi, A.K. Sjølie, J. Fuller, M. Porta.
Critical revision of the article for important intellectual content: R. Bilous, N. Chaturvedi, A.K. Sjølie, J. Fuller, R. Klein, T. Orchard, H.H. Parving.
Final approval of the article: R. Bilous, N. Chaturvedi, A.K. Sjølie, J. Fuller, R. Klein, T. Orchard, M. Porta, H.H. Parving.
Provision of study materials or patients: R. Bilous, N. Chaturvedi, A.K. Sjølie, M. Porta.
Obtaining of funding: R. Bilous, N. Chaturvedi, J. Fuller.
Administrative, technical, or logistic support: T. Orchard.
Collection and assembly of data: N. Chaturvedi, A.K. Sjølie, J. Fuller.
ClinicalTrials.gov registration numbers: NCT00252733, NCT00252720, and NCT00252694.
For a list of members and investigators of the DIRECT (Diabetic Retinopathy Candesartan Trials) Program Study Group, see the Appendix.
Bilous R, Chaturvedi N, Sjølie AK, Fuller J, Klein R, Orchard T, et al. Effect of Candesartan on Microalbuminuria and Albumin Excretion Rate in Diabetes: Three Randomized Trials. Ann Intern Med. 2009;151:11-20. doi: 10.7326/0003-4819-151-1-200907070-00120
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Published: Ann Intern Med. 2009;151(1):11-20.
Microalbuminuria in diabetes is strongly predictive of nephropathy, end-stage renal disease, and premature cardiovascular morbidity and mortality. Effective preventive therapies are therefore a clinical priority.
To determine whether the angiotensin-receptor blocker candesartan compared with placebo affects microalbuminuria incidence or rate of change in albuminuria in type 1 and type 2 diabetes.
3 randomized trials of the DIRECT (Diabetic Retinopathy Candesartan Trials) Program.
309 secondary care centers.
3326 and 1905 patients with type 1 and type 2 diabetes, respectively. Most were normotensive, and all had normoalbuminuria (median urinary albumin excretion rate, 5.0 Âµg/min).
Candesartan, 16 mg/d increasing to 32 mg/d, versus placebo. Assignment was done centrally using an interactive voice-response system. Patients, caregivers, and researchers were blinded to treatment assignment. During a median follow-up of 4.7 years, 793 patients discontinued therapy and 63 were lost to follow-up.
Urinary albumin excretion rate, assessed annually by 2 overnight collections; if it was 20 Âµg/min or greater, then 2 further collections were done. The primary end point was new microalbuminuria (3 or 4 collections of urinary albumin excretion rate â‰¥20 Âµg/min). The secondary end point was rate of change in albuminuria.
Individual and pooled results of the 3 trials showed that candesartan had little effect on risk for microalbuminuria (pooled hazard ratio, 0.95 [95% CI, 0.78 to 1.16]; PÂ = 0.60). Pooled results showed that the annual rate of change in albuminuria was 5.53% lower (CI, 0.73% to 10.14%; PÂ = 0.024) with candesartan than with placebo.
Investigators recruited mainly normotensive patients or patients with well-controlled hypertension who were at low overall vascular risk, which resulted in a low rate of microalbuminuria. Studies were powered for retinal and not renal end points.
Candesartan, 32 mg/d, for 4.7 years did not prevent microalbuminuria in mainly normotensive patients with type 1 or type 2 diabetes.
AstraZeneca and Takeda.
The role of angiotensin-receptor blockers in the primary prevention of microalbuminuria is unclear.
These 3 randomized trials assessed whether candesartan prevented microalbuminuria more than placebo in adults with normoalbuminuria. All participants had either type 1 or type 2 diabetes, and most were normotensive. Individual and pooled results of the 3 trials showed similar rates of development of microalbuminuria with candesartan or placebo over a 4- to 5-year follow-up.
Renin–angiotensin system blockade with an angiotensin-receptor blocker did not prevent microalbuminuria in mostly normotensive people with diabetes.
Microalbuminuria in diabetes, defined as a urinary albumin excretion rate (UAER) of 20 µg/min or greater, is strongly predictive not only of nephropathy and end-stage renal disease (1) but also of premature cardiovascular morbidity and mortality (2, 3). Effective preventive therapies are therefore a clinical priority.
Both the DCCT (Diabetes Control and Complications Trial) in type 1 diabetes (4) and UKPDS (United Kingdom Prospective Diabetes Study) in type 2 diabetes (5) have demonstrated the effectiveness of intensive glycemic control on prevention of microalbuminuria. However, this is not always easy to achieve, and nephropathy continues to occur, leaving an unmet need for definitive trials of primary prevention of microalbuminuria. Renin–angiotensin system (RAS) blockade once nephropathy is established is now almost universal practice, but whether it is beneficial at an earlier stage is uncertain. The angiotensin-converting enzyme (ACE) inhibitor trandolapril reduced progression to microalbuminuria in type 2 diabetic patients with established hypertension, but whether this would also be true in normotensive persons is not known (6). In type 1 diabetes, EUCLID (Eurodiab Controlled Trial of Lisinopril in Insulin-Dependent Diabetes) (7) reported a large but statistically nonsignificant effect of RAS blockade on progression to microalbuminuria in normotensive persons. Although these previous findings are promising, the role of RAS blockade in normoalbuminuric persons with diabetes remains unclear.
The DIRECT (Diabetic Retinopathy Candesartan Trials) Program was set up to investigate whether the angiotensin-receptor blocker candesartan could prevent development or progression of diabetic retinopathy in normoalbuminuric patients with type 1 or type 2 diabetes. Retinopathy results have previously been published (8, 9). The incidence of microalbuminuria was a prespecified primary end point in the pooled study population; the rate of change in UAER was a prespecified secondary end point in each study and in the pooled study population. These analyses make up the DIRECT-Renal study. The Appendix lists members and investigators of the DIRECT Program Study Group.
The DIRECT protocol and baseline patient characteristics are described elsewhere (8–11). In brief, the research program comprised 3 related studies to investigate the effect of candesartan on 1) incidence of retinopathy (DIRECT-Prevent 1) in 1421 type 1 diabetic patients (age 18 to 50 years; diabetes duration, 1 to 15 years) who were normotensive (mean sitting blood pressure ≤130/85 mm Hg) and normoalbuminuric (UAER <20 µg/min in at least 1 of 2 timed overnight urine collections); 2) progression of mild or moderate retinopathy (DIRECT-Protect 1) in 1905 type 1 diabetic patients (age 18 to 55 years; diabetes duration, 1 to 20 years) who were normotensive and normoalbuminuric; and 3) progression of mild or moderate retinopathy (DIRECT-Protect 2) in 1905 type 2 diabetic patients (age 37 to 75 years; diabetes duration, 1 to 20 years) who were normoalbuminuric and either were normotensive or had controlled hypertension (defined as blood pressure ≤160/90 mm Hg) with non–RAS-blocker therapy.
We excluded patients if they had eye conditions that precluded us from analyzing retinal photographs; clinically significant macular edema, proliferative retinopathy, or stenotic valvular heart disease; recent stroke or myocardial infarction; or a clinical indication for or contraindication to RAS-blocking agents. We also excluded pregnant or lactating women and patients with renal impairment (serum creatinine level ≥110 µmol/L [≥1.2 mg/dL] in women and ≥130 µmol/L [≥1.5 mg/dL] in men). Antihypertensive therapy was permitted only in patients with type 2 diabetes. Other exclusion criteria are listed in the study protocol, which is available at http://www.clinicaltrials.gov.
Recruitment commenced in August 2001, and the last patient was studied in March 2008. The minimum follow-up was 4 years. The DIRECT Program was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guideline for Good Clinical Practice. The studies were approved by each participating center's ethics committee, and all participants gave written informed consent.
A total of 309 study sites in 30 countries participated. The sites were secondary care facilities with access to retinal photography. Approximately 50% of randomly assigned patients were recruited in Russia and central and eastern Europe, 17% in western Europe, 14% in South Africa, 12% in Israel, 3% in Canada, and 3% in Oceania (including Australia and New Zealand). Investigators for all 3 studies recruited at all sites synchronously. Details of the baseline characteristics of the study participants have been published (11).
We randomly assigned eligible patients centrally using an interactive voice-response system to either placebo or candesartan, 16 mg/d increasing to 32 mg/d after 1 month. We generated separate randomization schedules for each study. We stratified randomization by hypertensive status in DIRECT-Protect 2 only, but we used no other stratification variable. Investigators, caregivers, and participants were unaware of treatment allocation. Dose adjustment to 16 mg or 8 mg could be made at any time. Full details of the retinal studies are published elsewhere (8, 9).
Patients were seen every 6 months for at least 4 years. Routine serum biochemistry, total and high-density lipoprotein cholesterol, and glycated hemoglobin A1c (HbA1c) (aligned to DCCT standards) were measured in a central laboratory.
We measured UAER in 2 timed overnight collections by using nephelometry (Beckmann Array, Beckmann Instruments, High Wycombe, United Kingdom) at baseline and annually thereafter. The lower limit of detection of albumin concentration was 20 µg/L, with a maximum allowable coefficient of variation of 5% in the mean range of 50 to 100 µg/L.
We asked patients who developed microalbuminuria (UAER ≥20 µg/min) in 1 or both urine samples at any time to provide 2 more samples. If 3 or 4 of these 4 consecutive samples were positive, we considered this to constitute a microalbuminuria event and allowed open-label ACE inhibitor therapy.
We measured blood pressure after the patient sat still for at least 5 minutes by using an automated device (Omron M4, Omron Healthcare Company, Kyoto, Japan) with an appropriate-size cuff. Among 3 readings, the mean of the last 2 was used in the analysis. Patients who were or became hypertensive (blood pressure >140/85 mm Hg) but whose UAER remained normal could be prescribed any non–RAS-blocking antihypertensive agent according to international and national clinical guidelines.
The main a priori–determined end point for the pooled analysis of the 3 trials was development of microalbuminuria. Rate of change in UAER was a predefined secondary end point for each trial, as well as for the pooled analysis. The primary outcome for all trials, results of which have been published (8, 9), was incidence and progression of retinopathy.
A steering committee of senior investigators and representatives of the funding companies oversaw the study. ICON (Dublin, Ireland) did site monitoring to standard quality control procedures. ICON staff collected all data centrally and transferred data to the study sponsors. An independent safety committee met regularly and reviewed unblinded data. An independent statistical advisor reviewed and verified all results before publication.
Statistical staff at AstraZeneca and Takeda did analyses according to the intention-to-treat principle. The 2-sided P values were calculated without any adjustment for multiple comparisons.
We analyzed the incidence of microalbuminuria by using the time from randomization to first incidence. Because urine was collected at prescheduled times, with microalbuminuria occurring between these collections, we did not know the exact date of the event and consider the data to be interval-censored.
To compare the incidence of renal end points in the placebo and candesartan groups, we used a stratified generalized log-rank test for interval-censored failure time data (12). The P value for this test was calculated together with the estimated time to microalbuminuria for the 2 groups. We also did the analysis for each study separately. We estimated the treatment effect by calculating a 95% CI for the hazard ratio (HR) by using a generalized Cox regression model (13). These analyses were adjusted for the following prespecified baseline characteristics: duration of diabetes, HbA1c, systolic blood pressure, UAER, and treatment of hypertension (DIRECT-Protect 2 only).
We based sample size on retinopathy end points for each study. For DIRECT-Renal, assuming an annual incidence of microalbuminuria of 2% in the placebo group, the log-rank test would have been able to detect a 24% relative risk reduction with a power of 80%.
The analysis of the annual rate of change in UAER used the estimate of the slope of a fitted regression line through the origin for each patient, excluding the baseline UAER. The log-transformed UAER served as the dependent variable and time from randomization in years as the independent variable. We then compared the mean slopes between placebo and candesartan in a linear multiple regression model with treatment, study, and log-transformed UAER as explanatory variables (14).
We calculated summary statistics for key baseline characteristics in patients who did versus those who did not develop microalbuminuria. We used a proportional hazard model, stratified for study only, to identify the variables that affect the progression of microalbuminuria. The following baseline characteristics were included in the model: age, duration of diabetes, HbA1c value, degree of retinopathy, serum non–high-density lipoprotein cholesterol level, systolic blood pressure, diastolic blood pressure, sex, smoking history, and randomized group.
We used SAS, version 8.2 (SAS Institute, Cary, North Carolina), for the analyses and East, version 5.2 (Cytel, Cambridge, Massachusetts), for the sample size calculations.
The DIRECT Program was funded by AstraZeneca and Takeda. The funding sources had no role in the study design, interpretation of the data, or preparation in or decision to submit the manuscript. Employees of the funding companies did the statistical analysis, which was checked by an independent consultant. Representatives of the funding companies were nonvoting members of the steering committee. The authors had complete control over the interpretation of the results and the writing of the manuscript.
Figures 1 and 2 show the numbers of patients who were enrolled and recruited and who completed, withdrew from, or did not complete the study (and reasons why). A total of 793 patients discontinued treatment during the trial and 63 patients were lost to follow-up. At the last visit, 80.6% of patients were receiving the maximum dose of candesartan (32 mg/d).
Number of patients who did not complete renal functional assessments includes those who died or were lost to follow-up. DIRECT = Diabetic Retinopathy Candesartan Trial; MA = microalbuminuria.
Table 1 shows baseline data by treatment group in the 3 studies and the pooled study population. Patients with type 1 diabetes were younger and had a lower body mass index than patients with type 2 diabetes. Blood pressure was within the normal range for the type 1 diabetic patients and was well controlled in the 62% of type 2 diabetic patients treated for hypertension. Among the type 2 diabetic patients treated for hypertension, 67% were receiving 1 drug and 27% were receiving 2 drugs. Hemoglobin A1c levels and smoking rates were similar in the 3 studies. Serum cholesterol levels were slightly higher in DIRECT-Protect 2 than in the studies of type 1 diabetes, but only 5% of patients had a history of myocardial infarction. Notably, UAER was low (median <5.0 µg/min) in the 3 studies.
Among patients with type 2 diabetes in the candesartan and placebo groups, 36% were receiving insulin, and approximately equal proportions in each group were receiving sulfonylureas (53.8% vs. 56.2%), metformin (22.7% vs. 20.4%), and thiazolidinediones (0.9% vs. 0.9%).
The median follow-up was 4.7 years for the pooled study population, DIRECT-Prevent 1, and DIRECT-Protect 2 and 4.8 years in DIRECT-Protect 1. For the pooled study population, blood pressure was 3.3/2.3 mm Hg lower in the candesartan group than in the placebo group by the end of the study (P < 0.001). In DIRECT-Prevent 1 and DIRECT-Protect 1, blood pressure was 2.6/2.7 mm Hg and 3.6/2.5 mm Hg lower in the candesartan group, respectively (P < 0.005). Among patients who did and did not receive antihypertensive therapy in DIRECT-Protect 2, blood pressure was 2.9/3.1 mm Hg and 4.3/2.5 mm Hg lower, respectively, in the candesartan group (P < 0.005). These blood pressure differences were apparent by the 3-month follow-up and were sustained throughout the trial.
Among patients in the candesartan and placebo groups, 47 and 31 in DIRECT-Prevent 1, 53 and 50 in DIRECT-Protect 1, and 46 and 53 in DIRECT-Protect 2, respectively, were censored at baseline because they did not complete the necessary number of urine collections for the renal end point (Figures 1 and 2).
Similar numbers of patients in the candesartan and placebo groups developed microalbuminuria in each of the 3 studies (Table 2). For the pooled study population, the unadjusted HR (candesartan vs. placebo) was 0.95 (95% CI, 0.78 to 1.16; P = 0.60) (Figure 3), with little change in response to adjustment for key baseline covariates or for systolic blood pressure over the duration of the trial. The HRs for the individual studies did not qualitatively differ from that of the pooled analysis.
Table 3 shows the cumulative percentage of patients who developed microalbuminuria in each study (separating the hypertensive and normotensive patients in DIRECT-Protect 2). The percentage of patients who began open-label RAS-blocker therapy and the median UAER are also included. The number of patients who developed microalbuminuria did not differ between groups for any of the studies, regardless of previous antihypertensive therapy. More patients in the placebo group than in the candesartan group received open-label RAS-blocking agents during the study (396 patients vs. 275 patients; chi-square P < 0.001) for various indications. The primary outcome was not affected by adjustment for open-label RAS-blocking agents or by censoring the data at the time of first use (data not shown).
An evaluation of the baseline characteristics of the 401 patients who developed microalbuminuria showed, in a multivariate model, that a 1-µg/min increase in baseline UAER (HR, 1.020 [CI, 1.016 to 1.023]), an increase in retinopathy by 1 ETDRS (Early Treatment Diabetic Retinopathy Study) level (HR, 1.180 [CI, 1.110 to 1.255]), a 1% increase in HbA1c value (HR, 1.265 [CI, 1.194 to 1.340]), and male sex (HR, 1.531 [CI, 1.233 to 1.901]) were predictive of microalbuminuria (P < 0.001).
Median UAER did not differ at any time point in both groups (data not shown). Table 2 shows the candesartan–placebo ratio for annual rate of change in UAER for the 3 studies. A 5.53% reduction (CI, 0.73% to 10.14%; P = 0.024) occurred in the pooled study population, which equates to an absolute reduction of 0.11 µg/min.
The frequency of reported adverse events was similar for both groups in all 3 studies (Table 4) and is reported elsewhere (8, 9). Reported hyperkalemia rates during the study were 2.5% in the candesartan group and 2.1% in the placebo group for the pooled study population. Table 4 lists the rates for the individual studies, together with serious adverse events and deaths.
In the DIRECT-Renal analysis, candesartan had no effect on incidence of microalbuminuria over 4.7 years in normoalbuminuric and normotensive patients with type 1 diabetes and normoalbuminuric patients with type 2 diabetes with or without treated hypertension. The adjusted rate of change in UAER, although statistically significantly lower with candesartan, was modest, and its clinical significance is uncertain.
A recent meta-analysis (searching MEDLINE from 1966 to September 2003, EMBASE from 1988 to September 2003, and the Cochrane Central Register of Controlled Trials) suggested that ACE inhibitor therapy was associated with a relative risk of 0.60 (CI, 0.43 to 0.84) for microalbuminuria, macroalbuminuria, or both in a mix of normotensive and hypertensive type 1 and type 2 diabetic patients who were normoalbuminuric at baseline (15). Our study had more patients and events than this meta-analysis, but we found a nonsignificant reduction of 5% in risk for microalbuminuria with candesartan. This is substantially below the lowest end of the treatment benefit spectrum found in the meta-analysis (16%). How can we account for this discrepancy?
Of the 6 studies included in the previous meta-analysis, 3 contributed around 85% of the information: the HOPE (Heart Outcomes Prevention Evaluation) Study (16), BENEDICT (Bergamo Nephrologic Diabetic Complications Trial) (6), and EUCLID (7). To facilitate a “like with like” comparison and include data from the recently reported ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation) trial (17), we compared the characteristics and outcomes of these studies (Table 5).
The HOPE Study data presented in the published meta-analysis refer only to patients who progressed from normoalbuminuria to macroalbuminuria, reporting a beneficial treatment effect of 0.71 (15). However, the incidence of new micro- and macroalbuminuria in the 2272 diabetic patients who were normoalbuminuric at baseline in the HOPE Study was reduced by 13% in favor of the ACE inhibitor ramipril (data supplied by the HOPE Study investigators). This is substantially greater than the 8% reduction with candesartan in the type 2 diabetic patients in our study (Table 5). Similarly, BENEDICT (6) reported a 44% reduction in incidence in favor of the ACE inhibitor trandolapril for progression to microalbuminuria. Patients in the HOPE Study and BENEDICT were older and had higher systolic blood pressures than patients in DIRECT-Renal (11 mm Hg greater than that in hypertensive patients receiving treatment and 32 mm Hg greater than that in normotensive type 2 diabetic patients). These differences may reflect greater RAS activity, which might make patients more responsive to RAS blockade. The ADVANCE trial (17) also observed a significantly reduced incidence of microalbuminuria of 17% for the ACE inhibitor perindopril, but these patients, like those in HOPE Study and BENEDICT, were at substantially greater risk for cardiovascular disease than those recruited to DIRECT-Renal, which might explain the small observed absolute risk reduction of 5.5% (Table 5). We therefore suggest that the baseline burden of vasculopathy (possibly a reflection of increased vascular RAS activity) may determine the response to RAS blockade in type 2 diabetes—the higher it is, the greater the effect.
The EUCLID (7) trial included patients with type 1 diabetes whose baseline UAER was greater than 5 µg/min (the median for DIRECT-Renal) in more than 70% of all patients, and the treatment effect of the ACE inhibitor lisinopril was observed in this subgroup alone. Our results for type 1 diabetes are completely consistent with previously published data (15).
As such, our data might question the orthodoxy of a definite benefit of RAS blockade in the primary prevention of diabetic nephropathy for all patients. However, important aspects of DIRECT-Renal need to be considered before reaching this conclusion. First, the study was not powered for a renal end point. Second, the microalbuminuria event rate in DIRECT-Renal was lower than that in many previously published studies (18–21), particularly for the patients with type 1 diabetes. In the DCCT, which used a single 4-hour timed collection (4), approximately 12% of the conventional treatment group in the primary prevention cohort (similar to the DIRECT-Prevent 1 sample) and 23% of the conventional treatment group in the secondary prevention cohort (similar to the DIRECT-Protect 1 sample) had a UAER greater than 28 µg/min at 4 years (compared with 0.5% and 1.6% in the placebo groups in DIRECT-Prevent 1 and DIRECT-Protect 1, respectively). For the patients with type 2 diabetes in DIRECT-Renal, however, the event rate (14.8%) was more similar to that in BENEDICT (10.0%), but was considerably less than that in the HOPE Study (38.2%) and the ADVANCE trial (19.6%) for the placebo groups. The higher rates in the HOPE Study and the ADVANCE trial might be a reflection of the stringency of the diagnosis, because both studies used a single urinary albumin–creatinine ratio (with a very low threshold [2 mg/mmol in the HOPE Study]) at only 2 time points over the duration of the trials, whereas DIRECT-Renal and BENEDICT used multiple timed collections at 12- and 6-month intervals, respectively.
The overall median baseline UAER of 5 µg/min in DIRECT-Renal is low. The rate of change in UAER from baseline may be so slow that the ability to detect an effect of treatment over 4.7 years would be limited. Moreover, many of these patients may never develop nephropathy—the cumulative incidence in type 1 diabetes is only 40% after 40 years (22) and may be decreasing, although most will show some retinopathy after this time (23).
Candesartan might not be as effective at blocking the RAS as an ACE inhibitor. The dosage of candesartan we used was 32 mg/d, and good blockade of the RAS has been demonstrated at this level (24). Moreover, angiotensin-receptor blockers have been shown to be highly effective in reducing progression of established diabetic nephropathy (25–27); therefore, it is unlikely that they would be less effective than ACE inhibitors in normoalbuminuric patients, and our results are consistent with EUCLID for type 1 diabetes. The clinical characteristics of the patients who developed microalbuminuria compared with those of patients who did not were similar to those previously published (18–21), so it is unlikely that the DIRECT-Renal study samples were in some way atypical.
The treatment effect of candesartan on the rate of change in UAER was clinically small. Such a modest reduction might result in a long-term clinical benefit for patients, but a much longer duration of follow-up would be necessary to confirm any effect.
We believe that DIRECT-Renal is the largest trial to date to address the question of the role of RAS blockade in preventing microalbuminuria in normoalbuminuric, mostly normotensive people with diabetes. In this patient sample with a low burden of vasculopathy, we could not show a beneficial effect of candesartan therapy on microalbuminuria prevention over 4.7 years. Studies of RAS blockade in diabetic patients with low vascular burden probably require much longer follow-up to establish whether it offers clinically beneficial treatment in the primary prevention of cardiorenal complications. A meta-analysis of individual patient data from the major studies might help to resolve this question, but our results would not support the use of candesartan or other RAS-blocking agents in the primary prevention of diabetic nephropathy in patients with type 1 diabetes or in patients with type 2 diabetes and a low vascular burden.
DIRECT Steering Committee: Anne Katrin Sjølie, Chair (Odense, Denmark); Rudy Bilous (Middlesbrough, United Kingdom); Nish Chaturvedi (London, United Kingdom); Ywonne Fox (Gothenburg, Sweden); John Fuller (London, United Kingdom); Michael George (London, United Kingdom); Anders Svensson (Gothenburg, Sweden; until August 2007); James Hainer (Princeton, New Jersey; from September 2007); Ronald Klein (Madison, Wisconsin); Trevor Orchard (Pittsburgh, Pennsylvania); Hans-Henrik Parving (Copenhagen, Denmark); Massimo Porta (Turin, Italy); Ingrid Warnold (Gothenburg, Sweden).
International Coordinators Group: Carl-David Agardh, Sweden; Rudy Bilous, United Kingdom; Francois Bonnici, South Africa; Bernard Charbonnel, France; Mark Cooper, Australia; Ivan Dedov, Russia; Robert Gardiner, Canada; Ramon Gomis, Spain; Hasan Ilkova, Turkey; Nicholas Katsilambros, Greece; Zsuzsa Kerenyi, Hungary; Stephan Martin, Germany; Pascale Massin, France; Valdis Pirags, Baltic states; Massimo Porta, Italy; Itamar Raz, Israel; Zdenek Rusavy, Czech Republic; Guntram Schernthaner, Austria; Marina Shestakova, Russia; Anne Katrin Sjølie, Denmark; Krzysztof Strojek, Poland.
Statisticians: Bertil Olofsson (AstraZeneca, Gothenburg, Sweden), Anders Malm (AstraZeneca, Gothenburg, Sweden), Jenny Wissmar (AstraZeneca, Gothenburg, Sweden), Nigel Brayshaw (Takeda, London, United Kingdom).
Independent statistician: Hans Wedel (Gothenburg, Sweden).
Independent Safety Committee: Lars Wilhelmsen, Chair (Gothenburg, Sweden); Alan Bird (London, United Kingdom); Hans Wedel (Gothenburg, Sweden).
DIRECT Project Team: Ingrid Warnold, Project Leader (AstraZeneca, Gothenburg, Sweden); Graham Price, Deputy Project Leader (Takeda, London, United Kingdom); Elisabeth Adler-Ekholm (AstraZeneca, Gothenburg, Sweden); Stephen Aldington (Retinopathy Grading Centre, London, United Kingdom); Magnus Dahl (AstraZeneca, Gothenburg, Sweden); Aaron Deveney (Takeda, London, United Kingdom); Eva Karlsten (AstraZeneca, Gothenburg, Sweden); Philippa Levins (ICON, Dublin, Ireland); Helen Lipinski (Retinopathy Grading Centre, London, United Kingdom); Carol Prenter (ICON, Dublin, Ireland); Helen Walkey (Academic Coordinating Centre, London, United Kingdom); Nicola Walters (Quest, London, United Kingdom).
Australia: Mark Cooper (National Coordinator), Roger Chen, Peter Colman, Peter Davoren, Thomas Donnelly, Michael d'Emden, George Jerums, Richard O'Brien, Pat Phillips, John Prins, Anthony Roberts, Gerald Watts, Dennis Wilson, Dennis Yue, Sophia Zoungas.
Austria: Guntram Schernthaner (National Coordinator), Anton Luger, Ernst Pilger, Rudolf Prager, Werner Klaus Waldhäusl, Raimund Weitgasser.
Belgium: Bart Keymeulen, Luc Van Gaal.
Bulgaria: Vladimir Christov, Kiril Hristozov, Lidia Koeva, Adreana Markova, Mihail Protich, Antoanela Slavcheva, Tsvetalina Tankova, Antoaneta Toneva, Natalia Veleva, Marga Zaharieva.
Canada: Robert Gardiner (National Coordinator), Sandra Babin, Andre Belanger, Chantal Godin, Carol Joyce, Erin Keely, Lawrence Leiter, Heather Lochnan, Ruth McManus, David Miller, Theodore Monchesky, George Pylypchuk, Stuart Ross, Irving Siegel, Sheldon Tobe, Ehud Ur, Vincent Woo, Ellen Toth.
Croatia: Damir Kovacevic, Velimir Profozic.
Czech Republic: Zdenek Rusavy (National Coordinator), Michal Andel, Petr Boucek, Petr Chmura, Anna Gregorova, Jana Havelkova, Jaroslava Karasova, Frantisek Musil, Jindrich Olsovsky, Frantisek Patek, Blanka Plesnikova, Yvona Pospisilova, Eva Racicka, Jana Zawadova.
Denmark: Anne Katrin Sjølie (National Coordinator), Toke Bek, Kjeld Hermansen, Hans-Henrick Lervang, Hans-Henrik Parving, Peter Rossing.
Estonia: Valdis Pirags (National Coordinator), Marju Past, Hiie Tupits, Toomas Podar.
France: Bernard Chabonnel (National Coordinator), Pascal Massin (National Coordinator), Brigitte Anton, P. Charpentier, Andre Grimaldi, Pierre-Jean Guillausseau, Veronique Kerlan, Jacques Marechaud, Michel Marre, Pierre Nocent, Alfred Penformis, Michel Rodier, Jean-Philippe Ruiz, Gerard Slama, Marie-Emmanuelle Combes.
Georgia: Nino Gagunashvili, Ramaz Kurashvili, David Metreveli.
Germany: Stephan Martin (National Coordinator), Bruno Allolio, Helmut Anderten, Klaus Badenhoop, Klaus Busch, Manfred Dreyer, Harald Etzrodt, Matthias Frank, Andreas Hamann, Hans-Peter Hammes, Hans-Peter Kempe, Raimund Konzok, Ulrich Alfons Mueller, Ralf Paschke, Matthias Pein, Andreas Pfeiffer, Ernst-Otto von Reis, Michael Schneider, Andreas Schäffler, Werner Stuermer, Klaus-Henning Usadel.
Greece: Nicholas Katsilambros (National Coordinator), Basil Karamanos, Andreas Melidonis, Ilias Mygdalis, Marina Noutsou, Emanuel Pagalos, Andreas Papadam, Angelos Pappas, Stavros Pappas, Konstantinos Phenekos, Georgios Piaditis.
Hungary: Zsuzsa Kerényi (National Coordinator), Marietta Baranyai, Tamás Bölcsvölgyi, Erzsebét Dömötör, Péter Faludi, József Fövényi, Laszlo Koranyi, Albert Szöcs, Gyula Tamás, Mihaly Tárko, Gyözö Vándorfi.
Ireland: Barry Ferriss, Joseph McKenna, Donal O'Shea, Sheila O' Sullivan.
Israel: Itamar Raz (National Coordinator), Faiad Adawi, Lidia Arcavi, Josef Cohen, Ohad Cohen, Dror Dicker, Hadassah Guttmann, Ilana Harman-Boehm, Tommy Herskovits, Anat Jaffe, Eddy Karnieli, Zahava Loewinger, Rafael Luboshitzky, Dan Nabriski, Shmuel Oren, Moshe Phillip, Mordechai Ravid, Ardon Rubinstein, Naim Shehadeh, Ladislav Slezak, Ervin Stern, Julio Wainstein, Yair Yerushalmi.
Italy: Massimo Porta (National Coordinator), Luciano Corgiat-Mansin, Rita Leoncavallo Gaetano Crepaldi, Aldo Galluzzo, Giovanni Ghirlanda, Cecilia Invitti, Claudio Noacco, Piermarco Piatti, Giuseppe Realdi, Franco Saccardi, Fausto Santeusanio, Giorgio Luciano Viviani.
Latvia: Valdis Pirags (National Coordinator), Baiba Jegere, Guna Laganovska, Ingvars Rasa, Irisa Vinsteine.
Lithuania: Valdis Pirags (National Coordinator), Juozas Danileviclus, Antanas Norkus, Rimantas Zalinkevicius.
Luxembourg: Georges Michel, Roger Wirion.
New Zealand: Paul Drury, Peter Dunn, Russel Scott, Robyn Toomath.
Poland: Krzysztof Strojek (National Coordinator), Elzbieta Bandurska-Stankiewicz, Barbara Idzior-Walus, Waldemar Karnafel, Malgorzata Koziol, Ewa Krzyzagorska, Jerzy Lopatynski, Krzysztof Markiewicz, Anna Mikolajczyk-Swatko, Miroslawa Polaszwska-Muszynska, Slawomir Pynka, Ewa Semetkowska-Jurkiewicz.
Portugal: Luis Gardete, Manuel Joao Gomes, Arnaldo Sa.
Romania: Monica Liliana Angelescu, Mariana Graur, Maria Mota, Gina Camelia Suciu, Constantin Ionescu Tirgoviste, Andrei Ioan Veresiu.
Russia: Ivan Dedoc (National Coordinator), Marina Shestakova (National Coordinator), Alexandr Ametov, Irina Bondar, Elena Bova, Olga Chizhova, Irina Demidova, Sergey Dogadin, Valentina Elpatova, Elina Gasparyan, Irina Ipatko, Tatyana Ivanova, Brovina Faina Jakovlevna, Irina Karpova, Tatyana Khintal, Elena Kholopova, Oleg Khrustalev, Oleg Kolenko, Viktor Korshennikov, Elena Kravez, Tatyana Krivolapova, Nadezhda Kudriashova, Galina Melnichenkov, Tatyana Milovanova, Ashot Mkrtumyan, Alla Morozova, Olga Nikiforova, Asia Ponomareva, Elena Rechkova, Tatyana Rodionova, Sergei Shustov, Elena Smimova, Ludmila Suplotova, Nelly Verbovaya, Serguei Vladislavovich, Natalia Vorokhobina, Vladimir Yakusevich, Ludmila Zarutskaya, Vaycheslav Zudaev, Tatyana Zykova.
South Africa: Francois Bonnici (National Coordinator), Aslam Amod, Elisabeth van den Berg, Jaysingh Brijkumar, G. Chidi, Lawrence Distiller, Anton Doubell, Pirie Fraser, Andrew Jacovides, Dudley Kelbe, Hilton Kaplan, Johanna Kok, Wilma Lourens, Leila Mayet, Ray Moore, Sean Murray, Visvakuren Naidoo, Puvanesveri Naiker, Hendrik Nortje, M.A.K. Omar, Geoffrey Parker, Areti Philotheou, Everard S. Polakow, Andre Postma, Andrew Ramdass, Hoosen Randeree, Leslie Robertson, M. I. Sarvan, Marthinus-Stephanus Smuts, Essop Solomon, Holger Wellman, Jeffrey Wing.
Spain: Ramon Gomis (National Coordinator), Ramon Albero, Alfonso Gentil Baldrich, Juan José Barberia Layana, Fernando Gomér Peralta, Olga González Albarrán, Forga Louis, Anna Novials Sarda, Fransico Pinon-Selles.
Sweden: Carl-David Agardh (National Coordinator), Ulf Adamson, Elisabet Agardh, Michael Alvarsson, Ibe Lager, Stina Lindmark, Anders Nilsson, Bengt Norberg, Maria Svensson.
Turkey: Hasan Ilkova (National Coordinator), Yalcin Aral, Goksun Ayvaz, Nilgun Baskal, Selcuk Dagdelen, Gurbuz Erdogan, Ahmet Kaya, Fulya Tanyeri, Candeger Yilmaz.
United Kingdom: Rudolf Bilous (National Coordinator), Thomas Akintewe, John Anderson, Stephen Beer, Leslie Borthwick, Andrew Boulton, Andrew Collier, Daniel Darko, John Doig, Philip Evans, Owain Gibby, Richard Greenwood, Patricia Hart, David Hopkins, Steve Hyer, Basil Issa, Geraint Jones, Ian Lawrence, Grayham Leese, John Lorrains, Una Martin, Dinesh Nagi, Joseph Paul O'Hare, Simon Page, Vinod Patel, Douglas Robertson, Mike Sampson, Derek Sandeman, Simon Walford, James Walker, Jonathan Webber, Philip Wiles, Peter Winocour, Solomon Tesfaye, John Tooke, Yit Yang.
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