Canagliflozin Cardiovascular Safety

2 Potential CV protection pathways of SGLT2i Diab Vasc Dis Res Mar;12(2):

ParametersCanagliflozin BP reduction 1 3.7/1.6 mm Hg Weight reduction 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 Apr;15(4): Cefalu et al. Lancet 2013; 382: 941–50 3.Yale JF, et al. Diabetes Obes Metab May;15(5): Davies MJ, et al. Diabetes Obes Metab Apr;17(4): Effect of Canagliflozin on potential CV risk factors Disclaimer: Canagliflozin is not approved for treatment of Hypertension/Obesity/Dyslipidemia/ Albuminuria/Hyperuricemia

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) Dec 10. doi: /jch

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) Dec 10. doi: /jch 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

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

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

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 Aug;166(2): e11.

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 Aug;166(2): e11.

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