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CREDENCE

CREDENCE. Canagliflozin 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

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CREDENCE

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  1. CREDENCE Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation

  2. 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

  3. CREDENCE Background and Design Rajiv Agarwal, MD

  4. 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

  5. Increasing Incidence and Prevalence of ESKD: US Data 800,000 700,000 600,000 500,000 400,000 300,000 200,000 100,000 0 1980 1985 1990 1995 2000 2005 2010 2015 • Kirchhoff S. Medicare coverage of end-stage renal disease (ESRD). https://fas.org/sgp/crs/misc/R45290.pdf. Accessed February 13, 2019. Incidence Prevalence

  6. Diabetes Is the Leading Cause of Kidney Failure: US Data 60,000 Diabetes 50,000 Hypertension Glomerulonephritis 40,000 Cystic kidney Number of patients 30,000 20,000 10,000 0 1995 1980 1985 1990 1995 2000 2005 2010 Year 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.

  7. Risk of Mortality, Cardiovascular, and Renal Outcomes in Relation to Kidney Disease UACR <30 mg/g UACR 30–299 mg/g UACR ≥300 mg/g Levey AS, et al. Kidney Int. 2011;80(1):17-28.

  8. The Only Proven Treatment for Renoprotection in T2DM Before CREDENCE: RENAAL & IDNT • Doubling of serum creatinine, ESKD, or death RENAAL • IDNT Risk reduction, 16% P = 0.02 Risk reduction, 20% P = 0.02 Brenner B, et al. N Engl J Med. 2001;345(12):861-869. Lewis EJ, et al. N Eng J Med. 2001;345(12):851-860.

  9. Many Renal Effects of SGLT2 Inhibition Have Been Proposed Intraglomerular pressure Glucose Albuminuria BP/arterial stiffness Oxidant stress Intrarenal angiotensinogen upregulation Volume Inflammation/fibrosis And many others…

  10. Timeline of Major SGLT2 Inhibitor Trials EMPA-REG OUTCOME CANVAS Program CREDENCE enrollment DECLARE 2014 2015 2016 2017 2018 2019 CREDENCE ended CREDENCE began while SGLT2 inhibitor CV outcomes trials were ongoing Renal effects were not the primary focus of the CV outcomes trials

  11. Low Renal Risk Populations in CV Outcomes Trials Albuminuria categories (mg/g) A1: <30 A2: 30-300 A3: >300 D ≥90 C D 60-90 C E E 45-59 GFR categories (mL/min/1.73 m2) Sustained RRT Events DECLARE Not reported CANVAS Program 18 EMPA-REG OUTCOME 11 30-44 <30 Moderately increased High Very high Low Total of 29 sustained RRT events reported across trials RRT, renal replacement therapy. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf.

  12. CV Death, MI, or Stroke by CV Disease History in SGLT2 Inhibitor CVOTs 1.0 2.0 0.5 • Zelnicker TA, et al. Lancet. 2019;393(10166):31-39. Favors Placebo Favors SGLT2i

  13. CV Death, MI, or Stroke by CV Disease History in GLP-1 Receptor Agonist CVOTs 1.0 2.0 4.0 0.5 0.25 • Zelnicker TA, et al. Circulation. 2019;139(17):2022-2031. Favors Placebo Favors GLP-1 RA

  14. 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) 1.0 2.0 0.5 • Zelnicker TA, et al. Lancet. 2019; 393(10166):31-39. • Zelnicker TA, et al. Circulation. 2019;139(17):2022–2031. Favors Placebo Favors GLP-1 RA/SGLT2i

  15. Objectives of the CREDENCE Trial In 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): • CV death or hospitalization for heart failure • Major cardiovascular events (3-point MACE: CV death, MI, or stroke) • Hospitalization for heart failure • ESKD, doubling of serum creatinine, or renal death • CV death • All-cause mortality • CV death, MI, stroke, hospitalization for heart failure, or hospitalization for unstable angina

  16. 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

  17. Study Design and Population

  18. Study Design Canagliflozin 100 mg 2-week placebo run-in Placebo Double-blind randomization (1:1) • Follow-up at Weeks 3, 13, and 26 (F2F) then every 13 weeks (alternating phone/F2F) R 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 labeleddose ofACEi 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 • 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 Jardine MJ, et al. Am J Nephrol. 2017;46(6):462-472.

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

  20. 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

  21. Study Timeline 2014 2015 2016 2017 2018 2019 Excluded participants with prior amputation (≤12 months) or active foot lesion (≤6 months) Required temporary interruption of study drug for patients who developed a lower-extremity event that could be a precursor to ampuation until fully resolved Ensured participants had general foot self-care education and foot evaluations at each visit First participant enrolled Protocol amendment for lower extremity foot care

  22. Study Timeline In July 2018, after the planned interim analysis, the IDMC made the recommendation to stop the CREDENCE trial based on demonstration of efficacy Interim analysis 2014 2015 2016 2017 2018 2019 Last participant randomized First participant enrolled Protocol amendment for lower extremity foot care Study concluded

  23. 34 Countries, 690 Sites, 4401 Participants *Analyzed as part of rest of world (n = 1414) in prespecified subgroup analyses.

  24. Enrollment and Follow-up 12,900 screened 8499 excluded 4401 randomized 2199 placebo 2202 canagliflozin 25 (1.1%) did not complete 11 (0.5%) withdrew consent 15 (0.7%) did not complete 5 (0.2%) withdrew consent 2187 (99.3%) completed study 2198 (99.8%) vital status known 2197 (99.9%) vital status known 2174 (98.9%) completed study 4395 (99.9%) vital status known; 4361 (99.1%) completed study* *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.

  25. CREDENCE Recap of Primary Results Meg J. Jardine, MBBS, PhD, FRACP

  26. 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

  27. Effects on Intermediate Outcomes

  28. Effects on Intermediate Outcomes HbA1c Systolic Blood Pressure UACR Body Weight Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.

  29. Effects on Renal Outcomes

  30. 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

  31. Primary Outcome:ESKD, Doubling of Serum Creatinine, or Renal or CV Death Placebo Hazard ratio, 0.70 (95% CI, 0.59–0.82) P = 0.00001 Canagliflozin 340 participants 245 participants Participants with an event (%) 6 12 18 24 30 36 42 Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.

  32. ESKD, Doubling of Serum Creatinine, or Renal Death Placebo Hazard ratio, 0.66 (95% CI, 0.53–0.81) P <0.001 Canagliflozin 224 participants Participants with an event (%) 153 participants 6 12 18 24 30 36 42 Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.

  33. End-stage Kidney Disease Placebo Hazard ratio, 0.68 (95% CI, 0.54–0.86) P = 0.002 Canagliflozin Participants with an event (%) 165 participants 116 participants 6 12 18 24 30 36 42 Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.

  34. Dialysis, Kidney Transplantation, or Renal Death* Placebo Hazard ratio, 0.72 (95% CI, 0.54–0.97) Canagliflozin Participants with an event (%) 105 participants 78 participants 6 12 18 24 30 36 42 *Post hoc analysis. Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.

  35. Summary Forest Plot 1.0 2.0 4.0 0.5 0.25 *Post hoc analysis. Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744. Favors Placebo Favors Canagliflozin

  36. Acute and Long-term Effects on eGFR Canagliflozin Placebo Baseline 56.4 56.0 60% reduction in the rate of eGFR decline with canagliflozin –1.85/year LS mean change (SE) in eGFR (mL/min/1.73 m2) –4.59/year Chronic eGFR slope Difference: 2.74/year (95% CI, 2.37–3.11) 6 12 18 24 30 36 42 Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744. On treatment

  37. Effects on Safety

  38. Safety Analyses • Renal-related AEs • Acute kidney injury • Hyperkalemia • Amputation • Male and female genital mycotic infections • Urinary tract infections • Volume depletion–related AEs • Independent blinded Adjudication Committees adjudicated all suspected fractures, pancreatitis, diabetic ketoacidosis, and renal cell carcinoma events • Other AEs of interest included

  39. Overall and Renal Safety 1.0 2.0 0.5 Includes all treated participants through 30 days after last dose. Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744. Favors Placebo Favors Canagliflozin

  40. Other AEs of Interest Includes all treated participants through 30 days after last dose except cancer, which includes all treated patients through the end of the trial. *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. 0.125 0.25 0.5 1.0 2.0 4.0 8.0 16.0 32.0 Favors Placebo Favors Canagliflozin Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.

  41. Fracture Placebo Hazard ratio, 0.98(95% CI, 0.70–1.37) Canagliflozin Participants with an event (%) 68 participants 67 participants 6 12 18 24 30 36 42 Includes all treated patients through the end of the trial.

  42. Lower ExtremityAmputation Placebo Hazard ratio, 1.11(95% CI, 0.79–1.56) Canagliflozin • 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. Participants with an event (%) 70 participants 63 participants 6 12 18 24 30 36 42 Includes all treated patients through the end of the trial.

  43. 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

  44. CREDENCE Detailed Effects on CV Outcomes Bruce Neal, MB ChB, PhD

  45. 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

  46. CV-related Baseline Demographics Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.

  47. CV Death or Hospitalization for Heart Failure Placebo Hazard ratio, 0.69 (95% CI, 0.57–0.83) P <0.001 Canagliflozin 253 participants Participants with an event (%) 179 participants 6 12 18 24 30 36 42

  48. Hospitalization for Heart Failure Placebo Hazard ratio, 0.61 (95% CI, 0.47–0.80) P <0.001 Canagliflozin Participants with an event (%) 141 participants 89 participants 6 12 18 24 30 36 42

  49. Major Cardiovascular Events: CV Death, MI, or Stroke Placebo Hazard ratio, 0.80 (95% CI, 0.67–0.95) P = 0.01 Canagliflozin 269 participants Participants with an event (%) 217 participants 6 12 18 24 30 36 42

  50. CV Death Placebo Hazard ratio, 0.78(95% CI, 0.61–1.00) P = 0.0502 Canagliflozin Participants with an event (%) 140 participants 110 participants 6 12 18 24 30 36 42 Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.

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