ISSN: 1524-4539
Copyright © 2011 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online
72514
Circ...
Blood Pressure Targets in Subjects With Type 2 Diabetes
Mellitus/Impaired Fasting Glucose
Observations From Traditional an...
BP therapy did not reduce the rate of a composite cardiovas-
cular events. However, intensive therapy reduced the risk of
...
some of the trials in the meta-analysis are small or the observed risks
are close to 0 or 1. To avoid this, the binomial d...
versus standard) by design.5,24,26,29,36 The Diabetes Reduction
Assessment With Ramipril and Rosiglitazone Medication
(DRE...
Figure 2. Intensive versus standard blood pressure control and (A) all-cause mortality and (B) cardiovascular mortality. R...
Figure 3. Intensive versus standard blood pressure control and (A) myocardial infarction and (B) heart failure. Results ar...
groups, and only a few studies reported these outcomes (data
not shown). In addition, none of these outcomes was signif-
i...
Using Monte Carlo permutation with 10 000 random permu-
tations, we identified a value of Pϭ0.035 (SE, 0.0018) for the
abo...
intensive therapy compared with standard therapy. This
begs the question of whether there is a relatively flat part
of the...
is necessary for a reduction in microvascular events. In our
analysis, although certain renal events benefitted from inten...
3. Whitworth JA. 2003 World Health Organization (WHO)/International
Society of Hypertension (ISH) statement on management ...
analysis from the PROVE-IT TIMI 22 Trial [abstract]. J Am Coll Cardiol.
2009;53:A337.
40. Turnbull F, Neal B, Algert C, Ch...
1
SUPPLEMENTAL MATERIAL
at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
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Supplemental Table 1. Trials excluded for violation of the blood pressure entry criteria
Criteria Violated Trial No. of
...
3
Supplemental Table 2. Inclusion and exclusion criteria of included trials
Study Inclusion Criteria Exclusion Criteria
AB...
4
current cigarette smoking, total
cholesterol > 6 mmol/L, HDL
cholesterol < 1 mmol/L,
microalbuminuria (urinary albumin-
...
5
GUARD17
Hypertension and Type II diabetes NR
NAVIGATO
R27
Impaired glucose tolerance,(a fasting
plasma glucose level 95-...
6
FIGURE LEGEND
Supplemental Figure 1. Funnel plot: all-cause mortality. The size of the data marker represents
the weight...
7
Supplemental Figure 1.
Supplemental Figure 2.
at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
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Supplemental Figure 3.
Supplemental Figure 4.
at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
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Supplemental Figure 5.
at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
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  1. 1. ISSN: 1524-4539 Copyright © 2011 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online 72514 Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 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 http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.110.016337/DC1 Data Supplement (unedited) at: http://circ.ahajournals.org/cgi/content/full/123/24/2799 located on the World Wide Web at: The online version of this article, along with updated information and services, is http://www.lww.com/reprints Reprints: Information about reprints can be found online at journalpermissions@lww.com 410-528-8550. E-mail: Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters http://circ.ahajournals.org/subscriptions/ Subscriptions: Information about subscribing to Circulation is online at at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  2. 2. Blood Pressure Targets in Subjects With Type 2 Diabetes Mellitus/Impaired Fasting Glucose Observations From Traditional and Bayesian Random-Effects Meta-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 Ͻ140/ 90 mm Hg, and a more aggressive goal of Ͻ130/80 mm Hg for patients with diabetes mellitus. However, in the recent Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, a lower BP was not beneficial. The optimal BP target in subjects with diabetes mellitus or those with impaired fasting glucose/glucose tolerance is therefore not well defined. Methods and Results—We performed PUBMED, EMBASE, and CENTRAL searches for randomized clinical trials from 1965 through October 2010 of antihypertensive therapy in patients with type 2 diabetes mellitus or impaired fasting glucose/impaired glucose tolerance that enrolled at least 100 patients with achieved systolic BP of Յ135 mm Hg in the intensive BP control group and Յ140 mm Hg in the standard BP control group, had a follow-up of at least 1 year, and evaluated macrovascular or microvascular events. We identified 13 randomized clinical trials enrolling 37 736 participants. Intensive BP control was associated with a 10% reduction in all-cause mortality (odds ratio, 0.90; 95% confidence interval, 0.83 to 0.98), a 17% reduction in stroke, and a 20% increase in 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 a bayesian random-effects model. More intensive BP control (Յ130 mm Hg) was associated with a greater reduction in stroke, but did not reduce other events. Meta–regression analysis showed continued risk reduction for stroke to a systolic BP of Ͻ120 mm Hg. However, at levels Ͻ130 mm Hg, there was a 40% increase in serious adverse events with no benefit for other outcomes. Conclusions—The present body of evidence suggests that in patients with type 2 diabetes mellitus/impaired fasting glucose/impaired glucose tolerance, a systolic BP treatment goal of 130 to 135 mm Hg is acceptable. However, with more aggressive goals (Ͻ130 mm Hg), we observed target organ heterogeneity in that the risk of stroke continued to fall, 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 Ⅲ diabetes mellitus, type 2 Ⅲ hypertension Ⅲ prognosis The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure (BP) recommends a systolic BP goal of Ͻ140 mm Hg in patients with hypertension and a more aggressive goal of Ͻ130 mm Hg in patients with diabetes mellitus or renal disease.1 Other major national and interna- tional guidelines have echoed this more aggressive BP goal in patients with diabetes mellitus.2–4 However, there is a paucity of data to support aggressive BP targets. Editorial see p 2776 Clinical Perspective on p 2810 The Action to Control Cardiovascular Risk in Diabetes (ACCORD) BP trial (ACCORD BP) tested the effect of a target systolic BP below 120 mm Hg on major cardiovascular events among participants with type 2 diabetes mellitus compared with standard therapy of targeting below 140 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. E-mail sripalbangalore@gmail.com © 2011 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.110.016337 2799at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  3. 3. BP therapy did not reduce the rate of a composite cardiovas- cular events. However, intensive therapy reduced the risk of stroke.5 The systolic BP achieved at the end of 1 year in ACCORD was 133.5 mm Hg in the standard therapy group and 119 mm Hg in the intensive therapy group. This finding begs the question of whether the BP goal should be Ͻ140 mm Hg, which is the standard for all non–high-risk hypertensives, Ͻ130 mm Hg on the basis of most national and international guidelines, or Ͻ120 mm Hg on the basis of the significant stroke reduction seen in the intensive arm of the ACCORD-BP trial. Our objective was to evaluate target BP goals for subjects with type 2 diabetes mellitus. Given that subjects with impaired fasting glucose (IFG) or glucose intolerance (IGT) are a spectrum in the continuum of insulin resistance and diabetes mellitus, we also evaluated these subsets. Methods Eligibility Criteria We conducted PUBMED, EMBASE, and CENTRAL searches using the terms “diabetes” and “diabetes mellitus” in humans from 1965 until October 2010 with the limit “randomized controlled trials.” We checked the reference lists of review articles, meta-analyses, and original studies identified by the electronic searches to find other eligible trials. There was no language restriction for the search. Authors of publications were contacted when results were unclear or when relevant data were not reported. Eligible trials had to fulfill the following criteria to be included in this analysis: (1) randomized clinical trials of participants with type 2 diabetes mellitus/IFG/IGT (2) reporting Ն1-year outcomes (3) and enrolling at least 100 patients (4) who achieved systolic BP Յ140 mm Hg in both arms. Additionally, because the objective of the present study was to test outcomes based on BP targets, the following criteria were required: (1) achieved systolic BP in the intensive BP group of Յ135 mm Hg, (2) achieved systolic BP in the standard BP group of Յ140 mm Hg, and (3) had a systolic BP difference between the intensive and standard BP group of at least 3 mm Hg. We chose this cut point because this difference in systolic BP between treatment arms was the minimum required to show a reduction in cardiovascular events.6 Studies in which there was no significant difference in BP between arms (Ͻ3 mm Hg) were excluded. For example, if studies evaluated 2 antihypertensive agents, but uptitrated or added medication to ensure no difference in final systolic BPs, they were excluded, because such studies are not expected to provide information on BP targets. Selection and Quality Assessment Two authors (S.B. and S.K.) independently assessed trial eligibility and trial bias risk and extracted data. The bias risk of trials was assessed by the use of the components recommended by the Cochrane Collaboration7: (1) sequence generation of allocation; (2) allocation concealment; (3) blinding of participants, personnel, and outcome assessors; (4) incomplete outcome data; (5) selective outcome reporting; and (6) other sources of bias. Of note, the studies did not differ for quality components 4 through 6. Trials with high or unclear risk for bias for any 1 of the first 3 components were considered trials with a high risk of bias. Otherwise, they were considered trials with low risk of bias. Data Extraction and Synthesis For the purpose of this analysis, the intensive BP group was defined as the group in which the final achieved systolic BP was Յ135 mm Hg, and the standard BP group as the group in which the final achieved systolic BP was Յ140 mm Hg. Of note, these terms are based on mean achieved systolic BP, are used for descriptive purposes for this article, and are not necessarily the strategy used in the trial (ie, not all trials tested a BP strategy). Long-term macrovascular and microvascular complications were evaluated. The macrovascular outcomes were all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, heart failure, angina pectoris, and revascularization. The microvascular outcomes evaluated were development of microalbuminuria, overt nephropa- thy, end-stage renal disease/dialysis, doubling of serum creatinine, neuropathy, and retinopathy. We also evaluated the serious adverse effects (SAEs) as reported between the 2 groups. The SAEs were variously defined as events that are life-threatening, cause permanent disability, or necessitate hospitalization or withdrawal owing to adverse effects. Statistical Analysis An intention-to-treat traditional meta-analysis was performed in line with recommendations from the Cochrane Collaboration and the Preferred 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 was assessed with the I2 statistic,10 with I2 Ͻ25% considered low and I2 Ͼ75% considered high. We used the Peto method for odds ratio (OR),11,12 which is viewed as the most optimal approach when there are relatively few events in individual trials. Publication bias was estimated visually by funnel plots and by use of the Begg and Egger test.13 Analyses were performed after the studies were further stratified on the basis of the achieved systolic BP in the intensive group: Ͼ130 but Յ135 mm Hg (less intensive group) versus Յ130 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 mean achieved systolic BP was used as a continuous variable. We used residual 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 permutation test for meta-regression using 10 000 random permutations.14 Sensitivity Analyses In a meta-analysis of clinical trials with binary outcomes such as those described above, a normal approximation for the summary treatment effect measure in each trial may not be appropriate when Figure 1. Study selection. RCT indicates randomized, controlled trial; SBP, systolic blood pressure; and IDDM, insulin-dependent diabetes mellitus. 2800 Circulation June 21, 2011 at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  4. 4. some of the trials in the meta-analysis are small or the observed risks are close to 0 or 1. To avoid this, the binomial distribution within trials can be used directly as described by Warn et al.15 The advantages of bayesian methods include a modeling framework that overcomes issues such as the appropriate treatment of small trials and the ability to consider distributions other than normal for the random effects.15 Of note, the Peto OR methodology used above more closely approximates a fixed-effect model; hence, in situations in which the results of the bayesian model differed from those of the traditional model, the bayesian model was used for inference (given that it is a random-effects model). The BUGS code for implementing the model is as described by Warn et al.15 Minimally informative prior distributions were used for log ORs and for random-effects standard deviation comparisons of treatments, so the findings are close to those obtained with frequentist methods. All bayesian analyses were conducted with WinBUGS 1.4.3. Subgroup Analyses Sensitivity analyses were performed for the following subgroups: trials with low to trials with high risk of bias; trials that tested a BP strategy versus others; and including and excluding trials that enrolled 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 PϽ0.10 to indicate that the effects of treatment differed between the tested subgroups. Results Study Selection We identified 1330 randomized, controlled trials through electronic and hand searches, of which a total of 13 random- ized, controlled trials5,17–29 fulfilled the inclusion criteria and were chosen for this analysis (Figure 1). The Antihyperten- sive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) included was the report on the subset of patients with new glucose disorder.18 We included the ACCORD-Eye substudy22 for the retinopathy outcome anal- ysis. Of note, 6 trials were excluded for violation of 1 or 2 BP inclusion criteria, and most of them would have been ex- cluded for violation of other criteria as well (Table I in the online-only Data Supplement).30–35 Only 3 of the 6 trials were excluded, because the difference in BP achieved was Ͻ3 mm Hg. Among these, the trial by Ahmad et al33 had no differences in BP, whereas the other 2 trials34,35 had a difference of 1 mm Hg between the 2 arms. The later trials would have been excluded anyway because the mean follow-up was Ͻ1 year. Characteristics of the Trials The baseline characteristics and bias-risk assessment are summarized in Tables 1 and 2 and Table II in the online-only Data Supplement. The 13 randomized, controlled trials en- rolled 37 736 participants, 19 042 (50.5%) in the intensive BP control group and 18 694 (49.5%) in the standard BP control group, and were followed up for 4.8Ϯ1.3 years (weighted mean). Of the 13 trials, only 5 tested a BP strategy (intensive Table 1. Baseline Characteristics of Included Trials Study Year n Comparison Follow-Up, mo Mean Age, y Men, % Hemoglobin A1C Final Systolic BP, mm Hg Final Diastolic BP, mm Hg ABCD (hypertension)29 2007 470 Intensive vs standard BP lowering 60 58 58 11.5 133 vs 139 78 vs 86 ABCD (normotension)29 2007 480 Intensive vs standard BP lowering 60 59 55 11.5 128 vs 137 75 vs 81 ABCD-2V24 2006 129 Intensive vs standard BP lowering 23 56.1 67 8.2 118 vs 124 75 vs 80 ACCORD5,22 2010 4733 Intensive vs standard BP lowering 60 62.2 52.3 8.3 119.3 vs 133.5 64.4 vs 70.5 ADVANCE28 2007 11140 Perinodpril-indapamide vs placebo 52 66 57 7.5 135 vs 140 74 vs 76 ALLHAT (New Diabetic)18 2004 1690 Doxazosine vs chlorthalidone 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 vs amlodipine 48 62 57 7 132.4 vs 140.4 82.3 vs 86.5 GUARD17 2008 304 Benazepril/amlodipine vs benazepril/ 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 BP lowering 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 Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; DIRECT, Diabetic Retinopathy Candesartan Trials; DREAM, Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication; GUARD, Gauging Albuminuria Reduction With Lotrel in Diabetic Patients With Hypertension; NAVIGATOR, Nateglinide and Valsartan in Impaired Glucose Tolerance 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 at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  5. 5. versus standard) by design.5,24,26,29,36 The Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) trial and the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trials enrolled patients with IFG. Of note, the BP achieved in the standard group of Fogari et al25 was 140.4 mm Hg, which was close to the threshold of Յ140 mm Hg; hence, it has been included in this analysis. In addition, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trial, the BP in the intensive group for most of follow-up was 134 to 135 mm Hg. Quality Assessments Among the 13 randomized, controlled trials considered for this analysis, 9 were considered trials with low risk of bias as described in the Methods section. The rest were considered to have an unclear or a high risk of bias (Table 2). Macrovascular Outcomes Intensive BP control group was associated with a 10% reduction in all-cause mortality compared with standard BP control, driven largely by the trials with achieved systolic BP Ͼ130 but Յ135 mm Hg (less intensive group; Figure 2A). The test for interaction was significant (Pϭ0.09), so that the point estimate was directionally opposite for systolic BP Յ130 mm Hg compared with the group with achieved systolic BP Ͼ130 but Յ135 mm Hg (Figure 2A). There was no heterogeneity (I2 ϭ0.0%), and bias was insignificant (Figure I in the online-only Data Supplement). For the outcomes of cardiovascular mortality (Figure 2B), myocardial infarction (Figure 3A), and heart failure (Figure 3B), there was no difference between the 2 groups, but the point estimate favored the intensive group, driven largely by the trials with achieved systolic BP Ͼ130 but Յ135 mm Hg (less intensive group). The results were similar for the more intensive versus less intensive group comparison (PinteractionϾ 0.10 for all comparisons; Figures 2B, 3A, and 3B). There was low to moderate heterogeneity (I2 ϭ6.8%, 0.0%, and 47.8%, respectively), and bias was insignificant (Figures II through VI in the online-only Data Supplement). For the outcome of stroke (Figure 4A), intensive BP control was associated with a 17% reduction in the odds compared with the standard control group, with a greater magnitude of benefit in trials in which the systolic BP was Յ130 mm Hg (Pinteractionϭ0.005), in which there was a 47% decrease in the odds of stroke compared with the standard control group. There was no to low heterogeneity (I2 ϭ27.0%), and bias was insignificant (Figure V in the online-only Data Supplement). There was no difference between the 2 groups in the outcomes of angina pectoris (OR, 1.07; 95% confidence interval [CI], 0.92 to 1.24) or revascularization (OR, 0.97; 95% CI, 0.85 to 1.12), with similar results for the more intensive versus less intensive group comparison (PinteractionϾ0.10 for all comparisons). The above results were similar in a sensitivity analysis using a bayesian random-effects model (Table 3) with an 11% decreased odds of all-cause mortality and a 30% decreased odds of stroke with intensive BP control with no difference for other outcomes. Serious Adverse Events In the few studies that reported SAEs, intensive control group was associated with a 20% increase in SAEs (OR, 1.20; 95% CI, 1.08 to 1.32), which was greater in magnitude in studies with more intense control of BP (Յ130 mm Hg) in which there was a 40% increase in SAEs (OR, 1.40; 95% CI, 1.19 to 1.64; Pinteractionϭ0.01). There was significant heterogeneity in this analysis (I2 ϭ78.8%). Microvascular Outcomes For the outcome of new-onset microalbuminuria, intensive control was associated with a 17% reduction in the odds compared 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 in the odds compared with the standard control group, with greater benefit with more intensive BP control (Յ130 mm Hg) in which there was a 36% reduction compared with standard control (Pinteractionϭ0.06; Figure 5). However, there was moderate heterogeneity in this analysis (I2 ϭ61.3%). Other measures of nephropathy 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 Study Testing a BP Strategy Bias Estimation* Source of Funding ABCD (normotension)29 Yes ϩϮϩ Industry and nonindustry ABCD-2V24 Yes ϩϩϩ Industry ACCORD5,22 Yes ϩϩϩ Nonindustry ADVANCE28 No ϩϩϩ Industry and nonindustry ALLHAT (New Diabetic)18 No ϩϩϩ Nonindustry Chan et al21 No ϩϮϮ Not reported DIRECT Protect 219 No ϩϩϩ Industry DREAM20 No ϩϩϩ Industry and nonindustry Fogari et al25 No ϩϩϪϪ Not reported GUARD17 No ϩϩϩ Industry NAVIGATOR27 No ϩϩϩ Industry PERSUADE23 No ϩϩϩ Industry SANDS26 Yes ϩϩϩ Nonindustry BP indicates blood pressure; ABCD, Appropriate Blood Pressure Control in Diabetes; 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, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; DIRECT, Diabetic Retinopathy Candesartan Trials; DREAM, Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication; GUARD, Gauging Albuminuria Reduction With Lotrel in Diabetic Patients With Hypertension; NAVIGATOR, Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; PERSUADE, Perindopril Substudy in Coronary Artery Disease and Diabetes; and SANDS, Stop Atherosclerosis in Native Diabetics Study. ϩ Indicates low bias risk; ϪϪ indicates high bias risk andϮunclear bias risk. *Based on allocation generation, allocation concealment, and blinding. 2802 Circulation June 21, 2011 at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  6. 6. 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. OR indicates 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 Coronary Artery 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 in Diabetic Patients With Hypertension; DIRECT, Diabetic Retinopathy Candesartan Trials; and ACCORD, Action to Control Cardiovascular Risk in Diabetes. Bangalore et al Diabetes Mellitus and Blood Pressure Targets 2803 at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  7. 7. 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 indicates odds 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 Tolerance Outcomes 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. 2804 Circulation June 21, 2011 at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  8. 8. groups, and only a few studies reported these outcomes (data not shown). In addition, none of these outcomes was signif- icantly different in a sensitivity analysis using a bayesian random-effects model (Table 3). For the outcome of retinopathy, there was no difference between the 2 groups (OR, 0.93; 95% CI, 0.83 to 1.05) with low heterogeneity (I2 ϭ21.5%) and similar results across the more intensive versus less intensive comparison (Pinteractionϭ 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 ϭ26.9%), with similar results across the more intensive versus less intensive comparison (Pinteractionϭ0.16). The results were similar in a sensitivity analysis using a bayesian random-effects model (Table 3). Meta–Regression Analysis The relationships between final achieved systolic BP (in the intensive control group) and the risk of macrovascular and microvascular outcomes are shown in Figure 6A through 6F. Results based on a sensitivity analysis using a bayesian random-effects model and evaluating the relationship be- tween final achieved systolic BP and outcomes are outlined in Table 3. For most of the macrovascular and microvascular out- comes (other than stroke), lower was not better (Figure 6A through 6F). For the outcome of stroke, lower was better, with benefit even down to a systolic BP of Ͻ120 mm Hg (Figure 6D). The residual maximum likelihood estimate of between-study variance (␶2 ) used was 0, and the percent residual 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 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; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; PERSUADE, Perindopril Substudy in Coronary Artery 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, Appropriate Blood 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 SBP to Outcomes* Slope† 95% Cr I Macrovascular All-cause mortality 0.89 (0.79–0.99) 0.010 Ϫ1.621 Ϫ4.305–0.867 CV mortality 0.93 (0.75–1.22) 0.057 Ϫ1.299 Ϫ7.786–9.538 Myocardial infarction 0.90 (0.72–1.13) 0.046 0.598 Ϫ5.440–7.669 Heart failure 0.88 (0.60–1.41) 0.193 Ϫ2.468 Ϫ18.980–9.983 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 Ϫ2.322 Ϫ20.450–11.680 Revascularization 0.96 (0.55–1.55) 0.188 3.992 Ϫ10.300–18.810 Microvascular Nephropathy 0.69 (0.45–1.12) 0.228 1.114 Ϫ11.410–17.320 Retinopathy 0.92 (0.57–1.33) 0.170 Ϫ1.484 Ϫ19.780–7.963 Neuropathy 1.27 (0.54–3.26) 0.481 0.523 Ϫ23.640–23.820 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 SBP associated with better outcomes). Bangalore et al Diabetes Mellitus and Blood Pressure Targets 2805 at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  9. 9. Using Monte Carlo permutation with 10 000 random permu- tations, we identified a value of Pϭ0.035 (SE, 0.0018) for the above analysis. For each 1-mm Hg-lower systolic BP, the odds of stroke reduced by 3% (95% CI, 1 to 7). The results were similar in a sensitivity analysis using a bayesian random-effects model (Table 3). Subgroup Analyses Subgroup analyses did not make a noticeable difference in the above results (Table 4). Discussion The principal finding of the present study is that no single optimal systolic goal BP level can be identified in patients with type 2 diabetes mellitus/IFG/IGT. Intensive BP control (Յ135 mm Hg) was associated with a significant reduction in macrovascular (all-cause mortality and stroke) events but with an increase in SAEs compared with standard BP control (Յ140 mm Hg). Although lower was better for stroke (even Ͻ120 mm Hg for systolic BP), this was not true for other cardiac, renal, or retinal outcomes. Thus, below a systolic BP of 130 mm Hg, there seems to be target organ heterogeneity in that there is continued reduction of stroke but an increase in SAEs without any further benefit for other cardiovascular outcomes. Type 2 Diabetes Mellitus and Blood Pressure Patients with diabetes mellitus are at increased risk for cardiovascular outcomes, so that these patients are considered coronary artery disease risk equivalents. As such, major national and international guidelines recommend a more aggressive BP goal of Ͻ130/80 mm Hg in patients with diabetes mellitus.1–4 Intensive therapy is not without drawbacks. In the ACCORD BP trial, the risk of serious adverse events was 2.6 times higher in the intensive group compared with the standard therapy group, with a 17-fold increase in hypotension and a 10-fold increase in hyperkalemia. However, the absolute rates of above adverse events were rather low. Moreover, in patients with coronary artery disease, a J-shaped curve relationship has been documented with BP (particularly diastolic) and cardiovascular events so that lower pressures are associated with increased risk of events.37 Regardless of the J-curve hypothesis, the principle of primum non- nocere mandates that we show evidence of benefit for intensive BP control before such a treatment strategy is advocated. The result of the present study shows that the relationship between systolic BP and target organ risk reduction is complex. For macrovascular outcomes, intensive BP control (Յ135 mm Hg) was associated with a reduction in death and stroke. Although there was a direct linear relationship be- tween systolic BP and stroke, so that lower was indeed better, the same was not true for death and other cardiac events. For cardiac events, further reduction below 130 mm Hg was not beneficial, with the point estimate of the OR directionally opposite that seen for the less intensive BP group (Ͼ130 and Յ135 mm Hg) for death. Of note, in ACCORD there was no difference in all-cause mortality (1.28%/y versus 1.19%/y; Pϭ0.55) or cardiovas- cular mortality (0.52%/y versus 0.49%/y; Pϭ0.74) with Figure 5. Intensive versus standard blood pressure control and nephropathy. Results are further stratified by achieved systolic pressure in 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. 2806 Circulation June 21, 2011 at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  10. 10. intensive therapy compared with standard therapy. This begs the question of whether there is a relatively flat part of the curve where there is neither benefit nor excess harm of a cardiac event. In analyses of both the Treating to New Targets (TNT) trial38 and the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myo- cardial Infarction 22 (PROVE IT TIMI 22) trial,39 we have shown 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 was seen at systolic BPs Ͻ110 mm Hg. However, once systolic BP is lowered to Ͻ130 mm Hg, there may be target organ heterogeneity, and clinicians will have to be cognizant of the increased risk of SAEs and possibly cardiac events. Our results are concordant with the analysis by the Blood Pressure Lowering Treatment Trialists’ Collaboration.40 Traditional teaching implies that good BP control will reduce 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 data marker represents the weight of each trial. Bangalore et al Diabetes Mellitus and Blood Pressure Targets 2807 at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  11. 11. is necessary for a reduction in microvascular events. In our analysis, although certain renal events benefitted from inten- sive BP control, the results were not consistently seen in the bayesian 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 more robust, suggesting no benefit of intensive BP control on any of the microvascular outcomes. Study Limitations All of the trials did not report all of the outcomes. The subgroup analyses might suffer from multiple testing and are best described as secondary and hypothesis generating only. In this analysis, we tested a BP goal of Յ140 mm Hg with that of Յ135 mm Hg and not, say, Յ130 mm Hg for several reasons: (1) We aimed to ensure that we use data from as many relevant studies as possible because the number of studies was limited if the criterion was tightened to 130 mm Hg; (2) we aimed to test whether evidence exists for even a 135-mm Hg goal; and finally, and more importantly, (3) the cut points are less relevant because, in our regression analy- sis, the mean achieved BP was treated as a continuous variable and our conclusions and recommendations are based on this. Moreover, the intensive group was substratified into a more intensive group (Յ130 mm Hg) versus less intensive group (Ͼ130 but Յ135 mm Hg). In addition, in some of the trials, the mean systolic BP achieved in the standard group was more than the systolic BP achieved in the intensive group of other trials. However, the regression analysis using systolic BP as continuous variable accounts for this; hence, the BP targets are derived from this. In trials not testing a BP strategy, the most commonly used antihypertensive agent was an angiotensin-converting enzyme inhibitor, and the possibil- ity that the beneficial effects on certain outcomes are due to this medication alone rather than a BP effect cannot be ruled out. In addition, our analysis is based on achieved BP, and many factors, including survivorship, will affect the end-of- study achieved BP. The definition of SAEs varied, and the trials did not consistently report the components to perform any additional analyses. Conclusions The present body of evidence suggests that intensive BP control (Յ135 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, similar to the achieved BP of 133.5 mm Hg in the standard therapy group of the ACCORD trial, is therefore acceptable, and more aggressive goals to 120 mm Hg can be considered in patients at higher risk of stroke. However, at a systolic BP Ͻ130 mm Hg, there may be target organ heterogeneity, and these cerebrovascular benefits have to be balanced against an increased risk of SAEs and a lack of benefit for cardiac, renal, and retinal outcomes. Disclosures Dr 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 research grants from GlaxoSmithKline, Pfizer, Novartis, and CardioVascular Therapeutics. The other authors report no conflicts. References 1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560–2572. 2. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Struijker Boudier HA, Zanchetti A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Erdine S, Kiowski W, Agabiti-Rosei E, Ambrosioni E, Lindholm LH, Manolis A, Nilsson PM, Redon J, Struijker-Boudier HA, Viigimaa M, Adamo- poulos S, Bertomeu V, Clement D, Farsang C, Gaita D, Lip G, Mallion JM, Manolis AJ, O’Brien E, Ponikowski P, Ruschitzka F, Tamargo J, van Zwieten P, Waeber B, Williams B; Task Force for the Management of Arterial Hypertension of the European Society of Hypertension, Task Force for the Management of Arterial Hypertension of the European Society of Cardiology. 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hyper- tension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2007;28: 1462–1536. Table 4. Subgroup Analysis Outcome High Bias Risk Low Bias Risk Pinteraction Testing BP Strategy Not Testing a BP Strategy Pinteraction All Trials Excluding NAVIGATOR or DREAM Pinteraction Macrovascular All-cause mortality 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 Assessment With Ramipril and Rosiglitazone Medication; CV, cardiovascular; and MI, myocardial infarction. Testing a BP strategy indicates trials in which the study was designed to test an intensive BP strategy versus standard. 2808 Circulation June 21, 2011 at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
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  13. 13. analysis from the PROVE-IT TIMI 22 Trial [abstract]. J Am Coll Cardiol. 2009;53:A337. 40. Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, Woodward M, MacMahon S. Effects of different blood pressure- lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med. 2005;165:1410- 1419. CLINICAL PERSPECTIVE Most guidelines for treatment of hypertension, including the seventh report of the Joint National Committee, recommend an aggressive blood pressure goal of Ͻ130/80 mm Hg for patients with diabetes mellitus. However, the evidence on which the guidelines are based is limited. In our analyses of 13 randomized trials with 37 736 participants, we noted that in patients with type 2 diabetes mellitus, a systolic blood pressure treatment goal of 130 to 135 mm Hg is acceptable. However, with more aggressive goals (Ͻ130 mm Hg), we observed target organ heterogeneity in that the risk of stroke continued to fall, 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. Go to http://cme.ahajournals.org to take the CME quiz for this article. 2810 Circulation June 21, 2011 at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  14. 14. 1 SUPPLEMENTAL MATERIAL at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  15. 15. 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. at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  16. 16. 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. at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  17. 17. 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 at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  18. 18. 5 GUARD17 Hypertension and Type II diabetes NR NAVIGATO R27 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. at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  19. 19. 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. at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  20. 20. 7 Supplemental Figure 1. Supplemental Figure 2. at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  21. 21. 8 Supplemental Figure 3. Supplemental Figure 4. at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from
  22. 22. 9 Supplemental Figure 5. at VA MED CTR BOISE on June 21, 2011circ.ahajournals.orgDownloaded from

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