ADA 2019 CREDENCE symposium FINAL for postingmed.stanford.edu/content/dam/sm/sccr/documents/June... · •HRs and 95% CIs for canagliflozin versus placebo were estimated separately

Presented at the 79th Scientific Sessions of the American Diabetes Association; June 11, 2019; San Francisco, CA.

CREDENCECanagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation


Presentation Outline

• Background and Design Rajiv Agarwal

• Recap of Primary Results Meg J. Jardine

• Detailed Effects on CV Outcomes Bruce Neal

• Outcomes by CV Disease History Kenneth W. Mahaffey

• Clinical Implications Bernard Zinman


CREDENCEBackground and DesignRajiv Agarwal, MD


Presenter Disclosures: Rajiv Agarwal, MD

• Research funding – GlaxoSmithKline

• Consulting– Akebia, Bayer, Johnson & Johnson, Boehringer Ingelheim, Takeda, Daiichi Sankyo, Amgen,

AstraZeneca, Sanofi, Celgene, Reata, Relypsa, GlaxoSmithKline, Gilead, ER Squibb and Sons, Fresenius, Ironwood Pharmaceuticals, Otsuka, Opko, and Eli Lilly

• Associate Editor – American Journal of Nephrology, Nephrology Dialysis and Transplantation

• Author – UpToDate


Increasing Incidence and Prevalence of ESKD: US Data

Kirchhoff S. Medicare coverage of end-stage renal disease (ESRD). https://fas.org/sgp/crs/misc/R45290.pdf. Accessed February 13, 2019.

1980

1985

1990

1995

2000

2005

2010

2015

800,000

700,000

600,000

500,000

400,000

300,000

200,000

100,000

0

Incidence Prevalence


Diabetes Is the Leading Cause of Kidney Failure: US Data

United States Renal Data System (USRDS). USRDS Annual Report, Chapter 1. https://www.usrds.org/2012/pdf/v2_ch1_12.pdf. Accessed March 15, 2019.

DiabetesHypertensionGlomerulonephritisCystic kidney

60,000

50,000

40,000

30,000

20,000

10,000

01995Year

Nu

mb

er o

f p

atie

nts

1985 1990 2000 2005 201019951980


Risk of Mortality, Cardiovascular, and Renal Outcomes in Relation to Kidney Disease

Levey AS, et al. Kidney Int. 2011;80(1):17-28.

UACR <30 mg/g UACR 30–299 mg/g UACR ≥300 mg/g


The Only Proven Treatment for Renoprotection in T2DM Before CREDENCE: RENAAL & IDNT

Brenner B, et al. N Engl J Med. 2001;345(12):861-869.

Risk reduction, 16%P = 0.02

RENAAL

Risk reduction, 20%P = 0.02

Lewis EJ, et al. N Eng J Med. 2001;345(12):851-860.

IDNT

Doubling of serum creatinine, ESKD, or death


Many Renal Effects of SGLT2 Inhibition Have Been Proposed

Intraglomerular pressure

Oxidant stressBP/arterial stiffness

AlbuminuriaGlucose

Intrarenalangiotensinogen upregulation

Volume

Inflammation/fibrosisAnd many others…


• CREDENCE began while SGLT2 inhibitor CV outcomes trials were ongoing

• Renal effects were not the primary focus of the CV outcomes trials

Timeline of Major SGLT2 Inhibitor Trials

2014

2015 2016 2017 2018 2019CREDENCE enrollment

CREDENCE ended

DECLAREEMPA-REGOUTCOME

CANVAS Program


Low Renal Risk Populations in CV Outcomes Trials

Low Moderatelyincreased

High Very high

<30

30-44

45-59

60-90

≥90

GFR

cat

egor

ies

(mL/

min

/1.7

3 m

2 )

Albuminuria categories (mg/g)A1: <30 A2: 30-300 A3: >300

DC E

DECLARECANVAS ProgramEMPA-REG OUTCOME

MedianUACR

(mg/g)131218

Mean eGFR(mL/min/1.73 m2)

857674

Total of 29 sustained RRT events reported across trials

Sustained RRT Events

DECLARE Not reportedCANVAS Program 18EMPA-REG OUTCOME 11

DCE

RRT, renal replacement therapy.KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management ofChronic Kidney Disease. https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf.


CV Death, MI, or Stroke by CV Disease History in SGLT2 Inhibitor CVOTs

Zelnicker TA, et al. Lancet. 2019;393(10166):31-39.

Events/Patients Hazard ratio (95% CI)

Patients with atherosclerotic CV disease (secondary prevention)EMPA-REG OUTCOME 772/7020 0.86 (0.74–0.99)

CANVAS Program 796/6656 0.82 (0.72–0.95)

DECLARE-TIMI 58 1020/6974 0.90 (0.79–1.02)

Overall (P = 0.0002) 0.86 (0.80–0.93)Patients with multiple risk factors (primary prevention)CANVAS Program 215/3486 0.98 (0.74–1.30)

DECLARE-TIMI 58 539/10,186 1.01 (0.86–1.20)

Overall (P = 0.98) 1.00 (0.87–1.16)

Favors SGLT2i Favors Placebo

0.5 1.0 2.0


CV Death, MI, or Stroke by CV Disease History in GLP-1 Receptor Agonist CVOTs

Zelnicker TA, et al. Circulation. 2019;139(17):2022-2031.


Patients with atherosclerotic CV disease (secondary prevention)ELIXA 805/6068 1.02 (0.89–1.17)LEADER 1051/6775 0.82 (0.73–0.93)SUSTAIN-6 235/2735 0.72 (0.55–0.93)EXSCEL 1508/10,782 0.90 (0.82–1.00)HARMONY 766/9463 0.78 (0.68–0.90)Overall (P <0.001) 0.87 (0.82–0.92)Patients with multiple risk factors(primary prevention)LEADER 251/2565 1.08 (0.84–1.38)SUSTAIN-6 19/562 1.00 (0.41–2.46)EXSCEL 236/3970 0.99 (0.77–1.28)Overall (P = 0.71) 1.03 (0.87–1.23)

Favors GLP-1 RA Favors Placebo

0.25 0.5 1.0 2.0 4.0


CV Death, MI, or Stroke by CV Disease History in SGLT2 Inhibitor and GLP-1 Receptor Agonist CVOTs

• To date, trials of antihyperglycemic agents for the treatment for T2DM have not shown a CV benefit in participants with CV risk factors (primary prevention) Zelnicker TA, et al. Lancet. 2019; 393(10166):31-39.

Zelnicker TA, et al. Circulation. 2019;139(17):2022–2031.


Patients with atherosclerotic CV disease (secondary prevention)GLP-1 receptor agonists 4365/35,823 0.87 (0.82–0.92)

SGLT2 inhibitors 2558/20,650 0.86 (0.80–0.93)

Overall (P = 0.002) 0.86 (0.80–0.93)Patients with multiple risk factors(primary prevention)GLP-1 receptor agonists 506/7097 1.03 (0.87–1.23)

SGLT2 inhibitors 754/13,672 1.00 (0.87–1.16)

Overall (P = 0.81) 1.01 (0.87–1.19)

Favors GLP-1 RA/SGLT2i Favors Placebo

0.5 1.0 2.0


Objectives of the CREDENCE TrialIn people with T2DM, eGFR 30 to 90 mL/min/1.73 m2, and UACR 300 to 5000 mg/g who are receiving standard of care including a maximum tolerated dose of an ACEi or ARB, to assess whether canagliflozin compared with placebo reduces Primary:

• Composite outcome of ESKD, doubling of serum creatinine, or renal or CV death

Secondary (tested in the prespecified sequence shown):1. CV death or hospitalization for heart failure2. Major cardiovascular events (3-point MACE: CV death, MI, or stroke)3. Hospitalization for heart failure4. ESKD, doubling of serum creatinine, or renal death5. CV death6. All-cause mortality7. CV death, MI, stroke, hospitalization for heart failure, or hospitalization for

unstable angina


New CREDENCE Analyses in This Presentation: ADA 2019

To examine the effects of the SGLT2 inhibitor, canagliflozin, in people with T2DM and established CKD on:

–A range of CV outcomes–The effects on CV and renal outcomes in subgroups with and without

established CV disease


Study Design and Population


Study Design

• Participants were eligible regardless of prior history of CV disease• Participants continued treatment if eGFR was <30 mL/min/1.73 m2 until chronic dialysis was

initiated or kidney transplant occurred

Key inclusion criteria• ≥30 years of age • T2DM and HbA1c 6.5% to 12.0%• eGFR 30 to 90 mL/min/1.73 m2

• UACR 300 to 5000 mg/g• Stable max tolerated labeled dose of

ACEi or ARB for ≥4 weeks

Key exclusion criteria• Other kidney diseases, dialysis, or kidney transplant• Dual ACEi and ARB; direct renin inhibitor; MRA• Serum K+ >5.5 mmol/L• CV events within 12 weeks of screening • NYHA class IV heart failure• Diabetic ketoacidosis or T1DM

2-week placebo run-in

Placebo

Canagliflozin 100 mg

RDouble-blind

randomization(1:1) Follow-up at Weeks 3, 13, and 26 (F2F)

then every 13 weeks (alternating phone/F2F)

Jardine MJ, et al. Am J Nephrol. 2017;46(6):462-472.


Statistical Methods

• Intent-to-treat (ITT) principle; event-driven duration

• Target of 844 events to provide 90% power to detect 20% relative risk reduction for the primary composite outcome

• Outcome analysis based on Cox proportional hazard model stratified by screening eGFR

• Sequential hypothesis testing prespecified for secondary outcomes

• Planned interim analysis with prespecified stopping guidance to occur after 405 confirmed primary efficacy endpoints and 2 years of exposure; reviewed by an Independent Data Monitoring Committee

Jardine MJ, et al. Am J Nephrol. 2017;46(6):462-472.


Analyses of Primary and Secondary Prevention Cohorts

• Analyses for the primary outcome were prespecified in the primary and secondary prevention cohorts; additional analyses were post hoc

• HRs and 95% CIs for canagliflozin versus placebo were estimated separately for the primary and secondary prevention cohorts

• Subgroup analyses within each prevention cohort were assessed by tests for the interaction between the randomized treatment group and the subgroup in stratified Cox proportional hazards models without adjustment for multiple testing


Study Timeline

2014 2015 2016 2017 2018 2019

First participant enrolled

Protocol amendment for lower extremity foot care

1. Excluded participants with prior amputation (≤12 months) or active foot lesion (≤6 months)

2. Required temporary interruption of study drug for patients who developed a lower-extremity event that could be a precursor to ampuationuntil fully resolved

3. Ensured participants had general foot self-care education and foot evaluations at each visit


Study Timeline

2014 2015 2016 2017 2018 2019

First participant enrolled

In July 2018, after the planned interim analysis, the IDMC made the recommendation to stop the CREDENCE trial based on demonstration of efficacy

Protocol amendment for lower extremity foot care

Last participant randomized

Study concluded

Interim analysis


34 Countries, 690 Sites, 4401 Participants

Europe (n = 1368)• Bulgaria• Czech Republic• France• Germany• Hungary • Italy• Lithuania• Poland

(29)(57)(61)(11)(135)(90)(7)(50)

• Romania • Serbia• Slovakia• Spain • Russia*• Ukraine*• United Kingdom

(59)(40)(66)(141)(133)(371)(118)

Asia Pacific* (n = 848)• Australia • China • India• Japan • Korea• Malaysia

(38)(129)(144)(110)(122)(135)

• New Zealand• Philippines• Taiwan• United Arab

Emirates

(61)(71)(37)(1)

Africa (n = 62)• South Africa* (62)

*Analyzed as part of rest of world (n = 1414) in prespecified subgroup analyses.

Central/South America (n = 941)• Argentina• Brazil• Chile• Colombia• Guatemala

(426)(314)(52)(94)(55)

North America (n = 1182)• Canada• Mexico • United States

(172)(303)(707)


Enrollment and Follow-up

4401 randomized

15 (0.7%) did not complete5 (0.2%) withdrew consent

25 (1.1%) did not complete11 (0.5%) withdrew consent

2199 placebo 2202 canagliflozin

2197 (99.9%)vital status known

2174 (98.9%)completed study

2198 (99.8%)vital status known

2187 (99.3%)completed study

4395 (99.9%) vital status known; 4361 (99.1%) completed study*

12,900 screened

8499 excluded

*Patients who completed the study included those who were alive with follow-up at the end of the study or died before final follow-up; 658 (29.9%) participants in the placebo arm and 543 (24.7%) participants in the canagliflozin arm discontinued study treatment before the end of the study.


CREDENCERecap of Primary ResultsMeg J. Jardine, MBBS, PhD, FRACP


Presenter Disclosures: Meg J. Jardine, MBBS, PhD, FRACP

• Supported by a Medical Research Future Fund Next Generation Clinical Researchers Program Career Development Fellowship

• Research funding– Gambro, Baxter, CSL, Amgen, Eli Lilly, and Merck

• Advisory boards – Akebia, Baxter, Boehringer Ingelheim, CSL, and Vifor

• Speaker– Janssen, Amgen, and Roche

• Any consultancy, honoraria, or travel support are paid to her institution


Effects on Intermediate Outcomes


Effects on Intermediate OutcomesHbA1c Systolic Blood Pressure

UACRBody Weight

Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.


Effects on Renal Outcomes


Primary Endpoint Definitions

• ESKD– Chronic dialysis for ≥30 days– Kidney transplantation– eGFR <15 mL/min/1.73 m2 sustained for ≥30 days by central laboratory assessment

• Doubling of serum creatinine– Doubling from the baseline average sustained for ≥30 days by central laboratory

assessment

• Renal death– Deaths in patients who have reached ESKD who die prior to initiating renal replacement

therapy and no other cause of death is adjudicated

• CV death– Death due to MI, stroke, heart failure, sudden death, death during a CV procedure or as a

result of procedure-related complications, presumed sudden CV death, death of unknown cause, or death resulting from a documented CV cause other than those listed


Primary Outcome:ESKD, Doubling of Serum Creatinine, or Renal or CV Death

0

5

10

15

20

25

0 26 52 78 104 130 156 182

Par

tici

pan

ts w

ith

an

eve

nt

(%)

Months since randomization

Hazard ratio, 0.70 (95% CI, 0.59–0.82)P = 0.00001

6 12 18 24 30 36 42

340 participants

245 participants

PlaceboCanagliflozin

No. at riskPlacebo 2199 2178 2132 2047 1725 1129 621 170

Canagliflozin 2202 2181 2145 2081 1786 1211 646 196

Par

tici

pan

ts w

ith

an

eve

nt

(%)



ESKD, Doubling of Serum Creatinine, or Renal Death

0

5

10

15

20

25

0 26 52 78 104 130 156 182

Months since randomizationNo. at risk

Placebo 2199 2178 2131 2046 1724 1129 621 170Canagliflozin 2202 2181 2144 2080 1786 1211 646 196

Hazard ratio, 0.66 (95% CI, 0.53–0.81)P <0.001

224 participants

153 participants

6 12 18 24 30 36 42Par

tici

pan

ts w

ith

an

eve

nt

(%)




End-stage Kidney Disease

0

5

10

15

20

25

0 26 52 78 104 130 156 182


Hazard ratio, 0.68 (95% CI, 0.54–0.86)P = 0.002

165 participants

116 participants

6 12 18 24 30 36 42Par

tici

pan

ts w

ith

an

eve

nt

(%)


Canagliflozin 2202 2182 2146 2091 1798 1217 654 199




Dialysis, Kidney Transplantation, or Renal Death*

0

5

10

15

20

25

0 26 52 78 104 130 156 182Months since randomization

Hazard ratio, 0.72 (95% CI, 0.54–0.97)

105 participants

78 participants


Canagliflozin 2202 2184 2148 2100 1811 1236 661 199

6 12 18 24 30 36 42Par

tici

pan

ts w

ith

an

eve

nt

(%)


*Post hoc analysis.Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.


Hazard ratio (95% CI) P value

Primary composite outcome 0.70 (0.59–0.82) 0.00001

Doubling of serum creatinine 0.60 (0.48–0.76) <0.001

ESKD 0.68 (0.54–0.86) 0.002

eGFR <15 mL/min/1.73 m2 0.60 (0.45–0.80) –

Dialysis initiated or kidney transplantation 0.74 (0.55–1.00) –

Renal death 0.39 (0.08–2.03) –

CV death 0.78 (0.61–1.00) 0.0502

ESKD, doubling of serum creatinine, or renal death 0.66 (0.53–0.81) <0.001

Dialysis, kidney transplantation, or renal death* 0.72 (0.54–0.97) –

Summary Forest Plot

Favors Canagliflozin Favors Placebo

0.25 0.5 1.0 2.0 4.0

Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744. *Post hoc analysis.


Acute and Long-term Effects on eGFR

-20-18-16-14-12-10

-8-6-4-20

0 26 52 78 104 130 156 182LS M

ean

Ch

ang

e (±

SE)

in

eG

FR (

mL/

min

/1

.73

m

2 )

Months since randomizationNo. of Participants

Placebo 2178 2084 1985 1882 1720 1536 1006 583 210Canagliflozin 2179 2074 2005 1919 1782 1648 1116 652 241

56.4 56.0Canagliflozin Placebo

Chronic eGFR slopeDifference: 2.74/year (95% CI, 2.37–3.11)

–4.59/year

6 12 18 24 30 36 42

LS m

ean

ch

ang

e (±

SE)

in

eG

FR (

mL/

min

/1.7

3 m

2)

Baseline

60% reduction in the rate of eGFR decline with canagliflozin

On treatment

–1.85/year



Effects on Safety


Safety Analyses

• Independent blinded Adjudication Committees adjudicated all suspected fractures, pancreatitis, diabetic ketoacidosis, and renal cell carcinoma events

• Other AEs of interest included

–Renal-related AEs–Acute kidney injury–Hyperkalemia–Amputation

–Male and female genital mycotic infections–Urinary tract infections–Volume depletion–related AEs


Overall and Renal SafetyNumber of participants

with an event, n

Canagliflozin(N = 2200)

Placebo(N = 2197)

Hazard ratio (95% CI)

All AEs 1784 1860 0.87 (0.82–0.93)

All serious AEs 737 806 0.87 (0.79–0.97)

All renal-related AEs 290 388 0.71 (0.61–0.82)

Hyperkalemia 151 181 0.80 (0.65–1.00)

Acute kidney injury 86 98 0.85 (0.64–1.13)


0.5 1.0 2.0Includes all treated participants through 30 days after last dose.



Other AEs of InterestNumber of participants

with an event, nCanagliflozin(N = 2200)

Placebo(N = 2197)


Male genital mycotic infections* 28 3 9.30 (2.83–30.60)Female genital mycotic infections† 22 10 2.10 (1.00–4.45)Urinary tract infections 245 221 1.08 (0.90–1.29)Volume depletion–related AEs 144 115 1.25 (0.97–1.59)Malignancies‡ 98 99 0.98 (0.74–1.30)Renal cell carcinoma 1 5 0.20 (0.02–1.68)Breast† 8 3 2.59 (0.69–9.76)Bladder 10 9 1.10 (0.45–2.72)

Acute pancreatitis 5 2 2.44 (0.47–12.59)Diabetic ketoacidosis 11 1 10.80 (1.39–83.65)

0.125 1.0 2.0 16.04.0 8.0 32.00.50.25*Includes male participants only (canagliflozin, n = 1439; placebo, n = 1466).†Includes female participants only (canagliflozin, n = 761; placebo, n = 731).‡Includes malignant tumors of unspecified type. Favors Canagliflozin Favors Placebo

Includes all treated participants through 30 days after last dose except cancer, which includes all treated patients through the end of the trial.



0

5

10

15

20

25


Fracture

68 participants67 participants


Canagliflozin 2200 2171 2121 2074 1785 1225 668 200

Hazard ratio, 0.98 (95% CI, 0.70–1.37)P

arti

cip

ants

wit

h a

n e

ven

t (%

)

6 12 18 24 30 36 42


Includes all treated patients through the end of the trial.



Canagliflozin 2200 2163 2118 2071 1788 1228 667 202

Lower Extremity Amputation

0

5

10

15

20

25



Hazard ratio, 1.11 (95% CI, 0.79–1.56)P

arti

cip

ants

wit

h a

n e

ven

t (%

)

6 12 18 24 30 36 42


There is no evidence that the protocol amendment had an effect on the hazard ratio for lower extremity amputation, which remained stable over time as events accrued.

Includes all treated patients through the end of the trial.


Summary

• Canagliflozin reduced the risk of:– ESKD, doubling of serum creatinine, or renal or CV death by 30%– ESKD, doubling of serum creatinine, or renal death by 34% – ESKD by 32% (exploratory outcome)– Dialysis, transplantation, or renal death by 28% (post hoc outcome)

• Canagliflozin attenuated the slope of chronic eGFR decline by 2.7 mL/min/1.73 m2/year (1.9 vs 4.6)

• No observed difference with canagliflozin compared with placebo for:– Fracture– Amputation

• Safety profile was otherwise consistent with previous canagliflozin studies


CREDENCEDetailed Effects on CV OutcomesBruce Neal, MB ChB, PhD


Presenter Disclosures:Bruce Neal, MB ChB, PhD

• Research support – Australian National Health, Medical Research Council Principal Research Fellowship

• Advisory boards and/or consultant – Janssen, Merck Sharpe and Dohme

• Any consultancy, honoraria, or travel support paid to his institution


CV-related Baseline DemographicsCanagliflozin(n = 2202)

Placebo(n = 2199)

Total(N = 4401)

Hypertension, % 97 97 97

Heart failure (NYHA I-III), % 15 15 15

CV disease, % 51 50 50

Renal and CV protective agents, %

RAAS inhibitor >99.9 99.8 99.9

Statin 70 68 69

Antithrombotic 61 58 60

Beta blocker 40 40 40

Diuretic 47 47 47Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.


CV Death or Hospitalization for Heart Failure

0

5

10

15

20

25


253 participants

179 participants

Hazard ratio, 0.69 (95% CI, 0.57–0.83)P <0.001


Canagliflozin 2202 2171 2132 2077 1789 1226 668 199

6 12 18 24 30 36 42Par

tici

pan

ts w

ith

an

eve

nt

(%)



Hospitalization for Heart Failure

0

5

10

15

20

25



Canagliflozin 2202 2171 2131 2076 1789 1226 668 199

Hazard ratio, 0.61 (95% CI, 0.47–0.80)P <0.001

141 participants

89 participants

6 12 18 24 30 36 42Par

tici

pan

ts w

ith

an

eve

nt

(%)



Major Cardiovascular Events: CV Death, MI, or Stroke


Canagliflozin 2202 2163 2106 2047 1756 1196 642 198

0

5

10

15

20

25


Hazard ratio, 0.80 (95% CI, 0.67–0.95)P = 0.01

269 participants

217 participants

6 12 18 24 30 36 42Par

tici

pan

ts w

ith

an

eve

nt

(%)



CV Death


Canagliflozin 2202 2187 2155 2120 1835 1263 687 212

0

5

10

15

20

25



Hazard ratio, 0.78 (95% CI, 0.61–1.00)P = 0.0502

6 12 18 24 30 36 42Par

tici

pan

ts w

ith

an

eve

nt

(%)




0

5

10

15

20

25

0 26 52 78 104 130 156 182


Fatal/Nonfatal MI


Canagliflozin 2202 2177 2133 2077 1789 1217 657 201

6 12 18 24 30 36 42Par

tici

pan

ts w

ith

an

eve

nt

(%)

Hazard ratio, 0.86 (95% CI, 0.64–1.16)




Fatal/Nonfatal Stroke


Canagliflozin 2202 2171 2122 2082 1795 1236 667 204

6 12 18 24 30 36 420

5

10

15

20

25

0 26 52 78 104 130 156 182

Part

icip

ants

with

an

Even

t (%

)


Hazard ratio, 0.77 (95% CI, 0.55–1.08)P

arti

cip

ants

wit

h a

n e

ven

t (%

)

6 12 18 24 30 36 42




All-cause Mortality


Canagliflozin 2202 2187 2155 2120 1835 1263 687 212

0

5

10

15

20

25


Hazard ratio, 0.83 (95% CI, 0.68–1.02)

201 participants

168 participants

6 12 18 24 30 36 42Par

tici

pan

ts w

ith

an

eve

nt

(%)




CV Death, MI, Stroke, Hospitalization for Heart Failure, or Hospitalization for Unstable Angina

0

5

10

15

20

25

0 26 52 78 104 130 156 182

Months since randomizationNo. at risk

Placebo 2199 2129 2065 1968 1659 1092 606 159Canagliflozin 2202 2149 2086 2014 1718 1172 628 189

Hazard ratio, 0.74 (95% CI, 0.63–0.86)361 participants

273 participants

Par

tici

pan

ts w

ith

an

eve

nt

(%)

6 12 18 24 30 36 42



Major Cardiovascular Events: CV Death, MI, or Stroke (Renal Subgroups)


InteractionP value

Screening eGFR 0.74

30 to <45 mL/min/1.73 m2 0.77 (0.57–1.03)

45 to <60 mL/min/1.73 m2 0.74 (0.53–1.04)

60 to <90 mL/min/1.73 m2 0.88 (0.65–1.19)

Baseline UACR 0.77

≤1000 mg/g 0.82 (0.63–1.07)

>1000 mg/g 0.78 (0.61–0.99)


0.25 0.5 1.0 2.0 4.0


Major Cardiovascular Events: CV Death, MI, or Stroke (Demographic and Risk Factor Subgroups)


InteractionP value

Sex 0.52

Male 0.76 (0.61–0.94)

Female 0.87 (0.63–1.20)

Age 0.39

<65 years 0.73 (0.56–0.96)

≥65 years 0.85 (0.67–1.09)

Baseline BMI 0.47

<30 kg/m2 0.84 (0.64–1.11)

≥30 kg/m2 0.75 (0.59–0.95)

Baseline HbA1c 0.60

<8% 0.84 (0.63–1.12)

≥8% 0.76 (0.61–0.96)

Systolic BP 0.29

≤Median 0.73 (0.56–0.94)

>Median 0.88 (0.68–1.13)


0.25 0.5 1.0 2.0 4.0


Major Cardiovascular Events: CV Death, MI, or Stroke (Demographic Subgroups)


InteractionP value

Race 0.66

White 0.77 (0.62–0.95)

Black or African American 0.84 (0.42–1.67)

Asian 0.75 (0.49–1.14)

Other 1.20 (0.59–2.43)

Ethnicity 0.15

Hispanic or Latino 0.61 (0.43–0.85)

Not Hispanic or Latino 0.89 (0.72–1.11)

Not reported/unknown –*

Region 0.18

North America 1.00 (0.72–1.39)

Central/South America 0.58 (0.38–0.87)

Europe 0.83 (0.56–1.24)

Rest of world 0.75 (0.55–1.05)

*Hazard ratios and 95% CIs were calculated for outcomes with >10 events. Favors Canagliflozin Favors Placebo

0.25 0.5 1.0 2.0 4.0


Major Cardiovascular Events: CV Death, MI, or Stroke (Disease History Subgroups)


InteractionP value

Diabetes duration ≥median 0.95

Yes 0.79 (0.62–1.00)

No 0.81 (0.61–1.06)

History of CV disease 0.25

Yes 0.85 (0.69–1.06)

No 0.68 (0.49–0.94)

History of amputation 0.06

Yes 0.49 (0.27–0.90)

No 0.84 (0.70–1.01)

History of heart failure 0.36

Yes 0.91 (0.62–1.34)

No 0.76 (0.62–0.93)


0.25 0.5 1.0 2.0 4.0


Cardiac Adverse Events


0.25 0.5 1.0 2.0 4.0

Number of participants with an event, n

Canagliflozin(N = 2200)

Placebo(N = 2197)

Hazard ratio(95% CI)

Cardiac adverse events 300 393 0.72 (0.62–0.84)


SummaryHazard ratio

(95% CI) P valueCV death or hospitalization for heart failure 0.69 (0.57–0.83) <0.001

Hospitalization for heart failure 0.61 (0.47–0.80) <0.001

CV death, MI, or stroke 0.80 (0.67–0.95) 0.01

CV death 0.78 (0.61–1.00) 0.0502

Nonfatal MI 0.81 (0.59–1.10) –

Nonfatal stroke 0.80 (0.56–1.15) –

Fatal/nonfatal MI 0.86 (0.64–1.16) –

Fatal/nonfatal stroke 0.77 (0.55–1.08) –

All-cause mortality 0.83 (0.68–1.02) –CV death, MI, stroke, hospitalization for heart failure, or hospitalization for unstable angina 0.74 (0.63–0.86) –


0.25 0.5 1.0 2.0 4.0


CREDENCEOutcomes by CV Disease HistoryKenneth W. Mahaffey, MD


Presenter Disclosures: Kenneth W. Mahaffey, MD

• Research support– Afferent, Amgen, Apple, Inc., AstraZeneca, Cardiva Medical, Inc., Daiichi, Ferring, Google

(Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, and Tenax

• Consultant (speaker fees for CME events only)– Abbott, Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol-Myers Squibb,

Elsevier, GlaxoSmithKline, Johnson & Johnson, MedErgy, Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, Springer Publishing, and UCSF


Objective

• To describe the effects of canagliflozin compared with placebo on a range of outcomes in participants with and without known CV disease from the CREDENCE trial


Classification of Primary or Secondary Prevention

• Based on CV medical histories collected by investigators during the screening period

• Participants were classified as belonging to the secondary prevention cohort if they had a history of coronary, cerebrovascular, or peripheral vascular disease

• All other participants were classified as belonging to the primary prevention cohort


Baseline Demographics and Risk Factors

Primary prevention(N = 2181)

Secondaryprevention(N = 2220)

Total(N = 4401)

Mean age, years 61 65 63

Female, % 37 31 34

Mean duration of diabetes, years 15 16 16

Mean HbA1c, % 8.3 8.3 8.3

Mean LDL-C, mg/dL 98 95 96


Baseline Disease History



Total(N = 4401)

Hypertension, % 96 98 97

Heart failure (NYHA I-III), % 6 24 15

CV disease, % 0 100 50

Prior amputation, % 0 11 5


Baseline Renal Characteristics



Total(N = 4401)

Mean eGFR, mL/min/1.73 m² 57 56 56eGFR ≥90, % 5 4 5eGFR ≥60 to <90, % 37 34 35eGFR ≥45 to <60, % 28 29 29eGFR ≥30 to <45, % 26 28 27eGFR <30, % 4 4 4

Median UACR (IQR), mg/g 943 (450–1841)

903 (484–1827)

927 (463-1833)

UACR <30, % <1 <1 <1UACR 30 to 300, % 12 11 11UACR >300 to ≤3000, % 76 77 77UACR >3000, % 11 12 11


CV Death or Hospitalization for Heart Failure

Secondary PreventionPrimary Prevention

0

5

10

15

20

25

0 26 52 78 104 130 156 182

Part

icip

ants

with

an

Even

t (%

)


0

5

10

15

20

25

0 26 52 78 104 130 156 182


Hazard ratio, 0.66 (95% CI, 0.52–0.83)Hazard ratio, 0.74 (95% CI, 0.54–1.03)

P interaction = 0.57


PlaceboCanagliflozinP

arti

cip

ants

wit

h a

n e

ven

t (%

)

Par

tici

pan

ts w

ith

an

eve

nt

(%)

6 12 18 24 30 36 42 6 12 18 24 30 36 42


CV Death, MI, or Stroke



0

5

10

15

20

25

0 26 52 78 104 130 156 182


6 12 18 24 30 36 42

Par

tici

pan

ts w

ith

an

eve

nt

(%)

0

5

10

15

20

25

0 26 52 78 104 130 156 182



6 12 18 24 30 36 42

Par

tici

pan

ts w

ith

an

eve

nt

(%)





CV Death


0

5

10

15

20

25

0 26 52 78 104 130 156 182


0

5

10

15

20

25

0 26 52 78 104 130 156 182


Hazard ratio, 0.79 (95% CI, 0.58–1.07)Hazard ratio, 0.75 (95% CI, 0.48–1.16)PlaceboCanagliflozin


Par

tici

pan

ts w

ith

an

eve

nt

(%)

Par

tici

pan

ts w

ith

an

eve

nt

(%)

6 12 18 24 30 36 42 6 12 18 24 30 36 42



CV Outcomes by Primary and Secondary Prevention Hazard ratio

(95% CI)Interaction

P value

CV death or hospitalization for heart failure

0.74 (0.54–1.03) 0.57

0.66 (0.52–0.83)

0.69 (0.57–0.83)

CV death, MI, or stroke

0.68 (0.49–0.94) 0.25

0.85 (0.69–1.06)

0.80 (0.67–0.95)

CV death

0.75 (0.48–1.16) 0.86

0.79 (0.58–1.07)

0.78 (0.61–1.00)


0.25 0.5 1.0 2.0 4.0

Secondary prevention

Primary prevention

Overall population


0

5

10

15

20

25


0

5

10

15

20

25


Primary Outcome:ESKD, Doubling of Serum Creatinine, or Renal or CV Death





arti

cip

ants

wit

h a

n e

ven

t (%

)

Par

tici

pan

ts w

ith

an

eve

nt

(%)

6 12 18 24 30 36 42 6 12 18 24 30 36 42



0

5

10

15

20

25

0 26 52 78 104 130 156 182


0

5

10

15

20

25

0 26 52 78 104 130 156 182


ESKD, Doubling of Serum Creatinine, or Renal Death





arti

cip

ants

wit

h a

n e

ven

t (%

)

Par

tici

pan

ts w

ith

an

eve

nt

(%)

6 12 18 24 30 36 42 6 12 18 24 30 36 42



Renal Outcomes by Primary and Secondary Prevention Hazard ratio

(95% CI)Interaction

P value

Primary composite outcome

0.69 (0.54–0.88) 0.91

0.70 (0.56–0.88)

0.70 (0.59–0.82)

ESKD, doubling of serum creatinine, or renal death

0.68 (0.51-0.89) 0.81

0.64 (0.47-0.87)

0.66 (0.53-0.81)

Dialysis, kidney transplantation, or renal death*

0.65 (0.43–0.97) 0.39

0.83 (0.54–1.27)

0.72 (0.54–0.97)


0.25 0.5 1.0 2.0 4.0

*Post hoc outcome.


Primary prevention

Overall population



Interaction P value

All adverse events0.88 (0.80–0.96) 0.970.87 (0.80–0.96)0.87 (0.82–0.93)

All serious adverse events0.84 (0.72–0.99) 0.620.89 (0.78–1.02)0.87 (0.79–0.97)

Renal-related adverse events (including acute kidney injury)

0.69 (0.55–0.85) 0.780.72 (0.58–0.90)0.71 (0.61–0.82)

Acute kidney injury0.70 (0.45–1.08) 0.230.99 (0.67–1.46)0.85 (0.64–1.13)

Amputation1.09 (0.48–2.47) 0.981.11 (0.76–1.61)1.11 (0.79–1.56)

Fracture1.05 (0.61–1.79) 0.740.93 (0.60–1.44)0.98 (0.70–1.37)

Safety by Primary and Secondary Prevention


0.25 0.5 1.0 2.0 4.0


Primary prevention

Overall population


Summary•The primary prevention group had lower CV risk but similar renal risk as the secondary prevention group

•Canagliflozin reduced major CV and renal outcomes in both the primary and secondary prevention groups

•No difference in risk was observed with canagliflozin compared with placebo for:–Fracture–Amputation

•Safety profile was consistent with previous canagliflozin studies


CREDENCEClinical Implications Bernard Zinman, MD


Presenter Disclosures:Bernard Zinman, MD

• Consultant and received honoraria – AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, MSD, Novo Nordisk, and Sanofi


Growing Problem of T2DM and CKD

~422MILLION

adults are living with diabetes

Deaths due to T2DM and CKD

1990 2012

94%

1. World Health Organization. Global Report on Diabetes. 2016. 2. Yee J. Diabetes Spectr. 2008;21(1):8-10. 3. Alicic RZ, et al. Clin J Am Soc Nephrol. 2017;12(12):2032-2045.

30 to 40%of these patients will develop CKD

Nu

mb

er o

f D

eath

s


Higher Renal Risk Population in CREDENCE

Low Moderatelyincreased

High Very high

<30

30-44

45-59

60-90

≥90

GFR

cat

egor

ies

(mL/

min

/1.7

3 m

2 )

Albuminuria categories (mg/g)A1: <30 A2: 30-300 A3: >300

DC E

DECLARECANVAS ProgramEMPA-REG OUTCOMECREDENCE

MedianUACR

(mg/g)131218

927

Mean eGFR(mL/min/1.73 m2)

85767456

Sustained RRT Events

DECLARE Not reportedCANVAS Program 18EMPA-REG OUTCOME 11CREDENCE 176

DCE

RRT, renal replacement therapy.


Risk Factor Management at Entry to CREDENCE

Glucose

BP

ACEi orARB

Lipids

Lower blood glucose

Manage BP levels

Initiate when albumin excretion is ≥30 mg/g

Lower LDL-C

1. Molitch ME, et al. Kidney Int. 2015;87(1):20-30.2. National Institute for Health and Care Excellence. NICE guideline (NG28). 2017. Accessed April 10, 2019.3. American Diabetes Association. Diabetes Care. 2019;42(Suppl 1):S182-S183.

Mean HbA1c 8.3% 99.9% on ACEi or ARB

Mean BP 140/78 mmHg ~70% on statinBaseline values from CREDENCE are shown.


Hazard ratio (95% CI) P value

Primary composite outcome 0.70 (0.59–0.82) 0.00001

Doubling of serum creatinine 0.60 (0.48–0.76) <0.001

ESKD 0.68 (0.54–0.86) 0.002

eGFR <15 mL/min/1.73 m2 0.60 (0.45–0.80) –

Dialysis initiated or kidney transplantation 0.74 (0.55–1.00) –

Renal death 0.39 (0.08–2.03) –

CV death 0.78 (0.61–1.00) 0.0502

CV death or hospitalization for heart failure 0.69 (0.57–0.83) <0.001

CV death, MI, or stroke 0.80 (0.67–0.95) 0.01

Hospitalization for heart failure 0.61 (0.47–0.80) <0.001

ESKD, doubling of serum creatinine, or renal death 0.66 (0.53–0.81) <0.001

Summary of Key Renal and CV Outcomes


0.25 0.5 1.0 2.0 4.0Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.


CV Death, MI, or Stroke in SGLT2 Inhibitor Outcome Trials With and Without Prior CV Disease

Zelniker TA, et al. Lancet. 2019;393(10166):31-39.

Hazard ratio(95% CI)

Patients with atherosclerotic CV disease (secondary prevention)

EMPA-REG OUTCOME 0.86 (0.74–0.99)CANVAS Program 0.82 (0.72–0.95)DECLARE-TIMI 58 0.90 (0.79–1.02)CREDENCE 0.85 (0.69–1.06)

Patients with multiple risk factors (primary prevention)

CANVAS Program 0.98 (0.74–1.30)DECLARE-TIMI 58 1.01 (0.86–1.20)CREDENCE 0.68 (0.49–0.94)

Favors SGLT2i Favors Placebo

0.5 1.0 2.0


Potential Mechanisms of Action of SGLT2 Inhibitors

REG, removal of excess glucose; UNa, urinary sodium.Butler J, et al. Eur J Heart Fail. 2017;19(11):1390-1400.

SGLT2 inhibition Pathway Possible cardio–renal benefits CV/renal outcomes


Acute and Long-term Effects on eGFR

-20-18-16-14-12-10

-8-6-4-20

0 26 52 78 104 130 156 182LS M

ean

Ch

ang

e (±

SE)

in

eG

FR (

mL/

min

/1

.73

m

2 )

Months since randomizationNo. of Participants

Placebo 2178 2084 1985 1882 1720 1536 1006 583 210Canagliflozin 2179 2074 2005 1919 1782 1648 1116 652 241

56.4 56.0Canagliflozin Placebo

Chronic eGFR slopeDifference: 2.74/year (95% CI, 2.37–3.11)

–4.59/year

6 12 18 24 30 36 42

LS m

ean

ch

ang

e (±

SE)

in

eG

FR (

mL/

min

/1.7

3 m

2)

Baseline

60% reduction in the rate of eGFR decline with canagliflozin

On treatment

–1.85/year



CREDENCE: NNT for Renal and CV Outcomes Over 2.5 Years

46

CV death, MI, or strokeHospitalization for heart failure

40

28

ESKD, doubling of serum creatinine, or renal death

ESKD

43

Primary composite outcome

22


CREDENCE Primary Outcome: Benefits in eGFR SubgroupsHazard ratio

(95% CI)Interaction

P value

Screening eGFR 0.11

30 to <45 mL/min/1.73 m2 0.75 (0.59–0.95)

45 to <60 mL/min/1.73 m2 0.52 (0.38–0.72)

60 to <90 mL/min/1.73 m2 0.82 (0.60–1.12)


0.25 0.5 1.0 2.0 4.0

16

NNT in patients with eGFR 30 to <45 mL/min/1.73 m2


Conclusion

•Canagliflozin safely reduced the risk of kidney failure and prevented CV events in people with T2DM and CKD

•In participants with T2DM and CKD, canagliflozin reduced major CV events and renal outcomes across a broad spectrum of subgroups including those without CV disease at baseline

•The overall safety profile was consistent with known side effects of canagliflozin, with no increased risk of amputation

•This finding suggests that canagliflozin can be effectively used for both primary and secondary prevention of major CV events in people with T2DM and CKD


ADA Standards of Care Updated With Renal Guidance Based on CREDENCE

• “The CREDENCE trial was the first sodium-glucose cotransporter 2 (SGLT2) inhibitor trial to assess renal-specific primary outcomes and ended early due to efficacy. Incorporating these findings into the Standards of Care now gives providers the latest evidence-based recommendations to treat people with type 2 diabetes and diabetes-related chronic kidney disease…” – William T. Cefalu, MD, Chief Scientific, Medical and Mission Officer of the ADA1

• Based on the Grade A evidence from the CREDENCE trial, the ADA living guidelines (updated on June 3, 2019)2 propose the following:– “For patients with type 2 diabetes and diabetic kidney disease, consider use of an

SGLT2 inhibitor in patients with an eGFR ≥30 mL/min/1.73 m2 and particularly in those with >300 mg/g albuminuria to reduce risk of CKD progression, cardiovascular events, or both.”

1. American Diabetes Association. http://www.diabetes.org/newsroom/press-releases/2019/updates-standards-medical-care-diabetes.html. Accessed June 5, 2019.

2. American Diabetes Association. Standards of Medical Care in Diabetes–2019. http://care.diabetesjournals.org/content/42/Supplement_1. Last updated June 3, 2019. Accessed June 5, 2019.


DiabetesKidneyCardiology

Use of Canagliflozin in Clinical Practice for Patients With T2DM

Canagliflozin as Treatment for DiabetesCanagliflozin as Treatment for Chronic Kidney DiseaseCanagliflozin as Treatment for Cardiovascular Disease


Thanks to the Participants and the following people for their contributions:


Independent Data Monitoring Committee: Darren K. McGuire (chair), Rury Holman, Philip Home, Dan Scharfstein, and Patrick Parfrey

National Lead Investigators: Diego Aizenberg (Argentina and Chile), Roberto Pecoits-Filho (Brazil), Adeera Levin and David Cherney (Canada), Gregorio Obrador (Mexico, Colombia, and Guatemala), Glenn Chertow and Tara Chang (United States), Carmel Hawley (Australia and New Zealand), Linong Ji and Hong Zhang (China), Takashi Wada (Japan), Vivekanand Jha (India), Soo Kun Lim (Malaysia), Mary Anne Lim-Abrahan and Florence Santos (Philippines), Dong-Wan Chae(South Korea), Shang-Jyh Hwang (Taiwan), Evgueniy Vazelov (Bulgaria), Ivan Rychlík(Czech Republic and Slovakia), Samy Hadjadj(France), Vera Krane (Germany), LászlóRosivall (Hungary), Luca De Nicola (Italy), Alexander Dreval (Lithuania and Russia), Michał Nowicki (Poland), Adalbert Schiller (Romania), Larry Distiller (South Africa), Jose L Górriz (Spain), Mykola Kolesnyk(Ukraine), and David C. Wheeler (United Kingdom)

Steering Committee: Vlado Perkovic (Chair), Kenneth W. Mahaffey (co-chair), Rajiv Agarwal, George Bakris, Barry M. Brenner, Christopher P. Cannon, David M. Charytan, Dick de Zeeuw, Tom Greene, Meg J. Jardine, Hiddo J.L. Heerspink, Adeera Levin, Gary Meininger (Sponsor), Bruce Neal, Carol Pollock, David C. Wheeler, Hong Zhang, and Bernard Zinman

Regional Lead Investigators: Meg Jardine (Global Scientific Lead), Hiddo J.L. Heerspink (Europe Regional Scientific Lead), David M. Charytan (Americas Regional Scientific Lead), Nicole Li, and Inna Kolesnyk (Asia Pacific Regional Scientific Leads)

Janssen and George Clinical Teams: Maria Ali, Jim Baldassarre, Dainius Balis, Scott Bull, William Canovatchel, George Capuano, Jun Chen, Pei-Ling Chu, Trokon Cooke, Jag Craig, Jacki Danyluk, Mehul Desai, Robert Edwards, Lyndal Hones, Alan Jenkins, Mary Kavalam, Cha-Chi Lo, Xinchao Luo, Rich Oh, Rose Qiu, Norm Rosenthal, Nicole Schmitt, Danielle Siebenkaess, Roger Simpson, Tao Sun, Anna Temu, Payal Thakkar, Michele Wells, Yshai Yavin, Renata Yong, and Kimberly Dittmar and Alaina Mitsch (MedErgy)

Endpoint Adjudication Committee: Rajiv Agarwal (chair), Kenneth W. Mahaffey (co-chair), Shahnaz Shahinfar, Phyllis August, Tara Chang, Arjun D. Sinha, James Januzzi, Daniel Kolansky, John Amerena, Graham Hillis, Philip Gorelick, Brett Kissela, Scott Kasner, Richard Lindley, and Greg Fulcher

Safety Adjudication:

Fracture Adjudication: Souhila Ounadjela, Karina Hufert, and Gabriele von Ingersleben(Bioclinica)

Diabetic Ketoacidosis Adjudication: Jason Gaglia, Ronald Harris, Margo Hudson, and Alexander Turchin (Baim)

Pancreatitis Adjudication: Adam Cheifetz, Sunil Sheth, and Joseph Feuerstein (Baim)

Renal Cell Carcinoma Adjudication: Samuel Cohen



Independent Data Monitoring Committee: Darren K. McGuire (chair), Rury Holman, Philip Home, Dan Scharfstein, and Patrick Parfrey

National Lead Investigators: Diego Aizenberg (Argentina and Chile), Roberto Pecoits-Filho (Brazil), Adeera Levin and David Cherney (Canada), Gregorio Obrador (Mexico, Colombia, and Guatemala), Glenn Chertow and Tara Chang (United States), Carmel Hawley (Australia and New Zealand), Linong Ji and Hong Zhang (China), Takashi Wada (Japan), Vivekanand Jha (India), Soo Kun Lim (Malaysia), Mary Anne Lim-Abrahan and Florence Santos (Philippines), Dong-Wan Chae(South Korea), Shang-Jyh Hwang (Taiwan), Evgueniy Vazelov (Bulgaria), Ivan Rychlík(Czech Republic and Slovakia), Samy Hadjadj(France), Vera Krane (Germany), LászlóRosivall (Hungary), Luca De Nicola (Italy), Alexander Dreval (Lithuania and Russia), Michał Nowicki (Poland), Adalbert Schiller (Romania), Larry Distiller (South Africa), Jose L Górriz (Spain), Mykola Kolesnyk(Ukraine), and David C. Wheeler (United Kingdom)

India: Oomman Abraham, Raju Sree Bhushan, Dewan Deepak, Fernando M. Edwin, Natarajan Gopalakrishnan, Noble Gracious, Alva Hansraj, Dinesh Jain, C. B. Keshavamurthy, Dinesh Khullar, Sahay Manisha, Jayameena Peringat,

Steering Committee: Vlado Perkovic (Chair), Kenneth W. Mahaffey (co-chair), Rajiv Agarwal, George Bakris, Barry M. Brenner, Christopher P. Cannon, David M. Charytan, Dick de Zeeuw, Tom Greene, Meg J. Jardine, Hiddo J.L. Heerspink, Adeera Levin, Gary Meininger (Sponsor), Bruce Neal, Carol Pollock, David C. Wheeler, Hong Zhang, and Bernard Zinman

Regional Lead Investigators: Meg Jardine (Global Scientific Lead), Hiddo J.L. Heerspink (Europe Regional Scientific Lead), David M. Charytan (Americas Regional Scientific Lead), Nicole Li, and Inna Kolesnyk (Asia Pacific Regional Scientific Leads)

Janssen and George Clinical Teams: Maria Ali, Jim Baldassarre, Dainius Balis, Scott Bull, William Canovatchel, George Capuano, Jun Chen, Pei-Ling Chu, Trokon Cooke, Jag Craig, Jacki Danyluk, Mehul Desai, Robert Edwards, Lyndal Hones, Alan Jenkins, Mary Kavalam, Cha-Chi Lo, Xinchao Luo, Rich Oh, Rose Qiu, Norm Rosenthal, Nicole Schmitt, Danielle Siebenkaess, Roger Simpson, Tao Sun, Anna Temu, Payal Thakkar, Michele Wells, Yshai Yavin, Renata Yong, and Kimberly Dittmar and Alaina Mitsch (MedErgy)

CREDENCE Investigators

Argentina: Rodolfo Andres Ahuad Guerrero, Diego Aizenberg, Juan Pablo Albisu, Andres Alvarisqueta, Ines Bartolacci, Mario Alberto Berli, Anselmo Bordonava, Pedro Calella, Maria Cecilia Cantero, Luis Rodolfo Cartasegna,

Endpoint Adjudication Committee: Rajiv Agarwal (chair), Kenneth W. Mahaffey (co-chair), Shahnaz Shahinfar, Phyllis August, Tara Chang, Arjun D. Sinha, James Januzzi, Daniel Kolansky, John Amerena, Graham Hillis, Philip Gorelick, Brett Kissela, Scott Kasner, Richard Lindley, and Greg Fulcher

Safety Adjudication:

Fracture Adjudication: Souhila Ounadjela, Karina Hufert, and Gabriele von Ingersleben(Bioclinica)

Diabetic Ketoacidosis Adjudication: Jason Gaglia, Ronald Harris, Margo Hudson, and Alexander Turchin (Baim)

Pancreatitis Adjudication: Adam Cheifetz, Sunil Sheth, and Joseph Feuerstein (Baim)

Renal Cell Carcinoma Adjudication: Samuel Cohen

Spain: Pere Alvarez Garcia, Luis AsmaratsMercadal, Clara Barrios, Fernando CeretoCastro, Secundino Cigarran Guldris, Marta Dominguez Lopez, Jesus Egido de los Rios, Gema Fernandez Fresnedo, Antonio Galan


Documents

ADA 2019 CREDENCE symposium FINAL for postingmed.stanford.edu/content/dam/sm/sccr/documents/June... · •HRs and 95% CIs for canagliflozin versus placebo were estimated separately