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Use of a Single Target Blood Pressure Level in Type 2 Diabetes Mellitus for All Cardiovascular Risk Reduction: Comment on “Intensive and Standard Blood Pressure Targets in Patients With Type 2 Diabetes Mellitus”

Use of a Single Target Blood Pressure Level in Type 2 Diabetes Mellitus for All Cardiovascular... For more than 15 years, all major clinical practice guidelines have recommended a target blood pressure (BP) of less than 130/80 mm Hg for patients with diabetes mellitus (DM).1 This BP value is based almost exclusively on the results of retrospective analyses of primary outcomes trials. The first prospective trial to randomize patients with type 2 DM (T2DM) to target BPs and examine their cardiovascular (CV) outcomes was the UKPDS 38 by the United Kingdom Prospective Diabetes Study Group.2 In that trial, the group randomized to tighter BP control had a mean BP of 144/82 mm Hg and demonstrated significant reductions in DM-related deaths and complications compared with the group randomized to usual control, whose mean systolic BP was 10 mm Hg higher. More recently, the Action to Control Cardiovascular Risk in Diabetes–Blood Pressure (ACCORD-BP) trial randomized 4733 high-risk patients with T2DM to a lower target systolic BP (SBP) of less than 120 mm Hg.3 After 4.7 years, no difference between randomization groups was observed for the primary outcomes of nonfatal stroke and nonfatal myocardial infarction or CV death and all-cause mortality. The lower BP goal was associated with fewer strokes but with more serious adverse events. Do the data from these 2 randomized trials clearly support a target BP of less than 130/80 mm Hg? One could argue no. While the ACCORD-BP trial achieved a mean SBP of 119.3 mm Hg, far below 130/80 mm Hg, there was no overall CV risk benefit. In addition, because of the factorial design and the achieved BPs, the power of the study was reduced, and the event rate was lower than expected. Therefore, the main conclusion in the ACCORD-BP trial was that a target SBP of less than 120 mm Hg does not reduce CV risk to a greater extent than a target SBP of less than 140 mm Hg. However, the issue of the optimal BP goal in patients with DM remains unresolved.4 Retrospective analyses of CV outcomes trials in subgroups of patients with T2DM demonstrated a curvilinear BP relationship for decreased myocardial infarction and a linear one for stroke reduction.1,5,6 A subgroup analysis of 6400 patients with DM, hypertension, or coronary artery disease from the International Verapamil SR–Trandolapril Study (INVEST)6 showed no additional benefit in patients having a target SBP of less than 130 mm Hg compared with 130 to 139 mm Hg. Moreover, patients with target SBP levels below 115 mm Hg trended toward increased CV risk. An exception to this is the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial,7 which randomized 11 140 patients with T2DM to a fixed combination therapy of perindopril-indapamide or to placebo. After 4.3 years, the mean BPs were 135/74 mm Hg for the combination therapy group and 140/76 mm Hg for the placebo group. A post hoc analysis demonstrated fewer CV outcomes among patients with lower BPs that extended below 130 mm Hg. These results should be interpreted with caution because the comparison involved a drug intervention, not randomized BP groups. McBrien et al8 provide further insight on the question of BP goals in patients with DM with their systematic review and meta-analysis of randomized studies in the field. The authors report on trials that compare prespecified target BP levels and describe primary CV end points, including 5 studies that involved 7312 participants. They followed a rigorous methodological approach with their search strategy, study selection, quality assessment, and quantitative data extraction. Target blood pressure levels were defined as intensive (≤130/80 mm Hg) or as standard (≤140-160 systolic and ≤85-100 mm Hg diastolic), and a random-effects model was correctly used because of between-study heterogeneity. Intensive targets were associated with insignificant decreases in the risk for mortality and myocardial infarction but with a significant decrease in the risk for stroke. The authors also performed pooled analyses comparing standard target BP levels and historical treatment, which demonstrated significant decreases in risk for all 3 outcomes with standard target BPs. They conclude that a small benefit in stroke reduction is apparent with intensive targets but that there is no conclusive evidence of benefit for the outcomes of death or myocardial infarction.8 An earlier meta-analysis9 included 13 randomized trials that involved 37 736 patients with T2DM or with impaired fasting glucose levels or impaired glucose tolerance who were followed up for at least 1 year and achieved an SBP of 135 mm Hg or less (intensive control) or 140 mm Hg or less (standard control). The intensive group had decreases of 10% for all-cause mortality and 17% for stroke but had a 20% increase in serious adverse effects. The results of the meta-analysis suggested continued risk reduction for stroke to SBP levels of less than 120 mm Hg but no overall CV risk advantage to SBP levels of less than 130 mm Hg. The work reported in this issue by McBrien et al has strengths (eg, high-quality methods, the inclusion only of trials that compared interventions targeted to different BP goals, and the use of target BP definitions that were highly relevant to the unanswered clinical questions). It also has limitations. The strict criteria identified only 5 studies for inclusion in the meta-analysis, 4 of which had randomized patients to target diastolic BP levels and 2 of which included normotensive patients at baseline. Furthermore, in the standard BP arms, the achieved BPs differed from the goal, and in one case (the Appropriate Blood Pressure Control in Diabetes Part 2 With Valsartan cohort study) the achieved BP was as low as 124/80 mm Hg. Finally, the results of the meta-analysis are greatly influenced by the inclusion of the ACCORD-BP study, conferring 64.7% of the meta-analysis population and having an achieved BP of 134/70 mm Hg in the standard BP arm. Given these limitations of the meta-analysis, McBrien et al cannot draw conclusions about any specific target BP level; as the authors correctly acknowledge, they may comment only on the comparative effectiveness of the level of BP lowering. Furthermore, the divergence of the achieved BPs from the target BPs in the standard BP arms of the meta-analysis presents problems similar to those in the ACCORD-BP study. Moreover, all the prospective randomized trials included in the meta-analysis used office BP measurements, which may misclassify patients' BP status because of the white-coat phenomenon. Recent findings suggest discrepancies between office-measured vs ambulatory BP levels and between BP control rates in the general population vs in high-risk individuals, including those with DM.10 Together with the results of previous prospective trials, the findings of the meta-analysis by McBrien et al do not support lower, more aggressive target BP levels for overall CV risk reduction. Newer guidelines for BP goals in patients with DM are likely to suggest a goal of less than 140/90 mm Hg based on the totality of evidence, including that presented by these authors. Physicians need to understand and discuss these goals with their patients. Back to top Article Information Correspondence: Dr Bakris, Department of Medicine, ASH Comprehensive Hypertension Center, Department of Medicine, The University of Chicago, 5841 S Maryland Ave, Mail Chute 1027, Chicago, IL 60637 (gbakris@medicine.bsd.uchicago.edu). Published Online: August 6, 2012. archinternmed.2012.4020 Financial Disclosure: Dr Bakris reported being a consultant for Takeda, Abbott Renal, Novartis, Medtronic, CVRx Relapsya, and Fibrogen and having received investigator-initiated grant funding from Forest Labs and Takeda. References 1. Kalaitzidis RG, Bakris GL. Pros and cons of aggressive blood pressure lowering in patients with type 2 diabetes. Curr Vasc Pharmacol. 2012;10(2):156-16122239626PubMedGoogle ScholarCrossref 2. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 [published correction appears in BMJ. 1999;318(7175):29]. BMJ. 1998;317(7160):703-7139732337PubMedGoogle ScholarCrossref 3. Cushman WC, Evans GW, Byington RP, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-158520228401PubMedGoogle ScholarCrossref 4. Nilsson PM. ACCORD and risk-factor control in type 2 diabetes. N Engl J Med. 2010;362(17):1628-163020228405PubMedGoogle ScholarCrossref 5. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321(7258):412-41910938049PubMedGoogle ScholarCrossref 6. Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA. 2010;304(1):61-6820606150PubMedGoogle ScholarCrossref 7. Chalmers J, Arima H. Importance of blood pressure lowering in type 2 diabetes: focus on ADVANCE. J Cardiovasc Pharmacol. 2010;55(4):340-34720422738PubMedGoogle ScholarCrossref 8. McBrien K, Rabi DM, Campbell N, et al. Intensive and standard blood pressure targets in patients with type 2 diabetes mellitus: systematic review and meta-analysis [published online August 6, 2012]. Arch Intern Med. 2012;172(17):1296-1303Google Scholar 9. Bangalore S, Kumar S, Lobach I, Messerli FH. 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. Circulation. 2011;123(24):2799-2810Google ScholarCrossref 10. Banegas JR, Messerli FH, Waeber B, et al. Discrepancies between office and ambulatory blood pressure: clinical implications. Am J Med. 2009;122(12):1136-114119958892PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Use of a Single Target Blood Pressure Level in Type 2 Diabetes Mellitus for All Cardiovascular Risk Reduction: Comment on “Intensive and Standard Blood Pressure Targets in Patients With Type 2 Diabetes Mellitus”

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Publisher
American Medical Association
Copyright
Copyright © 2012 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinternmed.2012.4020
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Abstract

For more than 15 years, all major clinical practice guidelines have recommended a target blood pressure (BP) of less than 130/80 mm Hg for patients with diabetes mellitus (DM).1 This BP value is based almost exclusively on the results of retrospective analyses of primary outcomes trials. The first prospective trial to randomize patients with type 2 DM (T2DM) to target BPs and examine their cardiovascular (CV) outcomes was the UKPDS 38 by the United Kingdom Prospective Diabetes Study Group.2 In that trial, the group randomized to tighter BP control had a mean BP of 144/82 mm Hg and demonstrated significant reductions in DM-related deaths and complications compared with the group randomized to usual control, whose mean systolic BP was 10 mm Hg higher. More recently, the Action to Control Cardiovascular Risk in Diabetes–Blood Pressure (ACCORD-BP) trial randomized 4733 high-risk patients with T2DM to a lower target systolic BP (SBP) of less than 120 mm Hg.3 After 4.7 years, no difference between randomization groups was observed for the primary outcomes of nonfatal stroke and nonfatal myocardial infarction or CV death and all-cause mortality. The lower BP goal was associated with fewer strokes but with more serious adverse events. Do the data from these 2 randomized trials clearly support a target BP of less than 130/80 mm Hg? One could argue no. While the ACCORD-BP trial achieved a mean SBP of 119.3 mm Hg, far below 130/80 mm Hg, there was no overall CV risk benefit. In addition, because of the factorial design and the achieved BPs, the power of the study was reduced, and the event rate was lower than expected. Therefore, the main conclusion in the ACCORD-BP trial was that a target SBP of less than 120 mm Hg does not reduce CV risk to a greater extent than a target SBP of less than 140 mm Hg. However, the issue of the optimal BP goal in patients with DM remains unresolved.4 Retrospective analyses of CV outcomes trials in subgroups of patients with T2DM demonstrated a curvilinear BP relationship for decreased myocardial infarction and a linear one for stroke reduction.1,5,6 A subgroup analysis of 6400 patients with DM, hypertension, or coronary artery disease from the International Verapamil SR–Trandolapril Study (INVEST)6 showed no additional benefit in patients having a target SBP of less than 130 mm Hg compared with 130 to 139 mm Hg. Moreover, patients with target SBP levels below 115 mm Hg trended toward increased CV risk. An exception to this is the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial,7 which randomized 11 140 patients with T2DM to a fixed combination therapy of perindopril-indapamide or to placebo. After 4.3 years, the mean BPs were 135/74 mm Hg for the combination therapy group and 140/76 mm Hg for the placebo group. A post hoc analysis demonstrated fewer CV outcomes among patients with lower BPs that extended below 130 mm Hg. These results should be interpreted with caution because the comparison involved a drug intervention, not randomized BP groups. McBrien et al8 provide further insight on the question of BP goals in patients with DM with their systematic review and meta-analysis of randomized studies in the field. The authors report on trials that compare prespecified target BP levels and describe primary CV end points, including 5 studies that involved 7312 participants. They followed a rigorous methodological approach with their search strategy, study selection, quality assessment, and quantitative data extraction. Target blood pressure levels were defined as intensive (≤130/80 mm Hg) or as standard (≤140-160 systolic and ≤85-100 mm Hg diastolic), and a random-effects model was correctly used because of between-study heterogeneity. Intensive targets were associated with insignificant decreases in the risk for mortality and myocardial infarction but with a significant decrease in the risk for stroke. The authors also performed pooled analyses comparing standard target BP levels and historical treatment, which demonstrated significant decreases in risk for all 3 outcomes with standard target BPs. They conclude that a small benefit in stroke reduction is apparent with intensive targets but that there is no conclusive evidence of benefit for the outcomes of death or myocardial infarction.8 An earlier meta-analysis9 included 13 randomized trials that involved 37 736 patients with T2DM or with impaired fasting glucose levels or impaired glucose tolerance who were followed up for at least 1 year and achieved an SBP of 135 mm Hg or less (intensive control) or 140 mm Hg or less (standard control). The intensive group had decreases of 10% for all-cause mortality and 17% for stroke but had a 20% increase in serious adverse effects. The results of the meta-analysis suggested continued risk reduction for stroke to SBP levels of less than 120 mm Hg but no overall CV risk advantage to SBP levels of less than 130 mm Hg. The work reported in this issue by McBrien et al has strengths (eg, high-quality methods, the inclusion only of trials that compared interventions targeted to different BP goals, and the use of target BP definitions that were highly relevant to the unanswered clinical questions). It also has limitations. The strict criteria identified only 5 studies for inclusion in the meta-analysis, 4 of which had randomized patients to target diastolic BP levels and 2 of which included normotensive patients at baseline. Furthermore, in the standard BP arms, the achieved BPs differed from the goal, and in one case (the Appropriate Blood Pressure Control in Diabetes Part 2 With Valsartan cohort study) the achieved BP was as low as 124/80 mm Hg. Finally, the results of the meta-analysis are greatly influenced by the inclusion of the ACCORD-BP study, conferring 64.7% of the meta-analysis population and having an achieved BP of 134/70 mm Hg in the standard BP arm. Given these limitations of the meta-analysis, McBrien et al cannot draw conclusions about any specific target BP level; as the authors correctly acknowledge, they may comment only on the comparative effectiveness of the level of BP lowering. Furthermore, the divergence of the achieved BPs from the target BPs in the standard BP arms of the meta-analysis presents problems similar to those in the ACCORD-BP study. Moreover, all the prospective randomized trials included in the meta-analysis used office BP measurements, which may misclassify patients' BP status because of the white-coat phenomenon. Recent findings suggest discrepancies between office-measured vs ambulatory BP levels and between BP control rates in the general population vs in high-risk individuals, including those with DM.10 Together with the results of previous prospective trials, the findings of the meta-analysis by McBrien et al do not support lower, more aggressive target BP levels for overall CV risk reduction. Newer guidelines for BP goals in patients with DM are likely to suggest a goal of less than 140/90 mm Hg based on the totality of evidence, including that presented by these authors. Physicians need to understand and discuss these goals with their patients. Back to top Article Information Correspondence: Dr Bakris, Department of Medicine, ASH Comprehensive Hypertension Center, Department of Medicine, The University of Chicago, 5841 S Maryland Ave, Mail Chute 1027, Chicago, IL 60637 (gbakris@medicine.bsd.uchicago.edu). Published Online: August 6, 2012. archinternmed.2012.4020 Financial Disclosure: Dr Bakris reported being a consultant for Takeda, Abbott Renal, Novartis, Medtronic, CVRx Relapsya, and Fibrogen and having received investigator-initiated grant funding from Forest Labs and Takeda. References 1. Kalaitzidis RG, Bakris GL. Pros and cons of aggressive blood pressure lowering in patients with type 2 diabetes. Curr Vasc Pharmacol. 2012;10(2):156-16122239626PubMedGoogle ScholarCrossref 2. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 [published correction appears in BMJ. 1999;318(7175):29]. BMJ. 1998;317(7160):703-7139732337PubMedGoogle ScholarCrossref 3. Cushman WC, Evans GW, Byington RP, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-158520228401PubMedGoogle ScholarCrossref 4. Nilsson PM. ACCORD and risk-factor control in type 2 diabetes. N Engl J Med. 2010;362(17):1628-163020228405PubMedGoogle ScholarCrossref 5. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321(7258):412-41910938049PubMedGoogle ScholarCrossref 6. Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA. 2010;304(1):61-6820606150PubMedGoogle ScholarCrossref 7. Chalmers J, Arima H. Importance of blood pressure lowering in type 2 diabetes: focus on ADVANCE. J Cardiovasc Pharmacol. 2010;55(4):340-34720422738PubMedGoogle ScholarCrossref 8. McBrien K, Rabi DM, Campbell N, et al. Intensive and standard blood pressure targets in patients with type 2 diabetes mellitus: systematic review and meta-analysis [published online August 6, 2012]. Arch Intern Med. 2012;172(17):1296-1303Google Scholar 9. Bangalore S, Kumar S, Lobach I, Messerli FH. 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. Circulation. 2011;123(24):2799-2810Google ScholarCrossref 10. Banegas JR, Messerli FH, Waeber B, et al. Discrepancies between office and ambulatory blood pressure: clinical implications. Am J Med. 2009;122(12):1136-114119958892PubMedGoogle ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Sep 24, 2012

Keywords: cardiovascular disease risk factors,diabetes mellitus, type 2,blood pressure

References