Aggressive blood pressure reduction and renin–angiotensin system blockade in chronic kidney disease: time for re-evaluation?
2013; Elsevier BV; Volume: 85; Issue: 3 Linguagem: Inglês
10.1038/ki.2013.355
ISSN1523-1755
AutoresPantelis Sarafidis, Luís M. Ruilope,
Tópico(s)Hormonal Regulation and Hypertension
ResumoOver the past decades, aggressive control of blood pressure (BP) and blockade of the renin–angiotensin–aldosterone system (RAAS) were considered the cornerstones of treatment against progression of chronic kidney disease (CKD), following important background and clinical evidence on the associations of hypertension and RAAS activation with renal injury. To this end, previous recommendations included a BP target of <130/80mmHg for all individuals with CKD (and possibly 1g/day), as well as use of angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers as first-line therapy for hypertension in all CKD patients. However, long-term extensions of relevant clinical trials support a low-BP goal only for patients with proteinuria, whereas recent cardiovascular trials questioned the benefits of low systolic BP for diabetic patients, leading to more individualized recommendations. Furthermore, our previous knowledge of the specific renoprotective properties of RAAS blockers in patients with proteinuric CKD is now extended with data on the use of these agents in patients with less advanced nephropathy and/or absence of proteinuria, deriving mostly from subanalyses of cardiovascular trials. This review discusses previous and recent clinical evidence on the issues of BP reduction and RAAS blockade by type and stage of renal damage, aiming to aid clinicians in their treatment decisions for patients with CKD. Over the past decades, aggressive control of blood pressure (BP) and blockade of the renin–angiotensin–aldosterone system (RAAS) were considered the cornerstones of treatment against progression of chronic kidney disease (CKD), following important background and clinical evidence on the associations of hypertension and RAAS activation with renal injury. To this end, previous recommendations included a BP target of <130/80mmHg for all individuals with CKD (and possibly 1g/day), as well as use of angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers as first-line therapy for hypertension in all CKD patients. However, long-term extensions of relevant clinical trials support a low-BP goal only for patients with proteinuria, whereas recent cardiovascular trials questioned the benefits of low systolic BP for diabetic patients, leading to more individualized recommendations. Furthermore, our previous knowledge of the specific renoprotective properties of RAAS blockers in patients with proteinuric CKD is now extended with data on the use of these agents in patients with less advanced nephropathy and/or absence of proteinuria, deriving mostly from subanalyses of cardiovascular trials. This review discusses previous and recent clinical evidence on the issues of BP reduction and RAAS blockade by type and stage of renal damage, aiming to aid clinicians in their treatment decisions for patients with CKD. Chronic kidney disease (CKD) is currently recognized as an independent risk factor for cardiovascular and all-cause mortality;1.Sarafidis P.A. Bakris G.L. Microalbuminuria and chronic kidney disease as risk factors for cardiovascular disease.Nephrol Dial Transplant. 2006; 21: 2366-2374Crossref PubMed Scopus (87) Google Scholar recent data further exemplify the importance of CKD for cardiovascular complications, in relation to established risk factors, such as diabetes.2.Tonelli M. Muntner P. Lloyd A. et al.Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study.Lancet. 2012; 380: 807-814Abstract Full Text Full Text PDF PubMed Scopus (523) Google Scholar Therefore, prevention of CKD or retardation of disease progression in affected individuals is proposed as another strategy toward cardiovascular protection.3.Couser W.G. Riella M.C. World Kidney Day 2011: protect your kidneys, save your heart.Kidney Int. 2011; 79: 483-485Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar On one hand, elevated blood pressure (BP) is a major risk factor for CKD, and on the other hand, kidney injury can cause hypertension.4.Sarafidis P.A. Bakris G.L. Kidney disease and hypertension.in: Lip G.Y. Hall J.E. Comprehensive Hypertension. Mosby Elsevier, Philadelphia, PA2007: 607-619Crossref Scopus (15) Google Scholar, 5.Kidney Disease Outcomes Quality Initiative (K/DOQI) K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.Am J Kidney Dis. 2004; 43: 1-290PubMed Google Scholar, 6.KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease.Kidney Int Suppl. 2013; 2: 337-414Google Scholar Observational studies suggested a strong association between high BP and the risk for renal function decline or end-stage renal disease (ESRD), whereas in various clinical trials, patients with BP below conventional thresholds showed better preservation of renal function.4.Sarafidis P.A. Bakris G.L. Kidney disease and hypertension.in: Lip G.Y. Hall J.E. Comprehensive Hypertension. Mosby Elsevier, Philadelphia, PA2007: 607-619Crossref Scopus (15) Google Scholar,5.Kidney Disease Outcomes Quality Initiative (K/DOQI) K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.Am J Kidney Dis. 2004; 43: 1-290PubMed Google Scholar Thus, in the past decade, relevant guidelines recommended a BP target of <130/80mmHg for all CKD patients (and possibly 1g/day),5.Kidney Disease Outcomes Quality Initiative (K/DOQI) K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.Am J Kidney Dis. 2004; 43: 1-290PubMed Google Scholar,7.Chobanian A.V. Bakris G.L. Black H.R. et al.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: 2560-2572Crossref PubMed Scopus (16541) Google Scholar, 8.Mancia G. De B.G. Dominiczak A. et al.2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).J Hypertens. 2007; 25: 1105-1187Crossref PubMed Scopus (4841) Google Scholar, 9.American Diabetes Association Standards of medical care in diabetes—2010.Diabetes Care. 2010; 33: S11-S61Crossref PubMed Scopus (3000) Google Scholar although evidence from trials with hard renal outcomes (that is, incidence of ESRD) randomizing patients to different BP targets was limited.8.Mancia G. De B.G. Dominiczak A. et al.2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).J Hypertens. 2007; 25: 1105-1187Crossref PubMed Scopus (4841) Google Scholar Recently, long-term cohort data of relevant trials supported a low-BP goal for patients with proteinuria, whereas cardiovascular trials questioned the beneficial effects of low BP for patients with diabetes,10.Nilsson P.M. ACCORD and risk-factor control in type 2 diabetes.N Engl J Med. 2010; 362: 1628-1630Crossref PubMed Scopus (60) Google Scholar,11.Sarafidis P.A. Bakris G.L. Use of a single target blood pressure level in type 2 diabetes mellitus for all cardiovascular risk reduction.Arch Intern Med. 2012; 172: 1304-1305Crossref PubMed Scopus (5) Google Scholar leading to recommendations for less aggressive approaches to BP lowering in the latter.6.KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease.Kidney Int Suppl. 2013; 2: 337-414Google Scholar,12.American Diabetes Association Standards of medical care in diabetes—2013.Diabetes Care. 2013; 36: S11-S66Crossref PubMed Scopus (3099) Google Scholar Angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are recommended as first-line therapy for hypertension in patients with CKD,5.Kidney Disease Outcomes Quality Initiative (K/DOQI) K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.Am J Kidney Dis. 2004; 43: 1-290PubMed Google Scholar,7.Chobanian A.V. Bakris G.L. Black H.R. et al.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: 2560-2572Crossref PubMed Scopus (16541) Google Scholar, 8.Mancia G. De B.G. Dominiczak A. et al.2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).J Hypertens. 2007; 25: 1105-1187Crossref PubMed Scopus (4841) Google Scholar, 9.American Diabetes Association Standards of medical care in diabetes—2010.Diabetes Care. 2010; 33: S11-S61Crossref PubMed Scopus (3000) Google Scholar following evidence ranging from background studies to major renal trials in proteinuric CKD that suggested these agents to slow nephropathy progression more effectively than other antihypertensive agents.13.Sarafidis P.A. Khosla N. Bakris G.L. Antihypertensive therapy in the presence of proteinuria.Am J Kidney Dis. 2007; 49: 12-26Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar However, for patients with less advanced nephropathy or absence of proteinuria, previous reports suggested inhibitors of renin–angiotensin–aldosterone system (RAAS) to confer no additional renoprotective benefit,14.Estacio R.O. Jeffers B.W. Gifford N. et al.Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes.Diabetes Care. 2000; 23: B54-B64PubMed Google Scholar,15.Rahman M. Pressel S. Davis B.R. et al.Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).Arch Intern Med. 2005; 165: 936-946Crossref PubMed Scopus (302) Google Scholar and recent trials showed combined RAAS blockade to increase the risk of acute renal failure and related complications.16.Mann J.F. Schmieder R.E. McQueen M. et al.Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial.Lancet. 2008; 372: 547-553Abstract Full Text Full Text PDF PubMed Scopus (1334) Google Scholar,17.Parving H.H. Brenner B.M. McMurray J.J. et al.Cardiorenal end points in a trial of aliskiren for type 2 diabetes.N Engl J Med. 2012; 367: 2204-2213Crossref PubMed Scopus (987) Google Scholar Overall, observations evolving over the past few years have made selection of appropriate BP targets and use of RAAS blockade a complicated issue for the average clinician. In this review, we attempt to delineate past major studies and recent developments in these fields by analyzing available clinical evidence for the different types of individuals with CKD. Two clinical trials with hard renal end points have evaluated different BP targets in patients with nondiabetic CKD: the Modification of Diet in Renal Disease (MDRD) and the African-American Study on Kidney Disease (AASK). MDRD included two studies in patients with CKD (585 patients in study A (glomerular filtration rate (GFR) 25–55ml/min per 1.73m2) and 255 in study B (GFR 13–24ml/min per 1.73m2)) with the rate of change in GFR (GFR slope) as primary outcome, and a mean follow-up of 2.2 years.18.Klahr S. Levey A.S. Beck G.J. et al.The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group.N Engl J Med. 1994; 330: 877-884Crossref PubMed Scopus (2051) Google Scholar Diabetic patients on insulin treatment were excluded by protocol; thus, only 26 patients with diabetic nephropathy participated. In a 2 × 2 factorial design, patients were randomized to different levels of dietary protein intake and to a usual-BP goal (mean arterial pressure <107mmHg for patients ≤60 years old (roughly corresponding to <140/90mmHg) and <113mmHg for patients ≥61 years old) or a low goal (mean arterial pressure <92mmHg for patients ≤60 years old (corresponding to <125/75mmHg) and 0.25g/day in study A and >1g/day in study B (Figure 1), and the results were not substantially altered after adjustment for 10 relevant covariates.18.Klahr S. Levey A.S. Beck G.J. et al.The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group.N Engl J Med. 1994; 330: 877-884Crossref PubMed Scopus (2051) Google Scholar,19.Peterson J.C. Adler S. Burkart J.M. et al.Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study.Ann Intern Med. 1995; 123: 754-762Crossref PubMed Scopus (1228) Google Scholar These findings indicated that a low target BP may be beneficial in proteinuric patients and was the basis of previous recommendations for BP <130/80mmHg in patients with CKD and 1g/day.5.Kidney Disease Outcomes Quality Initiative (K/DOQI) K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.Am J Kidney Dis. 2004; 43: 1-290PubMed Google Scholar,7.Chobanian A.V. Bakris G.L. Black H.R. et al.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: 2560-2572Crossref PubMed Scopus (16541) Google Scholar, 8.Mancia G. De B.G. Dominiczak A. et al.2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).J Hypertens. 2007; 25: 1105-1187Crossref PubMed Scopus (4841) Google Scholar, 9.American Diabetes Association Standards of medical care in diabetes—2010.Diabetes Care. 2010; 33: S11-S61Crossref PubMed Scopus (3000) Google Scholar A patient-level meta-analysis of trials on antihypertensive treatment with or without ACEIs in predominantly nondiabetic CKD confirmed the above: in patients with proteinuria >1g/day, levels of systolic blood pressure (SBP) between 110 and 119mmHg were associated with similar risk of CKD progression with levels between 120 and 129mmHg and significantly lower risk compared with SBP ≥130mmHg; in contrast, in patients with proteinuria 1g/day. The P-value for interaction of target BP with proteinuria was 0.09 for ESRD and 0.08 for the composite outcome.21.Sarnak M.J. Greene T. Wang X. et al.The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study.Ann Intern Med. 2005; 142: 342-351Crossref PubMed Scopus (431) Google Scholar AASK included 1094 African Americans with hypertensive CKD (GFR 20–65ml/min per 1.73m2, mean proteinuria 0.6g/day) randomized to goal mean arterial pressure 102–107 or ≤92mmHg, and to initial treatment with metoprolol, ramipril, or amlodipine in a 3 × 2 factorial design. The main outcomes were GFR slope and a composite of GFR reduction ≥50% (or ≥25ml/min per 1.73m2), ESRD, or death. The mean achieved BP was 128/78mmHg in the low-BP group and 141/85 in the usual-BP group. After a median of 3.8 years, neither GFR slope (-2.21±0.17 vs. -1.95±0.17ml/min per 1.73m2 per year; P=0.24) nor the composite outcome (risk reduction for low-BP group 2%; 95% CI: -22 to 21%) differed significantly between groups.22.Wright Jr., J.T. Bakris G. Greene T. et al.Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.JAMA. 2002; 288: 2421-2431Crossref PubMed Scopus (1629) Google Scholar After the trial phase, ∼700 subjects were enrolled in an observational phase with a total follow-up of 8.8–12.2 years; target BP during the cohort phase was 0.22 (both measured in 24-h urine collections and expressed in mg/dl), which roughly equals a proteinuria of 320mg/day, had lower risk of the primary outcome with intensive treatment (HR 0.73; 95% CI: 0.58–0.93; Figure 2). In those with urine protein-to-creatinine ratio of ≤0.22, there was no between-group difference (HR 1.18; 95% CI: 0.93–1.50).23.Appel L.J. Wright Jr., J.T. Greene T. et al.Intensive blood-pressure control in hypertensive chronic kidney disease.N Engl J Med. 2010; 363: 918-929Crossref PubMed Scopus (437) Google Scholar Taken together, the findings from MDRD and AASK indicate that a low-BP target is beneficial for long-term renal survival in patients with nondiabetic kidney disease and proteinuria >0.25–0.3g/day (equivalent to urinary albumin excretion (UAE) of ∼0.15g/day). Thus, a goal BP of 0.3g/day, whereas a lower BP target of 1g/day (Table 1). It must be noted, however, that all available evidence derives from subgroup analyses or from combination of randomized phases with long-term observational follow-up phases and, still, no direct evidence from randomized trials on the effect of different BP targets on hard renal end points in proteinuric or nonproteinuric populations is available. Furthermore, both trials randomized to mean arterial pressure levels that correspond on average, but not for every patient, to specific levels of SBP and diastolic BP (DBP).Table 1Possible blood pressure targets for patients with kidney disease according to available evidence from trials with renal and/or cardiovascular primary end pointsProtein excretion <0.3g/day (albumin excretion 1g/day (albumin excretion >500mg/day)Nondiabetic CKD<140/90mmHg<130/80mmHg<125/75mmHgaAs evident from Modification of Diet in Renal Disease (MDRD) study B trial phase and MDRD long-term study.Diabetic CKDSBP <130–140mmHgbFrom cardiovascular outcome trials.DBP <80mmHgbFrom cardiovascular outcome trials.<130/80mmHgcFollowing extrapolation of data from non-diabetic CKD studies and post hoc or observational analyses in diabetic CKD.<130/80mmHgcFollowing extrapolation of data from non-diabetic CKD studies and post hoc or observational analyses in diabetic CKD.(<125/75mmHgcFollowing extrapolation of data from non-diabetic CKD studies and post hoc or observational analyses in diabetic CKD. for young patients with heavy proteinuria)Abbreviations: CKD, chronic kidney disease; DBP, diastolic blood pressure; SBP, systolic blood pressure.a As evident from Modification of Diet in Renal Disease (MDRD) study B trial phase and MDRD long-term study.b From cardiovascular outcome trials.c Following extrapolation of data from non-diabetic CKD studies and post hoc or observational analyses in diabetic CKD. Open table in a new tab Abbreviations: CKD, chronic kidney disease; DBP, diastolic blood pressure; SBP, systolic blood pressure. To date, clinical trials with hard renal outcomes randomizing at different target BP in patients with diabetes are missing. Earlier studies in diabetic patients with varying levels of renal function and albumin excretion compared different BP goals with change in creatinine clearance (CrCl) as a primary outcome; they showed no difference in CrCl change between groups with ‘intensive’ or ‘moderate’ BP control but higher reductions of proteinuria and slower progression from micro- to macroalbuminuria with ‘intensive’ BP.24.Lewis J.B. Berl T. Bain R.P. et al.Effect of intensive blood pressure control on the course of type 1 diabetic nephropathy. Collaborative Study Group.Am J Kidney Dis. 1999; 34: 809-817Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar,25.Schrier R.W. Estacio R.O. Esler A. et al.Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes.Kidney Int. 2002; 61: 1086-1097Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar Another report showed no difference in CrCl or proteinuria progression between ‘intensive’ and ‘standard’ BP reduction.14.Estacio R.O. Jeffers B.W. Gifford N. et al.Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes.Diabetes Care. 2000; 23: B54-B64PubMed Google Scholar An analysis of mean achieved SBP versus estimated GFR (eGFR) decline in controlled trials of diabetic CKD suggested that lowering SBP down to 130mmHg may be associated with reduction of eGFR loss down to 2ml/min per 1.73m2 per year.5.Kidney Disease Outcomes Quality Initiative (K/DOQI) K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.Am J Kidney Dis. 2004; 43: 1-290PubMed Google Scholar A post hoc analysis of the RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study, which included 1513 patients with type 2 diabetes, hypertension, and macroalbuminuria (mean SCr 1.9mg/dl and median albumin-to-creatinine ratio (ACR) 1237mg/g) and compared the effects of losartan or placebo on CKD progression, showed that baseline SBP of 140–159mmHg increased the risk for ESRD or death by 38% (P=0.05) as compared with SBP 900mg/day, to compare the effects of irbesartan, amlodipine; and placebo) showed that SBP >149mmHg was associated with a 2.2-fold increase in the risk for doubling SCr or ESRD compared with SBP 1g/day), the above BP targets for nondiabetic CKD should apply.5.Kidney Disease Outcomes Quality Initiative (K/DOQI) K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.Am J Kidney Dis. 2004; 43: 1-290PubMed Google Scholar This argument is difficult to dispute, but the National Health and Nutrition Examination Survey (NHANES) 1999–2000 in the United States suggest that the prevalence of macroalbuminuria (ACR ≥300mg/g, equivalent to proteinuria >0.5g/day) in adult patients with diabetes is only ∼10%, whereas another 20% have microalbuminuria (ACR 30–300mg/g), and 70% normoalbuminuria. Simultaneously, ∼11% of diabetics (rising to 26% of diabetics >65 years old) have eGFR <60ml/min per 1.73m2.28.Coresh J. Byrd-Holt D. Astor B.C. et al.Chronic kidney disease awareness, prevalence, and trends among US adults, 1999 to 2000.J Am Soc Nephrol. 2005; 16: 180-188Crossref PubMed Scopus (690) Google Scholar Thus, an important proportion of diabetic patients (especially the elderly type 2 with concomitant hypertension) have CKD stage 3 or higher without proteinuria. For these individuals, BP <130/80mmHg may not be required for renoprotection. However, a lower BP target could also be warranted for cardioprotection and benefits in mortality, as discussed below. All clinical practice guidelines in previous decade recommended target BP <130/80mmHg for diabetic patients. The first evidence pointing toward that target derived from the UK Prospective Diabetes Study (UKPDS) 38 and Hypertension Optimal Treatment (HOT) trials.29.UK Prospective Diabetes Study Group Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38.BMJ. 1998; 317: 703-713Crossref PubMed Scopus (0) Google Scholar,30.Hansson L. Zanchetti A. Carruthers S.G. et al.Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group.Lancet. 1998; 351: 1755-1762Abstract Full Text Full Text PDF PubMed Scopus (5425) Google Scholar In UKPDS 38, 1148 hypertensive type 2 diabetic patients were randomized to BP of <150/85 or <180/105mmHg (and achieved mean BP values of 144/82 and 154/87 during 8.4 years); the ‘tight control’ group had significant reductions in diabetes-related deaths and complications.29.UK Prospective Diabetes Study Group Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38.BMJ. 1998; 317: 703-713Crossref PubMed Scopus (0) Google Scholar The HOT study randomized 18,790 hypertensives to DBP targets of ≤90, ≤85, or ≤80mmHg; no difference between groups was observed for the total study population, but a 51% reduction in cardiovascular events between the ≤80 and ≤90mmHg target was evident for the subgroup of 1501 diabetic patients.30.Hansson L. Zanchetti A. Carruthers S.G. et al.Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group.Lancet. 1998; 351: 1755-1762Abstract Full Text Full Text PDF PubMed Scopus (5425) Google Scholar The problem in recommending the <130/80mmHg target in diabetes was that of SBP. Observational data supported that SBP <130mmHg would confer cardiovascular benefits31.Adler A.I. Stratton I.M. Neil H.A. et al.Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study.BMJ. 2000; 321: 412-419Crossref PubMed Scopus (1706) Google Scholar but the ‘tight’ control arms in UKPDS and HOT achieved mean SBP values of 144 and 141mmHg.29.UK Prospective Diabetes Study Group Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38.BMJ. 1998; 317: 703-713Crossref PubMed Scopus (0) Google Scholar,30.Hansson L. Zanchetti A. Carruthers S.G. et al.Eff
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