New Therapeutic Glycemia Treatment for Type 2 Diabetes

New Therapeutic Glycemia Treatment for Type 2 Diabetes

DISCLOSURE Stewart B. Harris MD MPH FCFP FACPM Professor Ian McWhinney Chair For Studies in Family Medicine CDA Chair in Diabetes Management Relationships with commercial interests: Consulting and advisory board honoraria from: AstraZeneca, Janssen, Lilly, Novo Nordisk, Medtronic, Merck, Sanofi Lecture honoraria from: AstraZeneca, Janssen, Lilly, Novo Nordisk, Medtronic, Merck, Sanofi Funds given to his institution for research or educational initiatives by: Abbott, AstraZeneca, CIHR, JDRF, The Lawson Foundation, Novo Nordisk and Sanofi

DISCLOSURE OF COMMERCIAL SUPPORT Potential for conflict(s) of interest: Dr. Harris has received an honorarium from Jansen Inc. and AstaZenica whose product(s) are being discussed in this program. Janssen Inc. and AstraZenica may benefit from the future sales of a product that will be discussed in this program: Canagliflozin, Dapaglifozin

CFPC CoI Templates: Slide 3 MITIGATING POTENTIAL BIAS Only published data will be presented in this program and recommendations will be based on the CDA Clinical Guidelines The speaker will clearly identify when recommendations for off-label use are suggested

LEARNING OBJECTIVES 6 Describe the mechanism for the reabsorption of glucose in the kidneys; 5 Describe the SGLT2 inhibitors (sodium/glucose cotransporter 2), their mode of action and pharmacodynamic effects; Discuss the potential role of SGLT2 inhibitors in the treatment of type 2 diabetes.

Antihyperglycemic Medications Alpha-glucosidase Inhibitors Delay the absorption of glucose from starch and sucrose Biguanides Reduce hepatic gluconeogenesis Insulin Secretagogues Sulfonylureas and meglitinides stimulate insulin secretion SGLT2 Inhibitors Reduce the reabsorption of glucose by the kidneys : glucosuria Liver Adipose Tissues Muscles Pancreas Kidneys Intestine Thiazolidinediones Improve insulin resistance DPP-4 Inhibitors and GLP-1 Agonists Increase insulin secretion, inhibit glucagon secretion Krentz AJ, Bailey CJ. Drugs 2005; 65:385-411.

How to Choose the Best Second-line Agent After Metformin for an Individual Patient in Your Clinic? CDA Guidelines Match Patient & Agent Characteristics Patient States Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Comorbidities (renal, cardiac, hepatic) Preferences & access to treatment Other Agent States BG-lowering efficacy and durability Risk of inducing hypoglycemia Effect on weight Contraindications & side-effects Cost and coverage Other CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013; 37(suppl 1):S1-S212.

Add an Agent Best Suited to the Individual (Agents Listed in Alphabetical Order) Class -glucosidase inhibitor (acarbose) Incretin agents: DPP-4 inhibitors GLP-1 receptor agonists Relative A1C Lowering to Hypoglycemia Weight Other therapeutic considerations Cost Rare Rare Rare Neutral to N to Improved postprandial control, GI side-effects GI side-effects Insulin Yes No dose ceiling, flexible regimens $-$$$$ Insulin secretagogue: Meglitinide Sulfonylurea Yes* Yes *Less hypoglycemia in context of missed meals but usually requires TID to QID dosing Gliclazide and glimepiride associated with less hypoglycemia than glyburide $$ $$$ $$$$ $$ $ Thiazolidinediones Rare CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect $$ Weight loss agent (orlistat) None GI side effects $$$ Adapted from: CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013; 37(suppl 1):S1-S212.

Add an Agent Best Suited to the Individual (Agents Listed in Alphabetical Order) Class Relative A1C Lowering -glucosidase inhibitor (acarbose) Rare Incretin agents: DPP-4 inhibitors GLP-1 receptor agonists to Hypoglycemia Weight Other therapeutic considerations Cost Rare Rare Neutral to N to Improved postprandial control, GI side-effects $$ GI side-effects Insulin Yes No dose ceiling, flexible regimens $-$$$$ Insulin secretagogue: Meglitinide Sulfonylurea Relative A1C Lowering *Less hypoglycemia in context of missed meals but usually requires TID to QID dosing Gliclazide and glimepiride associated with less hypoglycemia than glyburide Yes* Yes Hypo- Thiazolidinediones Class glycemia Rare Weight CHF, Other edema, therapeutic fractures, considerations rare bladder Cost $$ cancer (pioglitazone), cardiovascular controversy Genital mycotic (rosiglitazone), infections 6-12 to weeks Urinary required tract infections for maximal effect SGLT2 inhibitors Rare $$$ Weight loss agent None GI Reduced side effects efficacy with egfr < 60 $$$ (orlistat) Volume-related side-effects Adapted from: Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(suppl 1):S1-S212. $$$ $$$$ $$ $

Antihyperglycemic Medications Added Therapy Change in A 1C (%) Change in Weight (kg) Hypoglycemia Odds Ratio vs placebo Sulfonylureas -0.82 2.17 8.86 Meglitinides -0.71 1.40 10.51 Thiazolidinediones -0.82 2.46 0.45 Alpha-glucosidase Inhibitors -0.66-1.01 0.40 DPP-4 Inhibitors -0.69 0.23 1.13 GLP-1 Receptor Agonists -1.02-1.66 0.92 Basal Insulin -0.88 1.38 4.77 Network Meta-analysis (add-on to metformin) Liu, Sung-Chen et al. Diab Obes & Metab 14:810-820, 2012.

ROLE OF KIDNEYS IN GLUCOSE REGULATION Glucose Homeostasis in the Body Glucose input: 250 g/day Dietary intake: 180 g/day Glucose production: 70 g/day Gluconeogenesis Glycogenolysis Glucose uptake : 250 g/day Brain : 125 g/day Rest of the body : 125 g/day + - Glucose reabsorbed by the kidneys: 180 g/day Glucose filtered by the kidneys: 180 g/day Wright EM et al. J Intern Med. 2007;261:32 43; 2. MarsenicO. Am J Kidney Dis. 2009;53:875 83 Net : approximately 0 g/day MENU

Glucose conservation Dromedary: Conserving water The kidneys: Conserving glucose MENU

RENAL GLUCOSE HANDLING IN THE NON-DIABETIC 15 Healthy patient (normal kidney function & glucose tolerance) Excess glucose Glomerulus Renal proximal tubule Glucose reabsorption Glucose Urinary excretion Adapted from: 1. Chao EC & Henry RR. Nature Reviews Drug Discovery 2010;9:551-559. 2. DeFronzo RA, et al. Diab Obes Metab 2012;14:5-14. 3. Washburn WN. J Med Chem 2009;52:1785-1794. 4. Guyton AC, Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Saunders; 2006.

Mechanism: of Induces action glucosuria A1c Weight Hypos BP Side Effects Summary At Beyond normal a glucose given glycemia, levels, the called amount the renal of glucose threshold filtered for glucose by the SGLT2 MECHANISM glomerulus (RT G ), this inhibition reabsorption reduces increases OF with ACTION mechanism the glucose glycemia, OF becomes reabsortion and SGLT2 is entirely saturated, INHIBITORS capacity reabsorbed and of the glucose renal tubule, from appears the SGLT2 leading proximal in the to = urine: SODIUM/GLUCOSE a decrease tubule glucosuria. in the by SGLT2 This RT transporters: is G a and CO-TRANSPORTER defense the appearance no mechanism of glucosuria against 2 glucosuria hyperglycemia. at normal or mildly elevated blood glucose levels. RT G Glomerulus Filtered Reabsorbed Renal Proximal Tubule Glucose reabsorption by SGLT2 Excreted 0 5 10 15 SGLT=sodium-dependent glucose transporter; GLUT=facilitative glucose transporter. Abdul-Ghani MA, DeFronzo, RA. Endocr Glycemia Pract. 2008;14(6):782-790. (mmol/l) Bays H. Curr Med Res Opin. 2009;25(3):671-681. Reprinted with permission. Glucosuria No glucosuria

MECHANISM OF ACTION OF SGLT2 INHIBITORS Glucose filtration Glomerulus S1 Proximal tubule S3 Distal tubule Collecting Duct Glucose Reabsorption ~90% SGLT2 and GLUT2 High capacity (10 nmol/mg/min) Low affinity (Km=2mM) (ex: BULLDOZER) ~10% SGLT=Sodium/GLucose co-transporter; GLUT=GLUcose Transporter. Abdul-Ghani MA, DeFronzo, RA. Endocr Pract. 2008;14(6):782-790. Bays H. Curr Med Res Opin. 2009;25(3):671-681. Loop of Henle SGLT1 and GLUT1 Low capacity (2 nmol/mg/min) High affinity (Km=0.4mM) (ex: BROOM) No/minimal glucose excretion MENU

Effects of SGLT2 Inhibitors on RT G 150 Glucose Excretion (g/day) 125 100 75 50 25 Under the RT G, no or minimal glucosuria occurs Under treatment with SGLT2 inhibitors Healthy RT G ~10 mmol/l Above the RT G, glucosuria occurs Adaptation in patients with diabetes 0 0 2 4 6 8 10 12 14 Plasma glucose (mmol/l) 16 Nair S & Wilding J. J Clin Endocrinol Metab. 2010;95:34-42. Polidori D, et al. American Diabetes Association Meeting, June 25-29, 2010, Orlando, Florida; Abstract 2186-PO MENU

Mechanism: Induces glucosuria A1c Weight Hypos BP Side Effects Summary SGLT2 INHIBITORS Agent Manufacturer Status Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin Janssen Inc. AstraZeneca Boehringer Ingelheim/Eli Lilly Merck/Pfizer Approved in Canada, United States, Australia, Europe, Mexico, Guatamala and the United Arab Emirates Approved in Canada, Europe Australia and United States Approved in Europe, US and Australia Ipragliflozin Astellas/Kotobuki Approved in Japan Luseogliflozin Tofogliflozin Taisho Chugai/ Roche

% Mechanism: Induces glucosuria Reduces A1c: 0.5 A1C to 1.2% Weight Hypos BP Side Effects Conclusion EFFECTS OF SGLT-2 INHIBITORS ON A1C LEVELS A1C DECREASES BY 0.6 TO 1.1% (0.5 TO 1.2% PLACEBO-CORRECTED) *These are not head to head trials Monotherapy + Metformin + SU + Met + SU + Pio ± SU + Insulin (-0.62) (-1.17) (-0.66) (-0.70) (-0.78) (-0.64) (-0.83) (-0.69) (-0.54) (-0.93) (-0.60) (-0.77) (-0.55) (-0.61) (-0.73) (-0.60) Canagliflozin 300 mg/d Dapagliflozin 10 mg/d Empagliflozin 25 mg/d Placebo 1. CANA: Adapted from http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm336236.pdf. Accessed January 23, 2013 2. DAPA: Available at: www.fda.gov/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm252891.htm 18 3. EMPA: ADA Annual Meeting 2013: Roden M et al 1085-P; Haring H et al: 1092-P; Kovacs C et al: 1120-P and Rosenstock J et al 1102P.

Change in A1c (%) A1 C : SGLT2 Inhibitors vs DPP-4 Inhibitors MONOTHERAPY 24 weeks A1c 7.9% + MET 52 weeks A1c 7.9% +MET +SU 52 weeks A1c 8.1% 0 Placebo 0.08 EMPA 10 EMPA 25 SITA 100 CANA 100 CANA 300 SITA 100 CANA 300 SITA 100 0.25-0.50-0.75-0.66-0.78-0.66-0.73-0.73-0.66 1.00 **p<0.05 vs sitagliptin -0.88** -1.03** Roden M et al. ADA Annual Meeting, 2013; 1085-P. Lavalle Gonzalez FJ et al. ADA Annual Meeting, 2013; 238-OR. Schernthaner G et al. Diabetes Care 2013. MENU

CAN WE COMBINE DAPA WITH DPP4I?

DAPA+SAXA VS DAPA VS SAXA ON MET BACKGROUND Key Eligibility Criteria T2DM and 18 years A1C 8.0% to 12.0% BMI 45 kg/m 2 C-peptide 1.0 ng/ml Stable MET therapy 1500 mg/day for 8 weeks prior to screening S 1:1:1 R n=179 n=176 n=179 SAXA 5 mg + DAPA 10 mg + MET XR SAXA 5 mg + MET XR + PBO DAPA 10 mg + MET XR + PBO 4-week lead-in 24-week active-controlled, double-blind treatment Primary end point: Change in A1C from BL at week 24 Prespecified secondary end points: Changes at week 24 from BL in 2h-PPG, FPG, and BW, and proportion of patients achieving A1C<7.0% after 24 weeks. S: switched to nearest MET XR (1500-2000 mg/d) at the beginning of the 4-week lead -in. BL, baseline; BMI, body mass index; BW, body weight; DAPA, dapagliflozin; FPG, fasting plama glucose; MET, metformin; MET XR, metformin extended release; PBO, placebo; PPG, post-prandial glucose; SAXA, saxatliptin; T2DM, type 2 diabetes mellitus. Rosenstock J et al. Diabetes Care. 2014 Oct 28. pii: DC_141142. NCT01606007

ADJUSTED MEAN CHANGE IN A1C AT 24 WEEKS FROM BASELINE Adjusted Mean ( 95% CI) Change From baseline in A1C, % SAXA+DAPA+MET SAXA+MET DAPA+MET Baseline, % 8.93 9.03 8.87 n a 158 143 151-0.88% -1.20% -1.47% -0.59% (-0.81%, -0.37%) P<0.0001-0.27% (-0.48%, -0.05%) P=0.0166 a Number of randomized patients with non-missing baseline values and week 24 values. Data are mean±se. DAPA, dapagliflozin; MET, metformin; SAXA, saxagliptin. Rosenstock J et al. Diabetes Care. 2014 Oct 28. pii: DC_141142. NCT01606007

BACKGROUND STUDY DESIGN Key Eligibility Criteria T2DM and 18 years A1C 8.0% to 12.0% BMI 45 kg/m 2 C-peptide 1.0 ng/ml Stable MET therapy 1500 mg/day for 8 weeks prior to screening S 1:1:1 R n=179 n=176 n=179 SAXA 5 mg + DAPA 10 mg + MET XR SAXA 5 mg + MET XR + PBO DAPA 10 mg + MET XR + PBO 4-week lead-in 24-week active-controlled, double-blind treatment Primary end point: Change in A1C from BL at week 24 Prespecified secondary end points: Changes at week 24 from BL in 2h-PPG, FPG, and BW, and proportion of patients achieving A1C<7.0% after 24 weeks. S: switched to nearest MET XR (1500-2000 mg/d) at the beginning of the 4-week lead -in. BL, baseline; BMI, body mass index; BW, body weight; DAPA, dapagliflozin; FPG, fasting plama glucose; MET, metformin; MET XR, metformin extended release; PBO, placebo; PPG, post-prandial glucose; SAXA, saxatliptin; T2DM, type 2 diabetes mellitus. Rosenstock J et al. Diabetes Care. 2014 Oct 28. pii: DC_141142. NCT01606007

DAPA+SAXA VS DAPA VS SAXA ON MET BACKGROUND ADJUSTED MEAN CHANGE IN A1C AT 24 WEEKS FROM BASELINE Adjusted Mean ( 95% CI) Change From baseline in A1C, % SAXA+DAPA+MET SAXA+MET DAPA+MET Baseline, % 8.93 9.03 8.87 n a 158 143 151-0.88% -1.20% -1.47% -0.59% (-0.81%, -0.37%) P<0.0001-0.27% (-0.48%, -0.05%) P=0.0166 a Number of randomized patients with non-missing baseline values and week 24 values. Data are mean±se. DAPA, dapagliflozin; MET, metformin; SAXA, saxagliptin. Rosenstock J et al. Diabetes Care. 2014 Oct 28. pii: DC_141142. NCT01606007

DAPA+SAXA VS DAPA VS SAXA ON MET BACKGROUND ADJUSTED MEAN PROPORTION OF PATIENTS ACHIEVING A1C <7.0% AT WEEK 24 Adjusted Mean ( 95% CI) Proportion of Pations with A1C <7.0% at week 24, % SAXA+DAPA+MET SAXA+MET DAPA+MET X/n a 74/177 29/175 40/173 23% (14.7%, 31.5%) 19% (10.1%, 28.1%) 41% 18% 22% a Number of responders (x)/number of patients with non-missing baseline values and week 24 values (LOCF). Data are mean±sd. DAPA, dapagliflozin; MET, metformin; SAXA, saxagliptin. Rosenstock J et al. Diabetes Care. 2014 Oct 28. pii: DC_141142. NCT01606007

DAPA+SAXA VS DAPA VS SAXA ON MET BACKGROUND PROGRESSIVELY GREATER REDUCTIONS IN A1C WITH PROGRESSIVELY HIGHER BASELINE A1C A1C change from baseline (%) a Number of randomized patients with non-missing baseline values and Week 24 value. Adapted from Rosenstock J, et al. Diabetes Care. Published online October 28, 2014.. Adjusted Mean Change From Baseline in A1C Stratified by Baseline A1C Subgroup Baseline, % n a 7.50 37 7.61 29 7.41 37 8.44 56 8.54 51 8.49 52 10.02 65 9.90 63 9.95 62 0-0.5-1 -0.45-0.51-1.5-0.8-0.69-1.17-0.84-1.32-2 -1.87-2.5 <8% Baseline mean 8% to <9% Baseline mean -2.03 9% Baseline mean SAXA+DAPA+MET SAXA+MET DAPA+MET

ADD ON TO INSULIN - LONG TERM DATA

Change in Mean HbA 1c (%)* CHANGE IN HBA1C At week 24, DAPA 2.5 mg, 5 mg and 10 mg significantly reduced BW from BL compared with PBO (P<0.001 for each group); differences were maintained to 104 weeks 0.0 PBO + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS -0.1-0.2-0.3-0.4-0.5-0.6-0.7-0.8-0.9-1.0-1.1-1.2-1.3 Sample size per time point PBO + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS ST period LT period 1 LT period 2 0 4 8 12 16 20 24 32 40 48 52 65 78 91 104 Study Week 193 183 173 169 167 164 166 163 159 157 122 116 114 109 107 202 198 190 187 185 181 179 175 176 172 147 142 140 136 132 211 201 195 191 187 187 185 184 180 173 150 143 133 131 128 193 188 184 183 179 176 173 175 173 164 148 145 144 140 139 *Data are adjusted mean change from baseline ± 95% CI derived from a mixed model and include data after insulin up-titration DAPA, dapagliflozin; INS, insulin; PBO, placebo; ST, short-term; LT, long-term J.P.H. Wilding, V. Woo, et al.: Diabetes, Obesity and Metabolism 16: 124 136, 2014.

Change in Mean Total Body Weight (kg)* CHANGE IN BODY WEIGHT At week 24, DAPA 2.5 mg, 5 mg and 10 mg significantly reduced BW from BL compared with PBO (P<0.001 for each group); differences were maintained to 104 weeks 3.0 PBO + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS 2.5 2.0 1.5 1.0 0.5 0.0-0.5-1.0-1.5-2.0-2.5-3.0 ST period LT period 1 LT period 2 0 4 8 12 16 20 24 32 40 48 52 65 78 91 104 Study Week Sample size per time point PBO + INS 193 185 175 170 170 165 168 164 158 157 122 118 114 110 107 DAPA 2.5 mg + INS 202 198 191 188 188 182 180 176 176 174 147 142 140 136 132 DAPA 5/10 mg + INS 211 201 196 193 190 188 187 184 181 174 150 143 134 132 128 DAPA 10 mg + INS 193 190 186 183 180 178 177 176 174 166 148 146 144 142 141 *Data are adjusted mean change from baseline ± 95% CI derived from a mixed model and include data after insulin up-titration DAPA, dapagliflozin; INS, insulin; PBO, placebo; ST, short-term; LT, long-term J.P.H. Wilding, V. Woo, et al.: Diabetes, Obesity and Metabolism 16: 124 136, 2014.

Change in Mean Daily Insulin Dose (U)* CHANGE IN INSULIN DOSE OVER TIME 24 PBO + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS 22 20 18 16 14 12 10-2 -4-6 -8 Sample size per time point 8 6 4 2 0 PBO + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS ST period LT period 1 LT period 2 0 4 8 12 16 20 24 32 40 48 Study Week 52 65 78 91 104 191 185 176 171 170 165 168 164 158 157 121 118 114 110 104 200 197 189 187 186 181 180 174 176 173 144 142 140 136 130 209 202 194 194 190 188 187 183 181 172 147 142 134 132 128 194 189 185 183 180 178 177 175 173 166 145 146 144 142 140 *Data are adjusted mean change from baseline ± 95% CI derived from a mixed model and include data after insulin up-titration DAPA, dapagliflozin; INS, insulin; PBO, placebo; ST, short-term; LT, long-term J.P.H. Wilding, V. Woo, et al.: Diabetes, Obesity and Metabolism 16: 124 136, 2014.

Weight- kg Mechanism: Induces glucosuria Reduces A1c: 0.7 to 1.2 Reduces Wt: 1.0 to 3.7 BW Kg Hypos BP Side Effects Conclusion EFFECTS BW DECREASES OF BY 0.1 SGLT-2 TO 3.9 KG INHIBITORS (1.0 3.7 KG PLACEBO-CORRECTED) ON BODY WEIGHT *These are not head to head trials 2 Monotherapy + Metformin + SU + Met + SU + Pio ± SU + Insulin 1 0 ( -1.6) -1-2 -3 ( -1.0) (-2.2) (-2.0) (-2.95) (-1.8) (-1.6) (-1.9) (-2.0) (-1.8) (-2.3) (-1.7) (-2.7) -4 (-3.2) (-2.9) (-3.7) Canagliflozin 300 mg/d Dapagliflozin 10 mg/d Empagliflozin 25 mg/d Placebo * 1. CANA: Adapted from http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm336236.pdf. Accessed January 23, 2013 2. DAPA: Available at: www.fda.gov/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm252891.htm 31 3. EMPA: ADA Annual Meeting 2013: Roden M et al 1085-P; Haring H et al: 1092-P; Kovacs C et al: 1120-P and Rosenstock J et al 1102P.

Variation versus baseline (kg) Variation versus baseline (kg) Body Composition Studies with SGLT-2 Inhibitor Treatment (DEXA measurements) Canagliflozin Variation at week 52 Dapagliflozin Variation at week 24 3 Glimepiride n = 68 3 2 1 0-1 1.02 1.06 CANA. 100 mg n = 71 CANA. 300 mg n = 69-0.89-1.12 2 1 0-1 Placebo + Met. n = 79-0.6-0.74 DAPA. + Met. n = 82-1.11-2 -3-2.89-2.51-2 - 3-2.22-4 - 4-5 - 5 Lean mass Fat mass Toubro S et al.easd Annual Meeting, 2012. Abstract 762. Bolinder J et al. J Clin Endocrinol Metab. 97; 2012. MENU

Body Weight: SGLT-2 Inhibitors vs SU (104 weeks) Canagliflozin vs Glimepiride Cefalu et al., ADA Annual Meeting, 2013. Abstract 65-LB MENU

Percentage of Hypos Mechanism: Induces glucosuria Reduces A1c: 0.7 to 1.2 Reduces Wt: 1.0 to 3.7 Kg Risk Hypos BP Side Effects Conclusion hypos LOW EFFECTS RISK OF SGLT-2 HYPOGLYCEMIA INHIBITORS ON HYPOGLYCEMIA *These are not head to head trials Monotherapy + Metformin + SU + Met + SU + Pio ± SU + Insulin 50 50 40 40 30 30 20 20 10 10 0 0 Canagliflozin 300 mg/d Dapagliflozin 10 mg/d Placebo 1. CANA: Adapted from http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm336236.pdf. Accessed January 23, 2013 2. DAPA: Available at: www.fda.gov/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm252891.htm

mmhg Mechanism: Induces glucosuria Reduces A1c: 0.7 to 1.2 Reduces Wt: 1.0 to 3.7 Kg Risk hypos Reduces BP: 1.7 BP to 6.6 Side Effects Conclusion EFFECTS BP DECREASES OF BY SGLT-2 2.4 TO 6.9 INHIBITORS MMHG (1.7 ON 6.6 PLACEBO-CORRECTED) BLOOD PRESSURE *These are not head to head trials 2 Monotherapy + Metformin + SU + Met + SU + Pio ± SU + Insulin 1 0-1 -2 ( -2.5) -3-4 -5 (-5.4) (-2.9) (-3.4) ( -6.6) ( -4.8) ( -1.8) ( -3.7) ( -1.7) ( -2.1) ( -3.5) ( -4.8) ( -4.7) -6-7 ( -5.8) ( -5.5) (-4.4) Canagliflozin 300 mg/d Dapagliflozin 10 mg/d Empagliflozin 25 mg/d Placebo 1. CANA: Adapted from http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm336236.pdf. Accessed January 23, 2013 2. DAPA: Available at: www.fda.gov/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm252891.htm 35 3. EMPA: ADA Annual Meeting 2013: Roden M et al 1085-P; Haring H et al: 1092-P; Kovacs C et al: 1120-P and Rosenstock J et al 1102P.

Percentage Percentage Mechanism: Induces glucosuria Reduces A1c: 0.7 to 1.2 Reduces BW: 1.0 to 3.7 Kg Risk hypos Reduces BP: 1.7 to 6.6 Side Effects: Side Effects Genital mycotic Conclusion EFFECTS INCREASE IN OF GENITAL SGLT-2 MYCOTIC INHIBITORS INFECTIONS; INFECTIONS UTI? *These are not head to head trials 20 URINARY TRACT INFECTIONS GENITAL MYCOTIC INFECTIONS Men Women Men Women 20 15 15 10 10 5 5 0 0 Canagliflozin 300 mg/d Dapagliflozin 10 mg/d Empagliflozin 25 mg/d Placebo 1.. CANA: Adapted from http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm336236.pdf. Accessed January 23, 2013 2. DAPA: Available at: www.fda.gov/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm252891.htm 3. EMPA: ADA Annual Meeting 2013: Roden M et al 1085-P; Haring H et al: 1092-P; Kovacs C et al: 1120-P and Rosenstock J et al 1102P.

TIME TO FIRST FEMALE GENITAL MYCOTIC INFECTION All non-cana CANA 100 mg CANA 300 mg All non-cana CANA 100 mg CANA 300 mg The highest rate of occurrence was observed during the first 4 months of treatment, followed by an attenuation in the rate of increase. Less than 1% withdrawal for this reason. Nyirjesky P et al. ADA Annual Meeting 2013. Abstract 1069-P. MENU

URINARY TRACT INFECTION WITH CANA Time to First UTI AE 30 ):

DAPAGLIFLOZIN POOLED DATA (12 TRIALS): GENITAL MYCOTIC INFECTIONS Percentage of subjects with clinical diagnosis of genital infection Higher rates of GMI in dapagliflozin treatment groups than placebo More in women than men All events were mild to moderate in intensity Rarely led to discontinuation (0.2%) 10 8 6 5.7 4.8 8.4 6.9 DAPA 5 mg DAPA 10 mg Placebo Most events responded to the initial course of standard therapy and rarely re-occurred 4 2 0 Total 0.9 Women 1.5 2.8 2.7 Men 0.3 Johnsson KM, et al. J Diabetes Complications 2013; 27(5):479-84.

Percentage of subjects with clinical diagnosis of UTI DAPAGLIFLOZIN POOLED DATA (12 TRIALS): UTI S Rates of clinically diagnosed UTI higher in the dapa groups than placebo Upper UTI were rare and balanced between groups More in women than men 12 DAPA 5 mg All events were mild to moderate in intensity 10 9.6 DAPA 10 mg Placebo Rarely led to treatment discontinuation (0.3%) Most events responded to the initial course of standard therapy and rarely re-occurred 8 6 4 2 5.7 4.3 3.7 7.7 6.6 1.6 0.8 1.0 0 Total Women Men Johnsson KM, et al. J Diabetes Complications 2013; 27(5):473-8.

Patients (%) Mechanism: Induces glucosuria Reduces A1c: 0.5 to 1.2% Reduces weight: 1.0 to 3.7 Kg Rare Hypos Reduces BP: 1.7 to 6.6 Side Effects Summary SIDE EFFECTS OF SGLT2 INHIBITORS VOLUME DEPLETION IN RELATION TO CIRCULATING VOLUME Canagliflozin pooled data 12 10 75 years Events of interest: 8 6 4 2 0 1.4% Other < 75 years 2.2% Cana 100 3.1% Cana 300 2.6% Other 4.9% Cana 100 8.7% Cana 300 Hypotension Postural Hypotension Dehydration Syncope Reduced urinary output http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm336236.pdf. Accessed January 23, 2013

Patients (%) Patients (%) RISK FACTORS FOR VOLUME DEPLETION SYMPTOMS 10 Patients on loop diuretics Canagliflozin pooled data 8.8 Dapagliflozin pooled data 9.7 8 6 4 2 0 10 8 6 4.7 All non-cana 4.7 3.2 Cana 100 Cana 300 Canagliflozin pooled data Placebo Patients with low baseline egfr Dapa 10 < 60mL/min 60 to < 90 ml/min 90 ml/min 8.1 1.8 Population at risk > 75 yo Events of interest: Hypotension Postural hypotension Dehydration Syncope Decreased urinary output 4 2 2.5 1.5 2.4 2.9 1.2 1.3 2.4 0 Others Cana 100 Cana 300 Others Cana 100 Cana 300 Others Cana 100 Cana 300 http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs /EndocrinologicandMetabolicDrugs AdvisoryCommittee/UCM336236.pdf. Consulted January 23, 2013. FDA Advisory Committee, July 19 2011 : http://www.fda.gov. MENU

EFFECTS of SGLT-2 INHIBITORS on egfr egfr (ml/min/1.73 m 2 ): Mean Change ±SE The egfr decreases slightly, then increases slowly towards baseline Glimepiride BL: 89.5 ml/min/1.73 m 2 0 CANA 100 mg BL: 89.7 ml/min/1.73 m 2 CANA 300 mg BL: 91.4 ml/min/1.73 m 2-1 -2-1.7 ml/min/1.73m 2-3 -4-5 -3.0 ml/min/1.73m 2-5.1 ml/min/1.73m 2-6 -7 Baseline 4 12 26 36 44 52 weeks http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs /EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013 MENU

EFFECTS of SGLT2 Inhibitors on egfr in presence of moderate renal failure The egfr decreases slightly, then increases slowly towards baseline in presence of moderate renal failure Yale JF et al. ADA Annual Meeting 2013. Abstract 1075-P. MENU

EFFECTS of SGLT2 Inhibitors on egfr in presence of moderate renal failure The egfr decreases slightly, then increases slowly towards baseline In presence of moderate renal failure Placebo Empagliflozin Yale JF et al. ADA Annual Meeting 2013. Abstract 1075-P. MENU

Change from Baseline (± 95% CI) A1C (%) EFFECTS of SGLT2 INHIBITORS on A1c LEVELS in CKD In moderate renal failure, the A1c reduction is halved Baseline mean A1C (%) Baseline mean egfr (ml/min/1.73m 2 ) Canagliflozin egfr 30 to <50 (N=269) 8.0 39.4 Dapagliflozin egfr 30 to 59 (N=252) 8.4 44.6 Empagliflozin egfr 30 to <60 (N=374) 8.0 43 0.2 0.05 0.0-0.03-0.2-0.4-0.32-0.37-0.44-0.44-0.6-0.40* -0.11 (-0.40,0.45) -0.42* (-0.56,-0.28) -0.8 Placebo CANA 300 mg Placebo DAPA 10 mg Placebo EMPA 25 mg * p <0.001; p <0.05. Yale JF et al. Diabetes Obesity & Metabolism 2013;15:463-473. Kohan D et al. J Am Soc Nephrol 2011;22:232A:TH-PO524. Barnett A et al. ADA Annual Meeting 2013. Abstract 1104-P. MENU

CANA MONOTHERAPY: CHANGE IN FASTING PLASMA LIPIDS AT WEEK 26 47 Triglycerides * LDL-C HDL-C LDL-C/HDL-C Non HDL-C Baseline (mmol/l) LS Mean Change (mmol/l) 2.22 1.95 1.97 3.12 3.05 2.87 1.14 1.20 1.17 0.08 0.07 0.07 4.14 3.94 3.75 0.07-0.16-0.18-0.07-0.003 0.12 0.04 0.11 0.11-0.005-0.005-0.003-0.05-0.05 0.04 * p=ns vs. PBO; Statistical comparison for CANA 100 and 300 mg vs. PBO not performed (not pre-specified); Unit of mg/mg for LDL-C/HDL-C; p<0.001 vs. PBO; p<0.01 vs. PBO. CANA: canagliflozin; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; LS: least squares; SE: standard error; PBO: placebo; NS: not significant; mitt: modified intent-to-treat; LOCF: last observation carried forward. 1. Stenlöf et al. 72 nd ADA Scientific Sessions; 2012 June 9. [Oral number 081-OR (study 3005)].

Percentage of Patients Dapagliflozin: Cardiovascular Risk Phase 2/3 Studies 4 3 DAPA. vs Controls Relative Risk: 0.674 98 % CI : 0.385 1.178 Controls Patients with an event Number of first events DAPA Event Rate Controls Number of first events Event Rate 48 1.13 % 30 1.66 % 2 CV Deaths 8 0.19 % 4 0.22 % 1 MI 18 0.42 % 18 1.00 % CVA 11 0.26 % 5 0.28 % 0 0 100 200 300 400 500 600 700 Unstable angina 11 0.26 % 3 0.17 % Time (days) Number of patients DAPA. 4 097 3 826 2 767 2 350 1 532 1 368 1 062 585 Controls 1 850 1 696 1 197 1 004 622 538 415 233 Langkilde A el al. American Heart Association Meeting, 2011; abstract 8947. MENU

Probability of a MACE-plus Event CANAGLIFLOZIN : MACE-PLUS All phase 2/3 studies, including CANVAS Kaplan-Meyer estimate 0.05 HR = 0.91 (95% CI : 0.68 1.22) 0.04 0.03 HR = 1.00 (0.72 1.39) CANVAS HR = 0.65 (0.35 1.21) Other trials All non-cana. All CANA. 0.02 0.01 0.00 0 6 12 18 26 39 52 65 78 91 104 Number of subjects at risk Study Week All non-cana. All CANA. 3 327 3 282 3 161 2 991 6 305 6 224 6 000 5 715 2 848 5 539 2 650 5 227 1 985 4 065 931 1 935 508 1 039 213 462 42 91 Note : Includes all studies with data base lock prior to January 31, 2012; mttt analysis set; events within 30 days of last dose http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs /EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Consulted January 23, 2013. MENU

ONGOING CARDIOVASCULAR OUTCOME TRIALS: SGLT2 INHIBITORS Therapies # Population Endpoints End Date CANVAS Canagliflozin/ Placebo 4,330 CVD or high-risk for CVD Noninferiority: CV death, NF MI or NF stroke June 2018 DECLARE Dapagliflozin/Pl acebo 17,150 CVD or high-risk for CVD Noninferiority safety, superiority efficacy: CV death, NF MI or NF stroke April 2019 EMPA-REG Outcome Empagliflozin/ Placebo 7,034 CVD Noninferiority (test for superiority if noninferiority met) CV death, NF MI or NF stroke April 2015 Ertugliflozin CVOT Ertugliflozin/ Placebo 3,900 CVD Noninferiority: CV death, NF MI or NF stroke April 2021 Adapted from: www.clinicaltrials.gov

How To Prescribe Available SGLT2 Inhibitors in Canada? Dapagliflozin FORXIGA Start at 5 mg od Canagliflozin INVOKANA Start at 100 mg od Increase to 10 mg od if required INVOKANA Product Monograph. Janssen Inc., November 2014. FORXIGA Product Monograph. AstraZeneca. December 2014. May be increased to 300 mg od if tolerated and additional glycemic control required

Approved Indications for SGLT2 Inhibitor Therapies in Canada SGLT2 Inhibitors Monotherapy DUAL THERAPY TRIPLE THERAPY Combination with any INSULIN regimen Metformin contraindicated or intolerable Add-on to MET Add-on to SU Add-on to MET + SU Add-on to MET + PIO Dapagliflozin Canagliflozin INVOKANA Product Monograph. Janssen Inc., November 2014. FORXIGA Product Monograph. AstraZeneca. December 2014.

CKD Approved Indications for SGLT2 Inhibitor Therapies in Canada egfr SGLT2 Inhibitors > 60 45-60 < 45 Dapagliflozin Contraindicated Canagliflozin Do not initiate; can continue only at 100 mg Contraindicated INVOKANA Product Monograph. Janssen Inc., November 2014. FORXIGA Product Monograph. AstraZeneca. December 2014.

HEALTH CANADA CAUTIONS ASSOCIATED WITH SGLT2 INHIBITORS Dapagliflozin Canagliflozin Not recommended for use in volume depletion Increased risk of volume-related AEs in: Elderly Not recommended for use in volume depletion or with loop diuretics Increased risk of volume-related AEs in: Low SBP Known CVD -Antihypertensives, therapies, particularly particularly loop Elderly diuretics e.g. Furosemide loop diuretic Low SBP No caution for hyperkalemia CAUTIONS FOR VOLUME DEPLETION* -Elderly -Low BP or low baseline volume status Moderate renal impairment Caution for hyperkalemia ACE-inhibitors, ARBs, or loop diuretics At-risk patients include moderate renal impairment Low SBP on meds (e.g., K + sparing diuretics, ACE inhibitors, ARBs) *SGLT2s are not recommended for use in volume depletion. INVOKANA Product Monograph. Janssen Inc., November 2014. FORXIGA Product Monograph. AstraZeneca. December 2014.

Mechanism: Induces glucosuria Reduces A1c: 0.5 to 1.2% Reduces weight: 1.0 to 3.7 Kg Rare Hypos Reduces BP: 1.7 to 6.6 Side Effects Summary SUMMARY: SGLT2 inhibitors induce glucosuria, resulting in a loss of glucose in the urine. A1c is reduced by 0.5 to 1.2 % Body weight is reduced by 1.0 to 3.7 kg SGLT2 inhibitors rarely induce hypoglycemia, except when added to insulin or insulin secretagogues. Blood pressure is reduced by 1.7 to 6.6 mm Hg The following side effects can be observed: genital mycotic infections and side effects related to volume depletion.

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LONGER TERM DATA

DAPA 10 MG RESULTS IN DURABLE IMPROVEMENTS IN HBA 1C OVER 2 YEARS HbA1C (%) adjusted mean change from BL HbA1C (%) adjusted mean change from BL HbA1C (%) adjusted mean change from BL HbA1C (%) adjusted mean change from BL Study 1: Add-on to metformin Study 2: Add-on to metformin 0.3 (N=135) DAPA 10 mg + MET (BL HnA1c 7.9%) (N=137) PBO + MET (BL HnA1c 8.1%) 0.4 (N=89) DAPA 10 mg + MET (BL HbA1c 7.19%) (N=91) PBO + MET (BL HbA1c 7.2%) 0.0 0.2-0.3 0.0-0.2-0.6-0.4-0.9-0.6-1.2-0.8 0 8 16 24 37 50 63 76 89 102 0 8 24 37 50 63 76 89 102 Study week Study week Dapa vs. SU Add-on to Insulin (N=400) DAPA 10 mg + MET (BL HnA1c 7.7%) (N=194) DAPA 10 mg + INS (BL HbA1c 8.6%) 0.2 (N=401) GLIP + MET (BL HbA1c 7.7%) 0.2 (N=193) PBO + INS (BL HbA1c 8.5%) 0.0 0.0-0.2-0.4-0.2-0.4-0.6-0.6-0.8-0.8-1.0-1.0-1.2 0 6 12 18 26 34 42 52 65 78 91 104 0 8 12 24 32 40 48 52 65 78 91 104 Study week Study week BL, baseline; DAPA, dapagliflozin; HbA 1c, hemoglobin A 1c ; MET, metformin.

DAPA 10 MG RESULTS IN DURABLE IMPROVEMENTS IN BODY WEIGHT OVER 2 YEARS Total body weight (kg) adjusted mean change from BL Total body weight (kg) adjusted mean change from BL Total body weight (kg) adjusted mean change from BL Total body weight (kg) adjusted mean change from BL Study 1: Add-on to metformin Study 2: Add-on to metformin 2.0 1.6 1.0 0.4-0.2-0.8-1.4-2.0-2.6-3.2-3.8 (N=135) DAPA 10 mg + MET (BL body weight 86.2 kg) (N=137) PBO + MET (BL body weight 87.7 kg) 0 8 16 24 37 50 63 76 89 102 Study week 2.0 0.0-2.0-4.0-6.0 (N=135) DAPA 10 mg + MET (BL body weight 92.1 kg) (N=137) PBO + MET (BL body weight 90.0 kg) 0 48 16 2437 50 63 76 89 102 Study week Dapa vs. SU Add-on to Insulin 3.0 2.0 1.0 0.0-1.0-2.0-3.0-4.0-5.0 (N=400) DAPA 10 mg + MET (BL body weight 88.4 kg) (N=401) GLIP + MET (BL body weight 87.6 kg) 0 6 12 18 26 34 42 52 65 78 91 104 Study week 3.0 2.6 2.2 1.8 1.4 1.0 0.8 0.4 0.0-0.4-0.8-1.2-1.6-2.0-2.4 (N=194) DAPA 10 mg + INS (BL body weight 94.5 kg) (N=193) PBO + INS (BL body weight 94.6 kg) 0 8 12 24 32 40 48 52 65 78 91 104 Study week BL, baseline; DAPA, dapagliflozin; GLIP, glipizide; INS, insulin; MET, metformin; PBO, placebo.

Change in HbA1c (%)* ADJUSTED MEAN CHANGE FROM BASELINE IN HBA1C UP TO WEEK 208 Dapagliflozin + Metformin Gilpizide+ Metformin 0.4 0.2 0.0-0.2-0.4-0.6-0.8-1.0 Mean baseline A1C=7.7% Dif. -0.30% (95% CI: -0.51, -0.09) -0.10% (95% CI: -0.25, 0.05) Recue therapy NOT available Recue therapy available 0 6 12 18 26 34 42 52 65 78 91 104 117 130 143 156 169 182 195 208 Study week Week 208 values 0.20% (95% CI: 1.05, 0.36) Sample size (excluding data after rescue) DAPA + MET 400 321 233 139 105 79 GLP + MET 401 315 208 129 102 71 Del Prato et al., 2013. ADA 2013, Chicago USA. Abstract 62-LB

SUSTAINED BODY WEIGHT REDUCTION OF ADD-ON DAPAGLIFLOZIN VS. ADD-ON GLIPIZIDE IN PATIENTS ON METFORMIN (208 WKS) Change in weight (kg)* Baseline weight DAPA + MET: 88.4 kg GLIP + MET : 87.6 kg Between-group difference at 52 weeks: 4.65 kg (95% CI; 5.14, 4.14), p<0.0001 Between-group difference at 104 weeks: 5.06 kg (95% CI; 5.73, 4.4) Between-group difference at 208 weeks: 4.38 kg (95% CI; 5.31, -3.46) 3 2 1 0-1 -2-3 -4-5 GLI + MET (n = 401) DAPA + MET (n = 400) 0 6 12 18 26 34 42 52 65 78 91 104 117 130 143 156 169 182 195 208 Sample size (excluding data after rescue), a Study week DAOA + MET 400 323 234 159 GLP + MET 401 315 211 140 Del Prato et al., 2013. ADA 2013, Chicago USA. Abstract 62-LB

BLOOD PRESSURE REDUCTIONS WITH DAPAGLIFLOZIN WERE SUSTAINED OVER 208 WEEKS Change in SBP (mmhg)* 4 3 2 1 0-1 -2-3 -4-5 -6-7 0 6 12 18 26 34 42 52 65 78 91 104 117 130 143 156 169 182 195 208 Sample size (excluding data after rescue), a DAOA + MET 399 323 234 159 GLP + MET 396 314 211 140-0.2 mmhg (95% CI: -1.56, 1.61) Dif. -3.67 mmhg (95% CI: -5.92, -1.41) -3.69 mmhg (95% CI: -5.24, -2.14) Del Prato et al., 2013. ADA 2013, Chicago USA. Abstract 62-LB

Mean change from baseline egfr (ml/min/1.73m 2 ) EGFR CHANGES IN NORMAL RENAL FUNCTION AND IN CKD Dapagliflozin in normal egfr 1 BL Mean egfr (ml/min/1.73m 2 ) 80.7 81.0 15 10 Placebo DAPA 10 mg 5 0-5 -10-15 1 4 8 16 24 37 50 63 76 89 102 Baseline Weeks 1. Ptaszynska, et al. Presented at EASD 2014. 2. Yale JF, et al. Presented at ADA 2013. Abstract 1075-P.

Mean change from baseline egfr (ml/min/1.73m 2 ) EGFR CHANGES IN NORMAL RENAL FUNCTION AND IN CKD Dapagliflozin in normal egfr 1 Canagliflozin in low egfr 2 BL Mean egfr (ml/min/1.73m 2 ) 80.7 81.0 40.1 39.4 38.5 15 10 Placebo DAPA 10 mg CANA 100 CANA 300 5 0-5 -10-15 1 4 8 16 24 37 50 63 76 89 102 Baseline Weeks Note: These are separate pooled analysis for Dapagliflozin and Canagliflozin. 1. Ptaszynska, et al. Presented at EASD 2014. 2. Yale JF, et al. Presented at ADA 2013. Abstract 1075-P.

Mean change from baseline egfr (ml/min/1.73m 2 ) EGFR CHANGES IN NORMAL RENAL FUNCTION AND IN CKD BL Mean egfr (ml/min/1.73m 2 ) 15 5 Dapagliflozin in normal egfr 1 80.7 81.0 40.1 Canagliflozin in low egfr 2 egfr decreases slightly at initiation of SGLT2 inhibitors, 10 then returns slowly towards baseline 39.4 38.5 0-5 -10-15 1 4 8 16 24 37 50 63 76 89 102 Baseline Weeks Note: These are separate pooled analysis for Dapagliflozin and Canagliflozin. 1. Ptaszynska, et al. Presented at EASD 2014. 2. Yale JF, et al. Presented at ADA 2013. Abstract 1075-P.

DAPA POOLED DATA: TUMOUR INCIDENCE Tumour origin Patients with Events Overall 140 Bladder 10 Breast (female only) 15 Pancreatic 8 Prostate (male only) 17 Hepatobiliary 3 Thyroid and endocrine 10 Skin 31 Respiratory and mediastinal 15 Reproductive (female only) 4 Metastases and site unspecified 5 Gastrointestinal 10 Renal tract 5 Blood and lymphatic 7 Musculoskeletal and soft tissue 1 One additional case of bladder cancer was found in study 93-005 which was not finished at the time of data cut for FDA resubmission. The incidence rate ratio with 95% CI including this case is 6.11 (0.827, 272.0). DAPA N = 5,936 Control N = 3,403 0.01 0.1 1 10 100 IRR with 95% CI Favours DAPA Favours Control DAPAGLIFLOZIN BMS-512148 NDA 202293. US Food & Drug Administration (FDA) Endocrinologic & Metabolic Drug Advisory Committee (EMDAC) Background Document. 2013. Available at: http://www.fda.gov/downloads/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm378079.pdf. Incidence Rate Ratio (95% CI) 1.03 (0.71, 1.51) 5.17 (0.68, 233.55) 2.47 (0.64, 14.10) 1.84 (0.31, 19.46) 1.60 (0.53, 5.35) 0.92 (0.04, 61.49) 0.88 (0.19, 4.46) 0.83 (0.37, 1.91) 0.79 (0.24, 2.81) 0.74 (0.05, 10.74) 0.66 (0.07, 8.96) 0.61 (0.13, 3.19) 0.40 (0.03, 3.82) 0.37 (0.05, 2.35) (0.010, )

Patients (%) VOLUME-RELATED ADVERSE EFFECTS: WHICH PATIENTS ARE MORE AT RISK? 10 Dapagliflozin 1 Canagliflozin 2 DAPA 10 mg CANA 100 8 Placebo CANA 300 All non-cana 8.7 8.8 8.1 6 4.9 4.7 4.7 4 2 0.9 0.7 1.7 0.8 3.1 1.2 1.9 1.5 2.5 1.5 2.2 3.1 1.4 2.6 2.5 3.2 0 <65 65 Age (years) 75 30-<60 egfr Yes Loop diuretic <75 75 Age (years) <60 egfr Yes Loop diuretic Not intended for comparisons between trials egfr measured in ml/min/1.73m 2 1. Johnsson et al. Presented at EASD 2014. Abstract 800-P. 2. Adapted from: http://www.fda.gov/downloads/advisorycommittees/ CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013.

The First SGLT Inhibitor: Phlorizine Phlorizine is found in the bark of apple trees, cherry trees and other fruit trees. It is a competitive inhibitor of SGLT-2 and SGLT-1. Phlorizine was isolated in 1885. Its glucosuric action was described in 1886. Not practical Low Bioavailability : 15% Causes diarrhea (SGLT-1) Phlorizine was the first inspiration for the inhibition of SGLT in the treatment of diabetes 1. Ehrenkranz JR et al, Diabetes Metab Res Rev 2005; 21: 31 38. 2. Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/dmrr.532 2. Chao EC. Core Evidence 2012;7:21-28. MENU

FAMILIAL RENAL GLUCOSURIA A benign autosomal dominant condition Results from a decrease in SGLT2 activity (lower number of transporters or decreased activity of the transporters) Asymptomatic condition that does not lead to renal failure Does not preclude the need for long-term safety data with SGLT2 inhibitors DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW ARTICLE Diabetes Metab Res Rev 2005; 21: 31 38. Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/dmrr.532 MENU