Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized...

for the SAVOR-TIMI 53 Steering Committee and InvestigatorsSteg and Deepak L. Bhatt

Boaz Hirshberg, Robert Frederich, Basil S. Lewis, Darren K. McGuire, Jaime Davidson, Ph. GabrielJarolim, Jacob A. Udell, Ofri Mosenzon, KyungAh Im, Amarachi A. Umez-Eronini, Pia S. Pollack,

Benjamin M. Scirica, Eugene Braunwald, Itamar Raz, Matthew A. Cavender, David A. Morrow, PetrRandomized Trial

Heart Failure, Saxagliptin and Diabetes Mellitus: Observations from the SAVOR - TIMI 53

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2014 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation published online September 4, 2014;Circulation.

http://circ.ahajournals.org/content/early/2014/09/04/CIRCULATIONAHA.114.010389World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://circ.ahajournals.org/content/suppl/2014/09/04/CIRCULATIONAHA.114.010389.DC1.htmlData Supplement (unedited) at:

http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer available in the

Permissions in the middle column of the Web page under Services. Further information about this process isOnce the online version of the published article for which permission is being requested is located, click Request

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.Circulation Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:

at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from

http://circ.ahajournals.org/content/early/2014/09/04/CIRCULATIONAHA.114.010389

http://circ.ahajournals.org/content/suppl/2014/09/04/CIRCULATIONAHA.114.010389.DC1.html

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://circ.ahajournals.org//subscriptions/

http://circ.ahajournals.org/































DOI: 10.1161/CIRCULATIONAHA.114.010389

1

Heart Failure, Saxagliptin and Diabetes Mellitus: Observations from the

SAVOR - TIMI 53 Randomized Trial

Running title: Scirica et al.; Saxagliptin and Heart Failure

Benjamin M. Scirica, MD, MPH1; Eugene Braunwald, MD1; Itamar Raz, MD3; Matthew A. Cavender, MD, MPH1; David A. Morrow, MD, MPH1; Petr Jarolim, MD, PhD2;

Jacob A. Udell, MD, MPH4; Ofri Mosenzon, MD3; KyungAh Im, PhD1; Amarachi A. Umez-Eronini, MPH1; Pia S. Pollack, MD5; Boaz Hirshberg, MD5; Robert Frederich, MD6; Basil S. Lewis, MD7; Darren K. McGuire, MD, MHSc8;

Jaime Davidson, MD9; Ph. Gabriel Steg, MD10; Deepak L. Bhatt, MD, MPH1 for the SAVOR-TIMI 53 Steering Committee and Investigators*

1TIMI Study Group, Cardiovascular Division; 2Department of Pathology, Brigham and Women’s

Hospital and Harvard Medical School, Boston, MA; 3Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel; 4Cardiovascular Division,

Women’s College Hospital and Toronto General Hospital, University of Toronto, Toronto, Canada; 5AstraZeneca Research and Development, Wilmington, DE; 6Bristol-Myers Squibb,

Princeton, NJ; 7Cardiovascular Research Institute, Lady Davis Carmel Medical Center and Ruth and Bruce Rappaport School of Medicine, Technion-IIT, Haifa, Israel; 8Cardiovascular Medicine; 9Division of Endocrinology, Dept of Internal Medicine, University of Texas

Southwestern Medical Center, Dallas, TX; 10Département Hospitalo-Universitaire FIRE, INSERM U-1148, Université Paris-Diderot, and Hôpital Bichat, AP-HP, Paris, France, and

NHLI Imperial College, ICMS, Royal Brompton Hospital, London, United Kingdom *A complete list of the SAVOR-TIMI 53 Steering Committee and Investigators can be found in

the Online Data Supplement Address for Correspondence:

Benjamin M. Scirica, MD, MPH

TIMI Study Group, Cardiovascular Division

Brigham and Women’s Hospital

75 Francis Street, Boston, MA 02115

Tel: 617-278-0145

Fax: 617-734-7329

E-mail: [email protected]

Journal Subject Codes: Heart failure:[110] Congestive, Diabetes:[190] Type 2 diabetes

TIMI Study Group, Cardiovascular Division; 2Department of Pathology, Brighhamamam andndnd WWWomomomenen’sHospital and Harvard Medical School, Boston, MA; 3Diabetes Unit, Division fof Internal

Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel; 4Cardiovascular Division,WoWomemem n’n s s s CoCollllllegege e Hospital and Toronto Gennererraaal l Hospital, Univerrsisiitytyty of Toronto, Toronto,

CaCaCannanadaa;; 555AAAstrraZZaZene eca Research and Developmmmennnt, Wilmingtononn,, DEDEE;; 666BrB istol-Myers Sqquibb,PPPrinnnceton, NNNJJ;J; 77CaCaCardrddioioiovavavasccscululararar RRReseseseaeaearcrcrch h InInInstststititutu eee, Ladaddy y y DaDaDaviviv s s s CaCaCarmrmrmelelel MeMM didiicacacalll CeCeCentnttererer aaandndnd RRRutu h

and Bruce RaRaRapppaaapooort t SScSchhohoololl oooff MeMeMediciinnee, TTeccchniniioonon-I-I-IITTT, HHaHaiiifa, IIsrsraeael;l;; 88CaCardrddioovavascccuulararr Mediciinenn ;; 999DDDivisssiooon ooff f EEnEndod crcrrininolologogyy,, DDDeppttt oofof IIntntnteernrnnall Mededicineee, UUnnnivveversr ityyy oofof TTeeexass

SoSoSoutututhwhwhwesesteteernrrn MMMeedediciccalala CCCenenenteter,r,r, DDalalllalalas,s,s, TTTX;X;X; 1010 éDéDépapapartrtrtemememenenent t t HoHoHospspspitittaalalo-o-UnUnUnivivivererersisisittatairirree e FIFIFIRERERE,, ,INININSESESERMRMRM UUU-11114141488,8, UUUnininiveveversrsrsitititééé PaPaPaririris-ss DiDiDidedederororott,t, aaandndnd HôHôHôpipipitatatalll BiBiBichchchatatat,, APAPAP-H-HHPP,P, PPParararisisis,, FrFrFrananancecece,, anananddd

NHLII IImpmpmperereriaiaall CoCoCollllegegegeee, IIICMCMCMS,SS RRRoyoyoyalalal BrBrBromomomptptptonono HHHososospipip tatatal,l,l LLLononondododon,n,n UUUniniiteteted dd KiKiKinnngdom *A l li f h SAVOR TIMI 53 S i C i d I i b f d i

at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from



2

Abstract

Background—Diabetes and heart failure frequently coexist. However, few diabetes trials have

prospectively evaluated and adjudicated heart failure as an endpoint.

Methods and Results—16,492 patients with type 2 diabetes and a history of, or at risk for,

cardiovascular events were randomized to saxagliptin or placebo (mean followup-2.1 years). The

primary endpoint was the composite of cardiovascular death, myocardial infarction, or ischemic

stroke. Hospitalization for heart failure was a predefined component of the secondary endpoint.

Baseline NT-proBNP was measured in 12,301 patients. More patients treated with saxagliptin

(289, 3.5%) were hospitalized for heart failure compared to placebo (228, 2.8%) (HR 1.27;

95%CI 1.07-1.51; p=0.007). Corresponding rates at 12-months were 1.9% vs.1.3% (HR 1.46,

95%CI 1.15-1.88, p=0.002, with no significant difference thereafter (time-varying interaction

p=0.017). Subjects at greatest risk for hospitalization for heart failure had prior heart failure,

eGFR <60 ml/min and/or elevated baseline levels of NT-proBNP. There was no evidence of

heterogeneity between NT-proBNP and saxagliptin (p for interaction=0.46), though the absolute

risk excess for heart failure with saxagliptin was greatest in the highest NT-proBNP quartile

(2.1%). Even in patients at high-risk for hospitalization for heart failure, the risk of the primary

and secondary endpoints were similar between treatment groups.

Conclusions—In the context of balanced primary and secondary endpoints, saxagliptin treatment

was associated with an increased risk for hospitalization for heart failure. This increase in risk

was highest among patients with elevated levels of natriuretic peptides, prior heart failure, or

chronic kidney disease.

Clinical Trial Registration Information— ClinicalTrials.gov. Identifier: NCT01107886.

Key words: heart failure, diabetes mellitus, saxagliptin

, p , g ( y gg

p=0.017). Subjects at greatest risk for hospitalization for heart failure had prior heheeararrtt fafafailililururure,e,e,

eGFR <60 ml/min and/or elevated baseline levels of NT-proBNP. There was no evidence of

heterogeg neity y between NT-proBNP and saxaglipptin (p for interaction=0.46), though the absolute

iisksksk eeexcxcessss fofofor hehearart t faaillurure e wiithth saxxagagliptptin waw ss ggrgreeatestst iinn the hihihighghg esest t NNT-pprooBNB P ququarrtit le

222.111%)% . Even iinn papapatiienenntsss aaattt hihihighggh-r-risisi kk k fofoorr hossppiiitalizzzaattionnn fofor r hheeararttt ffaaililururee, thehee rrriisisk k ofofof ttthehehe pppriririmmamarryry

anannd d seses cocondarararyy y enennddpdpoioinntss wewererer ssiimimiilalalar r bebeetwtweeeennn trtreeaeatmtmenenent t grgrrouupsps.

Concnclulu isionons——InI tthehe contetextt oof f babalal nceded ppririmamaryry andnd sesecocondndaaryy enendpdpoio ntnts,s ssaxaxaga liptptini ttrereatatmemen

was associatattededed wwwititith hh ananan iiincncrerereaaasededd rrrisisskk k fofoforr hohohospsppitittalalalizizzatatatioion n fofof rr r hehehearart fafafailililururureee. TTThihih ss inini crcrc eaeaeassse in risk




3

Introduction

Diabetes adds incremental risk for the development and subsequent exacerbation of heart failure

even after adjusting for common risk factors such as ischemic heart disease and hypertension. 1

Though incompletely understood, cardiac metabolic dysregulation of glycolysis and fatty acid

oxidation observed in the heart of patients with diabetes probably impairs cardiac function and

causes additional myocardial damage. 2-5 In addition, accelerated coronary atherosclerosis is

likely to play a role. 6 Moreover, the choice of antihyperglycemic agents in those patients with

diabetes with heart failure or at risk of developing it remains challenging. Some agents such as

thiazolidinediones and dual PPAR / agonists increase plasma volume and exacerbate heart

failure7-11 while sulfonylureas12 and insulin potentially exacerbating the dysregulation of

myocardial metabolism and worsening left ventricular function. 13, 14 Metformin, once felt to be

contraindicated in patients with heart failure, is now considered to be one of the safest options,

despite the absence of large randomized comparisons. 15, 16 Despite the observational

relationship between glycemic control and the risk of heart failure, there is no evidence that

improved glycemic control modifies this risk. 17 Therefore, identification of antihyperglycemic

agents that can be used safely in patients with heart failure or at risk of developing heart failure

remains an important unmet clinical need.

Saxagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor.18 The Saxagliptin

Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) –

Thrombolysis in Myocardial Infarction (TIMI) 53 trial was designed to evaluate the long-term

cardiovascular efficacy and safety of saxagliptin in patients with DM at risk for cardiovascular

events.19 Over a median of 2.1 years follow-up, saxagliptin neither increased nor decreased the

risk of the primary or secondary composite endpoints; however, there was an unexpected 27%

failure7-11 while sulfonylureas12 and insulin potentially exacerbating the dysreguulalaatitionono ooof f fr

myocardial metabolism and worsening left ventricular function. 13, 14 Metformin, once felt to be

coontntntrararaininindididicacac tetet d ininin ppatients with heart failure, is nonon www considered ttooo be onononeee of the safest options,

ddedespppite the absesenncncee ofofof laarargegege rrraanandodoommimizezeedd compmpmparisssoonns. 15,15,, 16166 DDeDessppiitte ththhee oobobseseserrvrvatatioioionananalll

eelalalatitiionononshshipipip bbbetetweweweenen ggglyyycecemimimic c cccononontrtrtrolol aandndnd ttthehee rrrisiskk oof hheaeaeartrtrt faaailililururre,e, tttheheherere iis s nnono eeeviviidededencceee tththatat

mproved glylyycececemimimic c c cococontntntrool l l momm dididififif esess thihihiss ririr sksksk.. 171717 TTThehehererefofoforerere,, , ididi enenentitit fiiicacacatititiononon ooof ff ananntititihyhyhypepepergr lycemic




4

increased relative risk (and 0.7% absolute risk over 2 years) of hospitalization for heart failure in

patients assigned to saxagliptin. 20 This report explores further the observation surrounding

hospitalizations for heart failure by examining baseline risk factors associated with an increased

risk of hospitalizations for heart failure, the timing of hospitalizations and the risk of recurrent

events, and the association between baseline levels of natriuretic peptides and future

hospitalizations for heart failure events.

Methods

Study Design and Oversight

As previously described19, SAVOR-TIMI 53 was a multicenter, randomized, double-blind,

placebo-controlled trial that randomized 16,492 patients at 788 sites in 26 countries between

May 2010 and December 2011 with type 2 diabetes mellitus, HbA1c between 6.5% and <12.0%

within 6 months of randomization, and either a history of established CV disease or multiple risk

factors for vascular disease to receive either saxagliptin 5 mg daily (or 2.5 mg daily in patients

with an estimated glomerular filtration rate (eGFR) of 50 mL/min or less) or matching placebo.

The full eligibility criteria and analysis plan have been reported previously. 19, 20 Written

informed consent was obtained from all patients. The relevant ethics committees at all

participating centers approved the protocol.

Endpoints

A clinical events committee, unaware of the study-group assignments, adjudicated all

components of the primary and secondary composite efficacy endpoints. The primary endpoint

was a composite of cardiovascular death, myocardial infarction (MI), or ischemic stroke. The

secondary endpoint included the primary composite endpoint together with hospitalization for

As previously described19, SAVOR-TIMI 53 was a multicenter, randomized, dououublblble-ee blblblininind,d,d,

placebo-controlled trial that randomized 16,492 patients at 788 sites in 26 countries between

MaMayyy 202020101010 aaandndn DDDecececeember 2011 with type 2 diabebeetttesss mellitus, HbAAA1c bbbetetetwween 6.5% and <12.0%

wwithhhini 6 monththss off rrananndododommimizazazattitiononn,,, aananddd eeeitheeer a hiisttoory y y oofof eeststababliliishshheded CCCVVV didiiseseeasasee ororor mmululu tititi lplpleee rrrisk

faactctctororrss s foforr vavavascscuululaarr ddiisseeaasese ttoo o rereecececeivivivee eieie thththererer saaaxaxax ggglipipiptiiin n 555 mgmgmg dddaaiilyyy (((ororr 2.5.5. mmmg g dadailililyy y inn paatatieiennntsss

with an estimamaateteed d glglglomommeree ulululararar fililltrtrtratatioioion n rararatetete (((eGeGeGFRFRR) )) ofofo 5550 00 mLmLmL/m/m/mff inini ooor rr lelelessssss) ) ) ororo mmmatatatchchchininnggg placebo.




5

heart failure, coronary revascularization, or unstable angina. Heart failure requiring

hospitalization was defined as an event that required hospitalization to an inpatient unit or a visit

to an emergency department that resulted in at least a 12 hour stay with clinical manifestations of

heart failure including at least one of the following signs or symptoms: new or worsening

dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema, pulmonary basilar crackles, jugular

venous distension, new or worsening third heart sound or gallop rhythm, or, radiological

evidence of worsening heart failure; together with additional or increased therapy that included:

initiation of intravenous diuretic, inotropic, or vasodilator therapy, uptitration of intravenous

therapy, if already on therapy, initiation of mechanical or surgical support/intervention, or the

use of ultrafiltration, hemofiltration, or dialysis that is specifically directed at treatment of heart

failure. 19, 20 The endpoint definitions were developed to be consistent with the draft Standardized

Definitions for End Point Events in Cardiovascular Trials created by an initiative from the

FDA.21 History of prior heart failure was a pre-defined subgroup based on medical history

obtained at randomization.

NT-proBNP was measured in 12,301 patients (74.6% of the overall trial) at

randomization and in a randomly selected subset of patients at 2 years or the end of treatment,

whichever was earlier. Blood samples were collected in serum separator plastic tubes and then

centrifuged and stored frozen in aliquots at -20° to -80°C at the enrolling site until shipped to the

Biomarker Research/TIMI Clinical Trials Laboratory, Boston, MA, USA where they were

maintained at -80°C. Serum NT-proBNP concentrations were measured at the first thaw using a

sandwich immunoassay (proBNP II, Roche Diagnostics, Indianapolis, IN). The analytic range

extends from 5 to 35,000 pg/mL. The reported within run coefficient of variation was 4.2% at a

level of 44 pg/mL and 2.7% at a level of 33,606 pg/mL. Plasma high-sensitivity TnT (hsTnT)

use of ultrafiltration, hemofiltration, or dialysis that is specifically directed at treeaaatmemm ntntnt ooof ff hehehearart

failure. 19, 20 The endpoint definitions were developed to be consistent with the draft Standardized

DeDefififinininitititiononnsss fofofor EnEnEnddd Point Events in Cardiovascululularar Trials created d byb aan n n iininitiative from the

FDFDAAA.21 Historyry ooof f prrioioior hehehearararttt ffafaililuururee e wwawass a pppreee-deefiinnedd d ssusubbgbgrroroupupp bbbasaseed dd oonon mmmeededicicalala hhhisiistotorryry

obbbtatatainininedede aatt t rararandndomomomizizaaatioioon.n.

NT-p-pprororoBNBNBNPPP wawaw sss mememeasasasururrededed iiin nn 121212,3,33010101 pppatata ieiei ntntntss s (7774.44 6%6%6% ooof f f thtt eee ovovoverereralalall l l trtriaiaial)l)l) aaatt t




6

was measured with an electrochemiluminescent immunoassay assay (Roche Diagnostics). The

lower limit of detection of the assay is 0.003 g/L. 22

Statistical Analysis

All analyses were conducted on an intention-to-treat basis among patients who underwent

randomization. Categorical variables were compared using chi-squared test and continuous

variable with either a t-test or Wilcoxon rank-sum test, as appropriate. Events rates are presented

as 2-year Kaplan-Meier estimates. The relative risks of hospitalization for heart failure between

saxagliptin and placebo were examined using an unadjusted Cox proportional hazards model

stratified by baseline renal impairment category and baseline cardiovascular risk group and with

treatment as a model term. A post hoc Bonferonni correction was applied for the multiple

comparisons of each composite of the secondary endpoint (n=6), providing a p-value of 0.0083

for the comparison of saxagliptin versus placebo. Recurrent events analyses accounted for

multiple hospitalizations for heart failure under a counting process assumption based on the

method described by Anderson-Gill.23 The risk for rehospitalization for heart failure following

an initial hospitalization for heart failure was examined by Prentice-Williams-Peterson Gap Time

model. 24 Multivariable modeling for the risk of hospitalization for heart failure in the overall

population was developed by first examining univariate associations, and then with backward

elimination method to reduce the pool of covariates base on a p-value of <0.05. It was refined

further to include clinically meaningful covariates in the final model. The hazard ratio and

95%CI were reported from landmark analyses based on subject-level censoring at 6 and 12

months that excluded subjects who did not have enough follow up time or experienced the event

prior to the landmarked time. A time –varying coefficient model was fitted as described by Gray

to evaluate any heterogeneity between saxagliptin and heart failure over time. 25

reatment as a model term. A post hoc Bonferonni correction was applied for the e mumuulttipipiplelele

comparisons of each composite of the secondary endpoint (n=6), providing a p-value of 0.0083

foor r thththee e cocompmpmpaaarissononon oof saxagliptin versus placebooo.. RRRecurrent eventntnts annalalalyyyses accounted for

mmulltltiple hospiitatalill zzzatitiiooonsss fofofor r hehehearart tt fafafaililuururee unnndeeer a cooounnntitingng pprroroceceessss aasssumumumptpttioioion n babaaseses d d d oonon ttthhehe

memeethththododod ddesesscrcrcribibeedd bbby y AnAnAndederssonono -G-G-Gililillll.23 TTThehehe rrrisskk k fofoor rrehhohospspspitititalllizizizatattiooonnn fofoor hheheararart t fafaf ililururureee fofoolllowowiiningg g

an initial hosspipipitatataliliizazazatit ononon fororor hhheaeaartrtr ffaiaiailulurerere wwwasasa eeexaxaxamimim nenen d d bybyby PPPrereentntnticii e-e-e-WiWiWilllllliaiaiamsmsm -P-PPetetetererersososon Gap Timmme




7

Results

There were a total of 741 hospitalizations for heart failure over a median follow-up of 2.1 years

in 517 patients across both treatment groups. A substantial proportion of patients hospitalized for

heart failure, regardless of the treatment assignment, were subsequently re-admitted for recurrent

heart failure episodes (n=137, 26.5%) and/or died (n=135, 26.1%), mostly due to cardiovascular

causes (n=121, 89.6% of deaths).

A comparison of the baseline variables in the patients hospitalized for heart failure

compared with those who were not are shown in Table 1. The former were older, more likely to

be male and have a history of heart failure, chronic kidney disease, established cardiovascular

disease, including prior MI, or coronary revascularization. In addition, they were more likely to

be treated with aspirin, beta-blockers, diuretics, statins, inhibitors of the renin-angiotensin-

system, and insulin, and less likely to be treated with metformin, sulfonylureas or

thiazolidinediones.

Risk Factors for Hospitalization for Heart Failure in the Overall Population

Unadjusted hazard ratios for the risk of hospitalization for heart failure by baseline

characteristics are presented in Table 1. In multivariable analysis, the strongest association with

hospitalization for heart failure (as assessed by chi-squared value) regardless of treatment

assignment, was prior heart failure, and two markers of renal disease, eGFR and

albumin:creatinine ratio. (Table 2) There was a step-wise increase in the risk of hospitalization

for heart failure in patients who had 0, 1, or 2 of the risk factors of history of heart failure or an

eGFR <60 m/min: 1.2% with 0 risk factors (n=10,418, 63.2%) (referent); 5.3% with 1 risk factor

(n=5,188, 31.5%), HR 4.48, 95%CI 3.62-5.54, p<0.001; and 14.3% with 2 risk factors (n=886,

5.4%), HR 13.51, 95%CI 10.55-17.31, p<0.001. When randomization is added to this model, the

disease, including prior MI, or coronary revascularization. In addition, they were e momomoreee lllikikikelelely y y tto

be treated with aspirin, beta-blockers, diuretics, statins, inhibitors of the renin-angiotensin-f

yyststtememem,, anannd d d inininsuulililinn,n, and less likely to be treated d wwiwitth metformin, susus lffononnyylylureas or

hhhiaaazoz lidinediiononesese .

RiRiisksksk FFFacaca tototorsrsrs ffororr HHHososspipiitatalil zazaatitiiononon ffforor HHHeeeararart FFaFailillururre ininn ttthhehe OOOveveeraraallllll PPPopppulullatata ioioion n

Unadjusted hhazazazarara dd d rarar tititiososo fffororo ttthehee rrrisisk k k offf hhososo pipipitatatalilil zazazatitiionono fffororor hhheaeaeartrtrt fffaiiilululurerere bbby yy babab seseselililinenene




8

risk associated with saxagliptin was consistent with the overall trial (HR 1.29, 95%CI 1.08-1.54).

The c-statistic for the model with eGFR and prior heart failure alone was 0.74, which increased

to 0.81 with the addition of all clinical variables in Table 2.

Saxagliptin and Hospitalization for Heart Failure

Over 2 years of follow-up, more patients in the saxagliptin group (289/8280, 3.5%) were

hospitalized for heart failure compared with the placebo group (228/8212, 2.8%) (HR 1.27;

95%CI 1.07 to 1.51 p=0.007). The corresponding rates at 6-months were 1.1% vs. 0.6% (HR

1.80, 95%CI 1.29 to 2.55, p=0.001) and 1.9% vs.1.3% (HR 1.46, 95%CI 1.15 to1.88, p=0.002 at

12 months. The rates for hospitalization for heart failure based on “investigator” reported events

were consistent with the adjudicated results. (Supplemental Table 1)

Based on landmark analysis beginning at 6 months and 12 months, the risk of

hospitalization for heart failure after in patients assigned to saxagliptin was similar to placebo

(2.4% vs. 2.1%, HR 1.11, 95%CI 0.91-1.36, p=0.31 beginning at 6 months and 1.7% vs. 1.5%,

HR 1.09, 95%CI 0.85-1.39, p=0.51 at 12 months). (Figure 1) To examine the attenuating effects

of saxagliptin on the risk of hospitalization due to heart failure over time, a time varying

coefficients model was developed (p-value for a time-time varying interaction term = 0.017).

The lower CI of the log HR crosses 0 at around 314 days, suggesting that the risk of

hospitalization for heart failure with saxagliptin subsided at 10-11 months after randomization. .

(Supplemental Figure 1) When the landmark analyses were restricted to patients taking study

drug, the corresponding risks were similar to the intent-to-treat analysis: from randomization to

12 months (HR1.52, 95%CI 1.17 to 1.96, p=0.0015) and from 12 months onward (HR 1.05,

95%CI 0.81-1.35, p=0.73).

When analyzing both first and recurrent events combined, 413 total events occurred in

were consistent with the adjudicated results. (Supplemental Table 1)

Based on landmark analysis beginning at 6 months and 12 months, the risk of t

hoospspspitititalalalizizizatatatioioion fofoorrr heh art failure after in patients aaasss iigned to saxaggglilil ptininn wwawas similar to placebo

222.444% % vs. 2.1%%, , HHRR 111.1. 1,11, 9995%5%5%CICI 000.9.9. 11-11.366,, ppp=0.3131 beeeggiginnnnninnngg aaat 666 mmooontthhs s ananandd 1.1.7%7%7% vvvs.. 111.55.5%%%,

HRHRR 111 0.0.09,9,9, 9995%5%5%CICII 000.8.855--11..3939, p=p=p=000.515151 aat t 12122 mmmonononththths)s)s). (((FiFiigugugurerere 1))) ToToTo eeexaxaxammminnene ttheheh atata teteenununuatttining g g efefffeectcts

of saxagliptinin ooon n n thththee e riririsksksk ooof f f hohoh spspspititi alallizii atatatioioon nn dududueee totoo hhheaeae rtt fffaiaiailululureree ooovevev rr r titiimememe,,, a a a titimememe vvvarara yiyiy ng




9

the saxagliptin group compared with 328 events in placebo (HR 1.26. 95%CI 1.02-1.55, p=0.04).

The risks for re-hospitalizations for heart failure following an initial hospitalization for heart

failure were similar in both groups (hospitalization for heart failure: 80, 27.7% saxagliptin vs. 57,

25.0% for placebo, HR 1.06, 95%CI 0.75-1.50, p=0.73; and mortality 26.3% vs. 25.9% placebo,

HR 1.01, 95%CI 0.72-1.43, p=0.95). The median length of stay for the initial adjudicated

hospitalization for heart failure was 7.0 days in both treatment groups. The most common

treatment was intravenous diuretics (88% in each group). Vasodilator therapy was used in 6.2%

for saxagliptin subjects and in 7.9% for placebo. Ultrafiltration/hemodialysis (2.8% and 2.2%

for saxagliptin and placebo, respectively) and advanced hemodynamic support (1.7% and 0.9%

for saxagliptin and placebo, respectively) were used infrequently.

At 1 year, weights were similar in the overall saxagliptin and placebo groups (87.6 ± 18.4

kg vs. 87.9 ± 19.4 kg, p=0.87) and in patients with a history of heart failure (91.5 ± 19.5 kg vs.

92.8 ± 20.5 kg, p=0.27) or eGFR <60 ml/min (87.1 ± 18.8 kg vs. 87.9 ± 19.7, p=0.47). Treatment

with saxagliptin did not result in clinically detectable fluid overload as reflected by similar rates

of adverse event reports of edema (45, saxagliptin vs. 46, placebo) and peripheral edema (347,

saxagliptin vs. 352, placebo).

While the absolute rate of hospitalization for heart failure varied considerably among the

pre-defined subgroups and in patients with and without prior heart failure, the relative risk in

patients treated with saxagliptin was similar across subgroups (Supplemental Figure 2).

Consequently, the absolute rates of heart failure difference between saxagliptin and placebo

varied according to the overall risk within each subgroup. This pattern was reinforced when

examining the relative and absolute risk differences in patients with the two clinical risk factors

that most greatly increased the risk of hospitalization for heart failure, eGFR <60 ml/min and a

for saxagliptin and placebo, respectively) were used infrequently.

At 1 year, weights were similar in the overall saxagliptin and placebo groups (87.6 ± 18.4

kgkg vvvs.s.. 888777.99 9 ±±± 199.44.4 kkg, p=0.87) and in patients wwititithh aa history of heaeaart ffaiaiailululure (91.5 ± 19.5 kg vs.

9922.888 ± 20.5 kgg, p=p=p=0.0.272727) ororor eeGFGFGFR R <<<66060 mmll/miiin (87..1 ± 181818.8.8 kkkggg vsvs. 88787.999 ±± 119.9..7,7,7, pp=0=00.4447)7)7).. TrTrTreaeatmtmtmen

wiwiiththth sssaxaxa agagaglililiptpptinin ddiidid nnotot rresesulullt t ininin ccclililinniniccacallllllyy y dddetetetectctaabablle ffluuuididid ooveveverlrlloaoaadd d asass reefefleleectctc edede bbby y y simmmillalar r rrrattees s

of adverse eveveentntnt rrrepepepororrtstss of f f edededememma a a (4(445,5, sssaxaxaxagagaglllipipiptitin n n vsvss.. 46466,,, plplplacacacebebebo)o)o aaandndnd ppperereripipipheheerararal l l edededemee a (347,




10

prior history of heart failure. (Figure 2) For example, in patients with neither of these risk factors

the absolute risk difference over 2 years between saxagliptin and placebo was 0.3% compared

with 1.7% in patients with both risk factors. The number of excess hospitalizations for heart

failure per year if 1000 patients were treated with saxagliptin ranged from 0 in patients with no

risk factors to 9 in patients with both risk factors.

Baseline NT-proBNP and Heart Failure

The median NT-proBNP in the 12,301 patients in whom it was measured at baseline was 141

pg/mL (IQR 64 - 332) and it was similar in patients assigned to saxagliptin (143 pg/mL, IQR 65

- 336) and placebo (139 pg/mL, IQR 63 - 330). There was a step-wise increased risk of

hospitalization for heart failure with higher quartiles of baseline NT-proBNP. (Figure 3) When

added to the clinical multivariable model, quartile 4 of NT-proBNP level was the factor most

strongly associated with the risk of hospitalization for heart failure (HR 5.51, 95%CI 4.24-7.16,

p<0.001). (Supplemental Table 2) The c-statistic increased from 0.81 to 0.85 (p<0.001) when

NT-proBNP was added to the clinical variables in Table 2. In the cohort with highest quartile of

NT-proBNP, the risk of hospitalization for heart failure in patients treated with saxagliptin was

similar to that observed in the overall trial (HR 1.31, 95%CI 1.04-1.66, p=0.02). While there was

no evidence of heterogeneity between levels of NT-proBNP, treatment with saxagliptin, and

hospitalization for heart failure (p for interaction=0.46), the absolute risk excess for heart failure

with saxagliptin was greatest in the highest NT-proBNP quartile (2.1%) compared with quartiles

1 (0.0%), 2 (0.7%), and 3 (0.2%). (Figure 3) Similar results were seen when evaluating NT-

proBNP according to deciles or an established dichotomous cutpoint. (Supplemental Figure 3)

The addition of the highest quartile of baseline NT-proBNP to the risk factors of history

of heart failure and eGFR further stratified patients according to baseline risk of hospitalization

hospitalization for heart failure with higher quartiles of baseline NT-proBNP. (FiFiiguguurere 333) ) ) WhWhWhenen

added to the clinical multivariable model, quartile 4 of NT-proBNP level was the factor most

ttroroongngnglylyly aaassssssocociaateteteddd wiw th the risk of hospitalizatioioon n ffor heart failurre ee (HHR R R 555.51, 95%CI 4.24-7.16,

p<00.0.000 1). (Suupppppleeemementntalalal TTTababablele 222)) ) ThThhee c-stttatttisticcc iinncrrreaeaasesed d frfromomm 00.888111 tooo 00.88.8555 (p(p<0<0<0.0.0.00010 ))) whwhwhenenn

NTNTT-p-p-prororoBNBNNPPP wawasss aadaddedeed toto thehehe cclililinininiccacal l vavavariririababableeesss ininn TTTabblbleee 222.. Innn tthhhe cccohoho ooortt t wiwiiththt hihih ghghgheeest quququarartitiilele oof

NT-proBNP,P,, ttthehehe rrrisisisk kk ofofof hososospipipitaaalililizzzatattioioi n n n fofoor rr heheheararart t fafafailillururu e e ininin pppatatatieieiennntst tttrerereatatatededed wwwitith hh sasasaxaxaxaglglg iptin was




11

for heart failure regardless of treatment assignment (Supplemental Figure 4). The addition of

the NT-proBNP to the two clinical variables increased the c-statistic from 0.74 to 0.82 (p<0.001).

Among the lowest quartiles of NT-proBNP, most patients had none of the aforementioned risk

factors for heart failure (n=6599, 53.6%), a correspondingly low rate of heart failure, and no

treatment difference between saxagliptin or placebo (0.6% v. 0.6%, HR 0.84, 95%CI 0.46-1.52,

p=0.56), whereas patients with NT-proBNP in the top quartile and 2 risk factors, the absolute

risk difference was 1.6% (Supplemental Figure 5). The baseline concentration of NT-proBNP

was a particularly strong risk factor for hospitalization for heart failure. Even among patients

with normal renal function and no reported history of heart failure, a level of NT-proBNP in

quartile 4 (>332 pg/ml) was associated with a higher risk of hospitalization for heart failure

(4.3% vs. 0.6% with lower levels of NT-proBNP) (Supplemental Figure 4), and a

correspondingly higher absolute risk with saxagliptin compared to placebo (5.35% vs. 3.33%,

p=0.083). (Supplemental Figure 5)

Change in NT-proBNP, hsTnT, and C-reactive Protein

In patients with both baseline and two years or end-of-treatment assessments, median NT-

proBNP (n=2026) increased both in patients treated with placebo (107 to 126 pg/ml, p<0.001)

and saxagliptin (107 to 122 pg/ml, p=0.001), with a slightly greater increase in placebo (median

change 10 vs. 4 pg/ml, p=0.001). The pattern of change was similar in patients with prior heart

failure (n=237) in placebo (230 to 287 pg/ml, p=0.149, n=100) and saxagliptin (187 to 214

pg/ml, p=0.238, n=117, median change 15 vs. 4 pg/ml, p=0.70), and patients without prior heart

failure (n=1809) in placebo (99 to 120 pg/ml, p<0.001) and saxagliptin (99 to 117 pg/ml,

p=0.003, median change 10 vs. 4 pg/ml, p<0.001). Similar results were observed after excluding

patients who experienced any of the primary or secondary endpoints (data not shown). In the

quartile 4 (>332 pg/ml) was associated with a higher risk of hospitalization for heheearrrtt fafafailili ururure e e

4.3% vs. 0.6% with lower levels of NT-proBNP) (Supplemental Figure 4), and a

coorrrrresesesppopondndndinininggly y hihihighg er absolute risk with saxaglgllipipi ttiin compared ttooo placaccebebebo (5.35% vs. 3.33%,

p=00.0.080 3). (Suupppppleeemementntalalal FFFigigiguurure e 55)))

ChChhananangegege iinnn NTNTN -p-p-prorooBNBNNPP,P, hhsTsTTnTnTnT, anaand d C-C-C-rerereacacctititivevee PPProooteeeininin

n patients wiwiththth bbototothhh bababasess liliinenene aandndnd ttwoww yyyeaeaarsrss ororo eendndnd-o-oof-f trtrreaeaeatmtmtmenenent t t asassesesessssssmemementntnts,s, mmmededediaiaiann n NT-




12

subset of patients with baseline and follow-up biomarkers, there were no differences between

placebo and saxagliptin in the median change in concentrations from baseline to 2-years or end

of treatment of hsTnT (n=1355) (0.71 vs. 0.52 vs. /ml, p=0.067) or C-reactive protein (n=513)

(0.08 vs. 0.15, p=0.75).

Patients with Prior Heart Failure

A total of 2,105 patients (12.8%) reported prior heart failure at baseline. They were older and

more likely to have established cardiovascular disease and renal impairment, though there was

no difference in the duration of DM and only a small difference in baseline HbA1c (7.7% in

prior heart failure vs. 7.6% in no prior heart failure, p=0.08). More patients with prior heart

failure were on aspirin, statins, B-blockers, and insulin, but fewer on metformin or sulfonylureas.

(Supplemental Table 3) Patient with prior heart failure were at increased risk for all

cardiovascular events compared to those without prior heart failure. The relative effect of

saxagliptin versus placebo was similar in patients with and without prior heart failure for the

primary and secondary composite endpoints as well as all-cause mortality. However, the absolute

increase in the rate of hospitalization for heart failure with saxagliptin was 1.5% in patients with

prior heart failure compared to 0.6% in patients without prior heart failure, p for

interaction=0.67. The rates of cardiovascular events as well as hypoglycemia, and adverse events

are presented in the Supplemental Table 4. We further evaluated the risk of hospitalization for

heart failure in patients with prior heart failure by NHYA Functional Classification.

(Supplemental Table 5).

Discussion

In patients with established cardiovascular disease or multiple cardiovascular risk factors, the

failure were on aspirin, statins, B-blockers, and insulin, but fewer on metformin ooor suss lflflfonnonylylylururu eae s

Supplemental Table 3) Patient with prior heart failure were at increased risk for all

caardrddioioiovvavascscculululaaar eevevevennts compared to those withoututut pprrrior heart failururre.e ThThThee e relative effect of

aaxaaaglg iptin veersrsuuus plalacecebobobo wwwasasas ssimimmiililararr inn paaatieeentss wwwithhh aaandnd wwwitithhoouutut ppriirioorr heheeararartt fafailililururree foff r r r hththeee

prprimimimarararyy y ananndd d sesecocoonnddararyy ccocompmpposositititeee eneendpdppoioiointntntsss asasas wwwelell l asass aaallllll-c-c-cauauuseses mmmororortataalitytyty. HoHoHowewew vevever,r, tthehehe aabsbssolollutu e

ncrease in thheee rarar tetete ooof f hohohospsppititi alala izzzatatatioioonnn fofoor r r heheheararartt t fafaf ilili ururureee wiwiwiththth ssaxaxaxagagaglil ptptptininn wawawas s s 1.1.1 5%5%5% iiin n n papapatients withh




13

DPP-4 inhibitor saxagliptin, when compared with placebo, increased the risk of hospitalization

for heart failure, in particular during the first 12 months of therapy. Several clinical features

easily identified patients at highest absolute risk of heart failure, regardless of treatment

assignment. While there were no individual pre-defined subgroups in which the relative risk

associated with saxagliptin treatment was particularly high or low, the incremental risk with

saxagliptin was greatest in patients at a high overall risk of heart failure (i.e., history of heart

failure, impaired renal function, or elevated baseline levels of NT-proBNP), and correspondingly

small in patients at lower risk. Therefore, a combination of clinical factors and biomarkers

identify a population of patients with diabetes in whom the excess risk of hospitalization for

heart failure with saxagliptin treatment is greatest, while conversely identifying a larger

population without those features in whom the absolute risk is small.

Based on saxagliptin’s mechanism of action and the accumulated preclinical and clinical

data of DPP IV antagonists, the observation of a higher incidence of hospitalization for heart

failure in patients treated with saxagliptin in SAVOR-TIMI 53 was unexpected and requires

confirmation with several ongoing cardiovascular outcomes trials of DPP-4 inhibitors and

glucagon-like-peptide (GLP)-1 agonists.26, 27 There was no signal of fluid retention, weight gain,

or heart failure with saxagliptin in the Phase 2 and 3 development program. 28 Moreover, prior

preclinical data and small studies with other incretin-based agents suggested potential

improvement of left ventricular function26, though these data are inconsistent. Two preliminary

reports of other studies in patients with DDP-4 inhibitors produced unanticipated findings that

highlight potential mechanisms by which treatment with DPP-4 inhibitors could exacerbate heart

failure. In one study in patients with reduced left ventricular function, after twelve months of

therapy, the DPP-4 inhibitor vildagliptin increased left ventricular end diastolic volumes.27 In

heart failure with saxagliptin treatment is greatest, while conversely identifying aaa llarara ggeer r

population without those features in whom the absolute risk is small. t

BaBaBaseses d dd onnn sssaaxaxagliptin’s mechanism of actititiononn and the accuumumm laatetetedd d preclinical and clinical

ddadataaa of DPP IVV aaannttagagoononisisistststs, , thththe e obobbseseservrvvaattionn ooff a hhhiggheeer r inincicciddeencncce ofof hhhoosospipitataalililizzatatioioion n fofof rr heheheararrt t

faailililururureee inin pppatatatiieientnts ttrtreaeateted d d wiwiththth ssaxaxaxagagaglilipptptininin iiinnn SASASAVOVOVOR-R--TITIIMIMIMI 555333 wwawasss unununexexexpepep cctctededed aandndnd reqeqquuiuireres ss

confirmationn wwwititi h h h seseseveveerarar l ononongogog inining g g cacac rdddioioiovavavascscscululu ararar oooututu cooomememes s trtrriaiaialslsl ooof ffr DPDPDPP-P-P 4 4 4 ininnhihihibibibitototorsrsr and




14

another six-week trial, several DPP-4 inhibitors worsened endothelial function as assessed by

flow-mediated dilation, independent of GLP-1 levels or DPP-4 activity.29 Regardless, no clear

mechanism of action to explain the increased risk of hospitalization for heart failure in SAVOR-

TIMI 53 could be identified.

Though unexpected, the incremental risk of heart failure hospitalization observed with

saxagliptin is likely valid, given the large number of events and the pre-specification of heart

failure hospitalizations as a component of the secondary endpoint, together with central blinded

adjudication. The observation of an increased risk of hospitalization for heart failure with

saxagliptin must however be taken in the context of multiple testing and the risk of a “false

positive” result, though there was a statistically significant difference between the two groups

after post hoc adjustment for multiple comparisons. Left ventricular function was not captured at

baseline and therefore the temporal changes, even in patients with prior heart failure, cannot be

evaluated.

The Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in

Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) trial that

evaluated the DPP-4 inhibitor alogliptin versus placebo also identified a numerically similar

trend for increased risk of hospitalization for heart failure, though the overall number of events

was smaller (106 [3.9%] vs. 89 [3.3%], HR 1.19, 95%CI 0.90-1.58, p=0.22). 30 When the 712

first hospitalization for heart failure events from both studies are combined, the overall odds of

hospitalization for heart failure with DPP-4 inhibition is 1.24 (95% 1.07-1.44, p=0.004)

(Supplemental Figure 6).

An increased risk of heart failure has been observed in some studies of other anti-

hyperglycemic agents, including sulfonylureas13, thiazolidinediones7-9, 11 and dual PPAR /

positive” result, though there was a statistically significant difference between thheee twtwwoo grgrgrouououpspsp

after post hoc adjustment for multiple comparisons. Left ventricular function was not captured at

baaseseelililinnene aaandndnd tttheererereffofore the temporal changes, eveeen nn iinn patients withthh priiororor hhheart failure, cannot be

evvalalluau ted.

ThThee e ExExE amammiinnatatiiionnn ofo CCCarrrdididiovovovasascucuculalalarr r OuOuutctct omomomesess wwwititithh h AlAlAlogogogliiptptptinini veerersusuus s StStS anannddadarddd oof f CaCaareee in

Patients with h TyTyTypepepe 222 DDDiaiai beeetetetesss MeMeMellllitititususs aaandndnd AcAcAcututu e ee CoCoCororonananaryryry SSynynyndrdromomome e e (E(E(EXAXAX MIMIMINENENE) ) ) trt ial that




15

agonists 10, 31 with divergent results in trials of intensive glucose management.32, 33 The lack of

adequate safety data on antihyperglycemic agents in heart failure is highlighted by the example

of metformin, which for many years was contraindicated in patients with heart failure, until

observational data demonstrated an acceptable safety profile.15, 16 Patients both diabetes and

heart failure are relatively under-represented in clinical trials that either excluded them 34-36 or

enrolled less than 5% of the population.37, 38 The 2105 patients with prior heart failure in

SAVOR-TIMI 53 therefore represent one of the largest cohorts of such patients with diabetes

studied. 1

There are presently no known mechanisms by which DPP-4 inhibition could precipitate

heart failure. The hemodynamic effects of glycemic modulation in myocardium accustomed to

years of hyperglycemia are unknown and could potentially exacerbate cardiac dysfunction as

glycemic changes may unfavorably alter the balance of free fatty acid oxidation and glycolysis.

39 Intensive glycemic control increased the risk of heart failure in one of the large glucose

lowering trials40, but not in two others.36,38 In contrast to the thiazolidinediones, there is no signal

of volume overload observed in SAVOR-TIMI 53 with saxagliptin nor did saxagliptin raise

levels of NT-proBNP. Interestingly though, treatment with the glitazones increases levels of

natriuretic peptides in some41, but not all studies.7 The cardiovascular consequences of DPP-4

inhibition on other peptide substrates such as natriuretic peptides or bradykinins are also

unknown. Nor was there evidence of direct myocardial toxicity with saxagliptin as reflected by

the similar change in concentrations of hsTnT and hsCRP between treatment groups.

With the possible exception of metformin 15, 16 and insulin42, most reported studies to date

evaluating effects on heart failure of specific glucose-lowering medications either increased the

risk of heart failure, or were insufficiently powered and therefore often discordant.33 Moreover,

heart failure. The hemodynamic effects of glycemic modulation in myocardium aaaccucuc ssttomomomededed tto o

years of hyperglycemia are unknown and could potentially exacerbate cardiac dysfunction as

glglycycycememmiicic ccchahahanngeseses mmay unfavorably alter the ballaaancnce of free fatty y acaa idd oooxxixidation and glycolysis. aaa

999 Inntntensive glylycceemmimic c cocoontntntrroroll l ininincrcreaeaeaseseddd ttthe rrrissk offf hhhearrtrt ffaiailulul rrere iinn onone e ofofo thehee llarargegee gglululuccoosesese

oowewweririringngng ttriririalalalss4040,,, bbubut t nonnot tt inin ttwowow ooothththeerers.s.366,6,3838 IIIn cococonntntraraastt tooo thththee thththiaiaazozoolililididinnenedidiononnesess, , , ththhererere iiis nnnoo sssigngnna

of volume ovverererlolol adadad oobsbsbsere veveved d d innn SSSAVAVAVOROROR-T-TTIMIMIMIII 53535 wwwitith h sasasaxaxaxaglglglipipiptitt n n n nononor r r dididid d d sasaxaxaxaglglglipipptititin n raise




16

the trials of metformin and insulin by design enrolled patients with recently diagnosed diabetes

in whom glycemic modulation may be better tolerated by the myocardium. In this well-powered

study of patients at high cardiovascular risk, we found that saxagliptin did not increase the

overall risk of the primary or secondary cardiovascular composite endpoints, even in those with

prior heart failure. However, patients treated with saxagliptin had an increased risk of

hospitalization for heart failure - an event that itself was associated with a high subsequent

mortality – and in particular in patients at the highest absolute risk of heart failure. The decision

to choose one antihyperglycemic agent versus another must balance the benefit in reducing

microvascular complications via improved glycemic control together with potential adverse

events such as hypoglycemia and heart failure. The results from contemporary large

cardiovascular outcome studies in patients with diabetes across the spectrum of classes of anti-

hyperglycemic agents will greatly improve our evidence-based approach to treatment of these

two commonly coexistent conditions.

Funding Sources: SAVOR-TIMI 53 was funded by AstraZeneca and Bristol-Myers Squibb.

Conflict of Interest Disclosures: Dr. Scirica reports research grants via the TIMI Study and

Brigham and Women’s Hospital from AstraZeneca and Bristol-Myers Squibb, Daichi-Sankyo ,

GlaxoSmithKline, Johnson and Johnson, Bayer Healthcare, Gilead, Eisai, Merck. Consulting fees

from AstraZeneca, Gilead, Lexicon, Arena, Eisai, St. Jude's Medical, Bristol-Myers Squibb, Forest

Pharmaceuticals, Boston Clinical Research Institute, Decision Resources, University of Calgary,

Elsevier Practice Update Cardiology, Forest Pharmaceuticals. Dr. Braunwald reports grants from

Astra Zeneca, grants from Bristol Myers Squibb, during the conduct of the study; grants from

Johnson & Johnson, grants from Merck & Co., grants from Sanofi Aventis, grants from Daiichi

Sankyo, grants from Glaxo Smith Kline, grants from Beckman Coulter, grants from Roche

Diagnostics, grants from Pfizer, grants from Eli Lilly, grants from Duke University, personal fees

from Eli Lilly, personal fees from Merck, personal fees from CVRx, personal fees from CV

events such as hypoglycemia and heart failure. The results from contemporary llararrgeee

cardiovascular outcome studies in patients with diabetes across the spectrum of classes of anti-r

hyhypepepergrgrglylylycececemimimic agaggeenents will greatly improve our evevevidddence-based appppp roacacchh h to treatment of these

wwooo coc mmonlyly cccoeeexixiistsstenennttt cococondndndititioioonnsns.

FuFuFundndndinininggg SoSoSourururcececes:s:s: SSSAVAVAVOROROR T-T-TIMIMIMIII 535353 wwwasasas fffununundedededdd bybyby AAAstststrararaZeZeZenenenecacaca aaandndnd BBBririristststololol M-M-Myeyeyersrsrs SSSquququibibibbbb.




17

Therapeutics, now Gilead, personal fees from Daiichi Sankyo, personal fees from Menarini

International, personal fees from Medscape, personal fees from Bayer, personal fees from

Genzyme, personal fees from Medicines Company, personal fees from Sanofi Aventis, outside the

submitted work. Dr. Raz reports grants from Astra Zeneca, grants from Bristol Myers Squibb,

during the conduct of the study; scientific board membership from Novo Nordisk, MSD, Eli Lilly,

Sanofi, Medscape, Andromeda, Insuline; Payment for lectures including service on speakers

bureaus for lectures from Eli Lilly, Novo Nordisk, Johnson and Johnson, Sanofi, MSD, Novartis;

stock options in Insuline. Dr. Cavender reports no conflicts. Dr. Morrow reports grants from

AstraZeneca during the conduct of the study; consultancy fees from Abbott Laboratories, BG

Medicine, Critical Diagnostics, Daiichi Sankyo, Genetech, Gilead, Instrumentation Laboratories,

Johnson & Johnson, Konica Minolta, Merck, Novartis, Provenchio, Roche Diagnostics, Servier;

grants from Abbott Laboratories, Beckman Coulter, BG Medicine, Critical Diagnostics, Bristol-

Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Merck, Novartis, , Roche Diagnostics, Sanofi

Aventis, Gilead. Dr. Jarolim reports grants from Abbott, AstraZeneca, Daiichi Sankyo, Merck,

Roche Diagnostics and Waters Technologies; consultancy fees from Biosystems and Quanterix.

Dr. Udell reports no conflicts. Dr. Mosenzon reports grants from AstraZeneca and Bristol-Myers

Squibb, during the conduct of the study; consulting fees from AstraZeneca and Bristol-Myers

Squibb; support for travel to meetings for the study from AstraZeneca and Bristol-Myers Squibb;

scientific advisory board membership from Novo Nordisk, Eli Lilly, sanofi, Norvartis, speakers

bureaus for Novo Nordisk, Eli Lilly, sanofi, Norvartis, Mercj, Sharpe and Dohme. Ms.Umez-

Eronini reports no conflicts. Dr. Pollack reports employment by AstraZeneca and having

stock/stock option in AstraZeneca. Dr. Hirshberg reports employment by AstraZeneca and having

stock/stock option in AstraZeneca. Dr. Frederich reports employment by Bristol-Myers Squibb and

having stock/stock option in Bristol-Myers Squibb. Dr. Lewis reports grants from AstraZeneca

during the conduct of the study; scientific advisory board membership from MSD and

AstraZeneca; grants from Bayer Healthcare, Amylin, Amgen, GDK, MSD, Eli Lilly, Sanofi. Dr.

McGuire reports grants from Brigham and Womens Hospital, personal fees from Brigham and

Womens Hospital, during the conduct of the study; personal fees from Boehringer Ingelheim,

personal fees from Janssen Research and Development LLC, personal fees from Sanofi Aventis

Groupe, personal fees from Genentech, Inc., personal fees from Merck Sharp and Dohme Corp.,

personal fees from Medscape Cardiology, personal fees from Pri-Med Institute, personal fees from

g , , , g ,,

Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Merck, Novartis, , Roche Diagngnnossstitit ccss,, SaSaSanononofifi

Aventis, Gilead. Dr. Jarolim reports grants from Abbott, AstraZeneca, Daiichi Sankyo, Merck,

Roche Diagnostics and Waters Technologies; consultancy fees from Biosysystems and Quanterix.

DrDrr. UUdUdele l rerepopoports s nono ccononfllicictst . DrDr. MoM ses nzzon repepoorrrtss granntsts ffrom AsAsA traZaZeneneca annd d Brisstool-MyM ers

SSSquuiuibbb , duringg tthheh cononnduduuctctct oofff tththe e ststs uududyyy; cconssusulltinggg ffeesss fffrorommm AsAsttrraaZZeneneeecaaa anannd d d BrBrisisistoool-l-l-MyMyMyeerers s

SqSqquiuiibbbbb ; ; supppppororo t t ffoforr trtraaaveeel to mmeeeee titingngngs s ffoforr r ththeee ssttududyyy ffrfromomm AAststtraaaZeeneneeca aandndnd BrBrrissstotot l-l-MyMyMyerss SSqSquiuiibbbb;

cieentntififiic aadvd issoro y boboara d mem mbmberershship froom m NoNovoo NNorrdidisksk, ElElii LLillyly,, sasanon fii, , NoNorvvara tis,s, sspeeakakerers

bureaus for NoNoNovovovo NNNoroordidid sksks , ElElElii i LiLiLilllllly,y, ssanannofofofi,i,i NNNooorvrvrvarartitit s,ss, MMMereercjcjcj, ShShShara pepee aaandndnd DDDohohmemem . MsMsMs U.UUmez-




18

The Brigham and Women's Hospital, Inc, personal fees from Duke Clinical Research Institute,

personal fees from The Cleveland Clinic Coordinating Center for Clinical Research, personal fees

from The University of Oxford, personal fees from Daiichi Sankyo, Inc., personal fees from Lilly

USA, personal fees from Novo Nordisk, personal fees from F. Hoffmann La Roche, non-financial

support from Gilead Sciences, personal fees from Axio Research, personal fees from Premier

Research, personal fees from INC Research LLC, personal fees from Glaxo Smith Kline, personal

fees from Takeda Pharmaceuticals North America, personal fees from Bristol-Myers Squibb,

personal fees from Eisai, personal fees from Omthera, personal fees from Regeneron, outside the

submitted work. Dr. Davidson reports personal fees from TIMI Group during the conduct of the

study. Dr. Steg reports personal fees from AstraZeneca, during the conduct of the study; personal

fees from Amarin, personal fees from Bayer, personal fees from Boehringer-Ingelheim, personal

fees from Bristol-Myers-Squibb, personal fees from Daiichi-Sankyo, personal fees from

GlaxoSmithKline, personal fees from Lilly, personal fees from Merck-Sharpe-Dohme, personal

fees from Novartis, personal fees from Otsuka, personal fees from Pfizer, personal fees from

Roche, personal fees from TheMedicines Company, grants and personal fees from Sanofi, grants

and personal fees from Servier, personal fees from Vivus, outside the submitted work. Dr. Deepak

L. Bhatt discloses the following relationships - Advisory Board: Elsevier Practice Update

Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research

Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Get With The

Guidelines Steering Committee; Data Monitoring Committees: Duke Clinical Research Institute,

Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria:

American College of Cardiology (Editor, Clinical Trials, Cardiosource), Belvoir Publications

(Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering

committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP

Communications (Editor in Chief, Journal of Invasive Cardiology), Population Health Research

Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology

Today’s Intervention), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy

Editor), Journal of the American College of Cardiology (Section Editor, Pharmacology); Research

Grants: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, Sanofi

Aventis, The Medicines Company; Unfunded Research: FlowCo, PLx Pharma, Takeda.

y q , p y , p

GlaxoSmithKline, personal fees from Lilly, personal fees from Merck-Sharpe-Doohmhmhme,ee pppererersososonanan ll m

fees from Novartis, personal fees from Otsuka, personal fees from Pfizer, personal fees from

Roche,, ppersonal fees from TheMedicines Compaanyy, , grants and personal fees from Sanofi, grants

anannddd ppepersr onnalalal ffeees s frfromom SSeervrvier,, ppersosonaal fef es fror mm VVVivus,s, ououtsiddeee thht e susubmbmitteed d wow rk. DrD . Deeppak

LL. BBBhah tt disclososees ttthee ffololllololowiwiwinnnggg rereelalalatitit oonnsshhipsss -- Addvivissoryryy BBooaarrdd:: EEElsseseviviieeer PPPraracctctiicice e UpUpUpdadadattte

CaCaardrddioi lologygy, MeMeM dddsccacapepe CCCardidiolologogo y,y, RRRegeggaaddo o BBiBiososcicienenncecees;s; BBooarrdrd ooff DDDireccctoorors:s: BBBosostotonnn VAVAVA RRReseseeearrrch

nsttititutute, SSoocieetyy oof f CaCarddioiovaascsculularar Patieentnt CCara e;e ChC aiair:r: AAmemeririccan n HeHearart t AAsss ocociaiatition GGet WWitith h ThThe

Guidelines SSSteteteerererinininggg CoCoCommmmmmititittetetee; DDDatattaa MoMoMoninitotot ririringngng CoCoCommmmmitititteteeseses:: DuDuDukekee CCCliliinininicacac ll RRReeseseaeae rcrcr hh h Institute,




19

References:

1. McMurray JJV, Gerstein HC, Holman RR, Pfeffer MA. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol. 2014 Mar 13. [Epub ahead of print]. 2. Rodrigues B, Cam MC, McNeill JH. Myocardial substrate metabolism: implications for diabetic cardiomyopathy. J Mol Cell Cardiol. 1995;27:169-179. 3. Opie LH, Yellon DM, Gersh BJ. Controversies in the cardiovascular management of type 2 diabetes. Heart. 2011;97:6-14. 4. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation. 2007;115:3213-23. 5. Schilling JD, Mann DL. Diabetic cardiomyopathy: bench to bedside. Heart Fail Clin. 2012;8:619-631. 6. Nichols GA, Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors. Diabetes Care. 2001;24:1614-1619. 7. Bhatt DL, Chew DP, Grines C, Mukherjee D, Leesar M, Gilchrist IC, Corbelli JC, Blankenship JC, Eres A, Steinhubl S, Tan WA, Resar JR, AlMahameed A, Abdel-Latif A, Wilson Tang WH, Brennan D, McErlean E, Hazen SL, Topol EJ. Peroxisome proliferator-activated receptor gamma agonists for the Prevention of Adverse events following percutaneous coronary Revascularization--results of the PPAR study. Am Heart J. 2007;154:137-143. 8. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289. 9. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. 2007;370:1129-1136. 10. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005;294:2581-2586. 11. Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373:2125-2135.

6. Nichols GA, Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 22 didid ababeteteses::prevalence, incidence, and risk factors. Diabetes Care. 2001;24:1614-1619.

7. Bhatt DL, Chew DP, Grines C, Mukherjee D, Leesar M, Gilchrist IC, Corbelli JC,Blankenshipp JC, , Eres A, Steinhubl S, Tan WA, Resar JR, AlMahameed A, Abdel-Latif A, WiWilslslsononon TTTananangg WHWHH,, BrB ennan D, McErlean E, Hazezezen SL, Topol EJJ. PeP roroxixixissome proliferator-acacctitivvvatet d receceepttororr ggamammmamama aaagogonininistststsss foforr ththee PrPrevevenenttioon oof f f AdAdAdvev rsrsseee eevevenentstss ffolllolowiwiwingngng pperercucucutataaneneneouous coorooonan ry Revasasccculllaririizzzatititiononon----rereresusultltltss s ofoff thhhe PPPAAAR sttuudy.y.y. AmAmm HHHeaeaartt JJ. 20202 0077;111545454:1:1373737-1-1- 43434 . JJJ

8.. DDDororormamam ndnddy yy JAJA, CChChaarrbboonnn elelel BBB, EcEcEckklklaanand dd DDJDJ, ErErE dmdmdmaannnnn EEE,, MaMaMasssss iii-BeBeBenenenededeettttii M,M,M, MMouououlless s IKKK,, SSkSkeeneneAMM, TaTan MHM ,, LeL fefebvbvre PPJJ, MMuru raray GDD, StStanandldl EE, WWililcocox x RGRG, WiWilhlhelelmsmsenen LL, BeBettereridi gege JJ,,Birkeland K,K,, GGGololo ayayay AAA, HeHeH ininine e e RJRJRJ,, KoKoKoraaanynynyii i L,L,L LLLaaaaaaksksksooo MMM,,, MoMoMokakakan n n M,M,M, NNNorororkukukusss A,A,, PPPiririragagagss s V, Podar TTTScScheheenen AA ScScheherbrbauaumm WW SSchchererntnthahanenerr GG SSchchmimitztz OO SkSkrhrhaa JJ SSmimithth UU TaTatotonn JJ SSececonondadaryry




20

12. Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care. 2005;28:2345-2351. 13. Nichols GA, Koro CE, Gullion CM, Ephross SA, Brown JB. The incidence of congestive heart failure associated with antidiabetic therapies. Diabetes Metab Res Rev. 2005;21:51-57. 14. Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J, Johnson JA. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ. 2007;335:497. 15. Eurich DT, Weir DL, Majumdar SR, Tsuyuki RT, Johnson JA, Tjosvold L, Vanderloo SE, McAlister FA. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail. 2013;6:395-402.

16. Roussel R, Travert F, Pasquet B, Wilson PW, Smith SC, Jr., Goto S, Ravaud P, Marre M, Porath A, Bhatt DL, Steg PG. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010;170:1892-1899. 17. Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, Selby JV. Glycemic control and heart failure among adult patients with diabetes. Circulation. 2001;103:2668-2673.

18. Inzucchi SE, McGuire DK. New drugs for the treatment of diabetes: part II: Incretin-based therapy and beyond. Circulation. 2008;117:574-584.

19. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Price DL, Chen R, Udell J, Raz I. The design and rationale of the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 53 study. Am Heart J. 2011;162:818-825 e6. 20. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326. 21. Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Stockbridge NL, Targum SL, Temple R. Standardized Definitions for End Point Events in Cardiovascular Trials. 2010. https://www.dcri.org/education-training/meetings/meeting-brochures/parc-meeting-materials/february-3rd-2012/articles/Standardized%20Definitions.pdf/view. 22. Giannitsis E, Becker M, Kurz K, Hess G, Zdunek D, Katus HA. High-sensitivity cardiac troponin T for early prediction of evolving non-ST-segment elevation myocardial infarction in patients with suspected acute coronary syndrome and negative troponin results on admission. Clin Chem. 2010;56:642-650.

Porath A, Bhatt DL, Steg PG. Metformin use and mortality among patients with didiabababeteteses aandnd atherothrombosis. Arch Intern Med. 2010;170:1892-1899.

17. Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, Selby JV. Glycemic control and heart failure among g adult patients with diabetes. Circulation. 2001;103:2668-2673.

18188. IInInzucchihi SSSE,E,, MMMcGcGuiuiu reree DDDK.K. NNNewewe ddrurugsgs fforor tthehee ttrreatmtmmenenentt t off dddiaiaiabebetetes:s:: pparrt t IIIIII::: InInI crcretetininn-b-basasasedede hhherrrapa y and beeyoyoonnd. CCiC rrcrc lululatatatioioionn. 20202008088;11117::57774-55844.

1999. ScScSciriri icicaa BMBMBM, , BhBhhatattt DDLDL, , BrBrBrauauunwnwnwalaald d E,E,E, SSSteteteg gg PGPGPG, DaDaDavividsdsdsoonon JJJ,, HHiHirsrsrshbhbh erergg g B,B,B OOOhmhmmananan PPP,, PPrPriciceee DDLDLChenen RR, UdUdelll J,J RRazaz II. ThThe dedesisigngn and rratatioionan lele of thhee sasaxaxaglglipi tiin n aassssese smmenent t ofof vasascuc laar routcomes reccororo deded d d d inini pppataa ieeentntnts ss wiwiwiththt dddiaaabebeb tetetesss mememelllllitititususus-t-thrhrromomombobobolylylysisis s ininin mmmyoyoyocacacardrddiaiaal ll ininnfafafarcr tion SSAVAVOROR T-TIMIMI)I) 5533 ststududyy AmAm HHeaeartrt JJ 20201111;1;16262:8:81818 8-82525 ee66JJ




21

23. Andersen PK, Gill RD. Cox’s regression model for counting processes: A large sample study. Ann Statistics. 1982;10:1100-1120. 24. Prentice RL, Williams BJ, Petersen V. On the regression analysis of multivariate failure time data. Biometrika 1981;68:373-379. 25. Gray RJ. Flexible methods for analyzing survival data using splines, with applications to breast cancer prognosis. Journal of the American Statistical Association. J Am Stat Assoc. 1992;87:942-951. 26. Khan MA, Deaton C, Rutter MK, Neyses L, Mamas MA. Incretins as a novel therapeutic strategy in patients with diabetes and heart failure. Heart Fail Rev. 2013;18:141-148. 27. McMurray JJ, Ponikowksi P, Bolli GB, Kozlovski P, Jhund P, Lewsey JD, Moeckel V, Lukashevich V, Kothny W, Krum H. Vildagliptin in Ventricular Dysfunction Diabetes Trial (VIVIDD). Eur J Heart Fail. 2013;12. 28. Iqbal N, Parker A, Frederich R, Donovan M, Hirshberg B. Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials. Cardiovasc Diabetol. 2014;13:33. 29. Ayaori M, Iwakami N, Uto-Kondo H, Sato H, Sasaki M, Komatsu T, Iizuka M, Takiguchi S, Yakushiji E, Nakaya K, Yogo M, Ogura M, Takase B, Murakami T, Ikewaki K. Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients. J Am Heart Assoc. 2013;2:e003277.

30. White WB. Cardiovascular Outcomes with Alogliptin in Patients with Type 2 Diabetes Mellitus and Recent Acute Coronary Syndromes. European Association for the Study of Diabetes. 2013. 31. Lincoff AM, Tardif JC, Schwartz GG, Nicholls SJ, Ryden L, Neal B, Malmberg K, Wedel H, Buse JB, Henry RR, Weichert A, Cannata R, Svensson A, Volz D, Grobbee DE. Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus: The AleCardio Randomized Clinical Trial. JAMA. 2014;311:1515-1525.

32. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, Lafont S, Bergeonneau C, Kassai B, Erpeldinger S, Wright JM, Gueyffier F, Cornu C. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ. 2011;343:d4169. 33. Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, Erqou S, Sattar N. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009;373:1765-1772. 34. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.

28. Iqbal N, Parker A, Frederich R, Donovan M, Hirshberg B. Assessment of the ccararardidiovovasascucullar afety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of f 202020 clliinninicacacal ll trtrt iials

Cardiovasc Diabetol. 2014;13:33.

29. Ayyaori M, Iwakami N, Uto-Kondo H, Sato H, Sasaki M, Komatsu T,, Iizuka M, Takiguchi S,YaYakukukushshshijijijiii E,E,E, NNNakakkayayayaa K, Yogo M, Ogura M, Takakakasesee B, Murakamimi TT, IkIkkewewewaki K. Dipeptidyl pepeeptttididase-44 inininhihibibibitotot rsrs aaattttt enenenuauatetee eeendndn otothehelilialal ffununctctiionnn ass eeevavavalulul attededed bbbyyy flflowowow-mmededdiaiaiatetet d d vvasooodilatationn iinn tyyypepe 2 dddiaiaiabebebetititicc papapatititienenntsss. J AmAmAm HHeaeaeart AAAsssssococc. 202011313;2;2:e:e0000 3232777777.

3000. WhWhWhititee WBWBWB. CaCaCardrdioioovavaascsculullarara OOOutututccocomememess s wwwithhh AAlllogoggliiptptp ininin iiinn PaPaPatitiienenntststs wwwittth h TyTyTypepepe 222 DDDiaiabbebettetess Meellllititusu aandnd RRece ennt t AAcututee CoCororonanary Synyndrdromomeses. Euuroropepeanan AAsss ocociaiatitiono fforo thehe SStut dydy of fDiabetes. 20013133...




22

Lancet. 1998;352:854-865.

35. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. 36. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572. 37. Gerstein HC, Miller ME, Byington RP, Goff DC, Jr., Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH, Jr., Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559. 38. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139. 39. Dutka DP, Pitt M, Pagano D, Mongillo M, Gathercole D, Bonser RS, Camici PG. Myocardial glucose transport and utilization in patients with type 2 diabetes mellitus, left ventricular dysfunction, and coronary artery disease. J Am Coll Cardiol. 2006;48:2225-2231. 40. Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, Goff DC, Jr., Probstfield JL, Cushman WC, Ginsberg HN, Bigger JT, Grimm RH, Jr., Byington RP, Rosenberg YD, Friedewald WT. Long-term effects of intensive glucose lowering on cardiovascular outcomes. New Engl J Med. 2011;364:818-828. 41. McGuire DK, Abdullah SM, See R, Snell PG, McGavock J, Szczepaniak LS, Ayers CR, Drazner MH, Khera A, de Lemos JA. Randomized comparison of the effects of rosiglitazone vs. placebo on peak integrated cardiovascular performance, cardiac structure, and function. EurHeart J. 2010;31:2262-2270. 42. Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Ryden LE, Yusuf S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319-328.

Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderssononon WWG,G, Huang GD. Glucose control and vascular complications in veterans with type 2 dddiaiabebeb tetetes.s. N N N EnEEnglg J Med. 2009;360:129-139.

39. Dutka DP, Pitt M, Pagano D, Mongillo M, GaG thercole D, Bonser RS,S, Camici PG. Myocardiaglglucuccososseee trtrtrananansppporrt tt aanand utilization in patients with hh tytyt pppe 2 diabetes memm llitittususus, , left ventricular dydyysfsffuunction,n, aaandnd cccororononnarara y yy arara teteryryry dddisiseaeasese. J J AmAm CCoololll Caardrdrdioioioll. 2000060606;4;4; 8:8:222222252 -2-22323231.1.1

40400. GGeG rsteinn HHC, MMMillleerr MEEE, GGGenunuththh SSS, IIsmmaaiill-Beeeigggi i F,F,F, BBBususee JBB, GGGofff DDDC,C, Jrr.r., Proobobststffifieelld JLLL,,CuCuushshshmamam nn WCWCWC,, GGGinnsnsbebeerggg HHN,N,N BBBigigiggegeger r JJTJT, GrGrGrimimmm m m RHRHRH, , JrJrJ .,, BBByiyiyingngn ttoton nn RPRPRP, RRoRoseseenbnbnbererrg g g YDYDYD, Frieededewaldld WWTT. LLonong-g termrm eeffffecectsts of inntetensnsivivee glg ucosose e loloweweriringg oon n cacarddioiovavascsculular ooutu cocomemes. New Engl J MMMededed.. 20202011111;3;336444:8:8818188-8-8828288..



https://www.researchgate.net/publication/230625037_Basal_Insulin_and_Cardiovascular_and_Other_Outcomes_in_Dysglycemia?el=1_x_8&enrichId=rgreq-f9903dd2-882f-4985-a72f-b533977f3ece&enrichSource=Y292ZXJQYWdlOzI2NTM5MjQyNTtBUzoxNDg0OTc1MzM3NzE3NzZAMTQxMjQxNTk3OTIyOQ==



https://www.researchgate.net/publication/5317395_Effects_of_Intensive_Glucose_Lowering_in_Type_2_Diabetes?el=1_x_8&enrichId=rgreq-f9903dd2-882f-4985-a72f-b533977f3ece&enrichSource=Y292ZXJQYWdlOzI2NTM5MjQyNTtBUzoxNDg0OTc1MzM3NzE3NzZAMTQxMjQxNTk3OTIyOQ==



https://www.researchgate.net/publication/45092512_Randomized_comparison_of_the_effects_of_rosiglitazone_vs_placebo_on_peak_integrated_cardiovascular_performance_cardiac_structure_and_function?el=1_x_8&enrichId=rgreq-f9903dd2-882f-4985-a72f-b533977f3ece&enrichSource=Y292ZXJQYWdlOzI2NTM5MjQyNTtBUzoxNDg0OTc1MzM3NzE3NzZAMTQxMjQxNTk3OTIyOQ==




https://www.researchgate.net/publication/50265497_Long-term_effects_of_intensive_glucose_lowering_on_cardiovascular_outcomes_ACCORD_Study_Group_N_Engl_J_Med_2011364818-28?el=1_x_8&enrichId=rgreq-f9903dd2-882f-4985-a72f-b533977f3ece&enrichSource=Y292ZXJQYWdlOzI2NTM5MjQyNTtBUzoxNDg0OTc1MzM3NzE3NzZAMTQxMjQxNTk3OTIyOQ==




https://www.researchgate.net/publication/279777919_Intensive_Blood-Glucose_Control_with_Sulphonylureas_or_Insulin_Compared_with_Conventional_Treatment_and_Risk_of_Complications_in_Patients_with_Type_2_Diabetes_UKPDS_33_UK_Prospective_Diabetes_Study_UK?el=1_x_8&enrichId=rgreq-f9903dd2-882f-4985-a72f-b533977f3ece&enrichSource=Y292ZXJQYWdlOzI2NTM5MjQyNTtBUzoxNDg0OTc1MzM3NzE3NzZAMTQxMjQxNTk3OTIyOQ==




23

Table 1. Baseline Characteristics

Characteristic

Hospitalization for Heart Failure

(n = 517)

No Hospitalization for Heart Failure

(n = 15,975) p-

value Unadjusted HR

(95%CI) Demographic Characteristics Age – years, Median (IQR) 68.0 (62.0 - 75.0) 65.0 (60.0 - 71.0) <0.01 1.05 (1.03 - 1.06)* Age 75 years, n(%) 137 (26.5%) 2,193 (13.7%) <0.01 2.27 (1.87 - 2.76) Male, n(%) 377 (72.9%) 10,660 (66.7%) <0.01 1.36 (1.12 - 1.65) Race <0.01 White, n(%) 424 (82.0%) 11,983 (75.0%) 1.45 (1.16 - 1.82)* Black, n(%) 32 (6.2%) 536 (3.4%) Asian, n(%) 35(6.8%) 1745(10.9%) Multiracial, n(%) 21(4.1%) 1505(9.4%) Other , n(%) 5 (1.0%) 206 (1.3) Hispanic, n(%) 68 (13.2%) 3,473 (21.7%) <0.01 0.55 (0.43 - 0.71) Weight – kg, Median (IQR) 89.9 (75.3 - 106.6) 86.0 (74.5 - 99.5) <0.01 1.01 (1.01 - 1.02)* Weight > 80 kg, n(%) 360 (69.8%) 10,196 (63.9%) 0.01 1.27 (1.05 - 1.54) Body-mass index - kg/m2, Median (IQR) 31.5 (27.6 - 36.3) 30.4 (27.2 - 34.4) <0.01 1.03 (1.01 - 1.04)* Body-mass index 30, n(%) 299 (57.9%) 8,517 (53.4%) 0.04 1.17 (0.98 - 1.40) Duration of diabetes, Median (IQR) 12.7 (7.3 - 20.2) 10.3 (5.2 - 16.6) <0.01 1.03 (1.02 - 1.04)* Established atherosclerotic disease, n(%) 470 (90.9%) 12,489 (78.2%) <0.01 3.29 (2.43 - 4.46) Hypertension, n(%) 421 (81.4%) 13,071 (81.8%) 0.82 0.99 (0.80 - 1.24) Dyslipidemia, n(%) 411 (79.5%) 11,328 (70.9%) <0.01 1.61 (1.30 - 1.99) Prior myocardial infarction, n(%) 282 (54.5%) 5,955 (37.3%) <0.01 2.11 (1.77 - 2.51) Prior heart failure, n(%) 226 (43.7%) 1,879 (11.8%) <0.01 5.77 (4.85 - 6.87) Prior coronary revascularization, n(%) 296 (57.3%) 6,827 (42.7%) <0.01 1.90 (1.60 - 2.26) Glycated hemoglobin, Median (IQR) 7.7 (7.0 - 8.7) 7.6 (6.9 - 8.7) 0.34 1.03 (0.97 - 1.10)* Glycated hemoglobin, n(%) 0.44

<6.5% 33 (6.5%) 1,230 (7.8%) Ref. 6.5 - <7.0% 81 (15.9%) 2,775 (17.7%) 1.09 (0.73 - 1.64) 7.0 - <8.0% 187 (36.7%) 5,229 (33.3%) 1.35 (0.93 - 1.96) 8.0 - <9.0% 98 (19.2%) 3,041 (19.4%) 1.24 (0.83 - 1.83)

9.0% 111 (21.8%) 3,414 (21.8%) 1.26 (0.85 - 1.86) Fasting serum glucose (mg/dl), Median (IQR)

146.0 (115.0 - 186.0) 145.0 (118.0 - 182.0)

0.92 1.005(0.99 - 1.02) †

Estimated glomerular filtration rate – mL/min, Median (IQR)

55.7 (41.3 - 75.0) 72.1 (57.8 - 86.7) <0.01 0.74 (0.71 - 0.77) †

Estimated glomerular filtration rate, n(%) <0.01 < 30 mL/min 44 (8.5%) 288 (1.8%) 7.26 (5.26 - 10.03) 30 - 60 mL/min 248 (48.0%) 4275 (26.8%) 2.98 (2.49 - 3.57 ) > 60 mL/min 225 (43.5%) 11412 (71.4%) Ref.

Albumin/creatinine ratio – mg/mmol, Median (IQR)

7.1 (1.7 - 43.1) 1.8 (0.7 - 7.3) <0.01 1.38 (1.32- 1.44)‡

Albumin/creatinine ratio, n(%) <0.01 < 3.4 mg/mmol 182 (36.9%) 9,514 (62.3%) Ref. 3.4 - 33.9 mg/mmol 177 (35.9%) 4,249 (27.8%) 2.20 (1.79 - 2.71) > 33.9 mg/mmol 134 (27.2%) 1,504 (9.9%) 4.70 (3.76 - 5.87)

Baseline Cardiovascular Medications, n(%)

Aspirin 416 (80.5%) 11,988 (75.0%) 0.01 1.41 (1.14 - 1.75) Beta-Blockers 417 (80.7%) 9,745 (61.0%) <0.01 2.71 (2.18 - 3.38) ACE Inhibitors 303 (58.6%) 8,637 (54.1%) 0.04 1.19 (1.00 - 1.41) Angiotensin Receptor Blockers 142 (27.5%) 4,453 (27.9%) 0.84 0.98 (0.81 - 1.19) Diuretics 386 (74.7%) 6,812 (42.6%) <0.01 3.88 (3.18 - 4.73)

Duration of diabetes, Median (IQR) 12.7 (7.3 - 20.2) 10.3 (5.2 - 16.6) <0.01 1.1..03030 ((1.1.0202 -- 11..04)Established atherosclerotic disease, n(%) 470 (90.9%) 12,489 (78.2%) <0.01 3.3.29299 (((2.2.2 434343 --- 444..46)Hypertension, n(%) 421 (81.4%) 13,071 (81.8%) 0.82 0.0 999999 (((0.00.808080 -- 111 2.2.24)4)4Dyslipidemia, n(%) 411 (79.5%) 11,328 (70.9%) <0.01 1.61 (1.30 - 1.99)Prior myocardial infarction, n(%) 282 (54.5%) 5,955 (37.3%) <0.01 2.11 (1.77 - 2.51)Prior heheart faillurure, nn(%(%( )) 226 (43.7%%) ) 1,879 (11.8%) ) <0.01 5.77 (4.85 - 6.87)Prrioioor rr cocoorroronanaaryryry rreevasasscucuculalarization, n(%) 296 (57.3%3%%) 6,827 (442.2.2 7%) ) <0.01 1.90 (1.60 - 2.26)GlGllycycaatateded hemmogogoglobibin,n, MMedediaian n (I(IQRQR)) 7.7.7 7 (7(7.0.0 -- 88.77) 7.7.6 (66.9.99 -- 88.77)) 0.0 3434 1.1.033 ((0.0.9797 - 11.1.10)GGGlycccata ed hemoglolobbibin,, nn(%(%(%) 0.0.0.444444

<<6<6.5% 33 ((6..5%)) 111,2230 (((7..88%) RRRef.f 6..5 5 5 - <7.0% % 81 ((155.9%))) 2,2,77775 (1177..7%) 1...0909 (00..73 -- 1..64)7.77.0 0 -- <8<8<8 0.0.0% % % 1818187 7 7 ((36.6.6 7%7%7%) 5,5,5,22229 99 (3(333.3 3%3%3%)) ) 11.1.3535 (0.0.9393 --- 1.99.96)68.8.0 0 - <9<9.0.0% % 9898 ((1919.22%)%) 3,3 040411 (19.9.4%4%) ) 1..2424 (0.0.8383 - 1.883)3

99.0%0% 111111 (2(2( 1.1.8%8%) ) 3,3,41414 4 (2(2( 11.8%8%8%) )) 1.1.2626 ((00.8585 - 11 8.86)6Fasting g serum m glgllucucososee (m(mg/g/dldld ),), MMMedediaan n 14146.66 00 (1(1151515 0.0 - 11868686 00.0)) 14144555.000 (1(11888 00.0 - 0.0 92922 1.1.00000 5(5(0.0.9999 - 1.0.02)2)




24

Characteristic

Hospitalization for Heart Failure

(n = 517)

No Hospitalization for Heart Failure

(n = 15,975) p-

value Unadjusted HR

(95%CI) Statins 429 (83.0%) 12,488 (78.2%) 0.01 1.39 (1.10 - 1.74) Calcium antagonists 174 (33.7%) 5,204 (32.6%) 0.61 1.04 (0.87 - 1.25)

Baseline Anti-hyperglycemic Medications, n(%)

Metformin 273 (52.8%) 11,200 (70.1%) <0.01 0.47 (0.39 - 0.56) Sulfonylurea 157 (30.4%) 6,476 (40.5%) <0.01 0.64 (0.53 - 0.77) Thiazolidinediones 18 (3.5%) 960 (6.0%) 0.02 0.56 (0.35 - 0.89) Insulin 304 (58.8%) 6,528 (40.9%) <0.01 2.08 (1.74 - 2.47)

Hazard ratio, CI and P-value for risk of event for subjects with characteristic relative to base category. * Per unit of measurement defined in the 1st column; † HR per 10 unit increase for fasting glucose and eGFR; ‡ HR per 1 unit increase for logACR Data on race/ethnicity were entered by study coordinators based on patient self-identification.




25

Table 2. Multivariable Analysis Evaluating the Relationship between Baseline Clinical Characteristics and Risk for Hospitalization for Heart Failure in the overall SAVOR-TIMI 53 population.

N Chi-Square Adjusted

Hazard Ratio 95% Confidence

IntervalsP

valuesPrior Heart Failure 1986 231.99 4.18 3.48 5.02 <0.01 Albumin/creatinine ratio > 33.9 mg/mmol 1,638 119.26 3.66 2.90 4.62 <0.01 Albumin/creatinine ratio 3.4 - 33.9 mg/mmol 4,426 35.77 1.89 1.54 2.34 <0.01 eGFR 60 ml/min 4602 49.86 2.00 1.65 2.42 <0.01 Age 75 years 2192 24.92 1.70 1.38 2.09 <0.01 Prior MI 5933 15.62 1.47 1.21 1.78 <0.01 Non-hispanic 12327 10.71 1.56 1.20 2.04 <0.01 Established CV disease 12344 8.81 1.64 1.18 2.28 <0.01 Saxagliptin 7916 7.77 1.29 1.08 1.54 0.01 Female 5205 6.93 0.76 0.62 0.93 0.01 Dyslipidemia 11213 4.63 1.27 1.02 1.59 0.03

R 60 ml/min 4602 49.86 2.00 1.65 22.4.422 <0 75 years 2192 24.92 1.70 1.388 222.00.0999 <0MI 5933 15.62 1.47 1.211 111.77.7888 <0<00hispanic 12327 10.71 1.56 1.20 2.04 <0lished CV disease 12344 8.81 1.64 1.18 2.28 <0

glipptin n 7916 7.77 1.29 1.08 1.54 0.lee 5205 6.93 0.00 76 0.62 0.93 0.ppididi mememiaia 1112121313 4.633 1.1.1 2727 1.1.0202 1.1.5959 0.




26

Figure Legends:

Figure 1. Kaplan-Meier (KM) Failure Estimates of Hospitalization for Heart Failure According

to Treatment with Saxagliptin versus Placebo. KM Estimates, and corresponding hazard ratios

(HR) are presented at 6 months, 12 months, and 2 years.

Figure 2. Risk of Hospitalization for Heart Failure with Saxagliptin or Placebo in Patients with

and without Baseline Risk Factors (eGFR < 60 ml/min, or history of prior heart failure). ARD –

Absolute risk difference; HR – hazard ration; # excess events per 1000 pt-years refers to the

number of excess hospitalizations for heart failure in patients treated with saxagliptin versus

placebo per 1000 patients-years.

Figure 3. Risk of Hospitalization for Heart Failure with Saxagliptin or Placebo According to

Baseline Quartile of NT-proBNP (pg/ml).

number of excess hospitalizations for heart failure in patients treated with saxaglglipiiptitiin vevev rsrsrsususus

placebo per 1000 patients-years.

FFiguugure 3. Riskk oof HoHoHospsspitittalalalizizizatatatiioion n fofofor r HeHeHeart FaFaailurrre withthth SSaaxxaagagliliptptinin oorrr PPlacaccebebebo o AAcAcccocordrdrdinnngg tototo

BaBaaseses lililinenen QQQuauauartrtililee oofof NNNTT--prproBoBBNPNPNP (((pgppg/m/mml)l)l). .



3.5%

2.8%

1.3%

0.6%

1.9%

1.1%

HR 1.80(1.29-2.55)

P=0.001

HR 1.46(1.15-1.88)

P=0.002

HR 1.27(1.07-1.51)

P=0.007

Placebo

Saxagliptin

8036

8064

7856

7867

7389

7375

4959

4978

8212

8280

Figure 1

2.8%

11..33%%

00.66%%

1.9%

11.11%%

HR 1.80(1.29-2.55)

P=0.0010

(1.15-1.88)P=0.002



4855 2105 10,418 8665,188# of excess HHF events/1000 pt-year 065 4 9

N=11637 1438711

Figure 2 at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from


Quartiles of NT-proBNP (pg/ml)

(5 - 64) (65 - 141) (1412- 333) (333 - 46,627)

p for interaction=0.46

N=3076 3076 3076 3073

ARD 0.2%HR 0.94

(0.57-1.55)P=0.82

ARD 0%HR 1.04

(0.04-26.30)P=0.98

ARD 0.7%HR 1.82

(0.86-4.09)P=0.12

ARD 2.1%HR 1.31

(1.04-1.66)P=0.02

# of excess HHF events/ 1000 pt-year

1 00 7

Figure 3

p for interaction=0.46

ARD 0.2%HR 0.9.94 4

(00.5.5. 7-1.1.555555)P=P=P 0.0.82282

ARRD D 0%0%0%HR 1 0.044

(0.04-4-4-2622 33. 0)00P=P=P=0.0.989898

ARD 0.7%HRHRHR 111.8.8.82220(0(0 8.86- .4. 90909)

=P=P=0. 211



Scirica BM, et al SAVOR-TIMI 53 Heart Failure

1

SUPPLEMENTAL MATERIAL

Heart Failure, Saxagliptin and Diabetes Mellitus –

Observations from the SAVOR - TIMI 53 Trial


2

Supplemental Figure Legends

Supplemental Figure 1

Risk of Hospitalization for Heart Failure Over Time According to Treatment with Saxagliptin.

To test for a differential relationship between saxagliptin and hospitalization for heart failure by time after

randomization, we created a time-varying interaction term (treatment*time) and found the p value for

interaction= 0.017, suggesting heterogeneity. To further examine the attenuating effects of saxagliptin on

the risk of hospitalization due to heart failure, a time varying coefficients model over 10 time intervals

where the number of events are equally distributed was developed. The figure represents this analysis.

The lower confidence interval of the log HR crosses 0 at around 314 days, suggesting that about 10-11

months is when the risk of hospitalization for heart failure with saxagliptin subsided in this trial.


The Risk of Hospitalization for Heart Failure according to Treatment with Saxagliptin versus Placebo in

Various Subgroups.


The Risk of Hospitalization for Heart Failure by Deciles (top) and Established Cutpoint (bottom). The

risk of hospitalization for heart failure is low in the lower levels of NT-proBNP but the risk associated

with saxagliptin is present at all levels of NT-proBNP. We have repeated our analysis using a cutpoint of

125 pg/mL for patients younger than 75 years and 450 pg/mL for patients 75 years or older which is listed

in the product insert for this assay and is based on data from an elderly cohort with stable coronary artery

disease, where the top quartile of NT-proBNP was > 450 pg/ml.1 In another cohort of patients with

T2DM, in whom the majority did not have established coronary disease, the highest quartile was 200

pg/ml.2

Reference:


3

1. Bruno G, Landi A, Barutta F, Ghezzo G, Baldin C, Spadafora L, et al. N-terminal probrain

natriuretic peptide is a stronger predictor of cardiovascular mortality than C-reactive protein and albumin

excretion rate in elderly patients with type 2 diabetes: the Casale Monferrato population-based study.

Diabetes Care. 2013;36(9):2677-82.

2. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. N-terminal pro-B-type

natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med.

2005;352(7):666-75.


Increased Risk of Hospitalization for Heart Failure in patients according to Baseline Quartiles of NT-

proBNP and Number of Baseline Risk Factors (eGFR < 60 mL/min or prior history of heart failure). ARD

– Absolute risk difference; HR – hazard ratio; # excess events per 1000 pt-years refers to the number of

excess hospitalizations for heart failure in patients treated with saxagliptin versus placebo per 1000

patients-years.


Risk of Hospitalization for Heart Failure with Saxagliptin or Placebo in Patients with Normal and

Elevated concentrations of NT-proBNP according to Baseline Risk Factors (eGFR < 60 ml/min or prior

history of heart failure). ARD – Absolute risk difference; HR – hazard ratio; # excess events per 1000 pt-

years refers to the number of excess hospitalizations for heart failure in patients treated with saxagliptin

versus placebo per 1000 patient-years.


Pooled Analysis of the Risk for Hospitalization for Heart Failure from the SAVOR-TIMI 53 and

EXAMINE Trials in patients treated with a DPP4 inhibitor.

Methods: The measure of effectiveness of DDP-IV inhibitors on hospitalization due to heart failure

(HHF) from individual trial is summarized as odds ratios using observed and expected number of events.

These individual odds ratios were then combined by Peto method (Yusuf et al. 1985) to yield a point

estimate of the pooled effect and 95% confidence interval. The pooled effect describes a weighted average

of the studies, giving more weight to a larger sized trial. Statistical heterogeneity across the two trials

was assessed by Cochran’s Q statistic.


4

This figure presents a meta-analysis of the effects of DDP-IV inhibitors (alogliptin and saxagliptin) on

hospitalization due to heart failure (HHF) endpoint from two recently completed randomized clinical

trials. The number of HHF events is given in the left two columns for treatment and placebo groups,

respectively. The treatment and control group sizes were comparable in each trial (8280 vs 8212 in

SAVOR; 2701 vs 2679 in EXAMINE trial26

). There was no statistical heterogeneity across these two

trials (Cochran’s Q=0.13 with df=1, p-value=0.714). Therefore, results are summarized from the fixed

effects estimates only. The pooled estimate of Peto odds ratios indicates there is a 24% increase in risk of

admission to hospital due to heart failure in DPP IV inhibitor treatment group (odds ratio 1.24; 95% CI

1.07-1.44). Nonetheless, these results should be interpreted with a caution as the combined estimate is

based upon only two trials.

Reference:

Yusuf S. Peto R. Lewis J. Colins R. Sleight P. Beta blockade during and after myocardial infaction. An

overview of randomized trials. Progress in Cardiovascular Disease 1985:27:335-371


5

Supplemental Table 1 Investigator reported events based on narrow and broad narrow Standardised MedDRA Query

(SMQ) terms for cardiac failure.

Saxagliptin

N=8280

Placebo

N=8212

Subjects

with events

n (%) 2-yr KM%

Subjects

with events

n (%) 2-yr KM% HR 95% CI

Any SMQ term (Narrow)-

Serious events only

325 (3.93) 3.9% 275 (3.35) 3.3% 1.18 1.01-1.39

Any SMQ term (Broad)-

Serious Events only

333 (4.02) 4.0% 281 (3.42) 3.4% 1.19 1.01-1.39


6

Supplemental Table 2

Multivariable Analysis Evaluating the Relationship between Baseline Clinical Characteristics and level of

NT-proBNP and Risk for Hospitalization for Heart Failure

N Chi-

Square

Adjusted

Hazard

Ratio 95% Confidence

Intervals P

values

NT-proBNP > 332 pg/ml (Quartile 4) 2949 161.9 5.47 4.21 7.10 <0.01

Prior Heart Failure 1537 99.0 2.98 2.40 3.69 <0.01

Albumin/creatinine ratio > 33.9 mg/mmol 1211 38.1 2.35 1.79 3.08 <0.01

eGFR ≤60 ml/min 3237 14.5 1.43 1.12 1.83 <0.01

Non-Hispanic 3463 14.0 1.54 1.23 1.92 <0.01

Albumin/creatinine ratio 3.4 - ≤ 33.9

mg/mmol 9129 8.2 1.80 1.32 2.45 <0.01

Saxagliptin 5915 6.4 1.30 1.06 1.60 0.01

Prior MI 4562 4.8 1.28 1.03 1.60 0.03

Female 3949 4.3 0.78 0.62 0.99 0.04

Age ≥ 75 years 1630 2.7 1.23 0.96 1.57 0.10

Dyslipidemia 8403 1.7 1.18 0.92 1.51 0.19

Established CV disease 9210 0.7 1.17 0.82 1.68 0.39


7


Baseline characteristics by history of heart failure

Characteristic

Prior Heart

Failure

(n = 2,105)

No Prior Heart

Failure

(n = 14,387) p-value

Demographic Characteristics

Age – years, Median (IQR) 65.0 (59.0 - 72.0) 65.0 (60.0 - 71.0) <0.01

Age ≥ 75 years, n(%) 391 (18.6%) 1,939 (13.5%) <0.01

Male, n(%) 1,399 (66.5%) 9,638 (67.0%) 0.63

Race <0.01

White, n(%) 1,778 (84.5%) 10,629 (73.9%)

Black, n(%) 82(3.9%) 486(3.4%)

Asian, n(%) 137(6.5%) 1638(11.4%)

Multiracial, n(%) 91(4.3%) 1435(10.0%)

Other , n(%) 17(0.8%) 199(1.4%)

Hispanic, n(%) 278 (13.2%) 3,263 (22.7%) <0.01

Weight – kg, Median (IQR) 90.0 (78.0 - 105.0) 85.5 (74.0 - 98.9) <0.01

Weight > 80 kg, n(%) 1,499 (71.3%) 9,057 (63.0%) <0.01

Body-mass index - kg/m2, Median (IQR) 31.6 (28.1 - 36.2) 30.3 (27.1 - 34.2) <0.01

Body-mass index ≥ 30, n(%) 1,292 (61.5%) 7,524 (52.4%) <0.01

Duration of diabetes, Median (IQR) 10.4 (5.0 - 17.7) 10.3 (5.3 - 16.6) 0.65

Established atherosclerotic disease, n(%) 1,920 (91.2%) 11,039 (76.7%) <0.01

Hypertension, n(%) 1,810 (86.0%) 11,682 (81.2%) <0.01

Dyslipidemia, n(%) 1,544 (73.3%) 10,195 (70.9%) 0.02

Prior myocardial infarction, n(%) 1,208 (57.4%) 5,029 (35.0%) <0.01

Prior coronary revascularization, n(%) 1,117 (53.1%) 6,006 (41.7%) <0.01

Glycated hemoglobin, Median (IQR) 7.7 (7.0 - 8.8) 7.6 (6.9 - 8.7) 0.08

Glycated hemoglobin, n(%) 0.11

<6.5% 170 (8.2%) 1,093 (7.7%)

6.5 - <7.0% 341 (16.5%) 2,515 (17.8%)

7.0 - <8.0% 660 (32.0%) 4,756 (33.6%)

8.0 - <9.0% 403 (19.6%) 2,736 (19.4%)

≥9.0% 487 (23.6%) 3,038 (21.5%)

Fasting serum glucose (mg/dl), Median (IQR) 148.0 (117.0 - 189.0) 145.0 (119.0 - 181.0) 0.12

Estimated glomerular filtration rate – mL/min, Median

(IQR)

64.9 (50.0 - 80.3) 72.7 (58.4 - 87.2) <0.01


8

Characteristic

Prior Heart

Failure

(n = 2,105)

No Prior Heart

Failure

(n = 14,387) p-value

Estimated glomerular filtration rate, n(%) <0.01

< 30 mL/min 72 (3.4%) 260 (1.8%)

30 - ≤60 mL/min 814 (38.7%) 3709 (25.8%)

> 60 mL/min 1219 (57.9%) 10418 (72.4%)

Albumin/creatinine ratio – mg/mmol, Median (IQR) 2.1 (0.8 - 9.5) 1.8 (0.7 - 7.5) <0.01

Albumin/creatinine ratio, n(%) <0.01

< 3.4 mg/mmol 1,169 (58.9%) 8,527 (61.9%)

3.4 - ≤ 33.9 mg/mmol 571 (28.8%) 3,855 (28.0%)

> 33.9 mg/mmol 246 (12.4%) 1,392 (10.1%)

Baseline Cardiovascular Medications, n(%)

Aspirin 1,684 (80.0%) 10,720 (74.5%) <0.01

Beta-Blockers 1,676 (79.6%) 8,486 (59.0%) <0.01

ACE Inhibitors 1,187 (56.4%) 7,753 (53.9%) 0.03

Angiotensin Receptor Blockers 615 (29.2%) 3,980 (27.7%) 0.14

Diuretics 1,484 (70.5%) 5,714 (39.7%) <0.01

Statins 1,710 (81.2%) 11,207 (77.9%) <0.01

Calcium antagonists 605 (28.7%) 4,773 (33.2%) <0.01

Baseline Anti-hyperglycemic Medications, n(%)

Metformin 1,138 (54.1%) 10,335 (71.8%) <0.01

Sulfonylurea 797 (37.9%) 5,836 (40.6%) 0.02

Thiazolidinediones 76 (3.6%) 902 (6.3%) <0.01

Insulin 1,029 (48.9%) 5,803 (40.3%) <0.01


9


Clinical endpoints in patients with and without Prior Heart Failure

Prior Heart Failure

(n=2105)

No Prior Heart Failure

(n=14387)

Saxa. (2yr-

KM%)

Plac. (2yr-

KM%) HR

p-

value

Saxa. (2yr-

KM%)

Plac. (2yr-

KM%) HR

p-

value

Interaction

p-value

1° Endpoint 13.9 12.3 1.13 0.32 6.4 6.5 0.97 0.61 0.28

2° Endpoint 23.9 22.9 1.06 0.50 11.2 10.9 1.01 0.87 0.63

CV Death 7.6 7.3 1.03 0.88 2.6 2.3 1.04 0.73 0.94

ytioatroM 4.9 8.8 5..1 ...1 9.4 5.1 5.55 ..59 ...9

Hospitalization for

Heart Failure 11.7 10.2 1.21 0.15 2.3 1.7 1.32 0.02 0.67

yMtiaiaratM

nIiaiiortI 1.5 9.1 5.4. ..49 4.4 5.4 ..8. ..4. ..55

Minor/Major

Hypoglycemia 51.. 59.. 5.4. ..54 51.. 55.5 5.5. ....5 ..85

Major

Hypoglycemia 5.. 4.5 5.9. ..59 5.4 5.. 5.45 ..5. ..1.

Hospitalization for

Hypoglycemia 1.3 0.5 2.55 0.04 0.5 0.5 1.02 0.94 0.09

sareiAeMsreIoAM Saxa. (n/N%)M

Plac. (n/N%)M ORM

p-

valueMSaxa. (n/N%)M

Plac. (n/N%)M ORM

p-

valueM

Interaction

p-valueM

sIMMsareiAeM

sreIoA .9.. .5.5 5..4 ..9. .5.1 .5.. ..44 ..85 ..54

eirtvAMsareiAeM

sreIoA 59.4 59.5 5..9 ...4 49.9 45.4 5..4 ..1. ..84

M Saxa. (%)M

Plac. (%)M M

p-

valueMSaxa.

(%)MPlac. (%)M M

p-

valueMM

A1c Reduction at

2yrs (median)M-0.2%M -0.1%M M 0.15M -0.2%M 0%M M <0.001M M

MMAbs5iM<.M%aoM4M

MeaiA 54.8 44.5 M .0..0> 9..5 5..9 M .0..0> M


10


Risk of hospitalization for heart failure in patients with prior heart failure according baseline New York

Heart Association (NYHA) Functional Classification

NYHA

Classification

Saxagliptin Placebo

N 2yr –

KM%

N 2yr –

KM%

HR 95%CI p-value for

interaction

I 320 8.0% 303 7.6% 1.09 (0.61-1.96) 0.52

II 623 11.4% 625 10.4% 1.12 (0.80-1.57)

III/IV 113 24.3% 121 15.6% 1.75 (1.75-3/36)

NYHA

Class Symptoms

I Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when

walking, climbing stairs etc.

II Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity.

III

Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short

distances (20–100 m).

Comfortable only at rest.

IV Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients.


11


Risk of Hospitalization for Heart Failure Over Time

According to Treatment with Saxagliptin

Days since randomization

Lo

g H

azard

Rati

o f

or

Ho

sp

itali

zati

on

fo

r H

eart

Fail

ure

1 62 116 173 251 314 397 482 550 610 697 1043

-0.5

0.0

0.5

1.0

upper 95% CI

lower 95% CI

log(HR)

Saxagliptin

worse

Saxagliptin

better


12

Overall 16492 3.5% 2.8% 1.27 (1.07, 1.51)

0.2 0.5 1 2 5

N Saxagliptin Placebo

1.27 (1.06, 1.51)

1.63 (0.64, 4.44)

No

YesBaseline

Thiazolidinedione 15514

978 2.1%

2.8%

1.5%

3.6%

0.78

1.17 (0.91, 1.51)

1.39 (1.09, 1.77)

No

YesBaseline

Metformin 5019

11473

5.2%

2.8%

4.6%

2.0% 0.35

1.28 (1.04, 1.57)

1.28 (0.93, 1.76)

No

YesBaseline

Sulfonylurea 9859

6633

4.1%

2.6%

3.3%

2.0% 0.99

1.36 (1.04, 1.79)

1.21 (0.96, 1.51)

No

YesBaseline

Insulin 9660

6832

2.5%

4.8%

1.9%

4.1% 0.51

1.03 (0.71, 1.50)

1.78 (1.19, 2.73)

1.06 (0.80, 1.42)

1.70 (1.17, 2.50)

≥9%

8-<9%

7-<8%

<7%Baseline

HbA1c

3525

3139

5416

4119

3.2%

3.8%

3.6%

3.5%

3.1%

2.2%

3.4%

2.1% 0.08

1.12 (0.80, 1.59)

1.58 (1.02, 2.47)

1.17 (0.82, 1.68)

1.05 (0.70, 1.57)

1.73 (1.12, 2.73)

≥20 yrs

15-<20 yrs

10-<15 yrs

5-<10 yrs

<5 yrsDuration of

Diabetes

3025

2111

3500

3925

3916

4.6%

4.9%

3.8%

2.5%

2.6%

4.0%

3.2%

3.3%

2.3%

1.6% 0.30

1.32 (1.04, 1.66)

1.21 (0.93, 1.58)

No

YesPrior Heart Failure

14387

2105

2.3%

11.7%

1.7%

10.2% 0.67

1.51 (1.00, 2.30)

1.22 (1.01, 1.48)

No

YesPrior Hypertension

3000

13492

3.8%

3.4%

2.6%

2.8% 0.31

1.35 (1.04, 1.77)

1.22 (0.97, 1.53)

<30

≥30Body-Mass Index

7647

8816

3.3%

3.7%

2.5%

3.0% 0.57

1.47 (1.05, 2.08)

1.21 (0.99, 1.48)≥ 75 years

< 75 yearsAge

2330

14162

6.8%

3.0%

4.9%

2.4% 0.34

1.29 (1.07, 1.55)

1.17 (0.73, 1.90)Non-Hispanic

HispanicEthnicity

12951

3541

3.9%

2.1%

3.0%

1.8% 0.74

1.12 (0.81, 1.57)

1.34 (1.09, 1.65)

Female

MaleSex

5455

11037

2.6%

3.9%

2.4%

3.0% 0.35

0.83 (0.46, 1.51)

1.46 (1.13, 1.89)

1.17 (0.90, 1.52)

<30

30-60

>60Glomerular

Filtration Rate

332

4523

11637

12.3%

6.4%

2.1%

14.2%

4.6%

1.8% 0.18

1.19 (0.67, 2.15)

1.28 (1.07, 1.53)

Risk Factors

EstablishedDisease

State 3533

12959

1.2%

4.2% 3.3%

0.9%

0.83

1.01 (0.72, 1.42)

1.31 (0.98, 1.77)

1.47 (1.10, 1.99)

≥300

30-300

<30Baseline albumin:

creatinine ratio(μg/mg) 1638

4426

9696

8.6%

4.4%

2.3%

8.1%

3.5%

1.5% 0.29

HR (95%CI)P for

interaction

Hazard Ratio Favors PlaceboFavors Saxagliptin

1.33 (0.94, 1.88)

1.25 (1.03, 1.53)

No

YesBaseline

Diuretic9294

7198

1.6%

6.0%

1.1%

4.9% 0.76

1.39 (1.12, 1.72)

1.08 (0.80, 1.46)

No

YesBaseline Calcium

Antagonist 11114

5378

3.6%

3.2%

2.6%

3.0% 0.17

1.60 (1.08, 2.41)

1.21 (1.00, 1.47)

No

YesBaseline

ACEi/ARB 3497

12995

3.4%

3.5%

2.4%

2.9% 0.28

1.20 (0.79, 1.84)

1.28 (1.06, 1.56)

No

YesBaseline

Statin 3575

12917

2.5%

3.8%

2.2%

2.9% 0.77

1.81 (1.21, 2.76)

1.18 (0.97, 1.43)

No

YesBaseline

Beta-Blocker 6330

10162

2.0%

4.4%

1.0%

3.9% 0.06


Scirica BM, et al SAVOR-TIMI 53 Heart Failure Online Material

13

Risk of Hospitalization for Heart Failure

According to Deciles of NT-proBNP

0.0% 0.2% 0.2% 1.2% 1.4% 1.5%

2.5% 3.5%

8.0%

17.8%

0.0% 0.2% 0.3% 0.2% 0.4% 0.6%

3.3% 2.4%

5.9%

15.2%

0%

5%

10%

15%

20%

1 2 3 4 5 6 7 8 9 10

Ho

sp

ita

liza

tio

n f

or

He

art

Fa

ilu

re

(2y

r K

M%

)

Deciles of NT-proBNP

Saxagliptin Placebo


Risk of Hospitalization for Heart Failure

According to Established Cutpoint

0.6%

6.8%

0.3%

5.5%

0%

2%

4%

6%

8%

10%

Low High

Ho

sp

. fo

r H

ea

rt F

ailu

re (

%)

Saxagliptin Placebo

NT-proBNP (High > 125 pg/ml if<75 yo, or > 450 pg/ml if >=75 yo)

N=6415 5886

ARD 1.3%

HR 1.25

1.02-1.55)

P=0.04

ARD 0.3%

HR 1.54

(0.78-3.18)

P=0.22


14


0.6%1.7%

3.1%4.3%

11.6%

19.2%

0%

5%

10%

15%

20%

25%

0 Risk Factors 1 Risk Factor 2 Risk Factors

Ho

sp

. fo

r H

eart

Fa

ilu

re (

%)

Quartile 1-3 Quartile 4

HR 6.45

(4.25-9.78)

p<0.001

Risk of Heart Failure According to Risk

Factors and NT-proBNP

HR 7.13

(5.06-10.05)

p<0.001

HR 6.06

(3.04-12.06)

p<0.001

N=6599 2385 4391135 1499 244


15

Risk of Heart Failure According to Risk

Factors and NT-proBNP

Q1-Q3 NT-proBNP

0.6%2.3%

3.2%

0.6% 1.1%

2.9%

0%

5%

10%

15%

20%

25%

0 Risk Factors 1 Risk Factor 2 Risk Factors

Ho

sp

. fo

r H

eart

Failu

re (

%)

Saxagliptin Placebo

Q4 NT-proBNP

ARD 0.0%

HR 0.84(0.46-1.52)

p=0.56

ARD 1.2%

HR 1.76(0.93-3.33)

p=0.08

ARD 0.3%

HR 1.05(0.28-3.91)

p=0.94

N=6599 2442385

5.4%

12.7%

19.9%

3.3%

10.4%

18.4%

0%

5%

10%

15%

20%

25%

0 Risk Factors 1 Risk Factor 2 Factors

Ho

sp

. fo

r H

eart

Failu

re (

%)

Saxagliptin Placebo

ARD 2.0%

HR 1.700.93-3.11

p=0.08

ARD 2.3%

HR 1.27(0.93-1.73)

p=0.13

ARD 1.6%

HR 1.22(0.79-1.88)

p=0.36

N=1135 4391499# of excess

HHF events/

1000 pt-year2 20 5 8 7



16

Peto odds ratio plot

0.5 1 2

SAVOR-TIMI 53 1.27 (1.06, 1.51)

EXAMINE 1.19 (0.89, 1.58)

combined 1.24 (1.07, 1.44)

Peto odds ratio (95% confidence interval)

EXAMINE

SAVOR-TIMI 53

Combined

106 89

289 228

DPP4i Placebo

1.19 (0.89-1.58)

1.27 (1.07-1.51)

1.24 (1.07-1.44)395 317

OR (95%CI)



17

Executive Committee: Eugene Braunwald (Study Chair), Deepak L. Bhatt (Co-Principal Investigator), Itamar Raz (Co-

Principal Investigator), Jaime A. Davidson, Robert Frederich (non-voting), Boaz Hirshberg (non-

voting), Ph. Gabriel Steg

Trial Organization

TIMI Study Group – Eugene Braunwald (Study Chair), Deepak L. Bhatt (Co-Principal Investigator),

Benjamin M. Scirica, Jacob A. Udell, Matthew A. Cavender, Nihar Desai, Timothy Abrahamsen,

Michelle Grossman, Suzanne Morin, Kyungah Im, Elaine Hoffman, Daniel Gabovitch, Alexandra

Pricken

Hadassah Medical Organization– Itamar Raz (Co-Principal Investigator), Ofri Mosenzon, Alona

Buskila

AstraZeneca – Peter Ohman, Boaz Hirshberg, Christina Stahre, Deborah Price, Solveig Billing-Clason,

Karin Sabel, John Monyak, Mikalea Sjöstrand, Cheryl Wei, Jane Lu, Elinor Miller, Joel Raichlen, Sandy

Fitt

Bristol-Myers Squibb – Robert Frederich, Nayyar Iqbal, Mark Donovan

Steering Committee

Members of the Operations Committee and Ph. Gabriel Steg (Executive Committee member), Jaime A.

Davidson (Executive Committee member) and Carlos Aguilar-Salinas (Mexico), Michael Alvarsson

(Sweden), John Amerena (Australia), Diego Ardissino (Italy), Oleg Averkov (Russia), Angelo Avogaro

(Italy), Anthony Barnett (United Kingdom), Reinhard Bretzel (Germany), Chern-En Chiang (Taiwan),

Verner Codoceo (Chile), Ramon Corbalan (Chile), Anthony Dalby (South Africa), Harald Darius

(Germany), Chaicharn Deerochanawong (Thailand), Mikael Dellborg (Sweden), Freddy Eliaschewitz

(Brazil), Armando Garcia-Castillo (Mexico), Ramon Gomis (Spain), Patrick Henry (France), Joost

Hoekstra (Netherlands), Gyorgy Jermendy (Hungary), John Kastelein (Netherlands), Anthony Keech

(Australia), Robert Kiss (Hungary), Michel Krempf (France), Markku Laakso (Finland), Lawrence

Leiter (Canada), Eran Leitersdorf (Israel), Basil Lewis (Israel), Leon Litwak (Argentina), Jose Lopez-

Sendon (Spain), Ronald Ma (Hong Kong), Darren McGuire (United States), Felix Medina (Peru),

Robert Moses (Australia), Jose C. Nicolau (Brazil), Grzegorz Opolski (Poland), Ton Oude Ophuis

(Netherlands), Ernesto Paolasso (Argentina), Kausik K. Ray (United Kingdom), Mikhail Ruda (Russia),

K.M. Prasanna Kumar (India), Marina Shestakova (Russia), Wayne H-H Sheu (Taiwan), Alena

Smahelova (Czech Republic), B. Soma Raju Bhupathiraju (India), Jindrich Spinar (Czech Republic),

Piyamitr Sritata (Thailand), Krysztof Strojeck (Poland), Jaime E. Villena-Chavez (Peru), Weiping Jia

(China), Young Huo (China)

Clinical Events Committee

TIMI Study Group - Chair: Stephen D. Wiviott; Director: Cheryl Lowe; Cardiovascular Specialists: Eric

Awtry, Clifford Berger, Akshay S. Desai, Eli Gelfand, David Leeman, Mark Link, Frederick Ruberg,

Joseph Vita; Neurology Specialists: Natalia Rost, Scott Silverman; Pancreas Specialists: Norton J.

Greenberger, Markus M. Lerch

Data Monitoring Committee

Chair: Bernard Gersh (USA); Members: Richard Nesto (USA), Stefano Del Prato (Italy), Jaakko

Tuomilehto (Finland), and Sheryl Kelsey (USA)


18

Investigators

Argentina

National Lead Investigators: L. Litwak and E. Paolasso

A. Alvarisqueta, Centro de Investigaciones Médicas, Mar del Plata, Buenos Aires; J. Cuadrado,

Framingham, La Plata, Buenos Aires; L. Rista, CEDyN Centro de Diabetes y Nutrición, Rosario, Santa

Fe; S. Hermida, CIAD Consultorio Integral de Atención al Diabético, Moron, Buenos Aires; C. Baccaro,

CIMeL, Lanus, Buenos Aires; C. Luquez, Centro Medico Luquez/Fundacion Luquez, San Vicente,

Cordoba; M. Lagrutta, Instituto de Investigaciones Clínicas de Rosario, Rosario, Santa Fe; L. Maffei,

Consultorios Asociados de Endocrionología, Ciudad Autonoma de Buenos Aires; I. Bartolacci, Instituto

de Investigaciones Clínicas de Córdoba, Cordoba; O. Montaña, DIM Clínica Privada, Ramos Mejia,

Buenos Aires; H. Cutuli, Centro Urológico Ballester SRL, Villa Ballester, Buenos Aires; M. Berli,

CEDIR Centro de Diagnostico y Rehabilitacion, Santa Fe; A. Lorenzatti, Fundación Rusculleda,

Cordoba; G. Frechtel, Hospital Sirio Libanés, Ciudad Autonoma de Buenos Aires; R. La Greca, Hospital

Churruca Visca, Ciudad Autonoma de Buenos Aires; O. Fretes, Saint Deniss Medical Group, Ciudad

Autonoma de Buenos Aires; M. Diaz, MD Investigaciones, Ciudad Autonoma De Buenos Aires; N.

Rodríguez Papini, INSARES, Mendoza; E. Farías, Instituto de Cardiología "Juana F. Cabral",

Corrientes; C. Issa, Sanatorio Güemes, Ciudad Autonoma de Buenos Aires; A. Elbert, CEREHA Centro

de Enfermedades Renales e Hipertensión Arterial, Sarandí, Buenos Aires.

Australia

National Lead Investigators: J. Amerena and R. Moses

R. Lehman, Adelaide Medical Research, Ashford; J. Amerena, Geelong Hospital, Geelong; M. Arya,

Australian Clinical Research Network, Maroubra; B. Singh, Launceston General Hospital, Launceston;

D. Colquhoun, Core Research Group, Milton; R. Jayasinghe, Gold Coast Hospital, Southport; F. de

Looze, AusTrials, Auchenflower; P. Blombery, Avenue Cardiovascular Centre, Windsor; F. de Looze,

AusTrials, Sherwood; G. Ward, St. Vincent's Hospital Melbourne, Fitzroy; G. Szto, Peninsula Heart

Centre, Frankston; W. Abhayaratna, Clinical Trials Unit - Canberra Hospital, Woden.

Brazil

National Lead Investigators: F. Eliaschewitz and J. Nicolau

J. Borges, Centro de Pesquisa Clínica do Brasil, Brasília; L. Russo, CCBR BRASIL Centro de Pesquisas

e Análises Clínicas, Rio De Janeiro; F. Eliaschewitz, CPClin - Centro de Pesquisas Clínicas, São Paulo;

J. Felício, Hospital Universitário João de Barros Barreto, Belém; F. Santos, Loema - Instituto de

Pesquisa Clínica, Campinas; F. Guimarães Filho, Instituto do Coração de Marília, Marília; M. Lazaretti

Castro, IMA Brasil - Instituto Medicina Avançada, São Paulo; P. Rossi, Núcleo de Pesquisa Clínica,

Curitiba; D. Armaganijan, Instituto Dante Pazzanese de Cardiologia, São Paulo; P. Leães, Irm. Santa

Casa de Misericórdia de Porto Alegre, Porto Alegre; F. Bandeira, Centro de Pesquisas Médicas Básica e

Clínica, Recife; M. Franken, Heart Institute (InCor) - University of São Paulo Medical School, São

Paulo; N. Rassi, Hospital Geral de Goiânia Dr Alberto Rassi, Goiânia; R. Réa, Serviço de

Endocrinologia do Hospital de Clínicas da UFPR, Curitiba; M. Zanella, Hospital do Rim e Hipertensão,

São Paulo; C. Amodeo, Instituto Dante Pazzanese de Cardiologia, São Paulo; L. César, Heart Institute

(InCor) - University of São Paulo Medical School, São Paulo; R. Betti, Heart Institute (InCor) -

University of São Paulo Medical School, São Paulo; A. Chacra, Centro de Pesquisa Clínica em Diabetes

- UNIFESP, São Paulo; H. Schmid, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto

Alegre.

Canada

National Lead Investigator: L. Leiter


19

A. Bell, Keele Medical Place, Toronto, ON; G. Syan, G.S. Cardiac Lab Medicine Professional Corp.,

Sudbury, ON; R. Zadra, Newmarket Cardiology Group, Newmarket, ON; H. Conter, MSHJ Research

Associates Inc., Halifax, NS; R. Dumas, Centre de Recherche Clinique de Laval, Laval, QC; D. Borts,

Brampton Research Associates, Brampton, ON; I. Dattani, Prairie Clinical Research Group, Saskatoon,

SK; P. Poirier, Institut de cardiologie et de pneumologie de Quebec, Quebec, QC; J. Cha, Dr. James Cha

MD, Oshawa, ON; P. Dzongowski, Milestone Research, London, ON; R. Labonte, Dr. R. Labonte

Professional Medicine Corporation, Sudbury, ON; B. St. Pierre, Centre de Recherche Godin and St.

Pierre, Sherbrooke, QC; D. Gaudet, ECOGENE-21 Clinical Trial Center/Centre de santé et de services

sociaux de Chicoutimi, Chicoutimi, QC; S. Kouz, CSSSNL/CHRDL, St-Charles-Borromee, QC; A.

Lamy, Hamilton Health Sciences, General Site, Hamilton, ON; S. Tishler, Mississauga Clinical

Research Centre Incorporated, Mississauga, ON; R. Chehayeb, Viacar Recherche Clinique Inc.,

Greenfield Park, QU; J. Bedard, Recherche Clinique London, Sherbrooke, QC; I. Hramiak, St. Josephs

Health Care London, London, ON; I. Teitelbaum, JJ DIG Research Ltd., Toronto, ON; C. Fortin,

Neufort Inc., St-Lambert, QC; V. Woo, Health Sciences Centre - Diabetes Research Group, Winnipeg,

MB; J. Conway, Diabetes Clinic, Smiths Falls, ON; P. Mehta, Laxmi Centre, Winnipeg, MB; S.

Robinson, Victoria Heart Institute Foundation, Victoria, BC; B. Sussex, Health Sciences Centre, St.

John's, NL; J. Chiasson, CRCHUM, Montréal, QC; N. Muirhead, London Health Sciences Centre,

London, ON; S. Bose, Dr. S Bose Medical Prof. Corp., Saskatoon, SK; A. Ouellet, ViaCar Recherche

Clinique, Longueuil, QC; J. Yale, MUHC - Royal Victoria, Montreal, QC; R. Bhargava, Heart Care

Research, Oshawa, ON; D. Lau, Clinical Trials Unit, University of Calgary, Calgary, AB; S. Tobe,

Sunnybrook Health Sciences Center, Toronto, ON; P. Perron, Centre Hospitalier Universitaire de

Sherbrooke, Sherbrooke, QC; J. Sigalas, Rouge Valley Metabolic Research Associates, Scarborough,

ON; L. Bilodeau, Centre Medical L'Enjeu/L'Enjeu Medical Center, Montreal, QC; R. Tytus, Hamilton

Medical Research Group, Hamilton, ON; G. Achyuthan, Regina Medical Centre, Regina, SK; M.

Pearce, St. Mary General Hospital, Kitchener, ON; A. Steele, Co-Medica Research Research Network

Inc., Courtice, ON; G. Bailey, The Bailey Clinic, Red Deer, AB; P. Ma, Heart Health Research, Calgary,

AB; F. St-Maurice, ViaCar Recherche Clinique Inc., Brossard, QC; D. Rupka, Fraser Clinical Trials Inc,

New Westminster, BC; R. Houlden, Kingston General Hospital, Kingston, ON; A. Bailey, BioQuest

Research, Spruce Grove, AB; G. Rewa, Toronto East Cardiology Research Associates, Toronto, ON; P.

Sohal, Surrey Medical and Travel Clinic, Surrey, BC; R. Ting, Corporate Medical Centre, Scarborough,

ON.

Chile

National Lead Investigators: V. Codoceo and R. Corbalan

J. Prieto, Hospital Clínico Universidad de Chile, Santiago; M. Rodriguez, Hospital Sótero del Río,

Santiago; G. Godoy, Servicios Medicos Godoy Ltda., Santiago; G. Larenas, Centro Médico Stockins y

Larenas, Temuco; C. Pincetti, Centro de Investigacion Clinica del Sur, Temuco; L. Cobos,

CARDIOCOB, Santiago; V. Saavedra, CECIM, Santiago; P. Varleta, Hospital DIPRECA, Santiago; F.

Lucero, Hospital San Borja Arriaran, Santiago; O. Kuzmanic, Hospital Militar, Santiago; M. Acevedo,

Centro de Investigaciones Clínicas UC, Santiago; M. Aguirre, ADICH, Santiago; F. Florenzano,

Psicomedica, Santiago.

China

National Lead Investigators: W. Jia and Y. Huo

J. Ma, Nanjing First Hospital, Nanjing; Y. Bao, Shanghai the 6th People's Hospital, Shanghai; M. Jiang,

1st Affiliated Hospital of Beijing University, Beijing; W. Xu, Second Affiliated Hospital of Suchow

University, Suzhou; y. Shi, Shanghai Changzheng Hospital, Shanghai; M. Zheng, The 2nd Affiliated

Hospital of Tianjin Medical Un, Tianjin; Y. Li, The First Affiliated Hospital of Sun Yat-sen University,


20

Guangzhou; Y. Dong, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou; W. Zhao,

Peking Union Medical Collegue Hospital, Beijing; M. Sun, Tianjin Medical University General

Hospital, Tianjin; M. Lei, Xiangya hospital of Center-South university, Changsha; Y. Li, Shanghai

Huashan Hospital, Shanghai; J. Wang, Sun Yat-Sen Memorial Hospital Sun Yat-Sen University,

Guangzhou.

Czech Republic

National Lead Investigators: A. Smahelova and J. Spinar

Z. Píštěk, Interní a diabetologická ambulance, Uherské Hradiště; I. Řiháček, Centrum pro zdraví s.r.o.,

Brno; D. Kučera, Kardiologická a angiologická ambulance, Ostrava; M. Brada, Privátní diabetologická

ambulance, Břeclav; R. Náplava, Lunacor s.r.o., Centrum pro choroby srdce a cév, Kroměříž; J. Špinar,

Fakultní nemocnice Brno, I. Interní kardiologická klinika, Brno; J. Karasová, Interní a diabetologická

ordinace, Cheb; H. Vlašicová, Diabetologická ambulance, Zlín; J. Skopeček, Interní a diabetologická

ambulance, Hořovice; L. Špinarová, Fakultní nemocnice U sv. Anny, I. Interní kardioangiologická

klinika, Brno; A. Šmahelová, Fakultní nemocnice Hradec Králové, Klinika gerontologická a

metabolická, Hradec Králové; L. Raclavská, Medicentrum Beroun, spol. s r.o., Beroun; R. Šarbochová,

Nemocnice Slaný, Interní oddělení, Slaný; L. Okénka, Diabetologická ambulance, Hodonín; E. Račická,

Poliklinika Mittal Steel, Interní a diabetologická ordinace, Ostrava; K. Urbancová, Diabetologická a

interní ambulance, Ostrava; M. Oznerová, Soukromá diabetologická a interní ambulance, Ostrava; Z.

Lorenc, Kardiologická ordinace, Plzeň; B. Wasserburger, DIKa centrum s.r.o., Havířov; E.

Záhumenský, Interní a diabetologická ordinace, Zlín; H. Grünfeldová, Městská nemocnice Čáslav,

Interní oddělení, Čáslav; J. Hradec, Interní a diabetologická ordinace, Chrudim; M. Lukáč, Nefromed

s.r.o., Praha; Š. Svačina, Všeobecná fakultní nemocnice, 3. Interní klinika - 1. Lékařská fakulta UK

VFN, Praha; J. Podzimek, Diabetologická a interní ordinace, Jablonec Nad Nisou; L. Hemžský,

Přeloučská poliklinika a.s., Ordinace diabetologie, Přelouč; I. Mikulková, Nemocnice Blansko, Interní a

diabetologická ambulance, Blansko; J. Pavlíčková, Diabetologická ambulance, Pardubice; T. Brychta,

Diabetologická a interní ambulance, Olomouc; J. Chochola, Nemocnice milosrdných sester sv. Karla

Boromejského, Interní oddělení, Praha.

France

National Lead Investigators: P. Henry and M. Krempf

P. Henry, Hôpital Lariboisiere, Paris; T. Couffinhal, Hôpital Haut Lévêque, Pessac; M. Krempf, CHU de

Nantes - Hôpital Nord Laennec, Nantes; M. Elbaz, CHU Rangueil, Toulouse; C. Petit, Centre

Hospitalier, Corbeil-Essonnes; B. Faller, Hôpitaux Civils de Colmar, Colmar; R. Marechaud, CHRU la

Milètrie, Poitiers; P. Moulin, Hôpital Louis Pradel, Bron; S. Fendri, Hôpital Sud - CHU Amiens,

Amiens; P. Nazeyrollas, CHR Robert Debré, Reims.

Germany

National Lead Investigators: R. Bretzel and H. Darius

U. Wendisch, Praxis Dr. med. U. Wendisch, Hamburg; K. Busch, Praxis Dr. med. K. Busch, Dortmund;

G. Klausmann, Studienzentrum Haematologie/Onkologie/Diabetologie, Aschaffenburg; H. Duengen,

Campus Virchow Klinikum der Charite Berlin Medizinische Klinik mit Schwerpunkt Kardiologie am

Campus Virchow, Berlin; K. Appel, Ambulantes Herzzentrum Kassel, Kassel; N. Toursarkissian, Praxis

Dr. med. N. Toursarkissian, Berlin; T. Jung, Praxis Dr. med. T. Jung, Deggingen; P. Ott, An der

Teleportalklinik, Dippoldiswalde; I. Schenkenberger, KFB- Klinische Forschung Berlin, Berlin; D.

Kuesters, Praxis Dr. med. D. Kuesters, Eschweiler; B. Landers, Praxis Dr. med. B. Landers, Mayen; R.

Nischik, medamed GmbH, Leipzig; H. Fischer, Zentrum für klinische Prüfungen in der Facharztzentrum

Dresden-Neustadt GbR, Dresden; D. Tschoepe, Herz- & Diabeteszentrum NRW Forschungsleitung


21

Diabeteszentrum, Bad Oeynhausen; B. Paschen, Praxis Dr. med. B.Paschen, Hamburg; K. Krause, Gem.

Praxis Drs. Krause und Menke, Goch; K. Derwahl, Institut für klinische Forschung und Entwicklung

Berlin GmbHam St. Hedwig Krankenhaus Elisabeth Haus 2. OG, Berlin; V. Wenzl-Bauer, Praxis Dr.

med. V. Wenzl-Bauer, Rehlingen-Siersburg; A. Hamann, Diabetes-Klinik Bad Nauheim GmbH, Bad

Nauheim; H. Strotmann, Medizin Consult GmbH, Rotenburg; K. Milek, Praxis Dr. med. K. Milek,

Hohenmölsen; S. Mueller, Gem. Praxis Drs. Hamann und Mueller, Gueglingen; R. Bretzel, Praxis Prof.

Dr. med. R.G. Bretzel, Giessen.

Hong Kong

National Lead Investigator: R. Ma

R. Ma, Prince of Wales Hospital, Sha Tin, Hong Kong; D. Chu, Chai Wan Health Centre, Hong Kong;

K. Tan, Queen Mary Hospital, Hong Kong; K. Kung, Lek Yuen General Outpatient Clinic, Hong Kong;

D. Chu, Violet Peel General Outpatient Clinic, Hong Kong; C. Tsang, Alice Ho Miu Ling Nethersole

Hospital, Hong Kong; D. Chu, Sai Wan Ho Health Centre, Hong Kong; B. Tomlinson, Prince of Wales

Hospital, Sha Tin, Hong Kong; K. Kung, Fanling Family Medicine Centre, Sha Tin, Hong Kong.

Hungary

National Lead Investigators: G. Jermendy and R. Kiss

L. Korányi, DRC Gyógyszervizsgáló Központ, Balatonfüred; Z. Kerényi, Csepeli Egészségügyi

Szolgálat Szakorvosi Rendelõ, Budapest; B. Benczúr, Jász-Nagykun-Szolnok Megyei Hetényi Géza

Kórház, Szolnok; L. Illyés, Kardiolódiai Szakrendelés Miskolc, 3530 Miskolc; T. Hidvégi, Petz Aladár

Megyei Kórház, Gyõr; A. Somogyi, Semmelweis Egyetem II. Belgyógyászati Klinika, Budapest; J.

Valcó, Ceglédi Toldy Ferenc Kórház, Cegléd; G. Jermendy, Bajcsy-Zsilinszky Kórház Medical

Department, Budapest; S. Ferenczi, Petz Aladár Megyei Kórház Immunnephrológia, Gyõr; J. Rapi,

Bugát Pál Kórház Belgyógyászat, Gyöngyös; P. Vörös, Fõvárosi Önk. Szent István Kórház, Budapest;

G. Winkler, Szent János Kórház II. Belgyógyászati Osztály, Budapest; T. Sydó, Jeruzsálemhegy

Egészségház, Veszprém; M. Hetey, Markhot Ferenc Kórház Egészségügyi Szolgáltató Non, Eger; K.

Simon, Siófok Városi Kórház-Rendelõintézet, Siófok; J. Pénzes, Konszenzus Plusz Kft., Csongrád; P.

Kempler, Semmelweis Egyetem I. Belgyógyászati Klinika, Budapest; B. Bakó, Borsod-Abaúj-Zemplén

Megyei Kórház, Miskolc; Z. Lengyel, Szent Margit Kórház Belgyógyászat-Nephrologia, Budapest; I.

Witmann, PTE ÁOK II. Belgyógyászati Klinika, Pécs; M. Dudás, Pándy Kálmán Megyei Kórház,

Gyula; G. Vándorfi, Veszprém Megyei Csolnoky Ferenc Kórház, Veszprém; J. Takács, Jahn Ferenc

Dél-Pesti Kórház, Budapest; A. Matoltsy, Kanizsai Dorottya Kórház Begyógyászat Kardiológia,

Nagykanizsa; R. Kiss, Állami Egészségügyi Központ Kardiológiai Osztály, Budapest; E. Ladányi, FMC

Miskolci Nefrológiai Központ, Miskolc; A. Gyimesi, Réthy Pál Kórház II. Belgyógyászati Osztály,

Békéscsaba.

India

National Lead Investigators: B. Somaraju, K. M. P. Kumar, and S. Sadikot

K. Parikh, Care Institute of Medical Sciences, Ahmedabad; S. Jain, Totall Diabetes Hormone Institute,

Indore; C. Yajnik, KEM Hospital, Pune; A. Sosale, DIACON Hospital and Research Centre, Bangalore;

P. Shamanna, Bangalore Clinisearch, Bangalore; S. Srikanta, Jnana Sanjeevini Medical Center,

Bangalore; S. Shah, Diabetes Action Centre, Mumbai; A. Srinivas, Vikram Hospital Private Limited,

Mysore; K. M. P.. Kumar, Bangalore Diabetes Hospital Bengaluru, Bangalore; D. Banker, Bankers

Heart Institute, Vadodara; P. Shah, Gujarat Endocrine Centre, Ahmedabad; A. Sharda, Endocrinology

and Diabetes Centre, Bangalore; B. Makkar, Diabetes and Obesity Centre, New Delhi; N. Desai,

Namana Medical Center, Bangalore; N. Rais, Chowpatty Medical Centre, Mumbai; H. Mardikar,

Spandan Heart Institute, Nagpur; A. Mishra, Fortis Flt. Lt. Rajan Dhall Hospital, New Delhi; S. Bhupati,


22

CARE Hospitals, Hyderabad; J. Menon, Mar Augustine Golden Jubilee Hospital, Ernakulam district; S.

Sathe, Dr Shireesh Sathe Clinic, Pune; R. Gupta, Fortis Escorts Hospital, Jaipur; V. Sharma, N.H.I.A.I.

Heart Foundation, New Delhi.

Israel

National Lead Investigators: B. Lewis and I. Raz

M. Darawsha, Diabetes and Lipid department Linn MC, Haifa; T. Herskovits, Western Galillee Hospital

Diabetes Institue, Nahariya; S. Hamoud, Rambam Medical Center Internal Medicine Haifa, Haifa; E.

Nikolsky, Rambam Health care Campus Department of Cardiology, Haifa; I. Raz, Hadassah Ein Karem

M.C diabetes unit, Jerusalem; F. Adawi, Ziv Medical Center Endocrinology Unit, Zefat; R. Zimlichman,

Tel Aviv Community Center, Tel Aviv; D. Tsalihin, Ben Yair Community Clinic Beer-Sheva, Beer

Sheva; J. Wainstein, Wolfson Medical Center Diabetes unit, Holon; E. Klainman, Gefen Cardiac Health

Center, Givatayim; M. Mosseri, Meir Medical Center Division of Cardiology, Kfar Saba; Y.

Yerushalmi, Clalit Tel Aviv Diabetes clinic, Tel Aviv; E. Karnieli, Rambam Medical Center Institute of

Endocrinology, Haifa; H. Knobler, Kaplan Medical Center Metabolic Unit, Rehovot; R. Zimlichman,

Wolfson Medical Center Medicine and Hypertension, Holon; S. Benchetrit, Meir MC Blood pressure

and Nephrology, Kfar Saba; A. Tsur, Clalit Health Services Diabetes clinic Jerusalem, Jerusalem; Y.

Yagil, Barzilai Medical Center Nephrology, Ashkelon; B. Lewis, Lady Davis Carmel Medical Center,

Haifa; S. Atar, Western Galilee Hospital cardiology, Nahriya; I. Beberashvili, Assaf Harofeh Medical

Center Nephrology, Be'er Ya'akov; S. Fuchs, Beilinson Hospital Department of Internal Medicine,

Petach Tikva; N. Stern, Sourasky Medical Center Metabolic Unit, Tel Aviv; A. Pollak, Hadassah

Medical Organization Heart Institute, Jerusalem; T. Chajek-Shaul, Hadassah Hospital Mount Scopus

Internal Medicine, Jerusalem; Y. Rozenman, Wolfson Medical Center Heart Institute, Holon; A. Biton,

Clalit Clinic Dimona, Dimona.

Italy

National Lead Investigators: D. Ardissino and A. Avogaro

D. Ardissino, A.O.U., Parma; E. Bramucci, O. P. San Matteo, Pavia; A. Fiscella, A.O. Cannizzaro,

Catania; V. Grassia, P.O. S. Maria delle Grazie, Pozzouli; P. Piatti, Istituto di Ricovero e Cura a

Carattere Scientifico e Universitario Ospedale San Raffaele, Milano; S. De Cosmo, Casa Sollievo della

Sofferenza, San Giovanni Rotondo; L. Di Lorenzo, Ospedale San Rocco, Sessa Aurunca; P. Merlini,

Ospedale Niguarda Cà Grande, Milano; E. Mannucci, A.O.U. Careggi, Firenze; S. Frontoni, Ospedale

Fatebenefratelli, Roma; R. Trevisan, Opedali Riuniti di Bergamo, Bergamo; L. Zenari, Ospedale Sacro

Cuore Don Calabria, Negrar; A. Avogaro, A.O. di Padova, Padova; C. Lambiase, Ospedale Amico

Gaetano Fucito, Mercato San Severino; A. Salvioni, Ospedale Cardiologico Monzino, Milano; O.

Silvestri, A.O. Cardarelli, Napoli; G. Ambrosio, Ospedale Santa Maria di Terni, Terni; P. Di Bartolo,

A.U.S.L. di Ravenna, Ravenna; L. Fattore, P.O. San Giuseppe, S. Maria Capua Vetere; P. Presbitero,

Istituo Clinico Humanitas, Rozzano; M. Calabrese, A.U.S.L. 4, Prato; R. Evola, Ospedale San Vincenzo

USL 5, Taormina.

Mexico

National Lead Investigators: C. Aguilar-Salinas and A. Garcia-Castillo

M. Alcocer Gamba, Instituto de Corazón de Queretaro, Querétaro; M. Odin de los Ríos Ibarra, Centro

para el Desarrollo de la Medicina y de Asistencia Médica Especializada S.C., Culiacán; E. Cardona

Muñoz, ICLE S.C., Guadalajara; D. Reyes Sánchez, Cardioprevent S.C., Durango; C. Hernandez

Herrera, Centro para el Desarrollo de la Medicina y de Asistencia Médica Especializada S.C. (CDMAE),

Monclova; J. Pérez Ríos, Oaxaca Site Management Organization, Oaxaca De Juárez; E. Bayram Llamas,

Fundación Cardiovascular de Aguascalientes A.C., Aguascalientes; G. Llamas Esperon, Hospital


23

Cardiológica Aguascalientes, Aguascalientes; E. García Cantú, Cardiolink Clin Trials S.C., Monterrey;

J. Nuñez Fragoso, Hospital General de Durango, Durango; J. González González, Hospital Universitario

"Dr. José Eleuterio González", Monterrey; G. Rivera Martinez, Hospital General de Tijuana, Tijuana; F.

Padilla Padilla, Consultorios Tarascos, Guadalajara; G. Meléndez Mier, Centro de Investigación Médica

de México (MENTRIALS S.A. de C.V.), México D.F.; D. Herrera Marmolejo, Torre Médica

Providencia, Guadalajara; J. Garza Ruiz, Internal Medicine Clin Trials, Monterrey; N. Caracas Portilla,

Hospital Ángeles de Lindavista, México D.F.; E. López Rosas, Centro de Especialidades Médicas del

Estado de Veracruz (CEMEV), Xalapa; C. Aguilar Salinas, Instituto Nacional de Ciencias Médicas y

Nutrición "Salvador Zubirán", México D.F.; G. Méndez Machado, Médica del Este, Xalapa; J. Chevaile

Ramos, Hospital Central "Dr. Ignacio Morones Prieto", San Luis Potosí; I. Rodríguez Briones,

Cardioarritmias e Investigación S.C., San Luis Potosí.

Netherlands

National Lead Investigators: J. Hoekstra and T. Oude Ophuis

M.W.J. van Hessen, Groene Hart Ziekenhuis locatie Bleuland, Gouda; S. Strikwerda, Amphia

Ziekenhuis locatie Molengracht, Breda; S.H.K. The, Bethesda Ziekenhuis, Hoogeveen; A. Kooy,

Bethesda Diabetes Research Center, Hoogeveen; E. Ronner, Reinier de Graaf Gasthuis, Delft; P.R.

Nierop, Sint Franciscus Gasthuis, Rotterdam; J.J. Remmen, Canisius-Wilhelmina Ziekenhuis, Nijmegen;

B.E. Groenemeijer, Gelre Ziekenhuizen loc. Lukas Ziekenhuis, Apeldoorn; B.J.B. Hamer, Meander

Medisch Centrum, Amersfoort; D.C.G. Basart, Vasculair Onderzoekscentrum Hoorn BV, Hoorn;

H.W.O. Roeters van Lennep, Admiraal de Ruyterziekenhuis, Goes; M. Nieuwdorp, AMC, Amsterdam;

M.P.M. van Dijk, Julius Centrum UMCU, Utrecht; S. Kentgens, Andromed Eindhoven, Eindhoven;

W.W. van Kempen, Andromed Rotterdam, Rotterdam; J. Hoogendijk, Andromed Oost, Velp; W.

Spiering, UMCU, Utrecht; C. Voors-Pette, Andromed Noord, Groningen; V. Köse, Andromed Breda,

Breda; D.E.P. de Waard, Antonius Ziekenhuis, Sneek; F. Gonkel, Saxenburgh Groep Röpcke Zweers

Ziekenhuis, Hardenberg; H.A.H. Kaasjager, Rijnstate ziekenhuis, Arnhem; G.M. Rojas Lingan,

Andromed Zoetermeer, Eindhoven; I. Agous, Andromed Leiden, Leiderdorp; H.J. Kruik, Ziekenhuis

Groep Twente lokatie Almelo, Almelo; B.P.M. Imholz, Tweesteden Ziekenhuis, Waalwijk; M. Pieterse,

Stichting Cardiologie Amsterdam, Amsterdam.

Peru

National Lead Investigators: F. Medina and J. Villena-Chavez

H. Manrique, Centro de Expertos en Diabetes obesidad y nutricion, Lima; F. Medina, Clinica Medica

Cayetano Heredia, Lima; J. Villena, Hospital Nacional Cayetano Heredia, Lima; L. Leon, Clinica Anglo

Americana, Lima; K. Kundert, Centro de Investigacion Ricardo Palma, Lima; J. Minchola, Clinica San

Gabriel, Lima; M. Pinto, Clínica Oftalmolaser, Lima; J. Heredia, Clinica Anglo Americana, Lima; A.

Rodriguez, Hospital Nacional Alberto Sabogal Sologuren, Callao; C. Guerreros, Clinica Internacional,

Lima; P. Berrospi, Clinica El Golf, Lima; C. Zubiate, METABOLICARE, Lima; A. Allemant, Hospital

Nacional Hipolito Unanue, Lima; H. Arbanil, Hospital Nacional Dos de Mayo, Lima; W. Ponciano,

Clinica San Borja, Lima; J. Calderon, Clínica Novocardio, Lima; R. Lisson, Hospital Nacional Edgardo

Rebagliati Martins, Lima; L. Segura, Instituto Medico Miraflores, Lima.

Poland

National Lead Investigators: G. Opolski and K. Strojek

A. Sidorowicz-Bialynicka, Synexus SCM, Wroclaw; R. Sciborski, Zespol Opieki Zdrowotnej w Olawie

SPZOZ, Olawa; I. Fares, NZOZ Medicus, Naklo Nad Notecia; P. Mader, NZOZ Praktyka Dentystyczno

- Internistyczna, Kamieniec Zabkowicki; J. Skierkowska, NZOZ JUDYTA, Skierniewice; T. Stasinska,

NZOZ Regionalna Poradnia Diabetologiczna, Wroclaw; W. Pomiecko, Samodzielny Niepubliczny ZOZ


24

Mazur-Med., Mragowo; M. Skorski, SPZOZ w Lecznej Szpital Powiatowy, Leczna; E. Krzyzagorska,

Praktyka Lekarska Ewa Krzyzagorska, Poznan; M. Polaszewska-Muszynska, Bydgoskie Centrum

Diabetologii i Endokrynologii SPZOZ, Bydgoszcz; D. Sowinski, Wojewodzki Zespol Specjalistycznej

Opieki Zdrowotnej we Wroclawiu SP ZOZ, Wroclaw; K. Strojek, Wojewodzka Przychodnia dla

Chorych na Cukrzyce, Zabrze; J. Rosinska-Migda, NZOZ Mig - Med, Wabrzezno; P. Romanczuk,

NZOZ Gdanska Poradnia Cukrzycowa, Gdansk; G. Golebiowski, Szpital Specjalistyczny sw. Wojciecha

Adalberta SP ZOZ, Gdansk; J. Kubica, NZOZ MEDICUS Jacek Kubica, Bydgoszcz; T. Mazurek, I

Katedra i Klinika Kardiologii Akademii Medycznej, Warszawa; L. Wojnowski, Lecznice Citomed,

Torun; D. Pasternak, NZOZ Centrum Zdrowia i Profilaktyki Dabie, Krakow; P. Stachlewski, NZOZ

Eskulap, Koluszki; E. Trzepla, Centrum Medyczne Warszawskiego Uniwersytetu Medycznego,

Warszawa; G. Bogdanowicz, PS ZOZ Wojewodzkie Centrum Medyczne, Opole; A. Uzunow,

Przychodnia Medycyny Rodzinnej Nowy Fordon, Bydgoszcz; I. Potakowska, Zespol Poradni Zdrowie

NZOZ, Sieradz; Z. Miszczyszyn, Prywatny Specjalistyczny Gabinet Lekarski, Przemysl; T.

Waszyrowski, Wojewodzka Stacja Ratownictwa Medycznego w Lodzi SPZOZ, Lodz.

Russian Federation

National Lead Investigators: O. Averkov, M. Ruda, and M. Shestakova

O. Smolenskaya, Hospital #14 Ural State Med Academy Ekat, Ekaterinburg; Y. Lukyanov, State

Medical University n.a. Pavlov, Saint Petersburg; N. Vorokhobina, Chair of Endocrinology Med

Postgrad Academy, Saint Petersburg; Y. Khalimov, Endocrinology NII Med Postgrad Academy, Saint

Petersburg; O. Orlikova, Research Institute of Cardiology Saratov, Saratov; A. Rebrov, SGMU n.a.

Razumovsky Saratov, Saratov; V. Kukharchuk, Atherosclerosis Problems Department Cardiocomplex,

Moscow; S. Boldueva, Cardiology Clinic Mechnikov Med Acad, Saint Petersburg; M. Arkhipov, MO

Novaya Ural State Med Academy Ekat, Ekaterinburg; T. Zhelninova, Out-patient Dep Almazov Federal

Center, Saint Petersburg; E. Pavlysh, Out-patient department #25, Saint Petersburg; M. Antsiferov,

Moscow Endocrinological Dispensary, Moscow; A. Panov, Cardiology Dep Almazov Federal Center,

Saint Petersburg; M. Pavlova, MMA n.a. Sechenov I.M., Moscow; S. Shustov, Military Medical

Academy n.a. Kirov, Saint Petersburg; E. Demchenko, Rehabilitation Lab Almazov Federal Center,

Saint Petersburg; A. Galyavich, KGMU Kazan, Kazan; E. Malakhina, Center of new medical

technology Novosibirsk, Novosibirsk; O. Semenova, Alexandrovskaya City Hospital, Saint Petersburg;

Z. Kobalava, City Clinical Hospital #64, Moscow; M. Shestakova, Institute of Diabetes Scientific Centre

of Endocri, Moscow; S. Kotova, Chair of Endocrinology Mechnikov Med Acad, Saint Petersburg; I.

Gavrisheva, OOO "AVA-Peter", Saint Petersburg; E. Oschepkova, Arterial Hypertension Department

Cardiocomplex, Moscow; Y. Karpov, Angiology Department Cardiocomplex, Moscow; B. Sidorenko,

Central Clinical Hospital, Moscow; O. Kislyak, City Clinical Hospital #79, Moscow; A. Ametov, Chair

of endocrinology RMAPO, Moscow; A. Dreval, Moscow Research Clinical Institute n.a.Vladimirsky,

Moscow; E. Grineva, Endocrinology Inst Almazov Federal Center, Saint Petersburg; A. Mkrtumyan,

MGMSU, Moscow; T. Tyurina, Leningrad Regional Cardiology Dispensary, Saint Petersburg; O.

Sazonova, Novosibirsk State Medical University, Novosibirsk.

South Africa

National Lead Investigators: F. Bonnici and A. Dalby

N. Ranjith, Dr Nash Ranjith Research Centre, Merebank, Durban; L. Burgess, TREAD Research -

Tygerberg Hospital, Parow; H. Nortje, Unit B1-N1 City Mews, Cape Town; L. Distiller, Centre for

Diabetes and Endocrinology, Johannesburg; I. Mitha, Worthwhile Clinical Trials - Lakeview Hospital,

Benoni; R. Moore, 14 Medigate Medical Centre, Umhlanga Rocks; M. Conradie, Endocrine Unit -

Tygerberg Hospital, Parow; A. Horak, Room 3000 2nd Floor - Vincent Pallotti Hospital, Pinelands; S.

Pillay, Dr SR Pillay Practice, Ottawa, Verulam; H. Wellmann, Helderberg Diabates and Medical Centre,


25

Somerset West, Cape Town; E. Berg, Dr EC Van den Berg Practice - Zuid Afrikaans Hospital, Pretoria;

P. Pillai, Drs Chetty and Pillai Medical Centre, Phoenix; T. Padayachee, Aliwal Shoal Medical Centre,

Umkomaas; C. Corbett, Panorama Medi-Clinic - Suite H01, Cape Town; H. Makan, Suite 6 - Seva

Sadan, Lenasia; J. Wing, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg; Z. Vawda,

Dr ZFA Vawda's Practice, Durban; I. Ebrahim, Suite 309 - Unitas Hospital, Centurion; A. Dalby, Suite

C Ground Floor - Milpark Hospital, Johannesburg; E. Mitha, Suite 3 - Newgate Centre, Johannesburg;

A. Bhorat, Soweto Clinical Trial Centre, Soweto.

Spain

National Lead Investigators: J. Lopez-Sendon and R. Gomis

J. Cruz Fernández, Hospital Universitario Virgen Macarena, Sevilla; C. Muñoz, Hospital General Jerez

de la Frontera, Jerez De La Frontera-Cádiz; J. Bruguera Cortada, Hospital del Mar, Barcelona; A. Castro

Conde, Hospital de Cantoblanco- La Paz, Madrid; C. Calvo, Hospital Universitario de Santiago,

Santiago De Compostela; B. Gil Extremera, Hospital Clínico San Cecilio, Granada; E. Delgado,

Hospital Universitario Central de Asturias, Oviedo; L. Masmiquel, Hospital Son Llàtzer, Palma De

Mallorca; J. García Puig, Hospital Universitario de La Paz, Madrid; L. de Teresa Parreño, Clínica

Mediterranea de Neurociencias, Alicante; D. Mauricio, Hospital Arnau de Vilanova, Lerida; J. Redón,

Hospital Clínico Universitario de Valencia, Valencia; M. Brito, Hosp. Universitario Puerta de Hierro-

Majadahonda, Majadahonda-Madrid; C. Lopez, Centro de Salud El Cristo, Oviedo; J. Segura de la

Morera, Hospital Universitario Doce de Octubre, Madrid;

Sweden

National Lead Investigators: M. Alvarsson and M. Dellborg

C. Linderfalk, Redeby Eksjö, Eksjö; H. Larnefeldt, Rättvikshälsan, Rättvik; A. Olsson, Sthlm Heart

Center, Stockholm; L. Lönneborg, Söråkers vårdcentral, Söråker; M. Ekelund, Hbg lasarett,

Helsingborg; B. Samad, Danderyd, Stockholm; B. Borgencrantz, Capio Läkargruppen AB Örebro,

Örebro; J. Nilsson, Skånes Universitetssjukhus Malmö, Malmö; O. Berglund, Ålidhem Umeå, Umeå; M.

Svensson, SU SS Gbg, Göteborg; T. Mooe, Östersunds sjukhus, Östersund; M. Alvarsson, KS Solna,

Stockholm; D. Curiac, Me3and Gbg, Göteborg; J. Albin, Söråkers vårdcentral, Söråker; E. Angesjö,

Brämhults VC, Brämhult; O. Lannemyr, Länssjukhuset Ryhov, Jönköping; M. Dellborg, SU Östra Gbg,

Göteborg.

Taiwan

National Lead Investigators: C. Chiang and W. Sheu

C. Chiang, Taipei Veterans General Hospital, Taipei; W. Sheu, Taichung Veterans General Hospital,

Taichung; J. Chen, Chang Gung Medical Foundation Kaohsiung Branch, Kaohsiung; K. Tien, Chi Mei

Medical Center, Tainan; K. Ueng, Chung Shan Medical University Hospital, Taichung; W. Lai,

Kaohsiung Medical University Hospital, Kaohsiung; W. Yin, Cheng Hsin General Hospital, Taipei; Y.

Hung, Tri-Service General Hospital, Taipei; K. Shyu, Shin Kong Wu Ho-Su Memorial Hospital, Taipei;

J. Hou, Mackay Memorial Hospital, Taipei; H. Lam, Kaohsiung Veterans General Hospital, Kaohsiung.

Thailand

National Lead Investigators: C. Deerochanawong and P. Sritara

P. Laothavorn, Phramongkutklao Hospital, Bangkok; P. Sritara, Ramathibodi Hospital, Bangkok; S.

Kuanprasert, MaharajNakornChiangMai Hospital, Chiangmai; C. Deerochanawong, Rajavithi Hospital,

Bangkok; W. Khovidhunkit, King Chulalongkorn Memorial Hospital, Bangkok; Y. Benjasuratwong,

Phramongkutklao Hospital, Bangkok; C. Chotinaiwattarakul, Siriraj Hospital, Bangkok; S. Mamanasiri,


26

Ratchaburi Hospital, Ratchaburi; S. Suraamornkul, Vajira Hospital, Bangkok; T. Pratipanawatr,

Srinagarind Hospital, Khon Kaen; W. Nitiyanant, Siriraj Hospital, Bangkok.

United Kingdom

National Lead Investigators: S. Heller, A. Barnett, and K. Ray

R. Pieters, Estuary View Medical Centre, Whitstable; C. Strang, Mortimer Surgery, Mortimer - Reading;

B. Bodalia, The Gables Medical Centre, Coventry; A. Middleton, Fowey River Practice, Fowey; T. Hall,

Knowle House Surgery, Plymouth; G. Chapman, Sunbury Health Centre, Sunbury On Thames; J.

Calvert, Waterloo Medical Centre, Blackpool; R. Reed, Westongrove Research Centre Aston Clinton

Surgery, Aston Clinton - Aylesbury; D. Tam, The Circle Practice, Kenton; G. Butcher, Ecclesfield

Group Practice, Ecclesfield, Sheffield; N. Jones, St Chad's Surgery, Midsomer Norton, Bath; A. Takhar,

Wansford and Kings Cliffe Practice, Wansford - Peterborough; W. Turner, Burbage Surgery, Burbage -

Leicester; D. McNally, Ormeau Health Centre, Belfast; O. Corey, The Avenue Surgery, Warminister; J.

Chapman, Widcombe Surgery, Bath; S. Mohr, The Porch Surgery, Corsham, Bath; S. Edwards, Elm

Tree Surgery, Shrivenham, Swindon.

United states of america

National Lead Investigators: D. Bhatt and J. Davidson

A. Ocampo, Future Care Solution, LLC, Miami, FL; D. Kandath, Saratoga Clinical Research, LLC,

Saratoga Springs, NY; Y. Aude, Valley Heart Consultants, McAllen, TX; W. Ervin, InterMed, PA,

Portland, ME; V. Savin, Kansas City VA Medical Center, Kansas City, MO; R. Anderson, VA

Nebraska-Western Iowa Healthcare System, Omaha, NE; R. Littlefield, Palmetto Research Center, LLC,

Spartanburg, SC; M. Oberoi, Central Jersey Medical Research Center, Elizabeth, NJ; G. Platt, George E.

Platt, MD, Green Cove Springs, FL; S. Yazdani, Virginia Cardiovascular Associates, Manassas, VA; R.

Mangoo-Karim, Gamma Clinical Research Institute, Mission, TX; J. Walder, Black Hills Cardiovascular

Research, Rapid City, SD; H. Gogia, Cardiology Consultants of Orange County Medical Group Inc.,

Anaheim, CA; Y. Chandrashekhar, VA Medical Center, Minneapolis, MN; F. Boccalandro, Permian

Research Foundation, Odessa, TX; W. Rogers Jr., University of Alabama Medical Center, Birmingham,

AL; S. Bilazarian, Pentucket Medical Associates, Haverhill, MA; F. Zieve, McGuire VA Medical

Center, Richmond, VA; Y. Siage, Deaconess Clinic, Inc., Evansville, IN; T. O'Connor, American Health

Network of Indiana, LLC, Greenfield, IN; S. Mudaliar, VA San Diego Healthcare System, San Diego,

CA; A. Nikas, Health Texas Research Institute, San Antonio, TX; R. Giusti, Clinical Research of

Central Florida, Winter Haven, FL; R. Glover, Heartland Research Associates, LLC, Newton, KS; S.

Chilka, Midland Clinical Research Center, Midland, TX; W. French, Los Angeles Biomedical Research

Institute at Harbor-UCLA Medical Center, Torrance, CA; E. Roth, Sterling Research Group, Ltd.,

Cincinnati, OH; N. Singh, Atlanta Heart Specialists, LLC, Cumming, GA; R. Christofferson, North

Ohio Research Ltd., Elyria, OH; M. Stich, Westside Center for Clinical Research, Jacksonville, FL; S.

Dagogo-Jack, University of Tennessee Health Sciences Center, Memphis, TN; J. Allison III, Three

Rivers Medical Associates, Columbia, SC; G. Arroyo Zengotita, Georgina Arroyo Zengotita - Medicina

de Familia, Jardines de Loiza, Loiza, PR; R. Ison, Community Health Care, Inc., Canal Fulton, OH; B.

Iteld, Louisiana Heart Center, Slidell, LA; M. Sulistio, University of Texas Southwestern Medical

Center, Dallas, TX; E. Gonzalez, Eastside Clinical Research Associates, Inc., Los Angeles, CA; T.

Gorman, Great Lakes Medical Research, Westfield, NY; E. Hage-Korban, Kore CV Research, Jackson,

TN; R. Reddy, T& R Clinic, PA, Fort Worth, TX; W. Byars, Mountain View Clinical Research, Greer,

SC; M. Antonishen, Northern Michigan Regional Hospital, Petoskey, MI; S. Benjamin, Universal

Research Group, Tacoma, WA; B. First, Ritchken & First MD's, San Diego, CA; J. Rosado, Florida

Heart and Vascular Center, Leesburg, FL; H. Bruschetta, Humberto Rafael Bruschetta, MD, Kingsville,

TX; P. Mehta, Heartland Research Associates, LLC, Wichita, KS; T. Poling, Heartland Research


27

Associates, LLC, Wichita, KS; C. Rosendorff, James J. Peters VA Medical Center, Bronx, NY; H.

Kerstein, Howard J. Kerstein, MD, Denver, CO; F. Saba, Professional Health Care of Pinellas, Inc., St.

Petersburg, FL; J. Willis, San Gabriel Clinical Research, Georgetown, TX; K. Adams, Baptist Heart

Specialists, Jacksonville, FL; E. Camilo Vazquez, Central Research Clinic of Puerto Rico, Aguas

Buenas, PR; H. Ellison, Rockdale Medical Research Associates, Conyers, GA; B. Kahn, Overlea

Personal Physicians, Baltimore, MD; D. Kereiakes, The Carl & Edyth Lindner Center for Research &

Education at The Christ Hospital, Cincinnati, OH; S. Powell, PMG Research of Bristol, Bristol, TN; P.

Raskin, University of Texas Southwestern Medical Center, Dallas, TX; K. Smith, Burke Primary Care,

Morganton, NC; S. Varma, Boice-Willis Clinic, P.A., Rocky Mount, NC; F. Whittier, Clinical Research

Limited, Canton, OH; R. Casanova, South East Medical Centre, Oakland Park, FL; S. Isserman, Clinical

Trials of America, Inc., Hickory, NC; W. Kaye, Metabolic Research Institute, Inc., West Palm Beach,

FL; W. McGuinn II, North Ohio Research Ltd., Sandusky, OH; A. Bartkowiak Jr., Blair Medical

Associates P.A., Altoona, PA; L. Dworkin, Rhode Island Hospital, Providence, RI; C. Labrador, Carlos

A Labrador, MD, St. Petersburg, FL; D. Podlecki, Longmont Medical Research Network, Longmont,

CO; M. Popovtzer, Southern Arizona VA Healthcare System, Tucson, AZ; S. Aronoff, Research

Institute of Dallas, P.A., Dallas, TX; C. Ballantyne, Baylor College of Medicine, Houston, TX; E.

Gonzalez Ortiz, Elena Gonzalez-Ortiz, M.D., Cidra, PR; A. Mora III, Southwest Clinic, San Antonio,

TX; T. Pitts, Diverse Clinical Research Center of Chicago, LLC, Chicago, IL; S. Reinhardt, Central

Bucks Cardiology, Doylestown, PA; G. Soucie, Blackfoot Medical Center, Blackfoot, ID; W.

Wainwright, Baptist Heart Specialists, Jacksonville Beach, FL; B. Henson, Essentia Institue of Rural

Health, Duluth, MN; N. Sklaver, Medical Specialists Associated, Dallas, TX; R. Arakaki, University of

Hawaii Diabetes and Endocrinology, Honolulu, HI; J. Brown, Internal Medical Associates of Grand

Island, PC, Grand Island, NE; G. Chalavarya, Florida Cardiology Group, Hudson, FL; R. Chochinov,

Ronald H. Chochinov, MD, Ventura, CA; T. Dixon, Northport Veteran Affairs Medical Center,

Northport, NY; M. Kutner, Suncoast Research Group LLC, Miami, FL; R. Perlman, Associated

Cardiovascular Consultants, Voorhess, NJ; A. Raisinghani, University of California San Diego Medical

Center, San Diego, CA; A. Salacata, Endeavor Medical Research, Alpena, MI; V. Awasty, Harrison

Community Research Center, Cadiz, OH; V. Elinoff, Regional Clinical Research, Inc., Endwell, NY; W.

George, Cadillac Clinical Research, LLC, Cadillac, MI; A. LaRochelle-Gryseels, Sharon Regional

Physician Services, Hermitage, PA; A. Mercado, Stewart Medical Group, Alhambra, CA; G. Miller,

Clinical Research Works, Bristol, CT; M. Qureshi, Michigan Heart, PC, Ypsilanti, MI; A. Steljes,

Steljes Cardiology, PC, Henderson, NV; F. Wefald, Clinical Trials of America, Inc., Smithfield, NC; J.

Wilson, PMG Research of Winston-Salem, Winston-Salem, NC; J. Chinn, VA Southern Nevada Health

Care System, North Las Vegas, NV; R. Chuang, Clinical Research Advantage, Inc/Rita B. Chuang,

M.D., Henderson, NV; A. Comulada-Rivera, Instituto de Endocrinologia, Diabetes & Metabolismo,

Bayamon, PR; I. Hartman, Discovery Clinical Trials, Arlington, TX; P. Narayan, Clinical Research

Institute of Northern Virginia, Burke, VA; T. Pacheco, North Ohio Research, Ltd., Lorain, OH; R.

Weiss, Central Maine Medical Center, Lewiston, ME; J. Beavins, American Health Network of Indiana,

LLC, Franklin, IN; J. Creevy, Intercoastal Medical Group, Sarasota, FL; G. Hamroff, NYU Hudson

Valley Cardiology, Cortlandt Manor, NY; R. Hodson, Providence Heart Clinic at The Oregon Clinic

Gateway, Portland, OR; E. Kosinski, Connecticut Clinical Research, LLC, Bridgeport, CT; P. Krichmar,

Research Physicians Network Alliance, Pembroke Pines, FL; R. Patel, Lycoming Internal Medicine,

Inc., Jersey Shore, PA; R. Schneider, Holy Cross Medical Group, Coral Springs, FL; J. Shapiro,

Philadelphia Health Associates - Adult Medicine, P.C., Philadelphia, PA; D. Sharp, Clinincal Research

Advantage, Inc/Internal Medicine Physicians, PC, Omaha, NE; J. Speer, Clinical Research

Advantage/Colorado Springs Health Partners, Colorado Springs, CO; R. Stegemoller, American Health

Network of Indiana, LLC, Avon, IN; F. Waxman, GSA Medical Research, Deerfield Beach, FL; F.

Young Chang, Pasco Cardiology Center, Hudson, FL; E. Braun, Midtown Medical Center, Tampa, FL;


28

F. Eder, United Medical Associates, Binghamton, NY; S. Minor, Austin Heart PLLC, San Marcos, TX;

M. Albert, Acadia Clinical Research, LLC, Bangor, ME; K. Carr, Kenneth W. Carr, M.D., Oceanside,

CA; B. Diaczok, St. Joseph Mercy Oakland, Pontiac, MI; I. Gastman, Waterford Medical Associates PC,

Waterford, MI; V. Gupta, Borgess Research Institute/Borgess Cardiovascular Research, Kalamazoo, MI;

K. Longshaw, Texas Health Physicians Group, Dallas, TX; J. M. Gonzalez-Campoy, MNCOME

Foundation, Eagan, MN; M. Raikhel, Torrance Clinical Research, Lomita, CA; J. Thomas, Medical

University of South Carolina, Charleston, SC; K. Wood, Belleville Family Medical Associates, Ltd.,

Belleville, IL; I. Diab, Paramount Medical Research & Consulting, LLC, Middleburg Hts., OH; J.

Furda, Minneapolis Heart Institute, Baxter, MN; M. Gelernt, Cardiovascular Associates of the Delaware

Valley, PA, Elmer, NJ; M. Halter, Ilumina Clinical Associates, Tyrone, PA; B. House, American Health

Network of Indiana, LLC, Fishers, IN; S. Kaster, Wenatchee Valley Medical Center, Wenatchee, WA;

G. Raad, PMG Research of Charlotte, Charlotte, NC; R. Stamatin, Remedica LLC, Rochester, MI; B.

Barker, Delaware Smith Clinic, Delaware, OH; R. Blonder, Colorado Health Medical Group, Colorado

Springs, CO; R. Bloomberg, Robert J. Bloomberg, MD, PC, Tempe, AZ; R. Burgos Calderon, RCMI-

Clinical Research Center, Rio Piedras, PR; A. Carrol, Center for Thyroid Diseases and Endocrinology,

Beachwood, OH; A. Comerota, Jobst Vascular Center, Toledo, OH; M. Feinglos, Duke University

Medical Center, Durham, NC; D. Henderson, Cardiology Research Associates, Daytona Beach, FL; R.

Kastelic, Ilumina Clinical Associates, Johnstown, PA; L. Stonesifer, Larry D Stonesifer, MD, Federal

Way, WA; J. Talano, Southwest Florida Research, LLC, Naples, FL; P. Ver Lee, EMMC Northeast

Cardiology Associates, Bangor, ME; J. Brosseau, Altru Health System, Grand Forks, ND; W. Clark,

Oregon Health and Sciences University (Oregon Stroke Center), Portland, OR; E. Cohen, Metabolic

Research Institute, Boynton Beach, FL; J. Fialkow, Cardiovascular Research Center of South Florida,

Miami, FL; K. Horton, IMED Healthcare Associated, PLLC, San Antonio, TX; H. Kozman, SUNY

Upstate Medical University, Syracuse, NY; J. McGill, Washington University, St. Louis, MO; C.

Mihills, Southlake Clinical Trials, Southlake, TX; R. Poonawala, Family Practice Centre South, Austin,

TX; K. Shore, Medical Clinic of North Texas, Plano, TX; L. Tejada, St. Luke's Hospital and Health

Network, Bethlehem, PA; R. Torres, Caribbean Clinical Trials, Corp, San Juan, PR; W. Wright, Esse

Health Cardiology Consultants, St. Louis, MO; G. Calatayud, Del Rosario Medical Center, Inc.,

Huntington Park, CA; H. Chandna, Victoria Heart and Vascular Center, Victoria, TX; R. Drozdiak,

Ilumina Clinical Associates, Clymer, PA; R. Fink, Diabetes and Endocrine Associates, La Mesa, CA; R.

Gill, Virginia Commonwealth University, Richmond, VA; M. Glandt, Bronx-Lebanon Hospital Center,

Bronx, NY; D. Gottlieb, Daniel W. Gottlieb, MD, PS, Burien, WA; T. Hack, Primary Care Cardiology

Research, Inc., Ayer, MA; J. Kay, Clinical Research Advantage, Inc/Ridge Family Practice, Council

Bluffs, IA; V. Mansouri, Saint Thomas Research Institute, Nashville, TN; T. McKnight, Prairie Fields

Family Medicine, P.C., Fremont, NE; E. Mostel, Palm Beach Gardens Research Center, LLC, Palm

Beach Gardens, FL; L. Schmidt, Genova Clinical Research, Tucson, AZ; H. Seide, Daytona Heart

Group, Daytona, FL; E. Sonel, VA Pittsburgh Healthcare System, Pittsburgh, PA; R. Taylor, North

Memorial Heart and Vascular Institute, Robbinsdale, MN; M. Velasquez, The George Washington

University (Medical Faculty Associates), Washington, DC; E. Bretton, Albuquerque Clinical Trials,

Inc., Albuquerque, NM; R. Feldman, MediQuest Research Group Inc. at Munroe Regional Medical

Center, Ocala, FL; A. Hartman, Virginia Research Center, LLC, Midlothian, VA; K. Hershon, North

Shore Diabetes and Endocrine Associates, New Hyde Park, NY; C. Leach, Charles R. Leach, MD,

Arlington, TX; E. Martin, Martin Diagnostic Clinic, Tomball, TX; F. Mohiuddin, Apollo Medical

Research, LTD, Niles, IL; Y. Naygandhi, Northwest Med Care P.A., Houston, TX; T. Riske, Hayden

Lake Family Physicians, Hayden Lake, ID; S. Schima, The Cardiac Center of Creighton University,

Omaha, NE; E. R. Uzoaga, Oxford Clinical Research, LLC, Houston, TX; H. Ward, Clinical Research

Works, LLC, Southington, CT; R. Weinstock, SUNY Upstate Medical University, Syracuse, NY; T.

Williams, Texas Health Physicians Group, Irving, TX; A. Altschuller, Hawthorn Medical Associates,


29

North Dartmouth, MA; T. Aoki, Aoki Diabetes Research Institute, Sacramento, CA; S. Blumenthal,

Zablocki VAMC, Milwaukee, WI; A. Cash, Ilumina Clinical Associates, Indiana, PA; G. Eisner, Gilbert

Eisner, M.D. Research, Washington, DC; J. Gutmann, Deaconess Clinic, Inc., Evansville, IN; M. Hagan,

Montana Health Research Institute, Inc., Billings, MT; A. Kabour, Cardiovascular Research Center,

LLC, Toledo, OH; T. Markus, The Dayton Heart Center, Dayton, OH; W. McKenzie, M & O Clinical

Research, LLC, Ft. Lauderdale, FL; M. Moursi, Central Arkansas Veteran's Healthcare System, Little

Rock, AR; P. Mystkowski, The Hope Heart Institute, Bellevue, WA; F. Ovalle, University of Alabama

at Birmingham, Birmingham, AL; R. Perkins, Texas Health Physicians Group, Grapevine, TX; L.

Popeil, Magnolia Research Group, Inc., Ocala, FL; R. Saniuk, Clinical Research Advantage,

Inc/Bellevue Family Practice, P.C., Bellevue, NE; Y. Sierra, Dra. Yolanda Sierra Quiñones, Medicina

Interna, Toa Baja, PR; O. Alvarado, Medical Group of Texas, Fort Worth, TX; J. Anderson, Integris

Cardiovascular Physicians LLC, Oklahoma City, OK; M. Bajaj, Baylor College of Medicine, Houston,

TX; R. Blank, Southern Peidmont Primary Care, Presbyterian Novant Heart & Wellness, Monroe, NC;

A. Chu, Amarillo Heart Clinical Research Institute Inc., Amarillo, TX; L. Levinsky, CPL Associates,

LLC, Buffalo, NY; P. Levy, Phoenix Endocrinology Clinic, Ltd., Phoenix, AZ; J. Osborne, State of the

Heart Cardiology, Grapevine, TX; H. Pavon, Internal Medicine, Kidney & Hypertension Center,

Norfolk, VA; D. Sanderlin, Lone Star Clinical Research, Houston, TX; G. Schaer, Rush University

Medical Center, Chicago, IL; S. Zarich, Bridgeport Hospital, Bridgeport, CT; K. Atassi, Northwest

Indiana Cardiovascular Physicians, P.C., Valparaiso, IN; C. Bayron, Interventional Cardiac Consultants,

PLC, Trinity, FL; M. Casagrande, West Houston Area Clinical Trial Consultants LLC, Houston, TX; D.

Das, St. Vincent Heart Clinic Arkansas, Little Rock, AR; M. Gimness, Clinical Research of Central

Florida, Plant City, FL; F. Handel, Schuster Cardiology Associates Inc., Kettering, OH; T. Kinstrey,

Family Medical Clinic, Shreveport, LA; S. Leu, Baptist Heart Specialists, Jacksonville, FL; K. Osei, The

Ohio State University Medical Center, Columbus, OH; J. Soba Nouel, Jose M. Soba Medicina General,

Juncos, PR; Z. Soltani, LSU Health Sciences Center, Department of Internal Medicine, Section of

Nephrology and Hypertension, Kenner, LA; H. Sussman, Iconic Clinical Trials, Pembroke Pines, FL; K.

Chiu, City of Hope National Medical Center, Duarte, CA; R. Duda Jr., Oklahoma Heart Institute, Tulsa,

OK; K. Farnsworth, Northern Indiana Research Alliance, Fort Wayne, IN; M. Lano, Ridgeview

Research, Chaska, MN; F. Lee, Guthrie Clinic Ltd. & Robert Packer Hospital, Sayre, PA; P. Levin,

MODEL Clinical Research, Baltimore, MD; S. Pratt, West Coast Research LLC, San Ramon, CA; R.

Richwine, Texas Health Physicians Group, Fort Worth, TX; L. Ruiz-Rivera, Endocrine Lipid Diabetes

Research Institute, Ponce, PR; J. Turner, Cardiac Wellness Consultants SC (Division of Diverse Clinical

Research Center of Chicago, LLC), Chicago, IL; J. Wood, Texas Health Physicians Group, Richardson,

TX; W. Zigrang, William D. Zigrang MD, Burlingame, CA; H. Baquerizo, Hernan R. Baquerizo, M.D.,

Miami, FL; C. Benitez-Colon, Dr. Carlos Benitez Colon-Medicinia Interna, San Juan, PR; J. Demattia,

JVC Family Medicine, Houston, TX; V. Desai, Charles River Medical Associates, Natick, MA; D. Fitz-

Patrick, East-West Medical Research Institute, Honolulu, HI; S. Goral, University of Pennsylvania,

Philadelphia, PA; A. Odhav, West Houston Area Clinical Trial Consultants LLC, Houston, TX; A.

Prentiss, Prentiss Family Medicine, Colleyville, TX; C. Ruff, Brigham and Women's Hospital, Boston,

MA; W. Wu, Central Cardiovascular Research Foundation, San Antonio, TX; K. Wyne, The Methodist

Hospital Research Institute, Houston, TX; L. Abbott, Lisa G. Abbott, MD, Reno, NV; R. Applegate,

Wake Forest University Baptist Medical Center, Winston-Salem, NC; J. Cabral, Cleveland Clinic

Florida, Weston, FL; P. Kotha, Purushotham and Akther Kotha MD, Inc., La Mesa, CA; P. Ortega,

Central Florida Primary Care, Winter Park, FL; D. Simmons, Central Arkansas Veteran's Healthcare

System, Little Rock, AR.

Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized...

Documents

Transcript of Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized...