1. Canagliflozin Cardiovascular Safety

2. 2 Potential CV protection pathways of SGLT2i Diab Vasc Dis Res. 2015 Mar;12(2):90-100.

3. ParametersCanagliflozin BP reduction 1 3.7/1.6 mm Hg Weight reduction 1 1.9 Kg Fat mass 2 2/3 rd contribution to weight loss Lean mass 2 1/3 rd contribution to weight loss Change in LDL/HDL ratio 1 Reduces LDL/HDL ratio by 5.8% Albuminuria 3 Decreased the urine albumin/creatinine ratio, and slowed the progression of albuminuria Uric acid 4 13% reduction 1.Stenlöf K, et al. Diabetes Obes Metab. 2013 Apr;15(4):372-82. 2.Cefalu et al. Lancet 2013; 382: 941–50 3.Yale JF, et al. Diabetes Obes Metab. 2013 May;15(5):463-73. 4.Davies MJ, et al. Diabetes Obes Metab. 2015 Apr;17(4):426-9. Effect of Canagliflozin on potential CV risk factors Disclaimer: Canagliflozin is not approved for treatment of Hypertension/Obesity/Dyslipidemia/ Albuminuria/Hyperuricemia

4. Canagliflozin rapidly reduces BP in patients with T2DM and hypertension Hourly mean 24-hour ambulatory blood pressure (BP) monitoring (ABPM) systolic BP (SBP) and diastolic BP (DBP) for canagliflozin (CANA) 100 mg, and placebo at baseline, day 2, and week 6 (last observation carried forward). The x axis indicates the hourly time after the morning dose of the study medication. SE indicates standard error J Clin Hypertens (Greenwich). 2015 Dec 10. doi: 10.1111/jch.12747.

5. Canagliflozin rapidly reduces BP in patients with T2DM and hypertension Hourly mean 24-hour ambulatory blood pressure (BP) monitoring (ABPM) systolic BP (SBP) and diastolic BP (DBP) for canagliflozin (CANA) 100 mg, and placebo at baseline, day 2, and week 6 (last observation carried forward). The x axis indicates the hourly time after the morning dose of the study medication. SE indicates standard error J Clin Hypertens (Greenwich). 2015 Dec 10. doi: 10.1111/jch.12747. Canagliflozin rapidly reduced 24 hour ABPM-assessed SBP: both of which are important predictors of clinical CV risk and future events and was generally well tolerated

6. Non-CANAAll CANA Events/PYs (per 100 patient- yrs) Primary Endpoint 71/3467 (2.05)130/6821 (1.91) CV Endpoint CV Death16/3496 (0.46)21/6888 (0.30) FNF MI27/3484 (0.78)45/6864 (0.66) FNF Stroke16/3489 (0.46)47/6859 (0.69) Unstable angina 18/3484 (0.52)26/6874 (0.38) Hazard Ratio Estimate (95% CI) 0.91 (0.68, 1.22) 0.65 (0.34, 1.24) 0.83 (0.52, 1.34) 1.47 (0.83, 2.59) 0.71 (0.39, 1.30) Favors CANA Favors Non- CANA Hazard Ratio Canagliflozin CV safety data from interim meta- analysis of Phase 2/3 Studies http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf

7. Non-CANAAll CANA Events/PYs (per 100 patient- yrs) Primary Endpoint 71/3467 (2.05)130/6821 (1.91) CV Endpoint CV Death16/3496 (0.46)21/6888 (0.30) FNF MI27/3484 (0.78)45/6864 (0.66) FNF Stroke16/3489 (0.46)47/6859 (0.69) Unstable angina 18/3484 (0.52)26/6874 (0.38) Hazard Ratio Estimate (95% CI) 0.91 (0.68, 1.22) 0.65 (0.34, 1.24) 0.83 (0.52, 1.34) 1.47 (0.83, 2.59) 0.71 (0.39, 1.30) Favors CANA Favors Non- CANA Hazard Ratio Interim analysis of Phase 2 & 3 trials showed a HR of 0.91 for composite primary endpoint Canagliflozin CV safety data from interim meta- analysis of Phase 2/3 Studies http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf

8. CANVAS: Canagliflozin Cardiovascular Assessment Study A close look at the study designDiabetes Diabetes with CV risk factors Diabetes with established CAD 40% of study population 60% of study population Am Heart J. 2013 Aug;166(2):217-223.e11.

9. The preliminary CV safety data from phase 2/3 studies including CANVAS trial suggest no increased CV risk CANVAS results expected in 2017 Am Heart J. 2013 Aug;166(2):217-223.e11.

10. Summary SGLT2 inhibitors can potentially modulate CV risk factors like blood pressure, weight, albuminuria, uric acid Canagliflozin have beneficial effects on these potential CV risk factors CANVAS study is designed to provide broader insights about CV safety of Canagliflozin The preliminary CV safety data from phase 2/3 studies including CANVAS trial suggest no increased CV risk