Impact of Blood Pressure Control and Angiotensin-Converting Enzyme Inhibitor Therapy on New-Onset Microalbuminuria in Type 2 Diabetes: A Post Hoc Analysis of the BENEDICT Trial
Piero Ruggenenti*,,
Annalisa Perna*,
Maria Ganeva*,
Bogdan Ene-Iordache*,
Giuseppe Remuzzi*, for the BENEDICT Study Group
* Clinical Research Center for Rare Diseases "Aldo & Cele Daccò," Mario Negri Institute for Pharmacological Research, and Unit of Nephrology, Azienda Ospedaliera Ospedali Riuniti, Bergamo, Italy
Address correspondence to: Dr. Piero Ruggenenti, "Mario Negri" Institute for Pharmacological Research, Negri Bergamo Laboratories, Via Gavazzeni, 11-24125 Bergamo, Italy. Phone: +39-035-319-888; Fax: +39-035-319-331; E-mail: manuelap{at}marionegri.it
Received for publication June 5, 2006.
Accepted for publication September 13, 2006.
For assessment of the independent renoprotective effect of BPcontrol and angiotensin-converting enzyme inhibitor (ACEi) therapy,the relationships of baseline BP, BP reduction, and follow-upBP with the incidence of persistent microalbuminuria were evaluatedin 1204 hypertensive patients who had type 2 diabetes and normoalbuminuriaand were included in the BErgamo Nephrologic Diabetic ComplicationsTrial (BENEDICT) study and were randomly assigned to 3.6 yrof treatment with the ACEi trandolapril (2 mg/d), the nondihydropyridinecalcium channel blocker (ndCCB) verapamil SR (240 mg/d), theirfixed combination Veratran (trandolapril 2 mg/d plus verapamilSR 180 mg/d), or placebo, plus other antihypertensive medicationstargeted at systolic/diastolic BP <130/80 mmHg. Follow-up(from month 3 to study end) systolic, diastolic, mean, and pulseBP and their reductions versus baseline—but not baselineBP—independently predicted (P < 0.001) the risk formicroalbuminuria. In patients with follow-up BP above medians,ACEi significantly reduced the risk for microalbuminuria tolevels that were observed among patients with BP below medians,regardless of ACEi treatment. The same trend was observed amongpatients with BP reductions below medians. ndCCB therapy didnot independently affect microalbuminuria. Patients who wereon Veratran had lower BP and less frequently received diuretics, blockers, or dihydropyridine dCCB. In hypertensive, normoalbuminuricpatients with type 2 diabetes, BP reduction and ACEi therapyboth independently may prevent microalbuminuria. ACEi therapyis particularly effective when BP is poorly controlled, whereasndCCB therapy is ineffective at any level of achieved BP. Ascompared with trandolapril, Veratran may help with achievementof target BP with less need for concomitant antihypertensivemedications.
Patients with type 2 diabetes and hypertension have a seven-foldgreater risk for progressing to ESRD and a two- to four-foldgreater risk for developing cardiovascular sequelae, such asmyocardial infarction, stroke, or death, as compared with age-matchedcontrol subjects and with patients with type 2 diabetes butnormal BP (1,2). In patients who had type 2 diabetes and overtnephropathy and were enrolled in the Reduction of Endpointsin NIDDM with the Angiotensin II Antagonist Losartan (RENAAL)study and in the Irbesartan Diabetic Nephropathy Trial (IDNT),there was a significant relationship between the BP levels thatwere achieved during the follow-up period and the incidenceof ESRD or cardiovascular events (3,4). Although at any levelof achieved BP the overall incidence of events was consistentlylower in patients on angiotensin II receptor blocker (ARB) thanin those who were on placebo treatment, it also was apparentthat the impact of achieved BP on clinical outcomes was independentof patient allocation to ARB or placebo treatment and was consistentwithin each treatment group (5). In patients with type 2 diabetesand established nephropathy, both renin-angiotensin-system (RAS)inhibition and BP control have specific and probably additivereno- and cardioprotective effects that may contribute to limitthe excess renal and cardiovascular risk via different pathways.Whether this applies also to patients with type 2 diabetes butstill no evidence of renal disease is not established so far.
The Bergamo Nephrologic Diabetic Complications Trial (BENEDICT)found that in patients with type 2 diabetes, arterial hypertension,and normoalbuminuria, angiotensin-converting-enzyme inhibitor(ACEi) therapy with trandolapril plus verapamil or trandolaprilalone delayed the onset of microalbuminuria, which is a majorrisk factor for renal and cardiovascular events in this population(6). Finding that this effect was significant even after adjustmentsfor baseline and follow-up systolic (SBP) and diastolic BP (DBP)provided the evidence of a specific renoprotective effect ofACEi therapy against the development of microalbuminuria thatwas independent of the level of achieved BP control. However,whether and to which extent the achieved BP control also hadan independent beneficial impact on clinical outcomes was notevaluated. If BP reduction per se were renoprotective, thenthis would provide a strong rationale for intensified BP controlin patients with type 2 diabetes. One has to take into account,however, that achieving and maintaining the recommended targets(7) often is difficult in patients with diabetes and may requiretwo or more antihypertensive medications in most cases (6,8,9).In this post hoc analysis of the BENEDICT data, we investigatedfirst whether effective BP control may reduce the risk for microalbuminuriain patients with type 2 diabetes and no evidence of renal diseaseand second whether this beneficial effect is enhanced when BPcontrol is achieved by ACEi therapy with trandolapril plus verapamilor trandolapril alone.
Patients and Study Design
This study is based on a post hoc analysis of data from theBENEDICT trial. Study design and patient characteristics havebeen described in detail elsewhere (6,10,11). In short, BENEDICTwas a prospective, randomized, double-blind, parallel-groupstudy that evaluated the possibility of preventing the onsetof persistent microalbuminuria in 1204 patients who had type2 diabetes (World Health Organization criteria), arterial hypertension(SBP or DBP >130 or 85 mmHg, respectively, or concomitantantihypertensive therapy), but normal urinary albumin excretion(UAE) rate (UAE <20 mg/min in at least two of three consecutiveovernight urine collections) and were randomly assigned to atleast 3 yr of treatment with one of the following study drugs:(1) A nondihydropyridine calcium channel blocker (ndCCB), verapamilSR, 240 mg/d; (2) an ACEi, trandolapril 2 mg/d; (3) the combinationof verapamil SR 180 mg/d plus trandolapril 2 mg/d, Veratran;and (4) placebo. The target BP after randomization and throughoutthe whole study period was <130/80 mmHg for all of the treatmentgroups. Other antihypertensive drugs (with the exception ofRAS inhibitors and ndCCB that were different from the studydrugs) could be used to achieve and maintain the target BP accordingto predefined guidelines (6,10,11). The study protocol was inaccordance with the Declaration of Helsinki and was approvedby the institutional review board at each center and by thesafety committee of the BENEDICT study. All patients gave writteninformed consent. Data showed that, as compared with placebo,Veratran and trandolapril delayed the onset of microalbuminuriaby factors of 2.6 and 2.1, respectively, whereas verapamil hadno significant effect (6,11). The incidence of microalbuminuriaversus placebo was reduced by 60% (hazard ratio [HR] 0.39; 95%confidence interval [CI] 0.21 to 0.73) with Veratran and by50% with trandolapril (hazard ratio 0.49; 95% CI 0.27 to 0.90)but was not affected appreciably by verapamil.
Aims and Outcome Variables
Our analysis was aimed primarily at evaluating whether BP atstudy entry (baseline BP), the mean BP control achieved from3 mo after randomization to study end (follow-up BP), and theextent of BP reduction achieved from baseline to follow-up BPpredicted the time to onset of persistent microalbuminuria inhypertensive patients who had type 2 diabetes and were includedin the BENEDICT study. Secondarily, the analyses evaluated theincidence of microalbuminuria in various strata of baselineBP, follow-up BP, and BP reduction according to concomitantACEi or ndCCB therapy.
The main outcome variable was time to onset of persistent microalbuminuria(UAE 20 mg/min in at least two of three consecutive overnighturine collections confirmed after approximately 2 mo, againin at least two of three consecutive overnight urine collections).UAE was measured at randomization and every 6 mo up to studyend. All UAE measurements were performed by nephelometry inthe Laboratories of the Clinical Research Center for Rare Diseases"Aldo & Cele Daccò," of the Mario Negri Institutefor Pharmacologic Research.
Trough SBP and DBP (Korotkoff phase I/V) BP were measured inthe morning before treatment administration with the use ofan appropriate cuff with a sphygmomanometer and the patientin the sitting position after at least 5 min of rest. Threemeasurements to the nearest 2 mmHg were obtained 2 min apartat each time point, and the average of the three measurementswas recorded for the statistical analyses. The pulse pressurewas calculated as the difference between SBP and DBP, and themean arterial pressure (MAP) was calculated as the diastolicBP plus one third of the pulse pressure.
Statistical Analyses
Patients were included in these analyses only when they had,in addition to baseline BP evaluation, at least one BP measurementat the 3-mo visit or thereafter, so relative risk for developmentof microalbuminuria was computed conditional on survival. Amongpatients who still were in the trial after the 3-mo visit, allmicroalbuminuria events from randomization to death or censorshipwere included in the analyses. For outcome analyses, SBP andDBP measurements were included separately in the model. Therefore,for each measurement, we considered the median values of baselineBP, follow-up BP, and corresponding absolute reductions frombaseline to follow-up BP. Then patients were stratified intotwo strata according to BP values above or below the correspondingmedians. BP variables were considered as continuous variablesor, alternatively, were dichotomized in two classes (below andabove the median value). To incorporate time-dependent covariates,we used proportional hazards models instead of the acceleratedfailure time model that was used for the primary analysis. TheHR and their 95% CI were determined using Cox proportional hazardsmodels. Unadjusted models included the BP variable of interestonly. Adjusted models included predefined baseline covariates(center, age, gender, smoking, and baseline log-transformedUAE) and the BP variable of interest. A further explorativemodel included these covariates and the randomization to ACEior CCB therapy (yes or no). A sensitivity analysis also wasperformed by using time-dependent covariates to confirm studyresults. Continuous variables were compared by unpaired t testor Wilcoxon rank sum tests. Categorical variables that are shownin Table 1 were compared by log-rank text; those that are shownin Table 2 were compared by 2 tests or Fisher Exact test. Allof the statistical analyses were performed using SAS version8.2 (SAS Institute, Cary, NC). P < 0.05 was considered asstatistically significant. No P value adjustment was carriedout for multiple comparisons.
Table 1. Patients who developed microalbuminuria according to baseline BP, follow-up BP, and BP reduction above or below the median and according to ACEi and ndCCB treatmenta
Table 2. Number (%) of patients in the trial who were on different antihypertensive treatments according to follow-up SBP, DBP, MAP, and pulse pressure above or below the median
Of the 1204 patients in the original study cohort, 24 had noBP measurements at the 3-mo visit or at subsequent visits becausethey either reached an end point or stopped regular study follow-upfor other reasons and were excluded from further analyses. Overall,the baseline SBP/DBP of the remaining 1180 patients was 150.9± 14.05/87.5 ± 7.66 mmHg and decreased by 6.5± 7.63/6.4 ± 7.47% to 140.5 ± 11.23/81.6± 5.74 mmHg on follow-up. Baseline MAP and pulse pressurewere 108.6 ± 8.33 mmHg and 63.3 ± 12.64 mmHg,respectively; they decreased by 6.5 ± 6.83 and 5.3 ±14.70% to 101.2 ± 6.47/58.9 ± 9.99 mmHg, respectively,on follow-up.
Predictors of Microalbuminuria Baseline BP.
In the unadjusted and adjusted Cox regression, baseline SBP,DBP, MAP, and pulse pressure failed to predict the onset ofmicroalbuminuria. Patients with SBP or DBP above the medianstended to have a higher incidence of microalbuminuria as comparedwith those with lower BP, but differences between strata werenot statistically significant (Table 1). Within each stratumat baseline, patients who subsequently were randomly assignedto ACEi therapy with trandolapril plus verapamil or trandolaprilalone had a lower incidence of microalbuminuria than did patientswho were on non-RAS inhibitor therapy (Table 1). Regardlessof BP strata, there were no significant differences in the incidenceof microalbuminuria between patients who were or were not onndCCB therapy.
Follow-Up BP.
Patients who developed microalbuminuria had significantly higherSBP, DBP, and MAP than those who did not develop microalbuminuria.A similar, nonstatistically significant difference was observedfor pulse BP (Table 3). In the unadjusted and adjusted Cox regressionmodels, higher follow-up SBP (unadjusted HR 1.05 [95% CI 1.03to 1.07; P < 0.0001]; adjusted HR 1.04 [95% CI 1.02 to 1.06;P = 0.0002]), DP (unadjusted HR 1.06 [95% CI 1.02 to 1.11; P= 0.0015]; adjusted HR 1.05 [95% CI 1.01 to 1.10; P = 0.0085]),MAP (unadjusted HR 1.09 [95% CI 1.05 to 1.13; P < 0.0001];adjusted HR 1.07 [95% CI 1.03 to 1.10; P = 0.0004]), and pulseBP (unadjusted HR 1.04 [95% CI 1.02 to 1.06; P = 0.0002]; adjustedHR 1.03 [95% CI 1.01 to 1.06; P = 0.0075]) all predicted anincreased risk for microalbuminuria. The associations betweenconsidered BP and microalbuminuria all were statistically significanteven after adding to the predefined baseline covariates therandomization to ACEi versus non-ACEi or to ndCCB versus non-ndCCBtherapy (data not shown). The incidence of microalbuminuriawas significantly higher in those with follow-up SBP, DBP, MAP,or pulse BP above the medians as compared with those with lowerBP (Table 1). The excess risk for microalbuminuria associatedwith follow-up SBP above the median was significant even afteradjustment for predefined baseline covariates and concomitantACEi or ndCCB treatment (Figure 1A). The excess risk that wasassociated with DBP above the median was significant after correctionfor baseline covariates and concomitant ndCCB therapy but failedto achieve the statistical significance after adjustment forconcomitant ACEi therapy (Figure 1). Similar trends were observedfor follow-up MAP and pulse pressure (data not shown). Of interest,patients with SBP, DBP, MAP, and pulse BP below the mediansas compared with those with corresponding BP above the mediansmore frequently were on ACEi therapy with trandolapril plusverapamil or trandolapril alone and, on the contrary, were lessfrequently on treatment with concomitant antihypertensive medicationssuch as diuretics, blockers, dCCB, and sympatholytic agents(Table 2). In BP strata above the medians, patients who wereon ACEi therapy had a significantly lower incidence of microalbuminuriathan those who were on non-ACEi therapy, whereas in BP stratabelow the median, the incidence of events on ACEi or non-ACEitherapy was comparable (Table 1). Of note, the incidence ofmicroalbuminuria in patients who were on ACEi therapy with BPabove the medians was decreased to levels that were comparableto those that were observed in patients with lower BP, regardlessof treatment randomization. The risk reduction that was achievedby ACEi therapy in patients with follow-up SBP or DBP abovethe median was highly significant even after adjustment forbaseline covariates and concomitant treatment with ndCCB (Figure 2).Regardless of BP strata, there were no significant differencesin the incidence of microalbuminuria between patients who wereor were not on ndCCB therapy (Table 1).
Figure 1. Patients who developed microalbuminuria throughout the study period according to follow-up systolic BP (SBP; A) or diastolic BP (DBP; B) above or below the median.
Figure 2. Patients who had follow-up SBP (A) or DBP (B) above the median and developed microalbuminuria throughout the study period according to concomitant angiotensin-converting enzyme inhibitor (ACEi) therapy (yes or no).
BP Reduction.
Patients who developed microalbuminuria had a significantlylower reduction in SBP as compared with those who did not developmicroalbuminuria. Similar differences were observed for reductionsin DBP, MAP, and pulse BP (Table 3), which, however, did notreach statistical significance. In the unadjusted and adjustedCox regression models, more consistent reductions in SBP (unadjustedHR 1.03 [95% CI 1.02 to 1.05; P = 0.0001]; adjusted HR 1.05[95% CI 1.03 to 1.07; P < 0.0001]), DBP (unadjusted HR 1.05[95% CI 1.02 to 1.08; P = 0.0018]; adjusted HR 1.07 [95% CI1.04 to 1.10; P < 0.0001]), MAP (unadjusted HR 1.05 [95%CI 1.03 to 1.08; P = 0.0001]; adjusted HR 1.08 [95% CI 1.05to 1.11; P < 0.0001]) and pulse BP (unadjusted HR 1.03 [95%CI 1.01 to 1.05; P = 0.0095]; adjusted HR 1.04 [95% CI 1.02to 1.06; P = 0.0008]) all predicted a decreased risk for microalbuminuria.The associations between considered changes in BP and microalbuminuriawere significant even adding to the predefined baseline covariatesthe randomization to ACEi versus non-ACEi or to ndCCB versusnon-ndCCB therapy (data not shown). The incidence of microalbuminuriawas significantly higher in those with reductions in follow-upSBP, DBP, MAP, or pulse BP below the medians as compared withthose with more BP reductions (Table 1). Baseline characteristicsof patients with SBP reduction above or below the median weresimilar (Table 4), with the only exception of gender distributionand BP (more women and higher BP in those with SBP reductionabove the median). In patients with more BP reduction, therealso was a nonsignificant trend to lower body mass index, whereasbaseline glycosylated hemoglobin, lipids, and albuminuria werevirtually identical in the two groups. The excess risk for microalbuminuriathat was associated with SBP and DBP reduction below the medianwas significant even after adjustment for predefined baselinecovariates and concomitant ACEi or ndCCB treatment (Figure 3).Similar trends were observed for MAP and pulse pressure reductionbelow the medians (data not shown). Adjusted Cox regressionmodels that did or did not include body mass index in additionto the predefined baseline covariates showed the same independentassociation between SBP reduction and microalbuminuria (HR 1.05;95% CI 1.03 to 1.07; P < 0.0001). Of interest, patients withSBP, DBP, MAP, and pulse BP reduction above the medians as comparedwith those with corresponding BP reductions below the mediansmore frequently were on ACEi therapy with trandolapril plusverapamil or trandolapril alone and, on the contrary, less frequentlywere on treatment with concomitant antihypertensive medicationssuch as diuretics, blockers, dCCB, and sympatholytic agents(Table 5).
Figure 3. Patients who developed microalbuminuria throughout the study period according to follow-up SBP (A) or DBP (B) reduction above or below the median.
Table 5. Number (%) of patients in the trial who were on different antihypertensive treatments according to SBP, DBP, MAP, and pulse pressure reduction above or below the median
Among patients with BP reductions below the medians, those whowere on ACEi therapy had a significantly lower incidence ofmicroalbuminuria than those who were on non-ACEi therapy, whereasamong those with BP reductions above the medians, the incidenceof events on ACEi or non-ACEi therapy was comparable (Table 1).Of note, the incidence of microalbuminuria in patients who wereon ACEi therapy with BP reductions below the medians was decreasedto levels that were comparable to those that were observed inpatients with BP reductions above the medians, regardless oftreatment randomization. The risk reduction that was achievedby ACEi therapy in patients with SBP (Figure 4A), MAP, and pulsepressure (data not shown) below the median was significant evenafter adjustment for baseline covariates and concomitant treatmentwith ndCCB. A similar trend was observed for DBP, but risk reductionwas NS after the previous adjustments (Figure 4B). Regardlessof BP strata, there were no significant differences in the incidenceof microalbuminuria between patients who were or were not onndCCB therapy (Table 1).
Figure 4. Patients who had follow-up SBP (A) or DBP (B) reduction below the median and developed microalbuminuria throughout the study period according to concomitant ACEi therapy (yes or no).
Antihypertensive Treatments According to Achieved Follow-Up BP
As compared with patients with follow-up BP above the medians,patients with follow up BP below the medians more frequentlywere on ACEi therapy, in particular with the trandolapril plusverapamil combination, and less frequently on concomitant treatmentwith diuretics, blockers, dCCB, and sympatholytic agents. Onthe contrary, patients with follow-up BP above the medians morefrequently were on verapamil or placebo and more frequentlyrequired treatment with concomitant BP-lowering medications,in particular with diuretics, dCCB, and sympatholytic agents.
Antihypertensive Treatments According to Achieved BP Reductions
As compared with patients with BP reduction below the medians,patients with BP reductions above the medians more frequentlywere on ACEi therapy, in particular with the trandolapril plusverapamil combination, and less frequently on concomitant treatmentwith diuretics, blockers, dCCB, and sympatholytic agents. Onthe contrary, patients with BP reductions below the mediansmore frequently were on verapamil or placebo and more frequentlyrequired treatment with concomitant BP-lowering medications,in particular with diuretics, dCCB, and sympatholytic agents.
Here we found that in patients with type 2 diabetes and arterialhypertension but normal urinary albumin excretion, effectiveBP reduction has a specific and independent protective effectagainst the development of microalbuminuria. ACEi therapy hasa further protective effect, in particular when the BP is poorlycontrolled, whereas ndCCB therapy is ineffective at any levelof achieved BP. Finding that the risk for development of microalbuminuriawas not associated with baseline BP provided consistent evidencethat the lower incidence of microalbuminuria that was observedwith more effective BP reduction reflected a benefit of treatmentand not simply a less severe hypertension at study entry. Therefore,our findings extend to the very early stages of diabetic renaldisease and previous evidence of renoprotective effect of BPcontrol in people with diabetes and established nephropathy(3,5,11–13).
All of the parameters that were considered in monitoring theBP throughout the trial—SBP, DBP, MAP, and pulse pressure—weresignificantly associated with the risk for microalbuminuria.SBP, however, appeared as the strongest risk predictor, andits reduction as the most protective factor against the developmentof microalbuminuria. This is consistent with previous evidencethat SBP, more effectively than DP, MAP, or pulse pressure,predicted renal disease progression in patients with type 2diabetes and overt nephropathy (5). Therefore, targeting SBPmay increase the protective effect of antihypertensive therapyagainst the onset and progression of diabetic renal disease.A major practical problem, however, may limit the effectivenessof this strategy. The recommended target of 130 mmHg for SBP(7) seldom is achievable in patients with type 2 diabetes, evenwhen several BP-lowering medications are used in combination(6,8,9). Sixty-two percent of BENEDICT patients received oneor more antihypertensive drugs in addition to the study drugs,and low-sodium intake was recommended all of them. Despite this,only 14% of them achieved an SBP of 130 mmHg or less. The highestproportion of patients who were on target was observed amongthose who were on combined trandolapril plus verapamil treatment,who, notably, less frequently required concomitant treatmentwith other antihypertensive medications. This is consistentwith our finding that the highest proportion of patients withSBP, DBP, MAP, and pulse pressure below the medians was observedamong those who were on combined trandolapril and verapamiltreatment who also less frequently required concomitant treatmentwith diuretics, blockers, dCCB, and sympatholytic agents. Whetherreducing the need for these medications may translate into long-termclinical benefit, however, remains to be addressed in ad hoctrials. For instance, diuretics may worsen insulin sensitivity,an effect that may increase the incidence of type 2 diabetesin those who are at risk (14), but also may increase the responseto ACEi therapy and are less expensive than more recent drugs,such as dCCB. dCCB increase albuminuria and may accelerate renaldisease progression in patients with diabetes or chronic renaldisease, but these effects are limited when they are used incombination with ACEi or ARB (15,16).
Data that BP has a specific and clinically relevant impact onrenal disease progression largely are generated by observationalstudies that show a higher incidence of ESRD in particular inpatients with severe and poorly controlled hypertension (17).A still debated issue, however, is whether BP has an independentpredictive value also among patients with BP that is maintainedat usual targets of diastolic <90 mmHg or mean <107 mmHgand whether further reduction to lower-than-usual targets (accordingto Seventh Report of the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressureguidelines: SBP/DBP <130/80 mmHg) may confer additional renoprotection.Whether treatment should target SBP, DBP, pulse pressure, orMAP also is far from being established in controlled studies.
The first evidence that reducing BP to lower-than-usual targets(mean <92 mmHg) may slow the rate of GFR decline in chronicrenal disease was generated by the Modification of Diet in RenalDisease (MDRD) study (18). As acknowledged by the authors, however,in this study, the proportion of patients who were on ACEi therapywas remarkably higher in the low-BP than in the usual-BP group.On the same line, the trial by Breyer-Lewis et al. (19) in type1 diabetic nephropathy showed that patients with lower BP target(mean <92 mmHg) had an effective reduction in urinary proteinsthat, by contrast, progressively increased in those with usualtarget (mean 100 to 107 mmHg). Again, however, data were biasedby the concomitant treatment with ACEi that were used at remarkablyhigher dosages in patients who were randomly assigned to lowerBP target than in those patients who were randomly assignedto usual BP target.
Three other trials that compared the effect of treatment thatwas targeted at two different BP levels on similar backgroundRAS inhibitor therapy failed to detect any specific benefitof intensified BP control. The African American Study of KidneyDisease and Hypertension (AASK) found the same rate of GFR declineand the same course of proteinuria in patients in the low (mean<92 mmHg) or usual (mean 100 to 107 mmHg) BP group (20).The Appropriate Blood Pressure Control in Diabetes (ABCD) trialshowed a similar time-dependent course of creatinine clearancein three large cohorts of patients who had type 2 diabetes andnormo-, micro-, or macro- albuminuria and were randomly assignedto DBP <75 mmHg or 80 to 89 mmHg, respectively (21). Finally,the Ramipril Efficacy in Nephropathy (REIN)-2 study found thesame rate of GFR decline, incidence of ESRD, and time-dependentcourse of proteinuria in two groups of patients with the sameACEi therapy but randomly allocated to low (SBP/DBP <130/80mmHg) or usual (DBP <90 mmHg) BP targets (22). Notably, thesestudies targeted therapy to different parameters (MAP, DBP,or SBP), and none of them evaluated the impact of BP and itsreduction on the risk for development of microalbuminuria. Inthis regard, the UK Prospective Diabetes Study (UKPDS) founda lower incidence of macrovascular complications and retinopathyin patients who had type 2 diabetes and were randomly assignedto intensified BP control but failed to detect a significantprotective effect of lower BP against the risk for developmentof microalbuminuria (23). On the same line, the ABCD trial founda trend to a lower incidence of microalbuminuria in patientswith type 2 diabetes and normal UAE who were allocated to thelow BP group, but the risk reduction versus those in the usualBP group was NS. Therefore, our analysis provides the firstevidence of an independent association between BP and risk formicroalbuminuria and between BP reduction and reduced risk inpeople with diabetes and well-controlled hypertension. Of note,finding that baseline characteristics—including glycosylatedhemoglobin, blood glucose, and lipids—of patients withBP reduction above or below the median were similar and didnot affect the predictive value of BP suggests that our datawere not confounded by concomitant patient characteristics thatmight have influenced individual response to antihypertensivetherapy. Conversely, finding that the benefit of BP reductionwas particularly consistent in patients who were predicted tobe at increased risk because of more severe hypertension reinforcedthe possibility of a cause-and-effect relationship between moreeffective BP reduction and reduced incidence of microalbuminuria.This, however, could be proved definitely only by a prospectiveclinical trial in hypertensive patients who were on the samebackground RAS inhibitor therapy and randomly allocated to twodifferent BP targets.
Evidence that BP reduction and ACEi therapy may have an independentand additive protective effect against microalbuminuria is inharmony with current theories on the pathophysiology of diabeticrenal disease (24). The impact of BP control on the risk fordevelopment of microalbuminuria reflects the specific vulnerabilityof the diabetic kidney to the barotrauma that is caused by arterialhypertension. Autoregulation of afferent arteriolar tone inresponse to changes in renal perfusion pressure is defectivein diabetes (25), and decreased afferent arteriolar resistancefacilitates the transmission of the systemic BP to the glomerularcapillary, which increases intracapillary pressure (24,26).In the long term, these hemodynamic changes may cause endothelialdysfunction, impaired sieving function of the glomerular barrier,increased albumin ultrafiltration, and albuminuria (27). Therefore,reducing systemic BP to normal ranges is crucial to ameliorateglomerular hypertension and prevent glomerular damage. Glomerularhypertension also is ameliorated by drugs, such as ACEi or ARB,which dilate the efferent arteriole (26,28). The incrementalbenefit of this specific hemodynamic effect would be particularlyrelevant when arterial hypertension is not controlled effectively(29). This likely explains why, in our study, the beneficialeffect of ACEi therapy against the development of microalbuminuriawas more consistent in patients who had higher BP on follow-up.The specific benefit of ACEi therapy is confirmed by data froma meta-analysis of 16 trials that included 7603 patients withtype 2 diabetes, hypertension, and normoalbuminuria and showeda 42% reduction in the risk for development of microalbuminuriawith ACEi, whereas the effects of other antihypertensive medicationsdid not differ from those of placebo (30). Given a 10% incidenceof microalbuminuria in patients with diabetes and hypertensionover 2 to 3 yr, approximately 25 people would need to be treatedto prevent one more case of microalbuminuria (31).
Because microalbuminuria is a strong predictor of kidney failureand cardiovascular morbidity/mortality, the specific protectiveeffect of ACEi therapy against the development of microalbuminuriashould be taken into consideration in treatment guidelines forthe practicing physician (27,32). Indeed, most guidelines recommendany agent in patients with diabetes and hypertension and withoutnephropathy and only ACEi or ARB once nephropathy occurs (7).This largely rests on data from hypertension trials that showedthat BP reduction limits cardiovascular morbidity and mortalityregardless of the antihypertensive agent used to achieve thetarget BP and overlooks that only ACEi have been proved to reducethe onset of microalbuminuria in hypertensive patients withdiabetes. Our data, consistent with previous evidence from BENEDICT(6) and other trials (30), provide the evidence that, comparedwith other agents, ACEi have an incremental benefit on renaloutcomes and so should be the treatment of choice in hypertensivepatients with diabetes.
Effective BP control and ACEi therapy both are key componentsof renoprotective treatments that aim to prevent the developmentof microalbuminuria in patients with type 2 diabetes. The combinationof an ACEi and an ndCCB may help in achievement of optimal BPcontrol and effective inhibition of the RAS while limiting theneed for concomitant antihypertensive medications that may adverselyaffect the metabolic control and the overall cardiovascularrisk profile of people with diabetes. Whether an antihypertensiveregimen that includes such a combination drug may effectivelylimit the excess morbidity and mortality that are associatedwith type 2 diabetes is worth investigating in prospective,randomized trials.
Acknowledgments
The BENEDICT Study Organization: Principal Investigator, G.Remuzzi (Bergamo); Study Coordinator, P. Ruggenenti (Bergamo);Coordinating Center, Mario Negri Institute (MNI) for PharmacologicResearch–Clinical Research Center for Rare Diseases "Aldoe Cele Daccò," Villa Camozzi, Ranica (Bergamo). Participatingcenters: G. Nastasi, A. Ongaro, F. Querci, A. Anabaya, (AlzanoLombardo); R. Trevisan, A.R. Dodesini, G. Lepore, I. Nosari,C.A. Aros Espinoza, A. Fassi (Bergamo); M. Songini, G. Carta,G. Piras (Cagliari); B. Minetti, P. Fiorina, G. Ghilardi, V.Grassia, E. Pezzali, E. Seghezzi, I. Villanova (Clusone); A.Spalluzzi, I. Codreanu, C. Flores (Ponte San Pietro, Villa d’Almè);C. Chiurchiu, F. Arnoldi, L. Mosconi, M. Monducci (Ranica);A. Bossi, M. Facchetti, V. Brusegan (Romano di Lombardia); F.Inversi, V. Bertone, R. Mangili, S. Bruno (Seriate); A. Bossi,A. Parvanova, I. Petrov Iliev, E. Terzieva (Treviglio). Ophthalmologists:M. Filipponi, I. Iliev, S. Tadini (Bergamo). Monitoring anddrug distribution (MNI): G. Gherardi, N. Rubis, S. Birolini,L. Bruni, W. Calini, V.A. Carrasco Oyarzun, R. D’Adda,O. Diadei, M. Ferrari, L. Mangili, A. Milani, G. Noris, K. Pagani,S. Quadri, A. Rossi, S. Secomandi, G. Villa (Ranica). Carriers(MNI): G. Gaspari, S. Gelmi, G. Gervasoni, L. Nembrini (Ranica).Database and data validation (MNI): A. Remuzzi, B. Ene-Iordache,V. Gambara (Ranica). Data analysis (MNI): A. Perna, B.D. Dimitrov,M. Ganeva, J. Zamora (Ranica). Laboratory measurements (MNI):F. Gaspari, F. Carrara, E. Centemeri, S. Ferrari, M. Pellegrino,N. Stucchi (Ranica). Genomic evaluations (MNI): M. Noris, P.Bettinaglio, S. Bucchioni, J. Caprioli, B. Giussani (Bergamo).Regulatory affairs (MNI): P. Boccardo (Ranica). Steering committee:Voting members: S. Kupfer (Abbott Park), L. Minetti (Bergamo),G. Remuzzi (Bergamo); nonvoting members: U.F. Legler (Ludwigshafen),B. Kalsch (Ludwigshafen), D. Nehrdich (Ludwigshafen), A. Nicolucci(S. Maria Imbaro), A. Perna (Bergamo), P. Ruggenenti (Bergamo).Safety committee: G.L. Bakris (Chicago), R. Kay (Sheffield),G.C. Viberti (London).
We thank Manuela Passera for help in preparing the manuscript.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
See the related editorial, "Prevention of Microalbuminuria inType 2 Diabetes: Millimeters or Milligrams?" on pages 3276–3278.
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Top
Abstract
Introduction
blockers, or dihydropyridine dCCB. In hypertensive, normoalbuminuric patients with type 2 diabetes, BP reduction and ACEi therapy both independently may prevent microalbuminuria. ACEi therapy is particularly effective when BP is poorly controlled, whereas ndCCB therapy is ineffective at any level of achieved BP. As compared with trandolapril, Veratran may help with achievement of target BP with less need for concomitant antihypertensive medications. 
20 mg/min in at least two of three consecutive overnight urine collections confirmed after approximately 2 mo, again in at least two of three consecutive overnight urine collections). UAE was measured at randomization and every 6 mo up to study end. All UAE measurements were performed by nephelometry in the Laboratories of the Clinical Research Center for Rare Diseases "Aldo & Cele Daccò," of the Mario Negri Institute for Pharmacologic Research. 
2 tests or Fisher Exact test. All of the statistical analyses were performed using SAS version 8.2 (SAS Institute, Cary, NC). P < 0.05 was considered as statistically significant. No P value adjustment was carried out for multiple comparisons. 
