 lost 0.5 kg of body weight relative to patients who were randomly assigned to placebo. This difference is suggestive of modest volume depletion possibly as a result of the diuretic component of the fixed combination drug used in ADVANCE and the more limited use of diuretics by patients who were randomly assigned to placebo treatment. However, because instructions to reduce body weight could be provided in relation to the intensive glucose control arm of the study32 and no data were collected on intake or excretion of sodium, this remains speculative. Although the diuretic component is likely to have contributed to the BP-lowering and antiproteinuric effect of the fixed combination perindopril-indapamide,33 ADVANCE was not designed and is therefore not able to determine the separate effects of its components, the results of which can reliably be attributed only to the combination as a whole. Moreover, BP lowering per se is probably more important than the means by which such lowering is achieved.10–13,34 The strong and continuous association we and others16,17 observed between achieved BP and renal events supports this assertion. The absence of a lower limit of BP below which the risks for renal events did not continue to decline reemphasizes the broad range of individuals with diabetes who could derive benefit from BP-lowering therapy.
These analyses show that routine treatment with a fixed combination of perindopril and indapamide significantly reduced the risk for renal disease progression in a large representative population of patients with type 2 diabetes. In absolute terms, this simple, well-tolerated treatment strategy prevented one renal event among every 20 patients who were treated for 5 yr, with no selection of patients on the basis of BP or BP-lowering treatment. These data therefore suggest that BP lowering may be considered routinely for the prevention of renal complications in all patients with diabetes, regardless of the baseline BP level.
CONCISE METHODS
ADVANCE is a randomized factorial trial of BP and glucose-lowering regimens. The ADVANCE study methods have been previously published35 and are described here in brief. The findings reported here relate to the double-blind BP-lowering component of the trial, which ended in June 2007. The results of the glucose-lowering arm have been reported separately.32
Participants
A total of 11,140 individuals who had type 2 diabetes and were aged ≥55 yr were enrolled from 215 centers in 20 countries. Patients with diabetes were potentially eligible when they had evidence of a substantially elevated risk for vascular disease, as described in detail elsewhere.18 Of note, there were no inclusion or exclusion criteria with respect to BP, albuminuria rate, renal function, or use of BP-lowering agents. Approval for the trial was obtained from each center's institutional review board, and all participants provided written informed consent.
Study Treatment
Eligible participants were randomly assigned to either fixed-combination perindopril-indapamide (2 mg/0.625 mg) or matching placebo after a 6-wk run-in period during which all patients received active treatment. Study treatment dosages were doubled after 3 mo so that participants were receiving either perindopril-indapamide 4 mg/1.25 mg or matching placebo. Other treatments were continued at the discretion of the responsible physician, except that ACEIs other than perindopril were substituted with open-label perindopril at a dosage of 2 or 4 mg/d, which could be prescribed at any time through to the end of follow-up, thereby ensuring that the maximum recommended dosage of 8 mg was not exceeded. Use of thiazide or thiazide-like diuretics was not permitted18; however, if at any time a definite indication arose for a thiazide or an ACEI other than perindopril 4 mg/d, study treatment could be withdrawn and open-label therapy provided. There were neither limitations nor instructions formulated with respect to the use of concomitant treatments, diets, or other lifestyle interventions during follow-up related to the BP-lowering comparison, which all remained at the discretion of the responsible physician.
Follow-up and Assessments
Participants were seen at 3, 4, and 6 mo after randomization and subsequently every 6 mo. Mean participant follow-up was 4.3 yr. At each study visit, BP was recorded as the mean of two measurements made in the seated position using an automated sphygmomanometer (Omron HEM-705 CP; Omron, Kyoto, Japan). Measurement of UACR was performed on spot urine samples at 24, 48, and 60 mo after randomization and at the end of follow-up. Serum creatinine was measured 4 and 12 mo after randomization and subsequently at yearly intervals. Both UACR and serum creatinine levels were measured at local laboratories. The Modification of Diet in Renal Disease (MDRD) equation was used to calculate eGFR.36
Outcomes
The main outcome for this analysis was a composite of renal events defined by new-onset microalbuminuria (UACR 30 to 300 μg/mg), new-onset nephropathy (new-onset macroalbuminuria defined as UACR >300 μg/mg, which required confirmation by a second sample), doubling of serum creatinine to >200 μmol/L, or end-stage kidney disease (defined as requirement for renal replacement therapy or renal death). Other outcomes included separate components of the main outcome; progression of albuminuria, defined as the worsening of at least one albuminuria stage (from normoalbuminuria to either micro- or macroalbuminuria or from micro- to macroalbuminuria); regression of albuminuria, defined as improvement of at least one albuminuria stage; and the composite of renal events, nonfatal macrovascular events (nonfatal stroke or nonfatal myocardial infarction), or all-cause mortality.
Statistical Analysis
The effects of randomized treatment on primary and secondary end points were estimated from unadjusted Cox proportional hazard models, based on the intention-to-treat principle. For participants with more than one outcome event during follow-up, survival time to the first relevant end point was used in each analysis. Participants were censored at their date of death or, for those still alive at the end of follow-up, the date of their last clinic visit before the termination of this study arm. Patients with unknown vital status were censored when they were last known to be alive. Relative risk reductions are described in the text and figures as percentage reductions ([1 − hazard ratio] × 100). Differences between randomized groups in BP during follow-up were estimated from linear mixed models.37 Numbers needed to treat were calculated as reciprocals of the absolute risk differences with their normally approximated 95% CIs.38
Separate estimates for treatment effects were calculated for subgroups of participants defined by demographic factors, ancillary treatments, and standard microvascular and macrovascular risk factors at study entry. For BP, participants were grouped into two sets of the following four ordinal categories: SBP <120, 120 to 139, 140 to 159, and ≥160 mmHg and DBP <70, 70 to 79, 80 to 89, and ≥90 mmHg. Trends for treatment effects assessed as both categorical and continuous variables were tested by adding interaction terms to the relevant Cox models.
Associations between achieved BP levels and renal outcomes were assessed using the pooling of repeated observations method.39,40 Briefly, each participant's follow-up period was divided into a series of intervals defined by the 2-yr visits. The presence or absence of the relevant outcome was documented during each interval and coupled to the time-weighted average of BP levels recorded during each interval. Missing follow-up BP values at any one visit (8.2% missing for all visits) were imputed by using the BP values recorded during the previous visit. The participants generated 28,969 intervals with follow-up SBP and DBP for the intervals ranging from 78 to 241 mmHg and from 41 to 121 mmHg, respectively. These intervals were then divided into seven ordinal achieved follow-up BP categories, separated by 10 mmHg for SBP and by 5 mmHg for DBP. Incidence rates of the relevant outcome were estimated using Poisson log-linear regression model that included risk factors for the development of chronic kidney disease.41 Trends in relationships between achieved BP levels and the risk for outcomes were tested using each median value of BP for BP categories. The SAS 9.1 for Windows (SAS Institute, Cary, NC) was used to perform all statistical analyses. All P values were calculated from two-tailed tests of statistical significance with a type I error rate of 5%.
DISCLOSURES
S.M. and J.C. hold research grants from Servier as principal investigators for ADVANCE. B.E.d.G., V.P., A.P., A.C., B.N., N.P., S.H., M.C., M.M., B.W., P.H., G.M., P.G., D.E.G., S.M., and J.C. have received lecturing fees from Servier.
Acknowledgments
This work was presented at the scientific meeting of the American Diabetes Association; June 6 through 10, 2008; San Francisco, CA; and published in abstract form (Diabetes 57[Suppl 1]: A218–A29, 2008).
ADVANCE was funded by grants from Servier and the National Health and Medical Research Council of Australia. The sponsors had no role in the design of the study, data collection, data analysis, data interpretation, and the writing of the manuscript. Study data were not made available to the sponsors. The Management Committee, whose membership did not include any sponsor representatives, had final responsibility for the decision to submit for publication. The first four authors had full access to the data of the study and take responsibility for the accuracy of the analysis.
The following are members of the writing committee of the ADVANCE Collaborating Group: Bastia