I

D2thlmmaapsddta7iphdac

liSocrbLprmdccmet

w

A

N THE LITERATURE

Blood Pressure Control in Type 2 Diabetes MellitusCommentary on ACCORD Study Group. Effects of intensive blood-pressure control in type 2

diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585.

mbcfimmmrBHvtebesTrcg(fp(s0ss

istnt0i

0

Sog

E

iabetes mellitus is among the developedworld’s most important diseases, affecting

3.6 million adults in the United States and morehan 171 million adults worldwide,1 most of whomave type 2 diabetes. Cardiovascular disease is theeading cause of death in persons with diabetesellitus.2 Because 75% of persons with diabetesellitus have systemic hypertension, which is alsomajor cardiovascular risk factor, a high level of

ttention to blood pressure (BP) control in thisopulation is essential. Treatment with antihyperten-ive agents in persons with type 2 diabetes hasecreased the risk of cardiovascular events andeath,3-5 and the Seventh Report of the Joint Na-ional Committee on Prevention, Detection, Evalu-tion, and Treatment of High Blood Pressure (JNC) recommends targeting BPs to �130/80 mm Hgn persons with diabetes.6 However, evidence sup-orting the 130/80 mm Hg target is scant. Of theandful of randomized trials in patients with type 2iabetes and hypertension,3,4,7 no prior trial haschieved average BPs �130/80 mm Hg, and trialonclusions have been mixed.

WHAT DOES THIS IMPORTANTSTUDY SHOW?

The ACCORD (Action to Control Cardiovascu-ar Risk in Diabetes) trial randomly assigned 10,251ndividuals from 77 clinical sites in the Unitedtates and Canada with type 2 diabetes at high riskf cardiovascular events to intensive or standard gly-emic therapy.8 Of these participants, 5,518 wereandomly assigned to receive simvastatin plus fenofi-rate or simvastatin plus placebo (the ACCORDipid trial),9 whereas the remaining 4,733 partici-ants were enrolled in the ACCORD BP trial10 andandomly assigned to a target systolic BP �120m Hg (intensive therapy) or �140 mm Hg (stan-

ard therapy). According to the study design, anyurrently available antihypertensive drug regimenould be used to achieve the target BPs. The pri-ary outcome for all 3 studies was the composite

nd point of nonfatal myocardial infarction, nonfa-al stroke, or cardiovascular death.

The ACCORD BP trial excluded participants

ith a serum creatinine concentration �1.5

merican Journal of Kidney Diseases, Vol 56, No 6 (December), 2

g/dL or protein excretion �1.0 g/24 h. Meanaseline serum creatinine level was 0.9 mg/dL,orresponding to a mean estimated glomerularltration rate (eGFR) of 91.6 � 28.8 mL/min/1.732; �15% of participants had an eGFR �60L/min/1.73 m2. Median baseline urinary albu-in-creatinine ratio was 14.3 mg/g (interquartile

ange, 6.9-44.8). By 4 months, average systolicP in the intensive-therapy group was 119.3 mmg (95% confidence interval [CI], 118.9-119.7)ersus 133.5 mm Hg (95% CI, 133.1-133.8) inhe standard-therapy group. An average differ-nce in diastolic BP of 6.1 mm Hg was observedetween the 2 groups. Similar intergroup differ-nces were maintained for the duration of thetudy, which had a mean follow-up of 4.7 years.he primary outcome was observed at an annual

ate of 1.87% in the intensive-therapy groupompared with 2.09% in the standard-therapyroup, corresponding to a hazard ratio of 0.8895% CI, 0.73-1.06; P � 0.20). The hazard ratioor total stroke (a prespecified secondary endoint) favored intensive over standard therapy0.59; 95% CI, 0.39-0.89), but overall rates oftroke were low in both groups (0.32% and.53% per year, respectively). There were noignificant differences in the other prespecifiedecondary outcomes, including all-cause death.

Although overall rates were low, participantsn the intensive-therapy group experienced moreerious adverse events (events that were life-hreatening, resulted in permanent disability, orecessitated hospitalization) than participants inhe standard-therapy group (3.3% vs 1.3%; P �.001). In terms of adverse kidney outcomes, thentensive-therapy group had a higher proportion of

Originally published online as doi:10.1053/j.ajkd.2010.8.007 on September 27, 2010.Address correspondence to Glenn M. Chertow, MD, MPH,

tanford University School of Medicine, Division of Nephrol-gy, 780 Welch Rd, Ste 106, Palo Alto, CA 94304. E-mail:chertow@stanford.edu© 2010 by the National Kidney Foundation, Inc. Published by

lsevier Inc. All rights reserved.0272-6386/10/5606-0004$36.00/0

doi:10.1053/j.ajkd.2010.08.007

010: pp 1029-1031 1029

ppftw�wrg

rnsittdTt(iB(twdImmtsv

vB(rdo1tm2rklp

aimiO1d1cH

weotcsBpsastjArwswJert�

srspefCitLI

Chang, Cheung, and Chertow1030

articipants with eGFR �30 mL/min/1.73 m2 com-ared with the standard-therapy group at the end ofollow-up (4.2% vs 2.2%; P � 0.001). However,he intensive-therapy group had fewer participantsith macroalbuminuria (albumin-creatinine ratio300 mg/g; 6.6% vs 9.7%; P � 0.009), and thereere no differences in the incidence of end-stage

enal disease or need for dialysis between the 2roups (2.5% vs 2.4%; P � 0.93).

HOW DOES THIS STUDY COMPARE WITHPRIOR STUDIES?

BP control in trials of nondiabetic participantsecently has been reviewed in the American Jour-al of Kidney Diseases.11 Directly comparing re-ults from theACCORD BPtrial with other random-zed trials of hypertension control in patients withype 2 diabetes is challenging given differences inargeted and achieved BPs, study protocols, andefinitions of primary and secondary outcomes.he ACCORD BP trial is the only randomized trial

o focus exclusively on systolic BP and to targetand achieve) the lowest BPs to date. The trial inndividuals with diabetes mellitus with achievedPs closest to the ACCORD BP trial is the ABCD

Appropriate Blood Pressure Control in Diabetes)rial, which randomly assigned 470 participantsith type 2 diabetes and hypertension to a goaliastolic BP �75 mm Hg versus 80-89 mm Hg.12

n theABCD trial, mean achieved BPs were 132/78m Hg in the intensive-therapy group and 138/86m Hg in the standard-therapy groups. Similar to

he results of the ACCORD BP trial, there were notatistically significant differences in risk of cardio-ascular events after 5 years of follow-up.

Other previous studies of type 2 diabetes hadastly different BP targets from the ACCORDP trial and yielded different results. The UKPDS

United Kingdom Prospective Diabetes Study)4

andomly assigned 1,148 individuals with type 2iabetes and hypertension to target BPs �150/85r �180/105 mm Hg and achieved mean BPs of44/82 and 154/87 mm Hg, respectively. In con-rast to the ACCORD BP trial, participants in theore intensive-therapy group in the UKPDS had a

4% (95% CI, 8-38) lower risk of any diabetes-elated macrovascular or microvascular (includingidney) event compared with participants in theess intensive-therapy group. However, only partici-

ants in the more intensive-therapy group were D

llowed to receive angiotensin-converting enzymenhibitors or �-blockers by study protocol, which

ight have conferred additional benefit to the morentensive-therapy group. In the HOT (Hypertensionptimal Treatment) study,3 subgroup analysis of,501 diabetic participants randomly assigned to aiastolic BP goal �90 mm Hg (mean achieved BP,44/85 mm Hg) had a 2-fold higher risk of majorardiovascular events compared with the �80–mmg group (mean achieved BP, 140/81 mm Hg).

WHAT SHOULD CLINICIANS ANDRESEARCHERS DO?

The ACCORD BP trial showed that participantsith type 2 diabetes at high risk of cardiovascular

vents did not have a significant decrease in the riskf composite cardiovascular events with target sys-olic BP �120 mm Hg (which is lower than theurrent JNC 7 guidelines) versus 140 mm Hg, but aignificant decrease in risk of stroke was observed.ased on observed absolute risk differences, 476atients per year would need to be treated to aystolic BP �120 mm Hg to prevent 1 stroke, butfter treating only 49 patients to this target, 1erious adverse event would be expected. Whetherhe benefit warrants the risk is up to the clinicaludgment of the individual practitioner. TheCCORD BP trial does not support or refute cur-

ent recommended systolic BP targets in patientsith type 2 diabetes of �130 mm Hg because the

tudy (initiated before publication of the JNC 7)as not designed to test the appropriateness of the

NC 7 BP target. However, given the low overallvent rates in the ACCORD BP trial in eitherandomly assigned group, along with results fromhe HOT study,3 targeting systolic BP to at least

140 mm Hg seems justified.Current clinical practice guidelines for per-

ons with chronic kidney disease (CKD) alsoecommend target BPs �130/80 mm Hg, withtronger evidence for slowing kidney diseaserogression than decreasing cardiovascular dis-ase risk.11,13 The uncertainty surrounding theundamental issue of BP control in persons withKD emphasizes the importance of the upcom-

ng SPRINT (Systolic Blood Pressure Interven-ion Trial), sponsored by the National Heart,ung, and Blood Institute (NHLBI), the National

nstitute of Diabetes and Digestive and Kidney

iseases (NIDDK), the National Institute of Neu-

rNah9cvi

(�reopSuotwviswiof

e

ifttC

Ffi

n

ops1

pl1

fivdt

HoHtoE7

GpwN

i2

t3

p2

vD

Ecd

tipM

cw

In the Literature 1031

ological Disorders and Stroke (NINDS), and theational Institute on Aging (NIA).14 SPRINT

nd SPRINT-Senior (a substudy of the elderlyypertensive population) will randomly assign,250 nondiabetic hypertensive adults at risk ofardiovascular disease to systolic BP targets �120ersus �140 mm Hg and determine the effect onncident cardiovascular events and dementia.

Importantly, SPRINT plans to enroll 4,30045%) individuals with moderate CKD (eGFR60 mL/min/1.73 m2), making it the largest

andomized trial of BP control on cardiovascularvents in patients with CKD. A main secondaryutcome for the CKD subgroup in SPRINT isrogression of kidney disease. Results fromPRINT, which will follow up participants forp to 6 years, will help inform our managementf hypertension, particularly in CKD subpopula-ions. At present, we can only speculate abouthether the results of SPRINT in nondiabetic indi-iduals will mirror those of the ACCORD BP trialn diabetic patients or tell a completely differenttory. Until then, clinicians will have to carefullyeigh the perceived risks and benefits of BP targets

n patients with and without diabetes, CKD, orther comorbid conditions while waiting for resultsrom future studies to guide practice.

Tara I. Chang, MD, MSStanford University School of Medicine

Palo Alto, California

Alfred K. Cheung, MDVeterans Affairs Salt Lake City Healthcare

SystemUniversity of Utah

Salt Lake City, Utah

Glenn M. Chertow, MD, MPHStanford University School of Medicine

Palo Alto, California

ACKNOWLEDGEMENTSDrs Cheung and Chertow are SPRINT investigators. The gen-

ral design of SPRINT and SPRINT-Senior are subject to change.Financial Disclosure: Because Dr Cheung is a SPRINT

nvestigator, his institution receives grants/grants pendingrom NHLBI. Because Dr Chertow is a SPRINT investiga-or, his institution receives grants/grants pending from NHLBIhrough a subcontract from the University of Utah. Dr

hang declares that she has no relevant financial interests. M

REFERENCES1. World Health Organization. Diabetes Programme,

acts and Figures. http://www.who.int/diabetes/facts/world_gures/en/. Accessed May 20, 2010.2. National diabetes statistics. 2007. http://diabetes.niddk.

ih.gov/dm/pubs/statistics/index.htm. Accessed May 20, 2010.3. Hansson L, Zanchetti A, Carruthers SG, et al. Effects

f intensive blood-pressure lowering and low-dose aspirin inatients with hypertension: principal results of the Hyperten-ion Optimal Treatment (HOT) randomised trial. Lancet.998;351(9118):1755-1762.4. UK Prospective Diabetes Study Group. Tight blood

ressure control and risk of macrovascular and microvascu-ar complications in type 2 diabetes: UKPDS 38. BMJ.998;317(7160):703-713.5. Patel A; ADVANCE Collaborative Group. Effects of a

xed combination of perindopril and indapamide on macro-ascular and microvascular outcomes in patients with type 2iabetes mellitus (the ADVANCE trial): a randomised con-rolled trial. Lancet. 2007;370(9590):829-840.

6. Chobanian AV, Bakris GL, Black HR, et al; Nationaleart, Lung, and Blood Institute Joint National Committeen Prevention, Detection, Evaluation, and Treatment ofigh Blood Pressure; National High Blood Pressure Educa-

ion Program Coordinating Committee. The Seventh Reportf the Joint National Committee on Prevention, Detection,valuation, and Treatment of High Blood Pressure: the JNCreport. JAMA. 2003;289(19):2560-2572.7. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL,

ifford N, Schrier RW. The effect of nisoldipine as com-ared with enalapril on cardiovascular outcomes in patientsith non-insulin-dependent diabetes and hypertension.Engl J Med. 1998;338(10):645-652.8. Dluhy RG, McMahon GT. Intensive glycemic control

n the ACCORD and ADVANCE trials. N Engl J Med.008;358(24):2630-2633.9. ACCORD Study Group. Effects of combination lipid

herapy in type 2 diabetes mellitus. N Engl J Med. 2010;62(17):1563-1574.10. ACCORD Study Group. Effects of intensive blood-

ressure control in type 2 diabetes mellitus. N Engl J Med.010;362(17):1575-1585.11. Shastri S, Sarnak MJ. Blood pressure target in indi-

iduals without diabetes: what is the evidence? Am J Kidneyis. 2010;56(3):434-438.12. Estacio RO, Jeffers BW, Gifford N, Schrier RW.

ffect of blood pressure control on diabetic microvascularomplications in patients with hypertension and type 2iabetes. Diabetes Care. 2000;23(suppl 2):B54-64.13. National Kidney Foundation. K/DOQI Clinical Prac-

ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease. 2004. http://www.kidney.org/rofessionals/KDOQI/guidelines_bp/index.htm. Accesseday 25, 2010.14. National Institutes of Health. NIH launches multi-

enter clinical trial to test blood pressure strategy. http://ww.nih.gov/news/health/oct2009/nhlbi-29.htm. Accessed

ay 20, 2010.