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n engl j med 362;16 nejm.org april 22, 2010 147

original article

Effect of Valsartan on the Incidenceof Diabetes and Cardiovascular Events

The NAVIGATOR Study Group*

The authors are listed in the AppendiAddress reprint requests to Dr. RobeM. Califf at the Duke Translational Medcine Institute, P.O. Box 17969, DurhamNC 27715, or at [email protected].

*The names of the investigators anmembers of the committees in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Researc(NAVIGATOR) Study Group are listed iSupplementary Appendix 1, available witthe full text of this article at NEJM.org

This article (10.1056/NEJMoa1001121) wapublished on March 14, 2010, and was lasupdated on March 29, 2010, at NEJM.org.

N Engl J Med 2010;362:1477-90.Copyright 2010 Massachusetts Medical Society.

A b s t ra c t

Background

It is not known whether drugs that block the reninangiotensin system reduce the riskof diabetes and cardiovascular events in patients with impaired glucose tolerance.

Methods

In this double-blind, randomized clinical trial with a 2-by-2 factorial design, weassigned 9306 patients with impaired glucose tolerance and established cardiovas-cular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily)or placebo (and nateglinide or placebo) in addition to lifestyle modification. We thenfollowed the patients for a median of 5.0 years for the development of diabetes (6.5years for vital status). We studied the effects of valsartan on the occurrence of threecoprimary outcomes: the development of diabetes; an extended composite outcomeof death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke,hospitalization for heart failure, arterial revascularization, or hospitalization forunstable angina; and a core composite outcome that excluded unstable angina andrevascularization.

Results

The cumulative incidence of diabetes was 33.1% in the valsartan group, as com-pared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86;95% confidence interval [CI], 0.80 to 0.92; P


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Th e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 362;16 nejm.org april 22, 20101478

Patients with impaired glucose tol-erance have an increased risk of type 2 dia-betes mellitus and cardiovascular disease.1-3Interventions that might reduce the incidence ofdiabetes and associated rates of death and com-plications from cardiovascular causes in such pa-tients are therefore of importance.3 Several trials

have shown that lifestyle modification, includingincreased physical activity and weight loss, re-duces the risk of diabetes, although these trialsdid not evaluate cardiovascular outcomes.3-8 Cer-tain drugs, including metformin, acarbose, androsiglitazone, also reduce the incidence of diabe-tes, although their effect on cardiovascular eventsis uncertain.6,9,10

Another pharmacologic approach to reducingthe risk of diabetes and cardiovascular disease isinhibition of the reninangiotensin system. Somestudies have shown that angiotensin-converting

enzyme (ACE) inhibitors and angiotensin-receptorblockers (ARBs) may reduce the incidence of dia-betes and the risk of cardiovascular events amongpatients with hypertension and other cardiovas-cular diseases.11-14 In most of these studies, how-ever, the incidence of diabetes was not the pri-mary outcome of the trial, nor was it confirmedby systematic glucose measurement.15

A single trial, the Diabetes Reduction Assess-ment with Ramipril and Rosiglitazone Medica-tion (DREAM) study (ClinicalTrials.gov number,NCT00095654), attempted to prospectively androbustly ascertain the effect of an ACE inhibitorin a population at high risk for diabetes, althoughthe study did not test this treatment in additionto lifestyle modification and was not powered toevaluate cardiovascular outcomes.16 Ramipril didnot reduce the incidence of diabetes, althoughplasma glucose levels measured 2 hours after anoral glucose load were significantly lower in theramipril group.16

We conducted a large, prospective trial, calledNateglinide and Valsartan in Impaired Glucose

Tolerance Outcomes Research (NAVIGATOR), toevaluate whether nateglinide, a blood glucoselowering drug in the meglitinide class, or valsar-tan, an ARB, would reduce the risk of diabetes andcardiovascular events among patients with im-paired glucose tolerance and established cardio-vascular disease or cardiovascular risk factors.This treatment was tested in addition to lifestyle

modification.17 Here we report the results of thevalsartan portion of the study; the results of thenateglinide portion are discussed elsewhere in thisissue of the Journal.18

Methods

Study Patients

From January 2002 through January 2004, we re-cruited patients at 806 centers in 40 countries. Alleligible patients had impaired glucose tolerance,3a fasting plasma glucose level of at least 95 mg perdeciliter (5.3 mmol per liter) but less than 126 mgper deciliter (7.0 mmol per liter), and one or morecardiovascular risk factors (if 55 years of age orolder) or known cardiovascular disease (if 50 yearsof age or older). A screening glucose-tolerancetest was performed 2 hours after a 75-g oral glu-cose load to determine study eligibility. Impaired

glucose tolerance was defined as a post-load plas-ma glucose level of at least 140 mg per deciliter(7.8 mmol per liter) but less than 200 mg per deci-liter (11.1 mmol per liter).3 (For details, see Sec-tion 2 in Supplementary Appendix 1, available withthe full text of this article at NEJM.org.)

Exclusion criteria were laboratory abnormali-ties or conditions that could interfere with as-sessment of the safety or eff icacy of a study drug,the use of an ACE inhibitor or ARB for the treat-ment of hypertension (although ACE inhibitorswere allowed for other indications), and the useof an antidiabetic medication within the previous5 years.17

The trial was approved by each centers ethicscommittee. All patients provided written informedconsent.

Study Treatment

We used a computerized, interactive voice-responsetelephone randomization system involving con-cealed study-group assignments to randomly as-sign patients to valsartan or matching placebo (and

nateglinide or matching placebo) in a 2-by-2 fac-torial design. Randomization was stratified ac-cording to center, with a block size of eight with-in each center. Valsartan was started at a dose of80 mg once daily, with an increase after 2 weeksto 160 mg once daily; dose reduction or interrup-tion because of adverse events or for other clini-cal reasons was permitted.

Downloaded from www.nejm.org on June 1, 2010 . Copyright 2010 Massachusetts Medical Society. All rights reserved.


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Effect of Valsartan on Diabetes and Cardiovascular Events


Lifestyle Modification

All patients were required to participate in a study-specific lifestyle-intervention program that wasdesigned to reduce the risk of diabetes. The ob-jective of the intervention was to help patientsachieve and maintain a 5% weight loss, reduceintake of saturated and total dietary fat, and in-

crease physical activity to 150 minutes weekly (seeSection 3 in Supplementary Appendix 1). Site per-sonnel were trained to administer this programand provided materials designed to facilitate adher-ence at each clinic visit, with reinforcement andmonitoring by telephone between study visits.

Study Procedures

After the dose-adjustment phase, patients wereseen every 6 months. Fasting plasma glucose lev-els were measured every 6 months for the first3 years and then annually. Oral glucose tolerance

tests were performed yearly. The morning dose ofa study drug was delayed until after glucose levelshad been measured.

Study Outcomes

Coprimary Outcomes

Initially, there were two coprimary outcomes: theincidence of diabetes and an extended cardiovas-cular outcome, a composite of death from cardio-vascular causes, nonfatal myocardial infarction,nonfatal stroke, hospitalization for heart failure,arterial revascularization, or hospitalization forunstable angina. A third coprimary core cardio-vascular outcome (a composite of death from car-diovascular causes, nonfatal myocardial infarction,nonfatal stroke, and hospitalization for heart fail-ure), which was initially a secondary compositeoutcome, was added, as described previously.17,19

Incidence of Diabetes

Diabetes was defined as a fasting plasma glucoselevel of 126 mg per deciliter (7.0 mmol per liter)or more or a plasma glucose level of 200 mg per

deciliter (11.1 mmol per liter) or more as mea-sured 2 hours after an oral glucose load,20,21 con-firmed within 12 weeks by a glucose tolerancetest. The date of onset of diabetes was defined asthe date of the first diagnostic glucose value. Anindependent committee whose members were notaware of study-group assignments adjudicated thesmall number of cases in which patients receiveda diagnosis of diabetes or were started on an an-

tidiabetic drug without undergoing the study-specified laboratory investigations.

Death, Hospitalization, and Other Cardiovascular

Events

An independent committee whose members wereunaware of study-group assignments adjudicated

the occurrence of death, hospitalization, and po-tential cardiovascular events that occurred in pa-tients who were not hospitalized (for definitionsof these events, see Section 4 in Supplementary Ap-pendix 1).

Study Oversight

The trial was sponsored by Novartis Pharma andwas designed in collaboration with an academicexecutive committee and monitored by an inde-pendent safety committee.17 Data were collected,managed, and analyzed by the sponsor, with over-

sight from the executive committee, and the analy-ses were replicated by an independent academicstatistician. The manuscript was prepared by awriting group, whose members had unrestrictedaccess to the data, and was subsequently revisedby all the authors. All authors decided to submitthe manuscript for publication and assume re-sponsibility for its accuracy and completeness.The trial protocol is available in SupplementaryAppendix 2.

Statistical Analysis

On the assumption that the study would continueuntil the extended cardiovascular outcome oc-curred in 1374 patients in the two study groupscombined, we anticipated a power of 90% to de-tect a 20% reduction in the hazard rate in the val-sartan group, assuming subadditivity of the effectsof valsartan and nateglinide and allowing for anannual discontinuation rate of 6.9%.17 These calcu-lations were revised after an updated meta-analysisof trials of reninangiotensin blockers suggestingthat the reduction in the hazard of the extended

cardiovascular outcome was more likely to be 12%(providing a power of 64%) and 18% for the corecardiovascular outcome (providing a power of 74%,assuming the occurrence of 784 core events); theestimated power to show a reduction in at leastone of the cardiovascular outcomes was 77%.17,19

While accumulating 1374 extended cardiovas-cular events, we anticipated that more than 3000patients would have progression to diabetes, en-



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suring a power of more than 99% to detect a haz-ard reduction of 18%. Because we examined theeffects of two drugs (valsartan and nateglinide)on three primary outcomes in a factorial manner,we adjusted for the three tests that were performedfor each study drug (but not across drugs). Two-sided P values are given, with protocol-specified

one-sided values for the coprimary outcomes andtheir components. The one-sided familywise type Ierror rate of 2.5% for each drug was controlledwith the use of a closed-testing procedure, withone fifth of the alpha assigned to diabetes andfour fifths to the two cardiovascular outcomes,since more cases of incident diabetes than cardio-vascular events were anticipated. This allowed fortesting of each primary outcome even if the othertwo outcomes did not show a significant result.An OBrienFlemingtype alpha spending ap-proach accounted for the interim efficacy analy-

sis performed with 30% of the target number ofextended cardiovascular events (a one-sided alphaof 0.00004) in November 2005.22 (For details, seeSection 5 in Supplementary Appendix 1.)

Log-rank tests that were stratified accordingto a history of cardiovascular disease and nateg-linide treatment were used to compare the val-sartan and placebo groups for the time to a firstevent in the extended or core composite outcome.Given the fixed-time schedule for glucose mea-surement, a discrete time proportional-odds modelwas used for the incidence of diabetes. We alsoconducted predefined analyses of the componentsof the composite cardiovascular outcomes, timeto death from any cause, time to cardiovascular-related hospitalization, indexes of hyperglycemia,and body weight. The possibility of interactionbetween valsartan and nateglinide was tested foreach outcome reported. The effects of study treat-ment were evaluated in prespecified subgroups.17We compared baseline characteristics, safety, andother trial assessments using summary statistics.

Results

Study Patients

Of 43,502 patients who underwent screening,9518 were randomly assigned to treatment. Afterrandomization, 212 patients were excluded fromthe analysis, since 10 sites were closed because ofdeficiencies in meeting Good Clinical Practiceguidelines, which left 9306 patients who could beevaluated (Fig. 1).

Among patients who were taking a study drug

at 6 months, 91.1% of those who were assignedto receive valsartan were taking the higher dose(160 mg daily); this proportion was 94.6% in theplacebo group (P


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decline in weight during follow-up that was slight-ly less in the valsartan group (0.313.9 kg) thanin the placebo group (0.604.0 kg), a difference

of 0.28 kg (95% CI, 0.12 to 0.44; P


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Table 1. Baseline Characteristics of the Patients and Concomitant Use of Medications during Follow-up.*

CharacteristicValsartan(N = 4631)

Placebo(N = 4675) P Value

Age yr 63.76.8 63.86.8 0.27

Female sex no. (%) 2314 (50.0) 2397 (51.3) 0.29

Race no. (%)

White 3849 (83.1) 3885 (83.1) 0.96

Black 113 (2.4) 123 (2.6)

Asian 298 (6.4) 315 (6.7)

Other 371 (8.0) 352 (7.5)

Weight kg 83.517.4 83.817.1 0.38

Body-mass index 30.45.5 30.65.3 0.29

Waist circumference cm

All patients 10114 10114 0.36

Men 10413 10412

Women 9814 9814

Sitting blood pressure mm Hg

Systolic 139.417.8 139.917.1 0.21

Diastolic 82.510.4 82.610.1 0.93

Cardiovascular risk factors no. (%)

Any 4565 (98.6) 4621 (98.8) 0.26

Family history of premature heart disease 782 (16.9) 762 (16.3) 0.44

Current smoker 518 (11.2) 507 (10.8) 0.59

Hypertension 3581 (77.3) 3635 (77.8) 0.62

Left ventricular hypertrophy 133 (2.9) 135 (2.9) 0.97

Microalbuminuria 61 (1.3) 53 (1.1) 0.42

Reduced HDL cholesterol 459 (9.9) 433 (9.3) 0.28Elevated non-HDL cholesterol 2066 (44.6) 2097 (44.9) 0.82

History of cardiovascular disease no. (%)

Any 1148 (24.8) 1118 (23.9) 0.30

Myocardial infarction 552 (11.9) 541 (11.6) 0.60

Angina or positive stress test 416 (9.0) 400 (8.6) 0.47

Percutaneous coronary intervention 190 (4.1) 172 (3.7) 0.29

Multivessel coronary-artery bypass grafting 182 (3.9) 198 (4.2) 0.46

Intermittent claudication 42 (0.9) 56 (1.2) 0.17

Peripheral-artery stenosis 32 (0.7) 22 (0.5) 0.16

Lower-limb angioplasty or bypass surgery 61 (1.3) 49 (1.0) 0.24Nontraumatic leg or foot amputation 5 (0.1) 2 (


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Table 1. (Continued.)

CharacteristicValsartan(N = 4631)

Placebo(N = 4675) P Value

Lipids mg/dl

Total cholesterol 21042 21042 0.78

HDL cholesterol 5013 5013 0.67

LDL cholesterol 12637 12737 0.99

Triglycerides 175105 173103 0.25

Median 151 150

Interquartile range 109209 108209

Creatinine mg/dl 0.90.2 0.90.2 0.29

Estimated GFR

Mean ml/min/1.73 m2 80.918.5 80.419.0 0.20


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No interaction between valsartan and nategli-nide was observed for any of the outcomes de-scribed (Section 6 in Supplementary Appendix 1).

Study Outcomes

Coprimary Diabetes Outcome

Diabetes mellitus developed in 1532 patients(33.1%) in the valsartan group and 1722 patients(36.8%) in the placebo group (Table 2 and Fig. 3).The hazard ratio for this outcome in the valsar-tan group, as compared with the placebo group,was 0.86 (95% CI, 0.80 to 0.92; P


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Adverse Events and Discontinuation

of Study Drug

Nasopharyngitis, back pain, and arthralgia werethe most commonly reported individual adverseevents (for a complete list, see Section 8 in Supple-mentary Appendix 1). There was no excess of re-nal dysfunction or hyperkalemia in the valsartan

group, but hypotension-related adverse events weremore common in the valsartan group (occurringin 42.4% of patients) than in the placebo group(35.9%) (P


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Discussion

When added to lifestyle intervention, a single dai-

ly dose of valsartan (up to 160 mg) reduced therisk of diabetes but not of cardiovascular eventsin patients with impaired glucose tolerance andestablished cardiovascular disease or risk factors.The relative reduction of 14% in the risk of diabe-tes in the valsartan group would translate into 38fewer cases of diabetes per 1000 patients treatedfor 5 years, a reduction that was consistent acrossall subgroups that we examined.

The decline was smaller than that suggestedby pooled analyses of previous trials of ACE in-hibitors and ARBs, which suggested a risk reduc-

tion of 25 to 30%.11-15,25

However, these trialsdiffered from our study in that not all subjects hadimpaired glucose tolerance, ascertainment andother biases may have led to an overestimationof the effect of these drugs, and study treatmentdid not include lifestyle modification.26 In addi-tion, by the end of follow-up in our study, 24%of patients in the placebo group were taking anopen-label ACE inhibitor or ARB, and many pa-

Incidence

ofDiabetes(%)

50

40

30

10

20

00 1 2 3 4 65

Years since Randomization

C Core Cardiovascular Outcome

A Incidence of Diabetes

Hazard ratio, 0.86 (95% CI, 0.800.92)P


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tients in the valsartan group had discontinuedthe study treatment, which probably reduced theobserved effect of the drug.

Despite these factors, the effect of valsartanwas greater than that of an ACE inhibitor in theonly previous trial that had the development ofdiabetes or death as the prospectively defined pri-

mary outcome. In the DREAM study, there wasa nonsignif icant trend toward a reduction in theincidence of diabetes in the ramipril group, with449 patients who had diabetes in the ramiprilgroup, as compared with 489 in the placebo group(hazard ratio, 0.91; 95% CI, 0.80 to 1.03; P = 0.15),over a median follow-up period of 3 years.16 Themechanism by which inhibitors of the reninangiotensin system reduce the incidence of dia-betes is unknown.27-30

Although indirect comparisons can be mislead-ing, the effect of valsartan was smaller than that

of lifestyle modification, which reduced the in-cidence of diabetes by 58% in two trials.5,6 How-ever, in these two studies, the patient populationsdiffered from that in our study, and the study pe-riods were shorter. In addition, we tested the ef-fect of valsartan combined with lifestyle modifi-cation. The effect of valsartan was also smallerthan that of acarbose, metformin, or rosiglita-zone, medications that have a recognized glucose-lowering action, although none of these drugswere tested in addition to lifestyle modification orfor as long as valsartan.

There are several possible reasons that valsar-tan did not improve cardiovascular outcomes, asexpected. Our patients differed from those in pre-vious trials of reninangiotensin antagonists withcardiovascular outcomes in that all the patientshad impaired glucose tolerance, only a minority(24%) had established cardiovascular disease, andblood pressure was relatively well controlled. Thebenefit of reninangiotensin system blockade has

also been smaller in recent studies than observedhistorically, possibly because of greater use ofother risk-reducing therapies.14,31-33 The patientswith cardiovascular disease in our study were ex-tensively treated with such therapies, including anACE inhibitor in 22% of patients at baseline, andthe use of nonstudy therapies, including open-

label ACE inhibitors and ARBs, increased duringfollow-up. These factors, coupled with the discon-tinuation of valsartan in a substantial proportionof patients, may have diluted any potential benefitof valsartan. Furthermore, lifestyle modificationimproves cardiovascular risk factors34 and, in thelong term, may also reduce the rate of cardiovas-cular events.35 Finally, the most convincing evi-dence of improved cardiovascular outcomes withvalsartan comes from trials in which patients re-ceived twice the daily dose that we used.36,37

Although lifestyle modification should remain

the primary intervention to reduce the risk of dia-betes in the general population, our findings mayhave implications for the treatment of hyperten-sion, since the use of both thiazide diuretics andbeta-blockers has been associated with an in-creased risk of diabetes.27-29

In conclusion, when added to a lifestyle inter-vention, valsartan at a daily dose of 160 mg re-duced the risk of diabetes but did not affect car-diovascular outcomes in patients with impairedglucose tolerance. No safety concerns were iden-tified.

Supported by Novartis Pharma.Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org.We thank Teresa Gerlock, Lineke Zuurman, Patricia Kobi,

Christian Leisner, Georgios Foteinos, Annette Meier, VirginieMarconot, Debra Gordon, Stephanie Le Breton, Andrea Fabel, andStephanie Heiss of Novartis Pharma for their contributions; An-thony Doll of the Duke Clinical Research Institute (DCRI) for as-sistance with earlier versions of the figures; Tim Collier for theindependent statistical analysis; and Jonathan McCall, also of theDCRI, for assistance in the preparation of the manuscript.

Appendix

The authors are as follows: John J. McMurray, M.B., Ch.B., M.D., Rury R. Holman, M.B., Ch.B., F.R.C.P., Steven M. Haffner, M.D., M.Angelyn Bethel, M.D., Bjrn Holzhauer, Dipl.Math., Tsushung A. Hua, Ph.D., Yuri Belenkov, M.D., Ph.D., Mitradev Boolell, M.D., JohnB. Buse, M.D., Ph.D., Brendan M. Buckley, M.D., D.Phil., Antonio R. Chacra, M.D., Ph.D., Fu-Tien Chiang, M.D., Bernard Charbonnel,M.D., Chun-Chung Chow, M.B., B.S., F.R.C.P., Melanie J. Davies, M.B., Ch.B., M.D., F.R.C.P., Prakash Deedwania, M.D., Peter Diem,M.D., Daniel Einhorn, M.D., Vivian Fonseca, M.D., Gregory R. Fulcher, M.B., B.S., M.D., F.R.A.C.P., Zbigniew Gaciong, M.D., Ph.D.,Sonia Gaztambide, M.D., Ph.D., Thomas Giles, M.D., Edward Horton, M.D., Hasan Ilkova, M.D., Trond Jenssen, M.D., Steven E. Kahn,M.B., Ch.B., Henry Krum, M.D., Ph.D., Markku Laakso, M.D., Ph.D., Lawrence A. Leiter, M.D., Naomi S. Levitt, M.D., ViacheslavMareev, M.D., Ph.D., Felipe Martinez, M.D., Chantal Masson, R.N., Theodore Mazzone, M.D., Eduardo Meaney, M.D., Ph.D., RichardNesto, M.D., Changyu Pan, M.D., Rudolf Prager, M.D., Sotirios A. Raptis, M.D., Ph.D., Guy E.H.M. Rutten, M.D., Ph.D., HerbertSandstroem, M.D., Frank Schaper, M.D., Andre Scheen, M.D., Ph.D., Ole Schmitz, M.D., Isaac Sinay, M.D., Vladimir Soska, M.D., SteenStender, M.D., Gyula Tams, M.D., Ph.D., Gianni Tognoni, M.D., Jaako Tuomilehto, M.D., Ph.D., Alberto S. Villamil, M.D., Juraj Vozr,M.D., Ph.D., and Robert M. Califf, M.D., on behalf of the NAVIGATOR Investigators.

The following are the authors affiliations: the British Heart Foundation, Glasgow Cardiovascular Research Centre, University ofGlasgow, Glasgow, United Kingdom (J.J.M.); Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology, and Metabolism, Uni-



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versity of Oxford, Oxford, United Kingdom (R.R.H., M.A.B.); University of Texas Health Science Center, San Antonio, TX (S.M.H.);Duke Clinical Research Institute, Duke University, Durham, NC (M.A.B.); Novartis Pharma, Basel, Switzerland (B.H., M.B., C.M.);Novartis Pharmaceuticals, East Hanover, NJ (T.A.H.); Lomonosov Moscow State University, Moscow (Y.B., V.M.); the Division of Gen-eral Medicine and Clinical Epidemiology, Diabetes Care Center, University of North Carolina School of Medicine, Chapel Hill, NC(J.B.B.); University College Cork, Cork, Ireland (B.M.B.); Federal University of So Paulo, So Paulo (A.R.C.); the Department of Cardi-ology, National Taiwan University Hospital, Taipei (F.-T.C.); the Endocrinology Department, University Hospital, Nantes, France (B.C.);the Department of Medicine and Therapeutics, Prince of Wales Hospital, the Chinese University of Hong Kong, Hong Kong (C.-C.C.);the Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (M.J.D.); the Division of Cardiology,University of CaliforniaSan Francisco Program at Fresno and Veterans Affairs (VA) Central California Health Care System, Fresno (P.

Deedwania); the Division of Endocrinology Diabetes and Clinical Nutrition, Inselspital, University Hospital and University of Bern, Bern,Switzerland (P. Diem); the University of California, San Diego, and Scripps Whittier Diabetes Institute, La Jolla (D.E.); the Endocrinol-ogy Department, Tulane University, New Orleans (V.F.); Royal North Shore Hospital, University of Sydney, Sydney (G.R.F.); the Depart-ment of Internal Medicine, Hypertension, and Vascular Diseases, Warsaw Medical University, Warsaw (Z.G.); the Department of Endo-crinology, Hospital Universitario de Cruces, CIBERDEM, Barakaldo, Spain (S.G.); the Heart and Vascular Institute, Tulane UniversitySchool of Medicine, New Orleans (T.G.); Joslin Diabetes Center, Boston (E.H.); the Department of Endocrinology, Diabetes, and Me-tabolism, Istanbul University, Istanbul (H.I.); Oslo University Hospital Rikshospitalet, Oslo, and Institute of Clinical Medicine, Univer-sity of Troms, Troms, Norway (T.J.); VA Puget Sound Health Care System and University of Washington, Seattle (S.E.K.); the ClinicalPharmacology Unit, Department of Epidemiology and Preventive Medicine, Monash UniversityAlfred Hospital, Prahan, VIC, Australia(H.K.); University of Kuopio and Kuopio University Hospital, Kuopio, Finland (M.L.); Keenan Research Centre, Li Ka Shing KnowledgeInstitute of St. Michaels Hospital, University of Toronto, Toronto (L.A.L.); the Department of Medicine, Groote Schuur Hospital, Uni-versity of Cape Town, Cape Town, South Africa (N.S.L.); Cordoba National University, Cordoba, Argentina (F.M.); the Department ofDiabetes and Metabolism, University of Illinois, Chicago (T.M.); Hospital Primero de Octubre, Mexico City (E.M.); Lahey Clinic, Burl-ington, MA (R.N.); the Department of Endocrinology, 301 Hospital, Beijing (C.P.); Hietzig Hospital (Krankenhaus Hietzing mit Neu-rologischen Zentrum Rosenhgel), Vienna (R.P.); the Second Department of Internal Medicine, Endocrinology, and Diabetology, At-tikon University Hospital, Hellenic National Diabetes Center, Athens (S.A.R.); Julius Center for Health Sciences and Primary Care,

University Medical Center, Utrecht, the Netherlands (G.E.H.M.R.); the Department of Public Health and Clinical Medicine, Umea Uni-versity, Umea, Sweden (H.S.); the Center for Clinical Studies, Metabolism and Endocrinology Knowledge, and Technology-Transfer ofDresden University of Technology, Dresden, Germany (F.S.); the Division of Diabetes and Clinical Pharmacology Unit, Centre Hospita-lier Universitaire de Lige, University of Lige, Lige, Belgium (A.S.); Medical Department MEndocrinology and Diabetes, and theDepartment of Clinical Pharmacology, rhus University, rhus, Denmark (O.S.); Instituto Cardiovascular de Buenos Aires, Buenos Aires(I.S.); the Department of Clinical Biochemistry and Second Clinic of Internal Medicine, Faculty Hospital of St. Anna, Brno, Czech Re-public (V.S.); the Department of Clinical Biochemistry, Gentofte Hospital, University of Copenhagen, Copenhagen (S.S.); 1st Depart-ment of Medicine, Diabetes Unit, Semmelweis University, Budapest, Hungary (G. Tams); Consorzio Mario Negri Sud, Santa MariaImbaro, Italy (G. Tognoni); Hjelt Institute and the Department of Public Health, Helsinki University, Helsinki, and South OstrobothniaCentral Hospital, Seinajoki, Finland (J.T.); the Hypertension Unit, Division of Cardiology, Argerich Hospital, University of Buenos Aires,Buenos Aires (A.S.V.); Diabetologic Outpatient Clinic, Jesenius Samaria, amorn, Slovak Republic (J.V.); and the Duke TranslationalMedicine Institute, Duke University, Durham, NC (R.M.C.).

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New England Journal of Medicine

CORRECTION

Effect of Valsartan on the Incidence of Diabetes and

Cardiovascular Events

Effect of Valsartan on the Incidence of Diabetes and Cardiovascular

Events (10.1056/NEJMoa1001121; published on March 14, 2010, at

NEJM.org). In Table 1 (page 7), all values given for Lipids and for

Ratio of urinary albumin to creatinine were incorrect in the Valsartan

and Placebo columns, and all values given for Angiotensin-receptor

blocker, including the P values, were incorrect. In the Statistical Anal-

ysis subsection of Methods (page 3), the first sentence should have

begun, ``On the assumption that the study would continue until the

extended cardiovascular outcome occurred in 1374 patients in the

two study groups combined rather than ``... in 1774 patients in the

placebo group. The article has been corrected at NEJM.org.

N Engl J Med 2010;362:1748-a

efect valsartan

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