21 june, 2011 blood pressure targets in subjects with type 2 diabetes mellitus

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DOI: 10.1161/CIRCULATIONAHA.110.016337 2011;123;2799-2810; originally published online May 31, 2011; Circulation

Sripal Bangalore, Sunil Kumar, Iryna Lobach and Franz H. Messerli Meta-Analyses of Randomized Trials

Fasting Glucose: Observations From Traditional and Bayesian Random-Effects Blood Pressure Targets in Subjects With Type 2 Diabetes Mellitus/Impaired

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Blood Pressure Targets in Subjects With Type 2 DiabetesMellitus/Impaired Fasting Glucose

Observations From Traditional and Bayesian Random-EffectsMeta-Analyses of Randomized Trials

Sripal Bangalore, MD, MHA; Sunil Kumar, MD; Iryna Lobach, PhD; Franz H. Messerli, MD

Background—Most guidelines for treatment of hypertension recommend a blood pressure (BP) goal of �140/90 mm Hg, and a more aggressive goal of �130/80 mm Hg for patients with diabetes mellitus. However, in therecent Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, a lower BP was not beneficial. Theoptimal BP target in subjects with diabetes mellitus or those with impaired fasting glucose/glucose tolerance istherefore not well defined.

Methods and Results—We performed PUBMED, EMBASE, and CENTRAL searches for randomized clinical trialsfrom 1965 through October 2010 of antihypertensive therapy in patients with type 2 diabetes mellitus or impairedfasting glucose/impaired glucose tolerance that enrolled at least 100 patients with achieved systolic BP of�135 mm Hg in the intensive BP control group and �140 mm Hg in the standard BP control group, had afollow-up of at least 1 year, and evaluated macrovascular or microvascular events. We identified 13 randomizedclinical trials enrolling 37 736 participants. Intensive BP control was associated with a 10% reduction in all-causemortality (odds ratio, 0.90; 95% confidence interval, 0.83 to 0.98), a 17% reduction in stroke, and a 20% increasein serious adverse effects, but with similar outcomes for other macrovascular and microvascular (cardiac, renal,and retinal) events compared with standard BP control. The results were similar in a sensitivity analysis using abayesian random-effects model. More intensive BP control (�130 mm Hg) was associated with a greater reductionin stroke, but did not reduce other events. Meta–regression analysis showed continued risk reduction for stroke toa systolic BP of �120 mm Hg. However, at levels �130 mm Hg, there was a 40% increase in serious adverseevents with no benefit for other outcomes.

Conclusions—The present body of evidence suggests that in patients with type 2 diabetes mellitus/impaired fastingglucose/impaired glucose tolerance, a systolic BP treatment goal of 130 to 135 mm Hg is acceptable. However, withmore aggressive goals (�130 mm Hg), we observed target organ heterogeneity in that the risk of stroke continued tofall, but there was no benefit regarding the risk of other macrovascular or microvascular (cardiac, renal and retinal)events, and the risk of serious adverse events even increased. (Circulation. 2011;123:2799-2810.)

Key Words: blood pressure � diabetes mellitus, type 2 � hypertension � prognosis

The seventh report of the Joint National Committee onprevention, detection, evaluation, and treatment of high

blood pressure (BP) recommends a systolic BP goal of�140 mm Hg in patients with hypertension and a moreaggressive goal of �130 mm Hg in patients with diabetesmellitus or renal disease.1 Other major national and interna-tional guidelines have echoed this more aggressive BP goal inpatients with diabetes mellitus.2–4 However, there is a paucityof data to support aggressive BP targets.

Editorial see p 2776Clinical Perspective on p 2810

The Action to Control Cardiovascular Risk in Diabetes(ACCORD) BP trial (ACCORD BP) tested the effect of atarget systolic BP below 120 mm Hg on major cardiovascularevents among participants with type 2 diabetes mellituscompared with standard therapy of targeting below140 mm Hg.5 At the end of 4.7 years of follow-up, intensive

Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.Received December 22, 2010; accepted March 23, 2010.From the Divisions of Cardiology and Biostatistics, New York University School of Medicine, New York, NY (S.B., I.L.); Division of Cardiology, University

of Nebraska, Omaha (S.K.); and St. Luke’s Roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York, NY (F.H.M.).The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.110.016337/DC1.Reprint requests to Sripal Bangalore, MD, MHA, FACC, FSCAI, Director of Research, Cardiac Catheterization Laboratory, Assistant Professor

of Medicine, New York University School of Medicine, Leon H. Charney Division of Cardiology, New York, NY 10016. [email protected]

© 2011 American Heart Association, Inc.

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BP therapy did not reduce the rate of a composite cardiovas-cular events. However, intensive therapy reduced the risk ofstroke.5 The systolic BP achieved at the end of 1 year inACCORD was 133.5 mm Hg in the standard therapy groupand 119 mm Hg in the intensive therapy group. This findingbegs the question of whether the BP goal should be�140 mm Hg, which is the standard for all non–high-riskhypertensives, �130 mm Hg on the basis of most nationaland international guidelines, or �120 mm Hg on the basis ofthe significant stroke reduction seen in the intensive arm ofthe ACCORD-BP trial.

Our objective was to evaluate target BP goals for subjectswith type 2 diabetes mellitus. Given that subjects withimpaired fasting glucose (IFG) or glucose intolerance (IGT)are a spectrum in the continuum of insulin resistance anddiabetes mellitus, we also evaluated these subsets.

MethodsEligibility CriteriaWe conducted PUBMED, EMBASE, and CENTRAL searches usingthe terms “diabetes” and “diabetes mellitus” in humans from 1965until October 2010 with the limit “randomized controlled trials.” Wechecked the reference lists of review articles, meta-analyses, andoriginal studies identified by the electronic searches to find othereligible trials. There was no language restriction for the search.Authors of publications were contacted when results were unclear orwhen relevant data were not reported.

Eligible trials had to fulfill the following criteria to be included inthis analysis: (1) randomized clinical trials of participants with type2 diabetes mellitus/IFG/IGT (2) reporting �1-year outcomes (3) andenrolling at least 100 patients (4) who achieved systolic BP�140 mm Hg in both arms. Additionally, because the objective ofthe present study was to test outcomes based on BP targets, thefollowing criteria were required: (1) achieved systolic BP in theintensive BP group of �135 mm Hg, (2) achieved systolic BP inthe standard BP group of �140 mm Hg, and (3) had a systolic BPdifference between the intensive and standard BP group of at least3 mm Hg. We chose this cut point because this difference in systolicBP between treatment arms was the minimum required to show areduction in cardiovascular events.6 Studies in which there was nosignificant difference in BP between arms (�3 mm Hg) wereexcluded. For example, if studies evaluated 2 antihypertensiveagents, but uptitrated or added medication to ensure no difference infinal systolic BPs, they were excluded, because such studies are notexpected to provide information on BP targets.

Selection and Quality AssessmentTwo authors (S.B. and S.K.) independently assessed trial eligibilityand trial bias risk and extracted data. The bias risk of trials wasassessed by the use of the components recommended by theCochrane Collaboration7: (1) sequence generation of allocation; (2)allocation concealment; (3) blinding of participants, personnel, andoutcome assessors; (4) incomplete outcome data; (5) selectiveoutcome reporting; and (6) other sources of bias. Of note, the studiesdid not differ for quality components 4 through 6. Trials with high orunclear risk for bias for any 1 of the first 3 components wereconsidered trials with a high risk of bias. Otherwise, they wereconsidered trials with low risk of bias.

Data Extraction and SynthesisFor the purpose of this analysis, the intensive BP group was definedas the group in which the final achieved systolic BP was�135 mm Hg, and the standard BP group as the group in which thefinal achieved systolic BP was �140 mm Hg. Of note, these termsare based on mean achieved systolic BP, are used for descriptive

purposes for this article, and are not necessarily the strategy used inthe trial (ie, not all trials tested a BP strategy).

Long-term macrovascular and microvascular complications wereevaluated. The macrovascular outcomes were all-cause mortality,cardiovascular mortality, myocardial infarction, stroke, heart failure,angina pectoris, and revascularization. The microvascular outcomesevaluated were development of microalbuminuria, overt nephropa-thy, end-stage renal disease/dialysis, doubling of serum creatinine,neuropathy, and retinopathy. We also evaluated the serious adverseeffects (SAEs) as reported between the 2 groups. The SAEs werevariously defined as events that are life-threatening, cause permanentdisability, or necessitate hospitalization or withdrawal owing toadverse effects.

Statistical AnalysisAn intention-to-treat traditional meta-analysis was performed in linewith recommendations from the Cochrane Collaboration and thePreferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement7,8 with the use of standard software(Stata 9.0, Stata Corp, College Station, TX).9 Heterogeneity wasassessed with the I2 statistic,10 with I2�25% considered low andI2�75% considered high. We used the Peto method for odds ratio(OR),11,12 which is viewed as the most optimal approach when thereare relatively few events in individual trials. Publication bias wasestimated visually by funnel plots and by use of the Begg and Eggertest.13 Analyses were performed after the studies were furtherstratified on the basis of the achieved systolic BP in the intensivegroup: �130 but �135 mm Hg (less intensive group) versus�130 mm Hg (more intensive group).

A meta-regression analysis was performed to explore the relation-ship between systolic BP and outcomes. For this purposes, the meanachieved systolic BP was used as a continuous variable. We usedresidual maximum likelihood to estimate the additive (between-study) component of variance �2 for the meta-regression analysis.Bootstrap analyses were performed with a Monte Carlo permutationtest for meta-regression using 10 000 random permutations.14

Sensitivity AnalysesIn a meta-analysis of clinical trials with binary outcomes such asthose described above, a normal approximation for the summarytreatment effect measure in each trial may not be appropriate when

Figure 1. Study selection. RCT indicates randomized, controlledtrial; SBP, systolic blood pressure; and IDDM, insulin-dependentdiabetes mellitus.

2800 Circulation June 21, 2011



some of the trials in the meta-analysis are small or the observed risksare close to 0 or 1. To avoid this, the binomial distribution withintrials can be used directly as described by Warn et al.15 Theadvantages of bayesian methods include a modeling framework thatovercomes issues such as the appropriate treatment of small trialsand the ability to consider distributions other than normal for therandom effects.15 Of note, the Peto OR methodology used abovemore closely approximates a fixed-effect model; hence, in situationsin which the results of the bayesian model differed from those of thetraditional model, the bayesian model was used for inference (giventhat it is a random-effects model). The BUGS code for implementingthe model is as described by Warn et al.15 Minimally informativeprior distributions were used for log ORs and for random-effectsstandard deviation comparisons of treatments, so the findings areclose to those obtained with frequentist methods. All bayesiananalyses were conducted with WinBUGS 1.4.3.

Subgroup AnalysesSensitivity analyses were performed for the following subgroups:trials with low to trials with high risk of bias; trials that tested a BPstrategy versus others; and including and excluding trials thatenrolled patients with IFG/IGT. We estimated the difference be-tween the estimates of the subgroups according to tests for interac-tion.16 We considered values of P�0.10 to indicate that the effects oftreatment differed between the tested subgroups.

ResultsStudy SelectionWe identified 1330 randomized, controlled trials throughelectronic and hand searches, of which a total of 13 random-

ized, controlled trials5,17–29 fulfilled the inclusion criteria andwere chosen for this analysis (Figure 1). The Antihyperten-sive and Lipid-Lowering Treatment to Prevent Heart AttackTrial (ALLHAT) included was the report on the subset ofpatients with new glucose disorder.18 We included theACCORD-Eye substudy22 for the retinopathy outcome anal-ysis. Of note, 6 trials were excluded for violation of 1 or 2 BPinclusion criteria, and most of them would have been ex-cluded for violation of other criteria as well (Table I in theonline-only Data Supplement).30–35 Only 3 of the 6 trials wereexcluded, because the difference in BP achieved was�3 mm Hg. Among these, the trial by Ahmad et al33 had nodifferences in BP, whereas the other 2 trials34,35 had adifference of 1 mm Hg between the 2 arms. The later trialswould have been excluded anyway because the meanfollow-up was �1 year.

Characteristics of the TrialsThe baseline characteristics and bias-risk assessment aresummarized in Tables 1 and 2 and Table II in the online-onlyData Supplement. The 13 randomized, controlled trials en-rolled 37 736 participants, 19 042 (50.5%) in the intensive BPcontrol group and 18 694 (49.5%) in the standard BP controlgroup, and were followed up for 4.8�1.3 years (weightedmean). Of the 13 trials, only 5 tested a BP strategy (intensive

Table 1. Baseline Characteristics of Included Trials

Study Year n ComparisonFollow-Up,

moMeanAge, y

Men,%

HemoglobinA1C

Final SystolicBP, mm Hg

FinalDiastolic

BP, mm Hg

ABCD (hypertension)29 2007 470 Intensive vs standard BPlowering

60 58 58 11.5 133 vs 139 78 vs 86

ABCD (normotension)29 2007 480 Intensive vs standard BPlowering

60 59 55 11.5 128 vs 137 75 vs 81

ABCD-2V24 2006 129 Intensive vs standard BPlowering

23 56.1 67 8.2 118 vs 124 75 vs 80

ACCORD5,22 2010 4733 Intensive vs standard BPlowering

60 62.2 52.3 8.3 119.3 vs 133.5 64.4 vs 70.5

ADVANCE28 2007 11140 Perinodpril-indapamide vsplacebo

52 66 57 7.5 135 vs 140 74 vs 76

ALLHAT (New Diabetic)18 2004 1690 Doxazosine vschlorthalidone

38 67 60 NA 139 vs 134 77 vs 75

Chan et al21 1992 102 Enalapril vs nifedipine 66 58 NA 7.5 137 vs 132.2 72.1 vs 72.6

DIRECT Protect 219 2009 1905 Candesartan vs placebo 58 57 50 8.2 119.4 vs 123 73.2 vs 76

DREAM20 2006 5269 Ramipril vs placebo 36 55 41 NA 127.9 vs 132.2 78 vs 80.4

Fogari et al25 2002 207 Fosinopril/amlodipine vsamlodipine

48 62 57 7 132.4 vs 140.4 82.3 vs 86.5

GUARD17 2008 304 Benazepril/amlodipine vsbenazepril/

hydrochlorothiazide

77 58 65.4 NA 129.5 vs 132.2 88.4 vs 87.2

NAVIGATOR27 2010 9306 Valsartan vs placebo 78 64 49.3 NA 133.1 vs 136.1 78.1 vs 79.6

PERSUADE23 2005 1502 Perindopril vs placebo 52 62 82 NA 132 vs 136.6 76.5 vs 78.3

SANDS26 2008 499 Intensive vs standard BPlowering

36 56 34.5 8.1 117 vs 129 67 vs 73

BP indicates blood pressure; ABCD, Appropriate Blood Pressure Control in Diabetes; ABCD-2V, ABCD-2 Valsartan; ACCORD, Action to Control Cardiovascular Riskin Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation; ALLHAT, Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack Trial; DIRECT, Diabetic Retinopathy Candesartan Trials; DREAM, Diabetes Reduction Assessment With Ramipril and RosiglitazoneMedication; GUARD, Gauging Albuminuria Reduction With Lotrel in Diabetic Patients With Hypertension; NAVIGATOR, Nateglinide and Valsartan in Impaired GlucoseTolerance Outcomes Research; PERSUADE, Perindopril Substudy in Coronary Artery Disease and Diabetes; and SANDS, Stop Atherosclerosis in Native Diabetics Study.

Bangalore et al Diabetes Mellitus and Blood Pressure Targets 2801



versus standard) by design.5,24,26,29,36 The Diabetes ReductionAssessment With Ramipril and Rosiglitazone Medication(DREAM) trial and the Nateglinide and Valsartan in ImpairedGlucose Tolerance Outcomes Research (NAVIGATOR) trialsenrolled patients with IFG. Of note, the BP achieved in thestandard group of Fogari et al25 was 140.4 mm Hg, which wasclose to the threshold of �140 mm Hg; hence, it has beenincluded in this analysis. In addition, in the Action inDiabetes and Vascular Disease: Preterax and Diamicron-MRControlled Evaluation (ADVANCE) trial, the BP in theintensive group for most of follow-up was 134 to135 mm Hg.

Quality AssessmentsAmong the 13 randomized, controlled trials considered forthis analysis, 9 were considered trials with low risk of bias asdescribed in the Methods section. The rest were considered tohave an unclear or a high risk of bias (Table 2).

Macrovascular OutcomesIntensive BP control group was associated with a 10%reduction in all-cause mortality compared with standardBP control, driven largely by the trials with achievedsystolic BP �130 but �135 mm Hg (less intensive group;Figure 2A). The test for interaction was significant(P�0.09), so that the point estimate was directionally

opposite for systolic BP �130 mm Hg compared with thegroup with achieved systolic BP �130 but �135 mm Hg(Figure 2A). There was no heterogeneity (I2�0.0%), andbias was insignificant (Figure I in the online-only DataSupplement).

For the outcomes of cardiovascular mortality (Figure 2B),myocardial infarction (Figure 3A), and heart failure (Figure3B), there was no difference between the 2 groups, but thepoint estimate favored the intensive group, driven largely bythe trials with achieved systolic BP �130 but �135 mm Hg(less intensive group). The results were similar for the moreintensive versus less intensive group comparison (Pinteraction�0.10 for all comparisons; Figures 2B, 3A, and 3B). There waslow to moderate heterogeneity (I2�6.8%, 0.0%, and 47.8%,respectively), and bias was insignificant (Figures II throughVI in the online-only Data Supplement).

For the outcome of stroke (Figure 4A), intensive BPcontrol was associated with a 17% reduction in the oddscompared with the standard control group, with a greatermagnitude of benefit in trials in which the systolic BP was�130 mm Hg (Pinteraction�0.005), in which there was a 47%decrease in the odds of stroke compared with the standardcontrol group. There was no to low heterogeneity(I2�27.0%), and bias was insignificant (Figure V in theonline-only Data Supplement).

There was no difference between the 2 groups in theoutcomes of angina pectoris (OR, 1.07; 95% confidenceinterval [CI], 0.92 to 1.24) or revascularization (OR, 0.97;95% CI, 0.85 to 1.12), with similar results for the more intensiveversus less intensive group comparison (Pinteraction�0.10 for allcomparisons).

The above results were similar in a sensitivity analysisusing a bayesian random-effects model (Table 3) with an11% decreased odds of all-cause mortality and a 30%decreased odds of stroke with intensive BP control with nodifference for other outcomes.

Serious Adverse EventsIn the few studies that reported SAEs, intensive control groupwas associated with a 20% increase in SAEs (OR, 1.20; 95%CI, 1.08 to 1.32), which was greater in magnitude in studieswith more intense control of BP (�130 mm Hg) in whichthere was a 40% increase in SAEs (OR, 1.40; 95% CI, 1.19to 1.64; Pinteraction�0.01). There was significant heterogeneityin this analysis (I2�78.8%).

Microvascular OutcomesFor the outcome of new-onset microalbuminuria, intensivecontrol was associated with a 17% reduction in the oddscompared with the standard control group (OR, 0.83; 95% CI,0.77 to 0.89). Similarly, for the outcome of overt nephropa-thy, intensive control was associated with a 27% reduction inthe odds compared with the standard control group, with greaterbenefit with more intensive BP control (�130 mm Hg) in whichthere was a 36% reduction compared with standard control(Pinteraction�0.06; Figure 5). However, there was moderateheterogeneity in this analysis (I2�61.3%). Other measures ofnephropathy such as end-stage renal disease/dialysis or dou-bling of serum creatinine were not different between the

Table 2. Quality of Trials, Design, and Source of Funding

StudyTesting a BP

StrategyBias

Estimation*Source ofFunding

ABCD (normotension)29 Yes �� Industry andnonindustry

ABCD-2V24 Yes �� Industry

ACCORD5,22 Yes �� Nonindustry

ADVANCE28 No �� Industry andnonindustry

ALLHAT (New Diabetic)18 No �� Nonindustry

Chan et al21 No �� Not reported

DIRECT Protect 219 No �� Industry

DREAM20 No �� Industry andnonindustry

Fogari et al25 No �� Not reported

GUARD17 No �� Industry

NAVIGATOR27 No �� Industry

PERSUADE23 No �� Industry

SANDS26 Yes �� Nonindustry

BP indicates blood pressure; ABCD, Appropriate Blood Pressure Control inDiabetes; ABCD-2V, ABCD-2 Valsartan; ACCORD, Action to Control Cardiovas-cular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease:Preterax and Diamicron-MR Controlled Evaluation; ALLHAT, Antihypertensiveand Lipid-Lowering Treatment to Prevent Heart Attack Trial; DIRECT, DiabeticRetinopathy Candesartan Trials; DREAM, Diabetes Reduction Assessment WithRamipril and Rosiglitazone Medication; GUARD, Gauging Albuminuria ReductionWith Lotrel in Diabetic Patients With Hypertension; NAVIGATOR, Nateglinide andValsartan in Impaired Glucose Tolerance Outcomes Research; PERSUADE,Perindopril Substudy in Coronary Artery Disease and Diabetes; and SANDS,Stop Atherosclerosis in Native Diabetics Study. � Indicates low bias risk; ��indicates high bias risk and�unclear bias risk.

*Based on allocation generation, allocation concealment, and blinding.




Figure 2. Intensive versus standard blood pressure control and (A) all-cause mortality and (B) cardiovascular mortality. Results are fur-ther stratified by achieved systolic pressure in the intensive group. The size of the data marker represents the weight of each trial. ORindicates odds ratio; CI, confidence interval; SBP, systolic blood pressure; ABCD, Appropriate Blood Pressure Control in Diabetes;ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; PERSUADE, Perindopril Substudy in CoronaryArtery Disease and Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation;NAVIGATOR, Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; ABCD-2V, ABCD-2 Valsartan; DREAM,Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication; GUARD, Gauging Albuminuria Reduction With Lotrel inDiabetic Patients With Hypertension; DIRECT, Diabetic Retinopathy Candesartan Trials; and ACCORD, Action to Control CardiovascularRisk in Diabetes.




Figure 3. Intensive versus standard blood pressure control and (A) myocardial infarction and (B) heart failure. Results are further strati-fied by achieved systolic pressure in the intensive group. The size of the data marker represents the weight of each trial. OR indicatesodds ratio; CI, confidence interval; SBP, systolic blood pressure; ABCD, Appropriate Blood Pressure Control in Diabetes; PERSUADE,Perindopril Substudy in Coronary Artery Disease and Diabetes; NAVIGATOR, Nateglinide and Valsartan in Impaired Glucose ToleranceOutcomes Research; DREAM, Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication; SANDS, Stop Atheroscle-rosis in Native Diabetics Study; ACCORD, Action to Control Cardiovascular Risk in Diabetes; and ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.




groups, and only a few studies reported these outcomes (datanot shown). In addition, none of these outcomes was signif-icantly different in a sensitivity analysis using a bayesianrandom-effects model (Table 3).

For the outcome of retinopathy, there was no differencebetween the 2 groups (OR, 0.93; 95% CI, 0.83 to 1.05) withlow heterogeneity (I2�21.5%) and similar results across themore intensive versus less intensive comparison (Pinteraction�0.36). In the 3 studies that reported the risk of neuropathy,there was no difference between the 2 groups (OR, 1.26; 95%CI, 0.98 to 1.62) with moderate heterogeneity (I2�26.9%),with similar results across the more intensive versus lessintensive comparison (Pinteraction�0.16).

The results were similar in a sensitivity analysis using abayesian random-effects model (Table 3).

Meta–Regression AnalysisThe relationships between final achieved systolic BP (in theintensive control group) and the risk of macrovascular andmicrovascular outcomes are shown in Figure 6A through 6F.Results based on a sensitivity analysis using a bayesianrandom-effects model and evaluating the relationship be-tween final achieved systolic BP and outcomes are outlined inTable 3.

For most of the macrovascular and microvascular out-comes (other than stroke), lower was not better (Figure 6Athrough 6F). For the outcome of stroke, lower was better,with benefit even down to a systolic BP of �120 mm Hg(Figure 6D). The residual maximum likelihood estimate ofbetween-study variance (�2) used was 0, and the percentresidual variation resulting from heterogeneity was 0.0%.

Figure 4. Intensive versus standard blood pressure control and stroke. Results are further stratified by achieved systolic pressure in theintensive group. The size of the data marker represents the weight of each trial. OR indicates odds ratio; CI, confidence interval; SBP,systolic blood pressure; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; PERSUADE, PerindoprilSubstudy in Coronary Artery Disease and Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron-MRControlled Evaluation; NAVIGATOR, Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; ABCD, AppropriateBlood Pressure Control in Diabetes; DREAM, Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication; SANDS,Stop Atherosclerosis in Native Diabetics Study; and ACCORD, Action to Control Cardiovascular Risk in Diabetes.

Table 3. Sensitivity Analysis: Random-Effects Bayesian Model

Outcome OR (95% Cr I) �2

Relationship of SBPto Outcomes*

Slope† 95% Cr I

Macrovascular

All-cause mortality 0.89 (0.79–0.99) 0.010 �1.621 �4.305–0.867

CV mortality 0.93 (0.75–1.22) 0.057 �1.299 �7.786–9.538

Myocardial infarction 0.90 (0.72–1.13) 0.046 0.598 �5.440–7.669

Heart failure 0.88 (0.60–1.41) 0.193 �2.468 �18.980–9.983

Stroke 0.70 (0.45–0.94) 0.147 5.044 0.574–11.750

Angina pectoris 1.06 (0.69–1.87) 0.275 �2.322 �20.450–11.680

Revascularization 0.96 (0.55–1.55) 0.188 3.992 �10.300–18.810

Microvascular

Nephropathy 0.69 (0.45–1.12) 0.228 1.114 �11.410–17.320

Retinopathy 0.92 (0.57–1.33) 0.170 �1.484 �19.780–7.963

Neuropathy 1.27 (0.54–3.26) 0.481 0.523 �23.640–23.820

OR indicates odds ratio; Cr I, credibility interval; �2, between-study variance;SBP, systolic blood pressure; and CV, cardiovascular.

*Final achieved SBP in the intensive group.†Negative slope represents an inverse relationship (lower SBP associated

with worse outcomes); positive slope, a direct relationship (lower SBPassociated with better outcomes).




Using Monte Carlo permutation with 10 000 random permu-tations, we identified a value of P�0.035 (SE, 0.0018) for theabove analysis. For each 1-mm Hg-lower systolic BP, theodds of stroke reduced by 3% (95% CI, 1 to 7). The resultswere similar in a sensitivity analysis using a bayesianrandom-effects model (Table 3).

Subgroup AnalysesSubgroup analyses did not make a noticeable difference in theabove results (Table 4).

DiscussionThe principal finding of the present study is that no singleoptimal systolic goal BP level can be identified in patientswith type 2 diabetes mellitus/IFG/IGT. Intensive BP control(�135 mm Hg) was associated with a significant reduction inmacrovascular (all-cause mortality and stroke) events butwith an increase in SAEs compared with standard BP control(�140 mm Hg). Although lower was better for stroke (even�120 mm Hg for systolic BP), this was not true for othercardiac, renal, or retinal outcomes. Thus, below a systolic BPof 130 mm Hg, there seems to be target organ heterogeneityin that there is continued reduction of stroke but an increasein SAEs without any further benefit for other cardiovascularoutcomes.

Type 2 Diabetes Mellitus and Blood PressurePatients with diabetes mellitus are at increased risk forcardiovascular outcomes, so that these patients are consideredcoronary artery disease risk equivalents. As such, majornational and international guidelines recommend a more

aggressive BP goal of �130/80 mm Hg in patients withdiabetes mellitus.1–4

Intensive therapy is not without drawbacks. In the ACCORDBP trial, the risk of serious adverse events was 2.6 timeshigher in the intensive group compared with the standardtherapy group, with a 17-fold increase in hypotension anda 10-fold increase in hyperkalemia. However, the absoluterates of above adverse events were rather low. Moreover,in patients with coronary artery disease, a J-shaped curverelationship has been documented with BP (particularlydiastolic) and cardiovascular events so that lower pressuresare associated with increased risk of events.37 Regardlessof the J-curve hypothesis, the principle of primum non-nocere mandates that we show evidence of benefit forintensive BP control before such a treatment strategy isadvocated.

The result of the present study shows that the relationshipbetween systolic BP and target organ risk reduction iscomplex. For macrovascular outcomes, intensive BP control(�135 mm Hg) was associated with a reduction in death andstroke. Although there was a direct linear relationship be-tween systolic BP and stroke, so that lower was indeedbetter, the same was not true for death and other cardiacevents. For cardiac events, further reduction below130 mm Hg was not beneficial, with the point estimate ofthe OR directionally opposite that seen for the lessintensive BP group (�130 and �135 mm Hg) for death. Ofnote, in ACCORD there was no difference in all-causemortality (1.28%/y versus 1.19%/y; P�0.55) or cardiovas-cular mortality (0.52%/y versus 0.49%/y; P�0.74) with

Figure 5. Intensive versus standard blood pressure control and nephropathy. Results are further stratified by achieved systolic pressurein the intensive group. The size of the data marker represents the weight of each trial. OR indicates odds ratio; CI, confidence interval;SBP, systolic blood pressure; ABCD, Appropriate Blood Pressure Control in Diabetes; ADVANCE, Action in Diabetes and Vascular Dis-ease: Preterax and Diamicron-MR Controlled Evaluation; and ACCORD, Action to Control Cardiovascular Risk in Diabetes.




intensive therapy compared with standard therapy. Thisbegs the question of whether there is a relatively flat partof the curve where there is neither benefit nor excess harmof a cardiac event. In analyses of both the Treating to NewTargets (TNT) trial38 and the Pravastatin or AtorvastatinEvaluation and Infection Therapy–Thrombolysis in Myo-cardial Infarction 22 (PROVE IT TIMI 22) trial,39 we haveshown a J-shaped relationship between BP and cardiovas-cular events. However, for systolic BPs between 110 and

140 mm Hg, the risk was relatively flat, and excess risk wasseen at systolic BPs �110 mm Hg. However, once systolicBP is lowered to �130 mm Hg, there may be target organheterogeneity, and clinicians will have to be cognizant of theincreased risk of SAEs and possibly cardiac events. Ourresults are concordant with the analysis by the Blood PressureLowering Treatment Trialists’ Collaboration.40

Traditional teaching implies that good BP control willreduce macrovascular events, whereas good diabetes control

Figure 6. Relationship between odds of (A) all-cause mortality, (B) cardiovascular mortality, (C) myocardial infarction, (D) stroke, (E)serious adverse events, and (F) nephropathy and final achieved systolic pressure (SBP) in the intensive group. The size of the datamarker represents the weight of each trial.




is necessary for a reduction in microvascular events. In ouranalysis, although certain renal events benefitted from inten-sive BP control, the results were not consistently seen in thebayesian random-effects model. Given the moderate to sig-nificant heterogeneity in most of the analysis for microvas-cular outcomes, the random-effects model is likely to be morerobust, suggesting no benefit of intensive BP control on anyof the microvascular outcomes.

Study LimitationsAll of the trials did not report all of the outcomes. Thesubgroup analyses might suffer from multiple testing and arebest described as secondary and hypothesis generating only.In this analysis, we tested a BP goal of �140 mm Hg withthat of �135 mm Hg and not, say, �130 mm Hg for severalreasons: (1) We aimed to ensure that we use data from asmany relevant studies as possible because the number ofstudies was limited if the criterion was tightened to 130mm Hg; (2) we aimed to test whether evidence exists for evena 135-mm Hg goal; and finally, and more importantly, (3) thecut points are less relevant because, in our regression analy-sis, the mean achieved BP was treated as a continuousvariable and our conclusions and recommendations are basedon this. Moreover, the intensive group was substratified intoa more intensive group (�130 mm Hg) versus less intensivegroup (�130 but �135 mm Hg). In addition, in some of thetrials, the mean systolic BP achieved in the standard groupwas more than the systolic BP achieved in the intensive groupof other trials. However, the regression analysis using systolicBP as continuous variable accounts for this; hence, the BPtargets are derived from this. In trials not testing a BPstrategy, the most commonly used antihypertensive agent wasan angiotensin-converting enzyme inhibitor, and the possibil-ity that the beneficial effects on certain outcomes are due tothis medication alone rather than a BP effect cannot be ruledout. In addition, our analysis is based on achieved BP, andmany factors, including survivorship, will affect the end-of-study achieved BP. The definition of SAEs varied, and thetrials did not consistently report the components to performany additional analyses.

ConclusionsThe present body of evidence suggests that intensive BPcontrol (�135 mm Hg) reduces the risk of macrovascular(death, stroke) events in patients with type 2 diabetes melli-tus/IFG/IGT. A treatment goal of 130 to 135 mm Hg, similarto the achieved BP of 133.5 mm Hg in the standard therapygroup of the ACCORD trial, is therefore acceptable, andmore aggressive goals to 120 mm Hg can be considered inpatients at higher risk of stroke. However, at a systolic BP�130 mm Hg, there may be target organ heterogeneity, andthese cerebrovascular benefits have to be balanced against anincreased risk of SAEs and a lack of benefit for cardiac, renal,and retinal outcomes.

DisclosuresDr Messerli has served on the speakers’ bureau for Abbott, Glaxo-SmithKline, Novartis, Pfizer, AstraZeneca, Bayer, Boehringer Ingel-heim, BMS, Forest, Sankyo, and Sanofi, and has received researchgrants from GlaxoSmithKline, Pfizer, Novartis, and CardioVascularTherapeutics. The other authors report no conflicts.

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Table 4. Subgroup Analysis

Outcome High Bias Risk Low Bias Risk Pinteraction

TestingBP Strategy

Not Testing aBP Strategy Pinteraction All Trials

ExcludingNAVIGATORor DREAM Pinteraction

Macrovascular

All-causemortality

0.71 (0.45–1.11) 0.91 (0.83–0.99) 0.29 0.96 (0.78–1.19) 0.89 (0.81–0.97) 0.52 0.90 (0.83–0.98) 0.89 (0.81–0.99) 0.87

CV mortality 1.31 (0.59–2.92) 0.92 (0.81–1.05) 0.39 1.10 (0.79–1.54) 0.90 (0.79–1.04) 0.28 0.93 (0.82–1.06) 0.87 (0.75–1.01) 0.51

MI 1.10 (0.68–1.79) 0.93 (0.77–1.13) 0.53 1.21 (0.74–1.98) 0.92 (0.76–1.11) 0.31 0.95 (0.80–1.14) 0.87 (0.65–1.15) 0.61

Stroke 0.36 (0.15–0.89) 0.85 (0.74–0.97) 0.06 0.53 (0.37–0.77) 0.89 (0.77–1.02) 0.009 0.83 (0.73–0.95) 0.85 (0.73–0.99) 0.82

Microvascular

Nephropathy 0.50 (0.35–0.70) 0.79 (0.68–0.91) 0.02 0.64 (0.53–0.77) 0.84 (0.69–1.03) 0.05 . . . . . . . . .

Retinopathy 0.75 (0.57–0.97) 1.04 (0.89–1.21) 0.06 0.87 (0.70–109) 1.01 (0.85–1.20) 0.06 . . . . . . . . .

Neuropathy 1.26 (0.98–1.62) . . . . . . 1.26 (0.98–1.62) . . . . . . . . . . . . . . .

BP indicates blood pressure; NAVIGATOR, Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; DREAM, Diabetes Reduction AssessmentWith Ramipril and Rosiglitazone Medication; CV, cardiovascular; and MI, myocardial infarction. Testing a BP strategy indicates trials in which the study was designedto test an intensive BP strategy versus standard.




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CLINICAL PERSPECTIVEMost guidelines for treatment of hypertension, including the seventh report of the Joint National Committee, recommendan aggressive blood pressure goal of �130/80 mm Hg for patients with diabetes mellitus. However, the evidence on whichthe guidelines are based is limited. In our analyses of 13 randomized trials with 37 736 participants, we noted that inpatients with type 2 diabetes mellitus, a systolic blood pressure treatment goal of 130 to 135 mm Hg is acceptable.However, with more aggressive goals (�130 mm Hg), we observed target organ heterogeneity in that the risk of strokecontinued to fall, but there was no benefit regarding the risk of other macrovascular or microvascular (cardiac, renal, andretinal) events, and the risk of serious adverse events even increased.

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1

SUPPLEMENTAL MATERIAL



2

Supplemental Table 1. Trials excluded for violation of the blood pressure entry criteria Criteria Violated Trial No. of

Subjects Specific Violation

BP in the standard arm >140 mm Hg or >135 mm Hg in the intensive arm

BENEDICT31 901 BP in the standard arm was 142 mm Hg. However, this study would have been excluded anyways as the BP in the comparator arm was 139 mm Hg (i.e., >135 mm Hg)

ASCOT (DM subgroup)30

5137 BP in the standard arm was 137 mm Hg and that in the intensive arm was 136 mm Hg. The study would have been excluded for number of violations including BP in the intensive arm >135 mm Hg, BP difference of only 1 mm Hg.

NESTOR32 569 BP in the standard arm was 139.3 mm Hg and that in the intensive arm was 137.3 mm Hg. The study would have been excluded for number of violations including BP in the intensive arm >135 mm Hg, BP difference of only 2 mm Hg.

BP difference between the comparator arms <3 mm Hg

Ahmad et al.33 103 Achieved BP of 134 mm Hg in both the treatment arms.

Fogari et al. (2007)34

174 Achieved BP of 127 and 126 mm Hg respectively. The study would have been excluded for a follow up of only 8 months.

MARVAL35 332 Achieved BP of 136 and 135 mm Hg respectively. The study would have been excluded for a follow up of only 6 months.



3

Supplemental Table 2. Inclusion and exclusion criteria of included trials Study Inclusion Criteria Exclusion Criteria ABCD29 NIDDM and DBP≥ 80mm Hg

receiving no antihypertensive Known allergy to dihydropyridine CCBs or ACEi; MI or CVA within the previous six months; CABG within the previous three months; USA within the previous six months; NYHA class III or IV CHF; an absolute need for therapy with ACEi or CCB; on hemodialysis or peritoneal dialysis; a serum creatinine level > 3 mg per deciliter (265 µmol per liter)

ABCD-2V24 Type 2 DM, 40 to 81 years of age, with a SBP <140 mm Hg, a DBP 80-90 mm Hg, and without evidence of overt albuminuria (<200 µg/min)

Pregnant or lactating women; need for any antihypertensive medications; documented MI or CVA within the past 6 months; severe PVD; history of bilateral renal artery stenosis or stenosis in a solitary kidney; evidence of severe liver disease; hyperkalemia; or history of active cancer

ACCORD5, 22 Type 2 DM, an HbA1C ≤ 7.5%, aged ≥ 40 years old with cardiovascular disease or ≥ 55 years old with anatomical evidence of a substantial amount of atherosclerosis, albuminuria, LVH, or at least two additional risk factors for cardiovascular disease (dyslipidemia, HTN, smoking, or obesity)

BMI > 45; a serum creatinine level of > 1.5 mg per deciliter (132.6 µmol per liter), and other serious illness

ADVANCE28 Type 2 DM diagnosed at ≥30 years of age and aged ≥55 years old at entry with ≥ 1 of the following: a history of major cardiovascular disease (stroke, MI, hospital admission for TIA, hospital admission for USA, coronary revascularization, peripheral revascularization, or amputation secondary to vascular disease), or at least one other risk factor for cardiovascular disease (defined by the presence of at least one of the following: a history of major microvascular disease (macroalbuminuria [urinary albumin-creatinine ratio >300 µg/mg], proliferative diabetic retinopathy, retinal photocoagulation therapy, macular edema, or blindness in one eye thought to be caused by diabetes),

Definite indication for, or contraindication to, any of the study treatments, or the HbA1C target (≤6.5%); a definite indication for long-term insulin therapy at study entry; or current participation in another clinical trial.



4

current cigarette smoking, total cholesterol > 6 mmol/L, HDL cholesterol < 1 mmol/L, microalbuminuria (urinary albumin-creatinine ratio 30–300 µg/mg), diagnosis of type 2 DM made 10 years or more before entry, or age 65 years or older at entry)

ALLHAT-DM18

Men and women aged 55 years or older with SBP ≥140mmHg and/or DBP ≥ 90 mm Hg or, on medication for hypertension, and with ≥ 1 additional risk factor for CHD (defined as previous MI or stroke, LVH by ECG or echocardiogram, history of type 2 DM, current cigarette smoking, and low HDL cholesterol level)

Patients with HF or known low ejection fraction

Chan et al21 Type 2 DM with no history of ketosis and HTN( defined as SBP 150-220 mm Hg and/or DBP ≥100 at the end of run in period); albuminuria

On insulin therapy; nondiabetic renal disease; appreciable renal impairment (plasma creatinine ≥ 200 µmol/l; plasma potassium ≥ 5 mmol/l; cardiac failure or any concurrent systemic diseases; or on treatment for any concurrent disorder

DIRECT Protect 219

Type 2 DM; aged 37 to 75 years; diabetes duration, 1 to 20 years; either normotension (mean SBP ≤130/85 mm Hg) or controlled HTN(defined as BP ≤160/90 mm Hg) with non–RAS-blocker therapy; and normoalbuminuria (urine AER <20 µg/min in at least 1 of 2 timed overnight urine collections)

Eye conditions precluding retinal photographs; clinically significant macular edema, proliferative retinopathy, or stenotic valvular heart disease; recent stroke or MI; or a clinical indication for or contraindication to RAS-blocking agents; pregnant or lactating women; renal impairment (serum creatinine level ≥110 µmol/L [≥1.2 mg/dL] in women and ≥130 µmol/L [≥1.5 mg/dL] in men)

DREAM20 Aged ≥30 years with impaired fasting plasma glucose levels (110-126 mg/dl) or impaired glucose tolerance (a plasma glucose level 140-200 mg per deciliter 2 hours after an oral glucose load)

DM(except gestational diabetes); current use of ACEi and/or thiazolidonediones and inability to discontinue these medications; intolerance of either ACEi or thiazolidonediones; cardiac disease; renal or hepatic disease

Fogari et al25 Type 2 DM well controlled by diet or by metformin alone or metformin plus a sulfonylurea; essential HTN (sitting DBP 90-110 mm Hg); urine AER ≥30 and ≤300 mg/24 h in two distinct 24-h urine collections during 7 days before enrollment; BMI <30 kg/m2; serum creatinine <1.5 mg/dL

History of previous CHD, stroke, CHF, cancer; smoking habits; ECG showing LVH; total cholesterol values exceeding 240 mg/dL; use of diuretics or β-blockers



5

GUARD17 Hypertension and Type II diabetes NR NAVIGATOR27

Impaired glucose tolerance,(a fasting plasma glucose level 95-126 mg/dl, and post load glucose level 140-200 mg/dl), and one or more cardiovascular risk factors (if 55 years of age or older) or known cardiovascular disease (if 50 years of age or older)

Laboratory abnormalities or conditions that could interfere with assessment of the safety or efficacy of a study drug; the use of an ACEi or ARB for the treatment of HTN; and the use of an antidiabetic medication within the previous 5 years

PERSUADE23 Men and women >18 years of age, with objective evidence of coronary Disease (previous MI, CABG, PCI, or angiographically documented coronary stenosis >70%), but without clinical heart failure

Clinical evidence of HF; planned revascularization; hypotension (sitting SBP of <110 mmHg) or uncontrolled hypertension (SBP >180 mm Hg and/or DBP of >100 mm Hg); recent (<1 month) use of ACEi or ARB therapy; and renal insufficiency (creatinine >150 µmol/L) or serum potassium >5.5 mmol/L

SANDS26 Documented type 2 DM, LDL-cholesterol of at least 100 mg/dL and SBP greater than 130 mm Hg within the previous 12 months

NYHA class III or IV heart failure; SBP > 180mmHg; liver transaminase levels more than twice the upper limit of normal; or diagnosis of primary hyperlipidemia or hypercholesterolemia due to hyperthyroidism or nephrotic syndrome

ACEi= Angiotensin converting enzyme inhibitor; AER=Albumin excretion rate; ARB= Angiotensin receptor blocker; BMI= Body mass index; BP=Blood pressure; CABG= Coronary artery bypass graft; CCB= Calcium channel blocker; CHD=Coronary heart disease; CHF= Congestive heart failure; CVA= Cerebrovascular accident; DBP= Diastolic blood pressure; DM= Diabetes mellitus; ECG= Electrocardiogram; GFR=Glomerular filtration rate; HbA1C=Glycosylated hemoglobin; HDL=High density lipoprotein; HF=Heart failure; HTN=Hypertension; IDDM=Insulin dependent diabetes mellitus; LDL= Low density lipoprotein; LVH=Left ventricular hypertrophy; MI=Myocardial infarction; NIDDM= Non-insulin dependent diabetes mellitus; NSAID=Nonsteroidal anti-inflammatory drug; NYHA=New York Heart Association; PVD=Peripheral vascular disease; SBP=Systolic blood pressure; TG=Triglyceride; TIA=Transient ischemic attack; USA=Unstable angina.



6

FIGURE LEGEND

Supplemental Figure 1. Funnel plot: all-cause mortality. The size of the data marker represents

the weight of each trial.

Supplemental Figure 2. Funnel plot: cardiovascular mortality. The size of the data marker

represents the weight of each trial.

Supplemental Figure 3. Funnel plot: myocardial infarction. The size of the data marker represents

the weight of each trial.

Supplemental Figure 4. Funnel plot: heart failure. The size of the data marker represents the

weight of each trial.

Supplemental Figure 5. Funnel plot: stroke. The size of the data marker represents the weight of

each trial.



7

Supplemental Figure 1.




8





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21 june, 2011 blood pressure targets in subjects with type 2 diabetes mellitus

Health & Medicine

systolic bp goal

aggressive bp goal

lower bp

target systolic bp

aggressive bp targets

blood pressure bp goal

systolic bp treatment

intensive bp control