Thank you for your interest in INVOKANA® (canagliflozin) Thank you for your interest in INVOKANA® (canagliflozin). The above information is presented in response to your inquiry. This information is taken from the references cited, but is not intended to serve as a substitute for review of these references. This information is not intended to advocate the use of our product in any manner other than as described in the product monograph. Please refer to the INVOKANA® Product Monograph available at http://www.janssen.com/canada/products for full prescribing information. For additional information, please see the accompanying full scientific summary. START

The Canagliflozin and Renal Endpoints in Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) CREDENCE (Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation), was a phase 3, randomized, double-blind, placebo-controlled, parallel group multicenter clinical trial assessing whether canagliflozin 100 mg has a renal and/or cardiovascular protective effect compared to placebo in patients with type 2 diabetes mellitus (T2DM), Stage 2 or 3 chronic kidney disease (CKD) and macroalbuminuria, who are receiving standard of care.1,2 Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy [published online ahead of print April 14 2019]. NEJM. 2019. doi:10.1056/NEJMoa1811744. Jardine MJ, Mahaffey KW, Neal B, et al. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol. 2017;46(6):462-472.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER Study Design & Methods Inclusion Criteria Exclusion Criteria Efficacy Endpoints Safety Outcomes Study Timeline STUDY DESIGN AND METHODS Phase 3, randomized, double-blind, placebo-controlled parallel group, multicenter, event driven trial. Conducted across 690 sites in 34 countries, with 4,401 participants. Patients randomly assigned to either canagliflozin 100 mg or matching placebo in a 1:1 ratio. The study consisted of a screening and run-in period, a double-blind treatment period (canagliflozin 100 mg vs. placebo), and a 30-day post treatment (after study completion or permanent discontinuation of study drug) follow-up. Total duration of the study was planned to be approximately 5.5 years. Placebo Canagliflozin 100 mg Double-blind randomization (1:1) Follow-up at Weeks 3, 13, and 26 (face-to-face) then every 13 weeks (alternating phone/face-to-face) 2-week placebo run-in R Participants continued treatment if eGFR was <30 mL/min/1.73 m2 until chronic dialysis was initiated or kidney transplant occurred. Jardine MJ, Mahaffey KW, Neal B, et al. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol. 2017;46(6):462-472.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER Study Design & Methods Inclusion Criteria Exclusion Criteria Efficacy Endpoints Safety Outcomes Study Timeline KEY INCLUSION CRITERIA ≥30 years of age with T2DM (HbA1c ≥6.5% to ≤12.0%) Estimated glomerular filtration rate (eGFR) ≥30 to <90 mL/min/1.73m2 and albuminuria (urine albumin:creatinine ratio [UACR] >300 mg/g and ≤5000 mg/g [33.9–565.6 mg/mmol])* On a stable maximum tolerated or labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) for at least 4 weeks prior to randomization * In order to ensure that the study was able to assess the impact of canagliflozin on the progression of CKD, the intent was that approximately 60% of the patient population have stage 3 CKD (rather than stage 2 CKD), with an eGFR of ≥30 to <60 mL/min/1.73 m2 at study entry. Jardine MJ, Mahaffey KW, Neal B, et al. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol. 2017;46(6):462-472.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER Study Design & Methods Inclusion Criteria Exclusion Criteria Efficacy Endpoints Safety Outcomes Study Timeline KEY EXCLUSION CRITERIA Nondiabetic kidney disease with a history of treatment of kidney disease with immunosuppression A history of treatment with dialysis or kidney transplantation A history of CV events within the previous 12 weeks or a history of New York Heart Association class IV heart failure at any time Combination use of an ACEi and ARB Use of direct renin-inhibitor or mineralocorticoid receptor antagonist (MRA) Concomitant use of an SGLT2 inhibitor within 12 weeks of randomization, current or past participation in another canagliflozin study Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy: Supplementary Appendix [published online ahead of print April 14 2019]. NEJM. 2019. Published 14 April 2019. doi:10.1056/NEJMoa1811744.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER Study Design & Methods Inclusion Criteria Exclusion Criteria Efficacy Endpoints Safety Outcomes Study Timeline EFFICACY ENDPOINTS Primary endpoint: Composite of end stage kidney disease (ESKD), doubling of serum creatinine, and renal or cardiovascular death (non-dialyzed) Secondary endpoints: Composite of cardiovascular death and 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 Prespecified exploratory endpoints: Composite endpoint of ESKD and renal or cardiovascular death Individual components of the composite endpoints ESKD Doubling of serum creatinine Renal death Cardiovascular death Fatal and nonfatal MI Fatal and nonfatal stroke Hospitalized congestive heart failure Hospitalized unstable angina Change in eGFR over time Change in albuminuria over time Jardine MJ, Mahaffey KW, Neal B, et al. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol. 2017;46(6):462-472.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER Study Design & Methods Inclusion Criteria Exclusion Criteria Efficacy Endpoints Safety Outcomes Study Timeline SAFETY EVALUATIONS AND OUTCOMES Adverse events: All adverse events were collected and coded using the MedDRA from randomization until 30 days after the last date of blinded study medication Adverse events of interest: All malignancies, fatal pancreatitis, hemorrhagic/necrotising pancreatitis, severe hypersensitivity reactions (e.g., angioedema, anaphylaxis, Stevens-Johnson syndrome), photosensitivity reactions, serious adverse events of hepatic injury, nephrotoxicity/acute kidney injury, venous thromboembolic events, fractures, diabetic ketoacidosis (and related adverse events including ketoacidosis, metabolic acidosis, or acidosis), amputation, and pregnancy Hypoglycemia: All episodes of hypoglycemia (both symptomatic and asymptomatic) were recorded on a dedicated hypoglycemia eCRF Safety laboratory tests: Chemistry, hematology, urinalysis Physical examination: Pulse, BP, weight Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy: Supplementary Appendix [published online ahead of print April 14 2019]. NEJM. 2019. Published 14 April 2019. doi:10.1056/NEJMoa1811744.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER Study Design & Methods Inclusion Criteria Exclusion Criteria Efficacy Endpoints Safety Outcomes Study Timeline STUDY TIMELINE In July 2018, after the planned interim analysis, The Independent Data Monitoring Committee (IDMC) made the recommendation to stop the CREDENCE trial based on demonstration of efficacy Interim analysis 2014 2015 2016 2017 2018 2019 First participant enrolled Last participant randomized Protocol amendment for lower extremity foot care Study concluded

DEMOGRAPHICS AND DISEASE HISTORY Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER DEMOGRAPHICS AND DISEASE HISTORY BASELINE THERAPIES BASELINE RISK FACTORS BASELINE RENAL CHARACTERISTICS DEMOGRAPHICS AND DISEASE HISTORY Canagliflozin (n = 2202) Placebo (n = 2199) Total (N = 4401) Mean age, years 63 Female, % 35 33 34 Mean duration of diabetes, years 16 Hypertension, % 97 Heart failure (NYHA I-III), % 15 CV disease, % 51 50 Prior amputation, % 5 Race, % White 68 66 67 Asian 19 21 20 Black or African American Other 8 9 Geographic region, % North America 26 28 27 Central/South America 22 Europe Rest of world 32 Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy: Supplementary Appendix [published online ahead of print April 14 2019]. NEJM. 2019. Published 14 April 2019. doi:10.1056/NEJMoa1811744.

Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER DEMOGRAPHICS AND DISEASE HISTORY BASELINE THERAPIES BASELINE RISK FACTORS BASELINE RENAL CHARACTERISTICS BASELINE THERAPIES Canagliflozin (n = 2202) Placebo (n = 2199) Total (N = 4401) Glucose-lowering agents, % Insulin 66 65 Metformin 58 Sulfonylurea 28 30 29 DPP-4 inhibitor 17 GLP-1 receptor agonist 4 Renal and CV protective agents, % RAAS inhibitor >99.9 99.8 99.9 Statin 70 68 69 Antithrombotic 61 60 Beta blocker 40 Diuretic 47 All patients were required to be receiving a stable dose of an angiotensin-converting–enzyme inhibitor or angiotensin-receptor blocker for at least 4 weeks before randomization Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy: Supplementary Appendix [published online ahead of print April 14 2019]. NEJM. 2019. Published 14 April 2019. doi:10.1056/NEJMoa1811744.

BASELINE RISK FACTORS Study Description Study Design Efficacy Outcomes Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER DEMOGRAPHICS AND DISEASE HISTORY BASELINE THERAPIES BASELINE RISK FACTORS BASELINE RENAL CHARACTERISTICS BASELINE RISK FACTORS Canagliflozin (n = 2202) Placebo (n = 2199) Total (N = 4401) HbA1c, % 8.3 BMI, kg/m2 31.4 31.3 Systolic BP, mmHg 140 Diastolic BP, mmHg 78 Total cholesterol, mmol/L 4.7 4.6 HDL-C, mmol/L 1.2 LDL-C, mmol/L 2.5 Triglycerides, mmol/L 2.2 Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy: Supplementary Appendix [published online ahead of print April 14 2019]. NEJM. 2019. Published 14 April 2019. doi:10.1056/NEJMoa1811744.

BASELINE RENAL CHARACTERISTICS Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER DEMOGRAPHICS AND DISEASE HISTORY BASELINE THERAPIES BASELINE RISK FACTORS BASELINE RENAL CHARACTERISTICS BASELINE RENAL CHARACTERISTICS Canagliflozin (n = 2202) Placebo (n = 2199) Total (N = 4401) Mean eGFR, mL/min/1.73 m² 56 eGFR ≥90, % 5 eGFR ≥60 to <90, % 36 35 eGFR ≥45 to <60, % 29 eGFR ≥30 to <45, % 27 eGFR <30, % 4 Median UACR (interquartile range), mg/g 923 (459-1794) 931 (473-1868) 927 (463-1833) UACR <30, % <1 UACR 30-300, % 11 UACR >300-≤3000, % 77 76 UACR >3000, % 12 Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy: Supplementary Appendix [published online ahead of print April 14 2019]. NEJM. 2019. Published 14 April 2019. doi:10.1056/NEJMoa1811744.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER PRIMARY OUTCOME SECONDARY OUTCOMES EXPLORATORY OUTCOMES EFFECT ON eGFR ESKD MACE PRIMARY OUTCOME HHF Composite outcome: End Stage Kidney Disease (ESKD), Doubling of Serum Creatinine, or Renal or CV Death Canagliflozin reduced the risk of the primary outcome by 30% (P = 0.00001) NNT = 22 over 2.5 years Adapted from Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy [published online ahead of print April 14 2019]. NEJM. 2019. doi:10.1056/NEJMoa1811744.

END STAGE KIDNEY DISEASE (ESKD) Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER PRIMARY OUTCOME SECONDARY OUTCOMES EXPLORATORY OUTCOMES EFFECT ON eGFR ESKD MACE END STAGE KIDNEY DISEASE (ESKD) HHF Component of the Primary Composite Outcome ESKD: defined as dialysis, renal transplantation, or sustained eGFR <15 mL/min/1.73m2 Canagliflozin reduced the risk of ESKD by 32% (P = 0.002) NNT = 43 over 2.5 years Adapted from Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy [published online ahead of print April 14 2019]. NEJM. 2019. doi:10.1056/NEJMoa1811744.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER PRIMARY OUTCOME SECONDARY OUTCOMES EXPLORATORY OUTCOMES EFFECT ON eGFR ESKD MACE SECONDARY OUTCOMES HHF Outcome Hazard ratio (95% CI) P value Significance 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) ESKD, doubling of serum creatinine, or renal death 0.66 (0.53–0.81) CV death 0.78 (0.61–1.00) 0.0502 Not significant All-cause mortality 0.83 (0.68–1.02) – Not formally tested* CV death, MI, stroke, hospitalization for heart failure, or hospitalization for unstable angina 0.74 (0.63–0.86) Patients in the canagliflozin group had a lower risk of several secondary outcomes tested in a hierarchical fashion *Prespecified secondary outcomes were tested hierarchically. Statistical significance was required before testing the next hypothesis in the hierarchical test procedure in the order listed above. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy [published online ahead of print April 14 2019]. NEJM. 2019. doi:10.1056/NEJMoa1811744. Jardine MJ, Mahaffey KW, Neal B, et al. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol. 2017;46(6):462-472.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER PRIMARY OUTCOME SECONDARY OUTCOMES EXPLORATORY OUTCOMES EFFECT ON eGFR ESKD MACE MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) HHF MACE: defined as composite of cardiovascular death, myocardial infarction (MI), or stroke Canagliflozin reduced the risk of the composite of cardiovascular death, MI, or stroke by 20% (P = 0.01) NNT = 40 over 2.5 years Adapted from Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy [published online ahead of print April 14 2019]. NEJM. 2019. doi:10.1056/NEJMoa1811744. Wheeler DC, Bakris G, Jardine MJ, et al. CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation). Symposium presented at the ISN World Congress of Nephrology (WCN); 15 April 2019; Melbourne, Australia.

HOSPITALIZATION FOR HEART FAILURE (HHF) Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER PRIMARY OUTCOME SECONDARY OUTCOMES EXPLORATORY OUTCOMES EFFECT ON eGFR ESKD MACE HOSPITALIZATION FOR HEART FAILURE (HHF) HHF Canagliflozin reduced the risk of HHF by 39% (P <0.001) NNT = 46 over 2.5 years Adapted from Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy [published online ahead of print April 14 2019]. NEJM. 2019. doi:10.1056/NEJMoa1811744. Wheeler DC, Bakris G, Jardine MJ, et al. CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation). Symposium presented at the ISN World Congress of Nephrology (WCN); 15 April 2019; Melbourne, Australia.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER PRIMARY OUTCOME SECONDARY OUTCOMES EXPLORATORY OUTCOMES EFFECT ON eGFR ESKD MACE EXPLORATORY OUTCOMES HHF Outcome Canagliflozin Placebo Hazard ratio (95% CI) P Value no./total no. events/1000 patient-yr ESKD 116/2202 165/2199 20.4 29.4 0.68 (0.54–0.86) 0.002 Doubling of serum creatinine 118/2202 188/2199 20.7 33.8 0.60 (0.48–0.76) <0.001 Renal death 2/2202 5/2199 0.3 0.9 NA Cardiovascular death 110/2202 140/2199 19.0 24.4 0.78 (0.61–1.00) 0.05 ESKD and renal or cardiovascular death† 214/2202 287/2199 37.6 51.2 0.73 (0.61–0.87) Hospitalization for heart failure 89/2202 141/2199 15.7 25.3 0.61 (0.47–0.80) NA – hazard ratios and 95% confidence intervals (CI) are reported only for outcomes with more than 10 events. † This outcome was exploratory. The effects of canagliflozin were also consistent across several renal and cardiovascular exploratory outcomes Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy: Supplementary Appendix [published online ahead of print April 14 2019]. NEJM. 2019. Published 14 April 2019. doi:10.1056/NEJMoa1811744.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER PRIMARY OUTCOME SECONDARY OUTCOMES EXPLORATORY OUTCOMES EFFECT ON eGFR ESKD MACE INTERMEDIATE RENAL OUTCOME HHF Effect on Estimated GFR –0.55 Patients treated with canagliflozin had a greater acute reduction in eGFR, but a slower decline in eGFR thereafter compared to placebo. Canagliflozin attenuated the slope of chronic eGFR decline by 2.7 mL/min/1.73 m2/year –3.72 Acute eGFR slope (3 weeks) Difference: –3.17 (95% CI, –3.87, –2.47) Adapted from Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy [published online ahead of print April 14 2019]. NEJM. 2019. doi:10.1056/NEJMoa1811744.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER SAFETY OUTCOMES Outcome Canagliflozin Placebo Hazard ratio (95% CI) no./total no. events/1000 patient-yr Any adverse events 1784/2200 1860/2197 351.4 379.3 0.87 (0.82–0.93) Any serious adverse event 737/2200 806/2197 145.2 164.4 0.87 (0.79–0.97) Serious adverse event related to trial drug 62/2200 42/2197 12.2 8.6 1.45 (0.98–2.14) Amputation 70/2200 63/2197 12.3 11.2 1.11 (0.79–1.56) Fracture 67/2200 68/2197 11.8 12.1 0.98 (0.70–1.37) Cancer Renal-cell carcinoma 1/2200 5/2197 0.2 0.9 NA Breast cancer 8/761 3/731 4.1 1.6 2.59 (0.69–9.76) Bladder cancer 10/2200 9/2197 1.7 1.10 (0.45–2.72) Acute pancreatitis 5/2200 2/2197 1.0 0.4 Hyperkalemia 151/2200 181/2197 29.7 36.9 0.80 (0.65–1.00) Acute kidney injury 86/2200 98/2197 16.9 20.0 0.85 (0.64–1.13) Diabetic ketoacidosis 11/2200 1/2197 2.2 10.80 (1.39–83.65) The overall rates of AEs and serious AEs were similar between the treatment groups. No difference in risk was observed with canagliflozin compared with placebo for fractures or amputations. Renal-related AEs were lower in the canagliflozin group compared with placebo. NA – hazard ratios and 95% confidence intervals (CI) are reported only for outcomes with more than 10 events. Adapted from Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy [published online ahead of print April 14 2019]. NEJM. 2019. doi:10.1056/NEJMoa1811744.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER SUMMARY Canagliflozin reduced the risk of the primary outcome of ESKD, doubling of serum creatinine, or renal or CV death by 30% (P = 0.00001), NNT = 22 over 2.5 years The results were consistent across a broad range of prespecified subgroups Canagliflozin reduced the risk of the secondary outcome of ESKD, doubling of serum creatinine, or renal death by 34% (P <0.001), NNT = 28 over 2.5 years Canagliflozin reduced the risk of major adverse cardiovascular events (CV death, MI, and stroke) by 20% (P = 0.01), NNT = 40 over 2.5 years Similar risk reductions were seen for exploratory outcomes assessing components of the primary outcome ESKD: 32% lower, NNT = 43 over 2.5 years Dialysis, transplantation, or renal death: 28% lower Canagliflozin reduced the risk of hospitalization for heart failure by 39% (P <0.001), NNT = 46 over 2.5 years Canagliflozin attenuated the slope of chronic eGFR decline by 2.7 mL/min/1.73 m2/year (-1.9 vs -4.6) The overall rates of AEs and serious AEs were similar between the treatment groups No difference in risk was observed with canagliflozin compared with placebo for: Fracture Amputation Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy [published online ahead of print April 14 2019]. NEJM. 2019. doi:10.1056/NEJMoa1811744.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER RESOURCES New England Journal of Medicine CREDENCE Publication: https://www.nejm.org/doi/full/10.1056/NEJMoa1811744 CREDENCE Presentation Slides: https://www.georgeinstitute.org/sites/default/files/credence-trial-results.pptx International Society of Nephrology (ISN) World Congress of Nephrology (WCN) 2019 Webcast: https://www.youtube.com/watch?v=gZC6PSN7Jt8 REFERENCE LIST Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy [published online ahead of print April 14 2019]. NEJM. 2019. doi:10.1056/NEJMoa1811744. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy: Supplementary Appendix [published online ahead of print April 14 2019]. NEJM. 2019. Published 14 April 2019. doi:10.1056/NEJMoa1811744. Jardine MJ, Mahaffey KW, Neal B, et al. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol. 2017;46(6):462-472. Wheeler DC, Bakris G, Jardine MJ, et al. CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation). Symposium presented at the ISN World Congress of Nephrology (WCN); 15 April 2019; Melbourne, Australia.

Baseline Characteristics Study Description Study Design Baseline Characteristics Efficacy Outcomes Safety Outcomes SUMMARY RESOURCES DISCLAIMER Thank you for your interest in INVOKANA® (canagliflozin). The above information is presented in response to your inquiry. This information is taken from the references cited, but is not intended to serve as a substitute for review of these references. This information is not intended to advocate the use of our product in any manner other than as described in the Product Monograph. Please refer to the INVOKANA® Product Monograph available at http://www.janssen.com/canada/products for full prescribing information. For additional information, please see the accompanying full scientific summary. For any questions, please contact Janssen Medical Information at: 1.800.567.3331 or 1.800.387.8781 http://www.janssenmedicalinformation.ca/