Saxagliptin and CardiovascularOutcomes in Patients With Type 2Diabetes and Moderate or SevereRenal Impairment: ObservationsFrom the SAVOR-TIMI 53 TrialDiabetes Care 2015;38:696–705 | DOI: 10.2337/dc14-1850

OBJECTIVE

The glycemic management of patients with type 2 diabetes mellitus (T2DM)and renal impairment is challenging, with few treatment options. We investigatedthe effect of saxagliptin in the Saxagliptin Assessment of Vascular OutcomesRecorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in MyocardialInfarction (TIMI) 53 trial according to baseline renal function.

RESEARCH DESIGN AND METHODS

Patients with T2DM at risk for cardiovascular events were stratified as havingnormal or mildly impaired renal function (estimated glomerular filtration rate[eGFR] >50 mL/min/1.73 m2; n = 13,916), moderate renal impairment (eGFR30–50 mL/min/1.73 m2; n = 2,240), or severe renal impairment (eGFR <30mL/min/1.73 m2; n = 336) and randomized to receive saxagliptin or placebo.The primary end point was cardiovascular death, myocardial infarction, orischemic stroke.

RESULTS

After a median duration of 2 years, saxagliptin neither increased nor decreasedthe risk of the primary and secondary composite end points compared with pla-cebo, irrespective of renal function (all P for interactions ‡0.19). Overall, the riskof hospitalization for heart failure among the three eGFR groups of patients was2.2% (referent), 7.4% (adjusted hazard ratio [HR] 2.38 [95% CI 1.95–2.91], P <

0.001), and 13.0% (adjusted HR 4.59 [95% CI 3.28–6.28], P < 0.001), respectively.The relative risk of hospitalization for heart failure with saxagliptin was similar(P for interaction = 0.43) in patients with eGFR >50mL/min/1.73m2 (HR 1.23 [95%CI 0.99–1.55]), eGFR 30–50 mL/min/1.73 m2 (HR 1.46 [95% CI 1.07–2.00]), and inpatients with eGFR <30 (HR 0.94 [95% CI 0.52–1.71]). Patients with renal impair-ment achieved reductions in microalbuminuria with saxagliptin (P = 0.041) thatwere similar to those of the overall trial population.

CONCLUSIONS

Saxagliptin did not affect the risk of ischemic cardiovascular events, increased therisk of heart failure hospitalization, and reduced progressive albuminuria, irre-spective of baseline renal function.

1Cardiovascular Division, Women’s College Hos-pital, University of Toronto, Toronto, Ontario,Canada2TIMI Study Group, Cardiovascular Division, Brig-ham and Women’s Hospital and Harvard Medi-cal School, Boston, MA3Diabetes Unit, Division of Internal Medicine,Hadassah Hebrew University Hospital, Jerusalem,Israel4Departement Hospitalo-Universitaire-FibrosisInflammation Remodelling, INSERM U-1148,Universite Paris-Diderot, and Hopital Bichat,AP-HP, Paris, France5Imperial College, Royal Brompton Hospital,London, U.K.6Division of Endocrinology, Department of Inter-nal Medicine, University of Texas SouthwesternMedical Center, Dallas, TX7Heart Institute (InCor), University of São PauloMedical School, São Paulo, Brazil8Cardiovascular Division, Pontificia UniversidadCatolica de Chile, Santiago, Chile9AstraZeneca Research and Development,Wilmington, DE10Bristol-Myers Squibb, Princeton, NJ11Division of Cardiovascular Medicine, Depart-ment of Internal Medicine, University of TexasSouthwestern Medical Center, Dallas, TX12Division of Endocrinology and Metabolism,Keenan Research Centre in the Li Ka Shing Knowl-edge Institute of St. Michael’s Hospital, Univer-sity of Toronto, Toronto, Ontario, Canada

Corresponding author: Benjamin M. Scirica,bscirica@partners.org.

Received 1 August 2014 and accepted 25 No-vember 2014.

Clinical trial reg. no. NCT01107886, clinicaltrials.gov.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc14-1850/-/DC1.

© 2015 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered.

Jacob A. Udell,1 Deepak L. Bhatt,2

Eugene Braunwald,2

Matthew A. Cavender,2 Ofri Mosenzon,3

Ph. Gabriel Steg,4,5 Jaime A. Davidson,6

Jose C. Nicolau,7 Ramon Corbalan,8

Boaz Hirshberg,9 Robert Frederich,10

KyungAh Im,2 Amarachi A. Umez-Eronini,2

Ping He,2 Darren K. McGuire,11

Lawrence A. Leiter,12 Itamar Raz,3 and

Benjamin M. Scirica,2 for the SAVOR-TIMI

53 Steering Committee and Investigators

696 Diabetes Care Volume 38, April 2015

CARDIOVASC

ULA

RANDMETABOLICRISK

Patients with concomitant type 2 diabe-tes mellitus (T2DM) and chronic kidneydisease (CKD) are at high risk for athero-thrombotic events and heart failure(1,2). Progressive albuminuria and dec-rements in estimated glomerular filtra-tion rate (eGFR) are each independentpredictors of adverse renal outcomes inpatients with T2DM (3), as well as car-diovascular (CV) death and all-causemortality (4–6). Therefore, patientswith T2DM and CKD represent a patientpopulation in which strategies to reduceCV risk are needed (7).There are few evidence-based treat-

ments of hyperglycemia available forpatients with T2DM and advanced renalimpairment, who are particularly sus-ceptible to adverse reactions such as se-vere hypoglycemia and reduced drugelimination (8–10). Moreover, thesehigh-risk patients have been relativelyunder-represented in large clinical out-comes trials. As a result, there are lim-ited data on the CV safety and efficacy ofglycemic control strategies or interven-tions aimed at the prevention of inci-dent or progressive atheroscleroticdisease in patients with concomitantT2DM and CKD (10,11).Saxagliptin is a selective dipeptidyl

peptidase-4 (DPP-4) inhibitor that isprimarily eliminated by the kidneys(12,13). The Saxagliptin Assessment ofVascular Outcomes Recorded in Pa-tients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction(TIMI) 53 trial randomized 16,492 pa-tients with T2DM who were at risk forCV events to receive saxagliptin or pla-cebo for a median period of 2 years (14).In the trial as a whole, saxagliptin hadno detectable effect on CV events, im-proved glycemic control, and reducedthe development and progression of al-buminuria. However, saxagliptin was as-sociated with a small but statisticallysignificant increase in the risk of hospi-talization for heart failure. The presentprespecified secondary analysis evalu-ated the efficacy and safety of saxaglip-tin compared with placebo according tobaseline renal function in patients withT2DM.

RESEARCH DESIGN AND METHODS

Study Design and ParticipantsThe design, baseline characteristics, andprimary results of the SAVOR-TIMI 53trial have been reported previously

(14–17). Briefly, this was an international,multicenter, double-blind, event-driven,randomized, controlled trial in stable pa-tients with T2DMwhowere atmoderate-to-high risk for CV events based oneither a history of established CV diseaseor multiple vascular risk factors. Patientswere randomly assigned to receive saxa-gliptin or matching placebo. Otherbackground glucose-lowering and CVtherapies, and recommendations fordiet and lifestyle, were at the discre-tion of the responsible physician (18).Open-label initiation and/or titration ofglucose-lowering therapies was allowedthroughout the trial in both arms, exclud-ing the use of DPP-4 inhibitors or GLP-1analogs. All participants provided writteninformed consent, and the study protocolwas approved by the relevant institu-tional review board at each participatingsite and the coordinating center.

Renal Function and Dose AssignmentPatients were excluded from SAVOR-TIMI 53 if they had either a history ofend-stage renal disease (ESRD) onlong-term dialysis, renal transplanta-tion, or a serum creatinine level of.6.0 mg/dL. The eGFR was determinedaccording to the Modification of Diet inRenal Disease formula (19). Randomiza-tion was stratified by baseline renalfunction category (normal or mildly im-paired renal function [eGFR .50mL/min/1.73m2] vs. moderate renal im-pairment [eGFR 30–50mL/min/1.73m2]or severe renal impairment [eGFR,30 mL/min/1.73 m2]) (20) and CV dis-ease status (primary or secondary pre-vention). At least 800 patients withmoderate-to-severe renal impairmentwere targeted for enrollment and ran-domization into the trial. Once ;300patients with severe renal impairmentwere randomized, enrollment of thisgroup was capped.

Saxagliptin is metabolized by the liverinto its main activemetabolite, and bothare primarily eliminated by the kidney.Based upon prior studies, patients withmoderate-to-severe renal impairment(eGFR#50 mL/min/1.73 m2) have max-imal serum concentrations of saxaglip-tin that are 40–100% higher than thosepatients with preserved renal function(21). As a result, one-half the usualdose of saxagliptin is recommended forpatients with moderate-to-severe renalimpairment or ESRD (12,21). Patients

were assigned to receive the studydrug dose at baseline based upon theeGFR calculated during the screeningvisit (5mg daily or 2.5 mg daily in patientswith an eGFR #50 mL/min/1.73 m2).There was a single dose adjustment to2.5 mg daily in those patients in whomrenal impairment developed (eGFR,50mL/min/1.73 m2) during the study pe-riod. Patients were to continue receivingthe study drug even if further renal im-pairment, ESRD, or initiation of long-termdialysis occurred.

End PointsThe primary end point was the time tothe first event of a composite of CVdeath, myocardial infarction (MI), or is-chemic stroke. Themajor secondary endpoint included the primary compositeplus hospitalization for heart failure,coronary revascularization, or unstableangina. Each component of the compos-ite primary or secondary end point wasadjudicated by an independent clinicalevents committee blinded to studygroup assignment, according to prespe-cified criteria that have been reportedpreviously (14,17). A prespecified renallaboratory end point included the risk ofprogressive microalbuminuria, whichwas defined as the number and propor-tion of patients with worsening of, nochange in, or improvement in urinaryalbumin-to-creatinine ratio (ACR),which was defined as a shift from base-line category (,3.4, $3.4 to #33.9, or.33.9 mg/mmol) to the end of treat-ment. Two prespecified clinical renalend points were defined as follows: 1)the composite of a doubling of serumcreatinine level, initiation of long-termdialysis, renal transplantation, or serumcreatinine level .6 mg/dL and 2) theprior composite renal end point to-gether with death. Hypoglycemic endpoints included hospitalization for hy-poglycemia and major hypoglycemicevents, identified by the investigator ifthe event required intervention by athird party. Other adverse events andsevere adverse events were also re-corded, as previously described (14,16).

Statistical AnalysisBaseline characteristics of patients wereexamined by categories of renal func-tion. Aggregate and treatment-specificevent rates across the three renal func-tion groups are presented as 2-yearKaplan-Meier estimates. Cumulative

care.diabetesjournals.org Udell and Associates 697

event rates were also calculated for theprimary end point by stratifying patientson the basis of renal function and estab-lished CV disease. The influence of renalfunction on outcomes was estimatedusing a Cox proportional hazards modelwith a restricted cubic spline function toderive hazard ratios (HRs) and 95% CIsfor decrement in eGFR levels and for athreshold effect (22,23). Models wereadjusted for clinical risk factors, includ-ing age, sex, current tobacco use, historyof hypertension, presence of hypercho-lesterolemia, established CV disease,and heart failure. Models containingthe aforementioned clinical variableswere further adjusted for urinary ACR.The statistical analysis plan prespeci-

fied testing the efficacy and safety of therandomized comparison in patients withmoderate and severe renal dysfunctionfor consistency with the overall trial results(14,16). All analyses were conducted on anintention-to-treat basis among patientswho underwent randomization. The ho-mogeneity of treatment effects on the oc-currence of the primary and secondary endpoints across subgroups of renal functionstatusdcategorized three-way (eGFR.50mL/min/1.73 m2, 30–50 mL/min/1.73 m2,and ,30 mL/min/1.73 m2) and dichoto-mously (eGFR .50 mL/min/1.73 m2 and#50 mL/min/1.73 m2)dwas examinedusing a Cox proportional hazards modelstratified by baseline CV disease status,and included terms for randomizedtreatment and an interaction betweentreatment and renal function category.Comparisons of emergent adverseevents by treatment assignment werecalculated using either a x2 test or aFisher exact test. The statistical soft-ware package SAS (version 9.3; SAS In-stitute, Cary, NC) was used for allanalyses, with a two-sided P value,0.05 considered to be statistically sig-nificant. All analyses were performed bythe TIMI Study Group. The academic au-thors take full responsibility for the in-tegrity of the database and analyses.

RESULTS

Baseline CharacteristicsAmong the 16,492 patients with T2DMwho were randomized, the medianeGFR was 71.7 mL/min/1.73 m2 (inter-quartile range 57.1–86.4). There were13,916 (84.4%) patients with normal ormildly impaired renal function (eGFR.50 mL/min/1.73 m2), 2,240 patients

(13.6%) with moderate renal impair-ment (eGFR 30–50 mL/min/1.73 m2),and 336 patients (2.0%) with severe renalimpairment (eGFR,30 mL/min/1.73 m2)at baseline. Baseline characteristicsbetween treatment groups were wellbalanced within each renal group.

Patients with more severe renal im-pairmentwere older andmore frequentlyfemale and had a longer duration ofdiabetes, a higher prevalence of priorheart failure, a lower fasting serum glu-cose level, a higher urinary ACR, andhigher levels of the N-amino terminalfragment of the prohormone B-type na-triuretic peptide compared with patientswith normal or mildly impaired renalfunction (Table 1). Additionally, patientswith moderate and severe renal impair-ment were less frequently treated atbaseline with metformin and sulfonylur-eas, and were more frequently treatedwith insulin (Supplementary Table 1).

CV and Other Outcomes According toRenal FunctionHigher rates of all CV, renal, and hypo-glycemic events were observed withprogressive renal impairment. For in-stance, in aggregate, patients with nor-mal or mildly impaired renal function(eGFR .50 mL/min/1.73 m2) had a2-year risk of CV death, MI, or ischemicstroke of 6.4% (referent), comparedwith 11.2% in patients with moderaterenal impairment (adjusted HR 1.48[95% CI 1.28–1.71], P , 0.001) and15.9% in patients with severe renal im-pairment (adjusted HR 2.52 [95% CI1.90–3.26], P , 0.001) (Fig. 1A). Risk ofhospitalization for heart failure amongthese three groups of patients was2.2% (referent), 7.4% (adjusted HR2.38 [95% CI 1.95–2.91], P , 0.001),and 13.0% (adjusted HR 4.59 [95% CI3.28–6.28], P , 0.001), respectively(Fig. 1B). A similar pattern was observedwith regard to CV death (Fig. 1C). Therisk associated with CV death, MI, orischemic stroke and hospitalization forheart failure remained significant evenafter further adjustment for urinary ACR(Supplementary Table 2).When patientswere further stratified by either thepresence of moderate-to-severe renalimpairment (eGFR #50 mL/min/1.73 m2)or a history of established CV disease,each group demonstrated a compara-ble elevated risk of ischemic CV events,with markedly elevated risk among

patients presenting with both risk fac-tors simultaneously (SupplementaryFig. 1).

Spline models demonstrated that theinfluence of eGFR on the risk of the pri-mary end point was nonlinear; a nadirin risk was observed at an eGFR of;86 mL/min/1.73 m2 (SupplementaryFig. 2). Progressively lower eGFRdemonstrated a linear association withthe risk of the primary end point inde-pendent of age, sex, current tobaccouse, and history of hypertension, hyper-cholesterolemia, established CV dis-ease, and heart failure. A more gradualrelationship of risk with an increasingeGFR of .86 mL/min/1.73 m2 was alsoobserved. Patients with an eGFR of#86mL/min/1.73 m2 had a significantlyhigher adjusted risk of CV death, MI, orischemic stroke compared with patientswith normal renal function (adjusted HR1.25 [95% CI 1.08–1.46], P = 0.003).

Efficacy and Safety of Saxagliptinin Patients With Moderate-to-SevereRenal ImpairmentThe relative risk of the primary endpoint and major secondary end pointwith saxagliptin relative to placebo wassimilar, irrespective of renal impairment(Table 2 and Fig. 2). Similarities in treat-ment effect were also observed for theother CV end points across renal cate-gories (all P for interactions $0.19),though, given the small size of the se-vere renal impairment cohort (n = 336),the number of events was small. Resultswere similar when renal function wasanalyzed dichotomously at an eGFR of#50 mL/min. (Supplementary Table 3and Supplementary Fig. 3).

The frequency of progressive diabeticnephropathy, as reflected in the urinaryACR, was significantly reduced with sax-agliptin compared with placebo in allpatients except those with severe renalimpairment (Table 3). Specifically, patientswith normal or mildly impaired renalfunction (P , 0.0001) and moderate-to-severe renal impairment (P = 0.041)randomized to saxagliptin had more im-provement and less worsening of uri-nary ACR compared with the placebogroup (Supplementary Table 4). Resultsin patients with severe renal impair-ment were not significant (P = 0.61).Other renal end points occurred at rela-tively balanced rates in patients treatedwith saxagliptin compared with placebo,

698 Saxagliptin in T2DM Patients and Renal Impairment Diabetes Care Volume 38, April 2015

irrespective of renal impairment (Fig. 2and Supplementary Table 5).Regarding glycemic end points, pa-

tients treated with saxagliptin had sig-nificantly lower HbA1c levels comparedwith those treatedwith placebo at 1 year,irrespective of baseline renal status. Forexample, median HbA1c at 1 year waslower in saxagliptin-treated patientswith normal or mildly impaired renalfunction (7.3% [56 mmol/mol] vs. 7.6%[60 mmol/mol], P , 0.0001), moderaterenal impairment (7.4% [57 mmol/mol]vs. 7.6% [60 mmol/mol], P = 0.0009),and severe renal impairment (7.1% [54

mmol/mol] vs. 7.7% [61 mmol/mol], P =0.002), and these differences persistedthroughout the follow-up period (datanot shown). Similarly, the relative likeli-hood of patients treated with saxagliptinrequiring the addition or increase ofany new anti-hyperglycemic medication,including the initiation of insulin therapy,was lower compared with placebo, irre-spective of renal impairment (both P forinteractions$0.17) (Fig. 2).

Few hospitalizations for hypoglyce-mia occurred during the study, thoughthe risk was highest in patients withmoderate or severe renal impairment

(Fig. 2). Similarly, the relative risk of ma-jor hypoglycemia with saxagliptin ther-apy compared with placebo was lowestin patients with severe renal impair-ment (4.84% vs. 6.39%, HR 0.65 [95%CI 0.26–1.58], P = 0.35) compared withpatients with both normal or mildlyimpaired renal function (1.45% vs.1.30%, HR 1.11 [95% CI 0.84–1.47],P = 0.46) and moderate renal impair-ment (5.73% vs. 3.31%, HR 1.91 [95%CI1.27–2.92],P=0.002,P for interaction=0.03) (Fig. 2). When considered dichoto-mously, the absolute risk difference withsaxagliptin was higher in patients with

Table 1—Baseline characteristics according to renal function

CharacteristicseGFR .50 mL/min/1.73 m2

(n = 13,916)eGFR 30–50 mL/min/1.73 m2

(n = 2,240)eGFR ,30 mL/min/1.73 m2

(n = 336) P

Demographic characteristicsAge, years 64.0 (59.0–70.0) 70.0 (64.0–75.0) 70.0 (64.0–75.0) ,0.0001Female sex 4,355 (31.3) 948 (42.3) 152 (45.2) ,0.0001Weight, kg 86.1 (74.8–99.8) 85.0 (73.5–100.0) 84.0 (72.2–97.0) 0.046BMI, kg/m2 30.4 (27.2–34.3) 31.0 (27.6–35.2) 31.0 (27.2–34.5) ,0.0001

Medical historyDuration of diabetes, years 10.0 (4.9–15.8) 13.2 (7.4–20.6) 15.7 (10.2–24.6) ,0.0001Established atherosclerotic disease 10,809 (77.7) 1,921 (85.8) 229 (68.2) ,0.0001Hypertension 11,301 (81.2) 1,895 (84.6) 296 (88.1) ,0.0001Dyslipidemia 9,760 (70.1) 1,714 (76.5) 265 (78.9) ,0.0001Prior MI 5,209 (37.4) 919 (41.0) 109 (32.4) 0.0006Prior heart failure 1,577 (11.3) 456 (20.4) 72 (21.4) ,0.0001Prior coronary revascularization 5,900 (42.4) 1,101 (49.2) 122 (36.3) ,0.0001

Clinical and laboratory measurementsSystolic blood pressure, mmHg 136.5 (125.0–147.0) 136.5 (124.5–148.0) 140.0 (129.0–151.5) 0.0002Diastolic blood pressure, mmHg 80.0 (71.5–85.5) 76.5 (69.0–83.25) 78.5 (70.0–84.0) 0.0001HbA1c% 7.6 (6.9–8.7) 7.6 (6.9–8.7) 7.6 (7.0–8.7) 0.49mmol/mol 60 (52–72) 60 (52–72) 70 (53–72) 0.49

Fasting serum glucose, mg/dL 146.0 (120.0–183.0) 139.0 (111.0–180.0) 137.0 (103.0–175.0) ,0.0001eGFR, mL/min/1.73 m2 75.6 (64.3–89.5) 42.9 (37.5–46.8) 24.7 (21.3–27.8) ,0.0001ACR, mg/mmol 1.6 (0.7–6.0) 4.6 (1.2–27.5) 36.2 (5.5–136.6) ,0.0001ACR ,0.0001,3.4 mg/mmol 8,691 (65.3) 944 (44.4) 61 (19.5)3.4 to #33.9 mg/mmol 3,624 (27.2) 708 (33.3) 94 (30.0).33.9 mg/mmol 1,004 (7.5) 476 (22.4) 158 (50.5)

NT-proBNP, pg/mL 121.2 (57.45–267.5) 328.5 (148.6–842.0) 668.6 (251.7–1,667.0) 0.0001

Baseline CV medicationsAspirin 10,501 (75.5) 1,669 (74.5) 234 (69.6) 0.036Statins 10,814 (77.7) 1,834 (81.9) 269 (80.1) ,0.0001b-Blockers 8,379 (60.2) 1,554 (69.4) 229 (68.2) ,0.0001Diuretics 5,503 (39.5) 1,447 (64.6) 248 (73.8) ,0.0001ACE inhibitors 7,611 (54.7) 1,182 (52.8) 147 (43.8) 0.0001Angiotensin receptor blockers 3,708 (26.6) 750 (33.5) 137 (40.8) ,0.0001Calcium antagonists 4,312 (31.0) 899 (40.1) 167 (49.7) ,0.0001

Baseline anti-hyperglycemic medicationsMetformin 10,355 (74.4) 1,051 (46.9) 67 (19.9) ,0.0001Sulfonylurea 5,702 (41.0) 829 (37.0) 102 (30.4) ,0.0001Thiazolidinediones 831 (6.0) 136 (6.1) 11 (3.3) 0.11Insulin 5,380 (38.7) 1,238 (55.3) 214 (63.7) ,0.0001None 632 (4.5) 88 (3.9) 15 (4.5) 0.43

Data are reported as the median (interquartile range) or n (%), unless otherwise indicated. NT-proBNP, N-amino terminal fragment of theprohormone B-type natriuretic peptide.

care.diabetesjournals.org Udell and Associates 699

moderate-to-severe renal impairment(Supplementary Table 5).

The emergence of any adverse eventor severe adverse event increased in pa-tients with progressive renal impairmentand occurred in similar proportions in pa-tients with normal or mildly impairedrenal function andmoderate renal impair-ment, respectively (Supplementary Table6). At least one adverse event occurred in152 (88%) saxagliptin-treated patientswith severe renal impairment comparedwith 126 (77%) patients treated with pla-cebo (P = 0.006), with no significant differ-ence in severe adverse events.

CONCLUSIONS

In this analysis of patients with T2DM inthe SAVOR-TIMI 53 trial, therewere fourmajor findings. First, subjects with moreadvanced nephropathy in the form ofprogressive renal impairment had a sig-nificantly higher risk of CV events com-pared with patients with normal ormildly impaired renal function. Second,the CV effect of saxagliptin, includinghospitalization for heart failure, in pa-tients with moderate-to-severe renalimpairment was consistent with that inpatients with normal or mildly impairedrenal function. Third, treatment withsaxagliptin resulted in a modest, but sig-nificant, improvement in glycemic con-trol, even though patients assigned toreceive placebo had higher rates ofadd-on glycemic therapy, which mayhave attenuated any differences seenwith saxagliptin (14). While saxagliptinalso prevented progressive microalbu-minuria in patients with moderate-to-severe renal impairment, it did notaffect other renal end points. Fourth,major hypoglycemia, although infre-quent, was approximately three timesmore frequent in patients with ne-phropathy, with higher rates in allpatients treated with saxagliptin com-pared with placebo except those withsevere renal impairment. This singlefinding of heterogeneity may be dueto differences in concomitant anti-hyperglycemic medications such as sulfo-nylureas or the play of chance (12). To thebest of our knowledge, this is the largestcohort of patients in a clinical outcomestrial to provide efficacy and safety data ofan anti-hyperglycemic agent in patientswith T2DM and CKD (10–12).

The presence of proteinuric nephrop-athy, including early microalbuminuria

Figure 1—Cumulative incidence curves for the composite of CV death, MI, or ischemic stroke (A);hospitalization for heart failure (B); and CV death (C) in the SAVOR-TIMI 53 trial (n = 16,492)categorized by renal function. Patients are categorized into normal ormildly impaired renal func-tion (eGFR .50 mL/min/1.73 m2), moderate renal impairment (eGFR 30–50 mL/min/1.73 m2),or severe renal impairment (eGFR ,30 mL/min/1.73 m2). P values are for trend across renalfunction groups.

700 Saxagliptin in T2DM Patients and Renal Impairment Diabetes Care Volume 38, April 2015

and decrement in eGFR, is considered anindependent risk factor of future ath-erothrombotic events and CV death inpatients with T2DM (3–6). In the pres-ent analyses, within each group of pa-tients with stepwise worsening of renalfunction, atherothrombotic risk in-creased nearly threefold; whereas therisk was elevated threefold to sixfoldfor those with heart failure. These pa-tients represent a growing populationfor targeting risk reduction with ade-quate glycemic control and preventionof progressive nephropathy (7,9,10).Whether improvement in levels ofeither serum glucose and/or urinary al-bumin may translate into a cardiopro-tective benefit remains controversial(24,25). Hypoglycemia, either majorevents or those requiring hospital-ization, occurred infrequently in thispopulation. Patients with moderate-to-severe renal impairment had higheroverall rates of hypoglycemia, thoughthe relative risk with saxagliptin wassimilar to that in patients with normalor mildly impaired renal function, likelyreflecting the preferential use of insulinversus sulfonylureas in patients withworsening renal function.

The choice of anti-hyperglycemicagent in patients with renal impairmentis challenging in light of the lack of out-comes data in patients with T2DM andCKD (9,10). For instance, metformin istypically recommended as first-linetherapy in patients with mild renal im-pairment (8,26). Historically, cautionhas been advised with the use of met-formin in patients with established CVdisease or moderate-to-severe renal im-pairment because of concerns about lac-tic acidosis in patients with reducedrenal clearance (27). However, largecontemporary registries with metfor-min suggest no additional risk and rela-tive effectiveness in CV protection andmortality in patients with T2DM andCKD or CV disease (28–30). There arelimited CV outcomes data for the useof sulfonylureas and insulin in patientswith T2DM and CKD, and these agentscan increase susceptibility to hypoglyce-mia as a result of reduced renal clear-ance (9,10).

Among the therapies with outcomesdata from large trials, glitazones reduceprogressive microalbuminuria in pa-tients with T2DM but increase weightand heart failure (31–35). Insulin

Table

2—Two-yearCV

endpoints

acco

rdingto

renalfunctio

n

Endpoint

eGFR

.50

mL/m

in/1.73

m2

eGFR

30–50

mL/m

in/1.73

m2

eGFR

,30

mL/m

in/1.73

m2

Pfor

interactio

n*

Saxagliptin

5mg

(n=6,986)

Placebo

(n=6,930)

HR

(95%CI)

P

Saxagliptin

2.5mg

(n=1,122)

Placeb

o(n

=1,118)

HR

(95%CI)

P

Saxagliptin

2.5mg

(n=172)

Placeb

o(n

=164)

HR

(95%CI)

P

CVdeath

,MI,isch

emicstro

ke6.55%

6.28%1.01

(0.88–1.15)

0.9311.0%

11.5%1.02

(0.79–1.30)

0.9014.7%

17.2%0.83

(0.49–1.39)

0.480.79

CVdeath

,MI,isch

emicstro

ke,hospitalizatio

nforHF,co

ronary

revascularizatio

n,U

A

11.7%11.1%

1.03(0.93

–1.13)0.61

18.7%18.6%

1.04(0.86

–1.27)0.66

21.3%25.4%

0.80(0.51

–1.23)0.31

0.56

CVdeath

2.59%2.28%

1.06(0.86

–1.31)0.58

6.29%6.36%

1.00(0.72

–1.38)1.00

8.01%7.58%

0.88(0.42

–1.81)0.73

0.87

MI

2.74%3.06%

0.88(0.73

–1.07)0.21

5.44%4.39%

1.30(0.89

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0.79(0.38

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care.diabetesjournals.org Udell and Associates 701

glargine had a neutral effect on CV out-comes in the Outcome Reduction WithInitial Glargine Intervention (ORIGIN)trial, but specific results in the 1,942 pa-tients with albuminuria have yet to bereported (36). The DPP-4 inhibitor

alogliptin had neutral effects on overallCV outcomes in patients with T2DM af-ter an acute coronary syndrome event inthe Examination of Cardiovascular Out-comes with Alogliptin versus Standardof Care (EXAMINE) trial (37). However,

among the 1,565 patients withmoderate-to-severe renal impairment, there was atrend toward an increase in CV death,MI, or stroke (HR 1.15 [95% CI 0.91–1.46]) compared with 3,815 patientswith normal or mildly impaired renal

Figure 2—Effect of saxagliptin on the risk of clinical outcomes in patients categorized by eGFR. Patients were categorized at baseline as havingnormal or mildly impaired renal function (eGFR.50 mL/min/1.73 m2, N = 13,916), moderate (eGFR 30–50 mL/min/1.73 m2, N = 2,240), or severerenal impairment (eGFR,30 mL/min/1.73 m2, N = 336). Shown are Kaplan-Meier (KM) rate estimates of each clinical end point through 2 years inthe saxagliptin (S) and placebo (P) arms, respectively. The squares indicate the point estimate, and horizontal lines indicate the 95% CI for the effectin each subgroup. The primary renal end point was defined as the composite of a doubling of serum creatinine level, initiation of long-term dialysis,renal transplant, or serum creatinine level.6mg/dL. Cor. Revasc., coronary revascularization; HF, heart failure; hosp., hospitalization; UA, unstableangina; yr, year.

702 Saxagliptin in T2DM Patients and Renal Impairment Diabetes Care Volume 38, April 2015

function (HR 0.84 [95% CI 0.68–1.04],P for interaction = 0.046). Details ofwhether this trend was observed forother CV end points, including hospitali-zation for heart failure, are yet to be re-ported (37).The strength of the present analysis is

that differences in saxagliptin effectwere ascertained in a large, contempo-rary, randomized, placebo-controlledtrial conducted in international centerswith patients with T2DM and varyingdegrees of renal impairment. This anal-ysis also has limitations: patients withmoderate and severe renal impairmentwere subgroups, with predefined enroll-ment goals that alone were not pow-ered to determine efficacy or safety.Thus, the number of events in the se-vere renal impairment group, in partic-ular, was relatively small. Nevertheless,the treatment effect for various endpoints in patients with and without ad-vanced renal impairment was consistentwith the results of the overall trial. Sec-ond, this analysis was limited to a me-dian of 2 years of follow-up, with noability to determine the effects of saxa-gliptin on CV or renal outcomes beyondthat time. Finally, data on baseline leftventricular function were not available.In conclusion, patients with T2DM

and CKD are a challenging group to treatwith respect to hyperglycemia and pre-vention of progressive nephropathy. In-tensive glucose management strategiesand certain anti-hyperglycemic medica-tions may confer inherent risks, includ-ing adverse CV, renal, and hypoglycemicevents. In the SAVOR-TIMI 53 trial, weobserved that the relative effects of sax-agliptin on CV, renal, and glycemic endpoints were consistent in patients withmoderate-to-severe renal impairment

compared with patients with normal ormildly impaired renal function. Thesefindings highlight the increased CV riskof patients with diabetic nephropathy,and provide data on the efficacy andsafety of saxagliptin to inform clinicianswhen formulating treatment strategiesfor their patients with concomitantT2DM and renal impairment.

Acknowledgments. The authors gratefullyacknowledge the patients, investigators, re-search coordinators, and committee membersof the SAVOR-TIMI 53 trial for their efforts.SAVOR-TIMI 53 Executive Committee: EugeneBraunwald (study chair), Deepak L. Bhatt (co-principal investigator), Itamar Raz (co-principalinvestigator), JaimeA.Davidson, Robert Frederich(nonvoting), Boaz Hirshberg (nonvoting), and Ph.Gabriel Steg.Funding and Duality of Interest. The SAVOR-TIMI 53 trial was funded by AstraZeneca/Bristol-Myers Squibb. J.A.U., M.A.C., K.I., A.A.U.-E., andP.H. report they are or were members of theTIMI Study Group, which received researchgrant support from AstraZeneca and Bristol-Myers Squibb. D.L.B. discloses the following re-lationships: advisory board for Elsevier PracticeUpdate Cardiology, Medscape Cardiology, andRegado Biosciences; board of directors forBoston VA Research Institute and Society ofCardiovascular Patient Care; chair of the Amer-ican Heart Association Get With The GuidelinesSteering Committee; data monitoring com-mittees for Duke Clinical Research Institute,Harvard Clinical Research Institute, Mayo Clinic,Population Health Research Institute; honorariafrom the American College of Cardiology (editor,Clinical Trials, Cardiosource), Belvoir Publications(editor in chief, Harvard Heart Letter), DukeClinical Research Institute (clinical trial steeringcommittees), Harvard Clinical Research Institute(clinical trial steering committee), HMP Commu-nications (editor in chief, Journal of InvasiveCardiology), Population Health Research Insti-tute (clinical trial steering committee), SlackPublications (chief medical editor, CardiologyToday’s Intervention), and WebMD (continuingmedical education steering committees); Clini-cal Cardiology (associate editor); Journal of the

American College of Cardiology (section editor,pharmacology); research grants from Amarin,AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon,Medtronic, Roche, Sanofi, and The MedicinesCompany; and unfunded research for FlowCo,PLx Pharma, and Takeda. E.B. discloses researchgrants through the TIMI StudyGroup andBrighamand Women’s Hospital from AstraZeneca andBristol-Myers Squibb. M.A.C. has receivedconsulting fees from AstraZeneca and MerckSharp & Dohme. O.M. discloses the followingrelationships: research grants throughHadassah Hebrew University Hospital fromAstraZeneca and Bristol-Myers Squibb;consulting fees from AstraZeneca and Bristol-Myers Squibb; travel support for attendance atscientific meetings from AstraZeneca andBristol-Myers Squibb; advisory board forAstraZeneca, Bristol-Myers Squibb, Eli Lilly,Novartis, Novo Nordisk, and Sanofi; and speakerfees from AstraZeneca, Bristol-Myers Squibb,Eli Lilly, Merck Sharp & Dohme, Novartis, NovoNordisk, and Sanofi. P.G.S. discloses thefollowing relationships: speaker fees fromAstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer,Roche, and The Medicines Company; consultingfees from Bristol-Myers Squibb, Daiichi-Sankyo,Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer,Sanofi, Servier, and Vivus; honoraria for clinicaltrial steering committee participation fromAstraZeneca, Amarin, GlaxoSmithKline, Otsuka,Sanofi, Servier, and Vivus; and honoraria forpreparation of educational material fromBoehringer Ingelheim. J.A.D. discloses the followingrelationships: honoraria for advisory boardparticipation from Aspire Bariatrics, AstraZeneca,Eli Lilly, Janssen, and Novo Nordisk; speaker feesfrom AstraZeneca, Janssen, Johnson & Johnson,and Novo Nordisk; President of WorldWIDEDiabetes, a not-for-profit foundation; The Execu-tive Committee CME of The University of TexasSouthwestern Medical Center; the editorialboards of The Journal of Diabetes and ALAD, theJournal of the Latin American Diabetes Associa-tion. J.C.N. discloses the following relationships:research grants through the Heart Institute(InCor) at the University of São Paulo MedicalSchool from AstraZeneca, Bristol-Myers Squibb,Daiichi-Sankyo, Eli Lilly, Johnson & Johnson, andSanofi; advisory boards for AstraZeneca, Bayer,and Sanofi; consulting fees from AstraZeneca;travel support for attendance at scientificmeetings from AstraZeneca; speaker fees from

Table 3—Frequency of progressive microalbuminuria by completion of follow-up according to renal function

Total Worsened No change Improved P value*

eGFR .50 mL/min/1.73 m2 (n = 10,621) ,0.0001Saxagliptin 5,380 (50.7) 682 (12.7) 4,139 (76.9) 559 (10.4)Placebo 5,241 (49.3) 790 (15.1) 4,003 (76.4) 448 (8.5)

eGFR 30–50 mL/min/1.73 m2 (n = 1,533) 0.037Saxagliptin 775 (50.6) 134 (17.3) 547 (70.6) 94 (12.1)Placebo 758 (49.4) 166 (21.9) 519 (68.5) 73 (9.6)

eGFR ,30 mL/min/1.73 m2 (n = 206) 0.61Saxagliptin 110 (53.4) 17 (15.5) 76 (69.1) 17 (15.5)Placebo 96 (46.6) 13 (13.5) 72 (75.0) 11 (11.5)

Data are reported as N (%), unless otherwise indicated. The risk of progressive microalbuminuria was defined as a treatment difference in thenumber and proportion of patients with worsening, no change, or improvement in urinary ACR, defined as a shift from baseline category(,3.4,$ 3.4 to# 33.9, or.33.9 mg/mmol) over the duration of follow-up among patients with complete data. *Based on x2 or Fisher exact test.

care.diabetesjournals.org Udell and Associates 703

AstraZeneca, Bayer, and Sanofi; and honorariafor the preparation of educational materialfrom AstraZeneca and Bayer. R.C. discloses hon-oraria through the Pontificia UniversidadCatolica de Chile from Brigham and Women’sHospital during the conduct of this study andserved on the Latin American Advisory Board.B.H. is employedbyAstraZeneca. R.F. is employedby Bristol-Myers Squibb. D.K.M. discloses the fol-lowing relationships: research grants and hono-raria from Brigham andWomen’s Hospital duringthe conduct of this study; personal fees fromBoehringer Ingelheim, Janssen Research andDevelopment LLC, Merck Sharp & Dohme,Brigham and Women’s Hospital, Duke ClinicalResearch Institute, Cleveland Clinic Coordinat-ing Center for Clinical Research, University ofOxford, Eli Lilly USA, Novo Nordisk, F. Hoffmann-LaRoche, GlaxoSmithKline, Takeda PharmaceuticalsNorth America, Bristol-Myers Squibb, Omthera,AstraZeneca, and Regeneron; and nonfinancialresearch support from Gilead Sciences. L.A.L.discloses the following relationships: consultingfees from AstraZeneca, Boehringer Ingelheim,Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline,Janssen, Merck Sharp & Dohme, Novo Nordisk,Roche, Sanofi, Servier, and Takeda; researchgrants through the Keenan Research Centre in theLi Ka Shing Knowledge Institute of St. Michael’sHospital, University of Toronto, fromAstraZeneca,Boehringer Ingelheim, Bristol-Myers Squibb, EliLilly, GlaxoSmithKline, Janssen, Merck Sharp &Dohme, Novo Nordisk, Roche, and Sanofi;speaker fees from Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck Sharp &Dohme, Novartis, Novo Nordisk, Roche, Sanofi,and Takeda; and honoraria for the preparationof educational material from AstraZeneca andBristol-Myers Squibb. I.R. discloses the followingrelationships: consulting fees from Andromeda,AstraZeneca, Bristol-Myers Squibb, and Insu-line; travel support for attendance at scientificmeetings from AstraZeneca; advisory boardsfor AstraZeneca, Bristol-Myers Squibb, Eli Lilly,Medscape, Merck Sharp & Dohme, Novartis,Novo Nordisk, and Sanofi; speaker fees fromAstraZeneca, Bristol-Myers Squibb, Eli Lilly,Johnson & Johnson, Merck Sharp & Dohme,Novartis, Novo Nordisk, and Sanofi; and equitystock ownership in Insuline. B.M.S. disclosesthe following relationships: research grantsthrough the TIMI Study Group and Brighamand Women’s Hospital from AstraZenecaand Bristol-Myers Squibb, Daiichi-Sankyo,GlaxoSmithKline, Johnson & Johnson, BayerHealthcare, Gilead, Eisai, and Merck Sharp &Dohme and consulting fees from Gilead,Lexicon, Arena, Eisai, St. Jude’s Medical, Bristol-Myers Squibb, Forest Pharmaceuticals, BostonClinical Research Institute, Decision Resources,University of Calgary, and Elsevier PracticeUpdate Cardiology. No other potential conflictsof interest relevant to this article were reported.Author Contributions. J.A.U., D.L.B., E.B., P.G.S.,J.A.D., B.H., R.F., I.R., and B.M.S. conceivedand designed the study; helped to acquire,analyze, and interpret the data; helped todraft the manuscript and revise the manu-script for important intellectual content; andapproved the final version of the manu-script submitted. M.A.C., O.M., J.C.N., R.C., K.I.,A.A.U.-E., P.H., D.K.M., and L.A.L. helped to

acquire, analyze, and interpret the data; helpedto draft the manuscript and revise the manu-script for important intellectual content; andapproved the final version of the manuscriptsubmitted. J.A.U. and B.M.S. are the guarantorsof this work and, as such, had full access to all thedata in the study and take responsibility for theintegrity of the data and the accuracy of the dataanalysis.

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