NEW TREATMENT OPTIONS IN INDIVIDUALIZED TYPE 2 DIABETES MELLITUS MANAGEMENT TARGETING THE KIDNEY TO REDUCE HYPERGLYCAEMIA

Transcription

1 NEW TREATMENT OPTIONS IN INDIVIDUALIZED TYPE 2 DIABETES MELLITUS MANAGEMENT TARGETING THE KIDNEY TO REDUCE HYPERGLYCAEMIA Richard Yazbeck, MD Endocrinologist Lebanese Hospital (Geitaoui) 11/26/2016

2 Disclosures: Richard Yazbeck, MD Advisor or consultant: AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi-aventis, Eli Lilly Speaker: AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofiaventis, Janssen,

3 Presentation Objectives Pathogenesis of type 2 diabetes Understand the role of the kidney in type 2 diabetes Review the mechanism of action for Canagliflozin Update about the latest guidelines in treating T2DM Review the efficacy and safety profile for Canagliflozin in the treatment of type 2 diabetes 3

4 Relative % Development and Progression of Type 2 Diabetes Almost 50% of ß cells not functioning upon diagnosis 100 Progression of Disease Insulin resistance 50 0 Hepatic glucose production Insulin level β-cell function 4 7 years Postprandial glucose Fasting glucose Impaired Glucose Tolerance Diabetes Diagnosis Frank Diabetes *Conceptual representation. Adapted with permission from Ramlo-Halsted et al. Prim Care. 1999;26:

5 Type 2 Diabetes Pathophysiology Adipose tissue Pancreas Insulin secretion Gut Glucose uptake carbohydrate absorption FFA output Liver Hyperglycemia Muscle Glucose uptake Insulin Resistance Hepatic glucose output Neurons Pancreas Glucose reabsorption Kidneys Neurotransmitters dysfunction GLP-1 Incretin effect Glucagon secretion

6 The ominous octet of factors which are responsible for the pathophysiologic disturbances of type 2 diabetes

7 (Frightful)

8 Visceral Fat Distribution: Normal vs Type 2 Diabetes Normal Type 2 Diabetes

9 Adapted from Nutrition and Health: Nutrition and Metabolism. Christos S.Mantzoros, 2009 The Adipose tissue as an Endocrine organ Cardiovascular diseases Adiponectin PAI-1 HB-EGF Coagulation Factors PAI-1, TF Hypertension Agiotensinogen Reproduction Energy balance, Reproduction Glucose Metabolism Leptin TNFα Resistin FFA Adipose tissue Leptin Androgen Estrogen Lipid Metabolism LPL, CETP, Apo E Acylation stimulating factor IL-1b, IL-6, IL- 8 IL-18, TGFb TNFα Adpsin Complement factors Unknown factors Immune function

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11 Weight loss in diabetes provides multiple clinical benefits Norris SL, et al. Arch Intern Med. 2004;164(13):

12 BP reductions as little as 2 mmhg reduce the risk of CV events by up to 10%¹

13 Cumulative incidence of any CV event (%) Steno-2: intensive multifactorial therapy associated with improved outcomes Multi-target Approach (The Steno Model) HR 0.41 (95% CI ); P < at 13.3 years 50 Conventional therapy Cardiovascular Event (%) 20 Cumulative Incidence of Any Intensive therapy Years Adapted from Gaede P, et al. N Engl J Med 2008; 358:

14 Role of the kidneys in T2D Normal glucose homeostasis 1,2 Net balance ~0 g/day + Glucose input ~250 g/day: Dietary intake ~180 g/day Glucose production ~70 g/day Gluconeogenesis Glycogenolysis The kidney filters circulating glucose Glucose uptake ~250 g/day: Brain ~125 g/day Rest of the body ~125 g/day The kidney reabsorbs and recirculates glucose Glucose filtered ~180 g/day Glucose reabsorbed ~180 g/day 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10 18; 2. Gerich, JE. Diabetes Obes Metab 2000;2:

15 Urinary Glucose Excretion (g/d) THE RENAL GLUCOSE THRESHOLD (RT G ) CONCEPT Usual RT G in healthy subjects reported to be approximately 10 mmol/l (180mg/dL) Below RT G Minimal Glucosuria Occurs Above RT G Glucosuria Occurs Healthy RT G ~10 mmol/l (180mg/dL) Plasma Glucose (mmol/l) RT G, renal threshold for glucose excretion. Polidori D et al Presented at: European Association for the Study of Diabetes. September 20-24, 2010; Stockholm, Sweden

16 Glucose handling in Type 2 diabetes + Glucose input >280 g/day: Dietary intake >180 g/day Glucose production ~100 g/day Gluconeogenesis* Glycogenolysis Average blood glucose concentration 150 mg/dl Kidney filters all circulating glucose Glucose uptake >250 g/day: Brain ~125 g/day Rest of the body >125 g/day Increased reabsorption and recirculation of glucose Glucose filtered ~270 g/day Above the renal threshold for glucose (~200 mg/dl), glucose is excreted in the urine (glucosuria) *Elevated glucose production in patients with Type 2 diabetes attributed to hepatic and renal gluconeogenesis Gerich JE. Diabet Med 2010;27:136 42; 2. Abdul-Ghani MA, DeFronzo RA. Endocr Pract 2008;14:

17 Increased SGLT-2 expression Chao EC, et al. Nat Rev Drug Discovery. 2010;9:

18 Upregulation of SGLT-2 activity in Hyperglycaemic state New Pathophysiologic defect in T2D Glucose directly stimulates hepatocyte nuclear factor-1 alpha Hepatocyte nuclear factor-1 alpha is a direct promoter of the SGLT-2 gene This increased SGLT-2 activity results in greater glucose and sodium reabsorption Osorio H, et al 2010 J Nephrol;23: Freitas HS, et al 2008 Endocrinology;149:

19 Sodium- Glucose Cotransporters Site SGLT1 Mostly intestine with some kidney SGLT2 Sugar Specificity Glucose or galactose Glucose Affinity for glucose Capacity for glucose transport Role High Km= 0.4 Mm Low Dietary glucose absorption Renal glucose reabsorption Almost exclusively kidney Low Km = 2 Mm High Renal glucose reabsorption Lee YJ, at al. Kidney Int Suppl. 2007;72:S27-S35.

20 SGLT2 is a sodium glucose cotransporter 1,2 Segment S1 2 SGLT2 Basolateral membrane GLUT2 Glucose Na + Glucose Glucose Na + Na + K + K + Lateral intercellular space Na + /K + ATPase pump SGLTs transfer glucose and sodium from the lumen into the cytoplasm of tubular cells through a secondary active transport mechanism Na + :glucose coupling ratio for SGLT1 = 2:1 and for SGLT2 = 1:1 ATP, adenosine triphosphate; GLUT, glucose transporter; SGLT, sodium glucose cotransporter. 1. Wright EM, et al. Physiology. 2004;19: Bakris GI, et al. Kidney Int. 2009;75: Figure adapted from Mather A, Pollock C. Kidney Int Suppl. 2011;120:S1 S6.

21 Urinary Glucose Excretion (g/day) The Renal Glucose Threhold (RT G ) is Increased in Subjects with Type 2 Diabetes Below RT G minimal glucosuria occurs Above RT G glucosuria occurs Healthy RT G ~10 mmol/l (180mg/dL) T2DM RT G ~13.8 mmol/l (248mg/dL) Plasma Glucose (mmol/l) Renal glucose reabsorption is increased in diabetes, which could contribute to further increasing plasma glucose levels RT G, renal threshold for glucose excretion. Polidori D et al Abstract 2186-PO. American Diabetes Association. June 25-29, 2010; Orlando, Florida. Polidori D et al Presented at: European Association for the Study of Diabetes. September 20-24, 2010; Stockholm, Sweden.

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23 SGLT2 Inhibitors From apple bark to an insulin-independent treatment option Phlorizin Isolated from apple tree bark (1835) Inhibitor of SGLT1 and SGLT2 a Glycosuric effect (1886) Renal actions identified in rat (1903) and man (1933) Antidiabetic effect discovered (1987) a SGLT2, sodium-glucose cotransporter 2. Ehrenkranz JRL, et al. Diabetes Metab Rev. 2005;21:31 38.

24 Selectively inhibiting SGLT2 cotransporters is key for efficacy and safety Transporter Major site of action Function Disease Associated with Malfunction SGLT1 Small intestine, heart, trachea and kidney Co-transports sodium, glucose and galactose across the brush border of the intestine and proximal tubule of the kidney Congenital glucosegalactose malabsorption syndrome SGLT2 SGLT3 SGLT4 Kidney Small intestine, uterus, lungs, thyroid and testis Small intestine, kidney, liver, stomach and lung Co-transports sodium and glucose in the S1 segment of the proximal tubule of the kidney Transports sodium (not glucose) Transports glucose and mannose Familial renal glucosuria Unknown Unknown SGLT5 Kidney Unknown Unknown SGLT6 Spinal cord, kidney, brain, and small intestine Transports myo-inosotol and glucose Unknown Bays H. Curr Med Res Opin. 2009;25:

25 SGLT2 inhibitors efficacy requires sufficient kidney function The efficacy of SGLT2 inhibitors is dependent on renal function 1,2 Efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment SGLT2 inhibitors are not recommended for use in patients with moderate-to-severe renal impairment (egfr <60 ml/min/1.73 m2) *1

26 GLIFLOZIN: A NOVEL INSULIN-INDEPENDENT APPROACH TO REMOVE EXCESS GLUCOSE 1 3 Reduced glucose reabsorption Gliflozin SGLT2 Proximal tubule Gliflozin SGLT2 Glucose Glucose filtration Increased urinary excretion of excess glucose (~70 g/day, corresponding to 280 kcal/day*) Canagliflozin selectively inhibits SGLT2 in the renal proximal tubule *Increases urinary volume by only ~1 additional void/day (~375 ml/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes Wright EM. Am J Physiol Renal Physiol 2001;280:F10 18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14 21; 4. Dapagliflozin. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, 2012.

27 Urinary Glucose Excretion (g/d) SGLT2 Inhibition Lowers RT G Healthy subjects Below RT G minimal glucosuria occurs Above RT G glucosuria occurs 75 RT G RT G mmol/L (90mg/dl) SGLT2i-treated Untreated healthy Untreated T2DM Plasma Glucose (mmol/l) SGLT2 inhibition lowers RTG Appreciable UGE occurs only when plasma glucose exceeds RTG SGLT2, sodium glucose co-transporter 2; RTG, renal threshold for glucose excretion; UGE, urinary glucose excretion. Polidori D et al Abstract 2186-PO. Presented at: American Diabetes Association. ADA Polidori D et al Abstract 875. Presented at: European Association for the Study of Diabetes. EASD 2010.

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30 Plasma glucose (mg/dl) NAP1002: CANA treatment lowers plasma glucose concentrations throughout the entire day Example: CANA 100 mg treatment in subjects with T2DM Day Placebo (n = 19) CANA 100 mg (n = 16) Time (hours) CANA lowers fasting, postprandial, and 24-hour mean plasma glucose Sha S, et al Presented at American Diabetes Association. Orlando, Florida; June Janssen Core Slides for the January 10, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee. Available from: EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM pdf. Accessed January 2014.

31 Plasma glucose (mg/dl) Serum insulin (µu/ml) UGE 0 2h (g) NAP1001: CANA doses > 200 mg reduced postprandial glucose and insulin more than explained by UGE1 Plasma glucose 160 Placebo 150 CANA 100mg and 200mg CANA >200mg Serum insulin Urinary glucose excretion Time (hours) Time (hours) mg and 200 mg > 200 mg Reductions in glucose and insulin observed only in first meal after dosing Hypothesis: higher doses of CANA transiently inhibit intestinal SGLT1 during drug absorption UGE, urinary glucose excretion. Sha S, et al. Diabetes Obes Metab. 2011;13:

32 LS mean % change (±SE) from baseline PERCENT CHANGE IN BODY WEIGHT Baseline (kg) PBO CANA 100 mg CANA 300 mg Time point (wk) LS mean % change 0.0% (0.0 kg) 1.8% ( 1.9 kg) 2.7% ( 2.7 kg) Difference vs PBO 1.8% (95% CI: 2.7, 0.9) ( 1.9 kg [95% CI: 2.9, 1.0]) 2.7% (95% CI: 3.6, 1.8) ( 2.8 kg [95% CI: 3.7, 1.9]) Rosenstock J et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun ; Chicago, Illinois, (P1084).

33 Body weight (%) BODY WEIGHT RESULTS IN ANALYZED STUDIES * 86.8 kg 87.2 kg 92.8 kg 94.1 kg 97.0 kg 97.0 kg 89.5 kg DIA Diet/Ex % LS Mean Change from Baseline DIA MET DIA MET/SU DIA MET/Pio DIA insulin DIA SU DIA Any Baseline body weight PBO CANA 100 mg CANA 300 mg * Only studies enrolling patients with normal/mild chronic renal insufficiency are shown % -0.4% -0.5% -1.0% -0.6% -1.4% -0.7% Stenlof et al. Diabetes Obes Metab. 2013;15(4): Lavalle-González -4.5 FJ et al. Diabetologia Sep 13. [Epub ahead of print] Wilding JP et al. Int J Clin Pract Oct 13. [Epub ahead of print] Matthews D. et al. Poster presented at the 48th European Association for the Study of Diabetes (EASD);2012;Oct.1-5: Berlin, Germany, (P764). Bode B et al. Hosp Pract. 2013;41(2): Forst T et al. Poster presented at the 4th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy), 2012;Nov.8-11; Barcelona, Spain, (P64) P <0.05 vs PBO for both CANA doses in all studies except CANA 100 mg in DIA SU 300 mg vs 100 mg

34 LS Mean % Change from Baseline ± SE Body Weight Change from baseline (kg) * p <0.001 Based on ANCOVA model, data prior to rescue (LOCF) CHANGES IN BODY COMPOSITION AND WEIGHT ACTIVE (GLIMEPIRIDE)-CONTROLLED ADD-ON TO METFORMIN STUDY (DIA3009) BL Mean Weight Body Loss Weight Over (kg): Time 86.6 N =1450 Week BL Glimepiride CANA 100 mg -5.2%* (-4.4 kg) -5.7%* (-4.7 kg) CANA 300 mg Change in Body Composition (DXA Analysis Subgroup) N=312 Glimepiride Lean Mass CANA 100 mg 52 week data CANA 300 mg Fat Mass Weight changes relative to glimepiride in DXA analysis subgroup (- 5.3 kg and -5.0 kg for CANA 100 mg and 300 mg, respectively) were similar to overall cohort. et al. Efficacy Sodium Glucose Co-Transporter 2 Inhibitor, Compared With Glimepiride in Patients With Type 2 Diabetes on Background Metformin presented at the 72nd American Diabetes Association (ADA) Scientific Sessions, which took place in Philadelphia, USA, from 8-12 June 2012

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36 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metformin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Sulfonylurea high moderate risk gain hypoglycemia low Metformin + Thiazolidinedione high low risk gain edema, HF, fxs low Metformin + DPP-4 inhibitor intermediate low risk neutral rare high Metformin + SGLT2 inhibitor intermediate low risk loss GU, dehydration high Metformin + GLP-1 receptor agonist high low risk loss GI high Metformin + Insulin (basal) highest high risk gain hypoglycemia variable Triple therapy Metformin + Sulfonylurea + If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): TZD Metformin + Thiazolidinedione + SU Metformin + DPP-4 Inhibitor + SU Metformin + SGLT-2 Inhibitor + SU Metformin + GLP-1 receptor agonist + SU Metformin + Insulin (basal) + TZD or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin or SGLT2-i or GLP-1-RA or GLP-1-RA or Insulin or Insulin or GLP-1-RA or Insulin or Insulin Combination injectable therapy If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Basal Insulin + Metformin + Mealtime Insulin or GLP-1-RA Diabetes Care 2015;38: ; Diabetologia 2015;58:

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38 Phase III Canagliflozin Clinical Development Program: 9 Studies conducted in more than patients Monotherapy Dual Combination Triple Combination Insulin +/- oral(s) Monotherapy (DIA3005) 26 / 26 wks N=587 Combo with MET vs SITA (DIA3006) 26 / 26 wks N=1284 Combo with MET/PIO (DIA3012) 26 / 26 wks N=344 Combo with INSULIN (Substudy DIA3008) 18 wks N=1718 Combo with SU (Substudy DIA3008) Combo with MET/SU (DIA3002) 18 wks N= / 26 wks N=469 Pbo-control Active-control Combo with MET vs GLIM (DIA3009) 52 / 52 wks N=1452 Combo with MET/SU vs SITA (DIA3015) 52 wks N=756 Studies in Special T2DM Populations Placebo-controlled studies / add-on to current diabetes treatment Older Subjects - Bone Safety and Body Comp (DIA3010) 26 / 78 wks N=716 Renal Impairment (DIA3004) 26 / 26 wks N=272 CV Safety Study (DIA3008: CANVAS) Event-driven N=4330

39 A1c (%) HBA1C RESULTS IN PLACEBO-CONTROLLED STUDIES * % DIA % DIA % DIA DIA Diet/Ex + MET + MET/SU % + MET/Pio 0.14 Change from Baseline 8.27% 8.35% 7.7% Baseline A1C DIA insulin DIA SU DIA Any PBO CANA 100 mg CANA 300 mg % -0.16% -0.21% -0.14% -0.09% -0.09% -0.13% 300 mg vs 100 mg P <0.05 vs PBO for both CANA doses in all studies * excluding the study in patients with chronic renal impairment Stenlof et al. Diabetes Obes Metab. 2013;15(4): Lavalle-González FJ et al. Diabetologia Sep 13. [Epub ahead of print] Wilding JP et al. Int J Clin Pract Oct 13. [Epub ahead of print] Matthews D. et al. Poster presented at the 48th European Association for the Study of Diabetes (EASD);2012;Oct.1-5: Berlin, Germany, (P764). Bode B et al. Hosp Pract. 2013;41(2): Forst T et al. Poster presented at the 4th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy), 2012;Nov.8-11; Barcelona, Spain, (P64). Fulcher G et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun ; Chicago, Illinois, (P1124).

40 (%) HBA1C CHANGE FROM BASELINE OVER TIME ACTIVE (GLIMEPIRIDE)-CONTROLLED ADD-ON TO METFORMIN STUDY (DIA3009) LS Mean Change from Baseline ± SE HbA 1c Baseline Mean HbA 1c (%): 7.8 N = 1450 Glimepiride dose: Mean (median) of highest dose reached mg (6.0 mg) 82% of subjects on 4 mg/day Glimepiride CANA 100 mg CANA 300 mg -0.01% (95% CI: ; 0.085) -0.12% (95% CI: ; ) 52 week data -1.2 BL Weeks Based on ANCOVA model, data prior to rescue (LOCF) and Safety Sodium Glucose Co-Transporter 2 Inhibitor, Compared With Glimepiride in Patients With Type 2 Diabetes on Background Metformin presented at the 72nd American Diabetes Association (ADA) Scientific Sessions, which took place in Philadelphia, USA, from 8-12 June 2012

41 ADD-ON TO MET: CANAGLIFLOZIN VS GLIMEPIRIDE Incidence of Hypoglycemia with Canagliflozin vs Glimepiride at 104 Weeks Canagliflozin Canagliflozin Hypoglycaemic episodes were defined as biochemically documented with a glucose test reported of 3.9 mmol/l (70 mg/dl), or severe hypoglycaemic events (requiring the assistance of another person, or with loss of consciousness or a seizure regardless of whether biochemically documented). When INVOKANA is used as add-on with insulin or an insulin secretagogue, a lower dose of insulin or the insulin secretagogue may be considered to reduce the risk of hypoglycaemia

42 LS mean % change (±SE) from baseline Canagliflozin: Add on to Metformin vs Glimepiride: Percent Change in Body Weight (LOCF)* Canagliflozin GLIM CANA 100 mg CANA 300 mg 104 week data Baseline (kg) LS mean % change 0.9% (0.8 kg) Time point (wk) % ( 3.6 kg) 4.2% ( 3.6 kg) 5.1% (95% CI: 5.6, 4.5) ( 4.3 kg) ([95% CI: 4.8, 3.8]) 5.2% (95% CI: 5.7, 4.6) ( 4.4 kg) ([95% CI: 4.9, 3.9]) *N = 1,450 (Baseline); N = 1,425 (Week 4); N = 1,436 (Week 8); N = 1,438 (Weeks 12, 18, 26, 36, 44, 52, 64, 78, 88, and 104). 42 Leiter L.A., et al. (2014). Diabetes Care. Sep 9. pii: DC_ [Epub ahead of print]

43 ADD-ON TO MET: CANAGLIFLOZIN VS SITAGLIPTIN HbA1c Reductions with Canagliflozin vs Sitagliptin at 52 Weeks CANA 100 mg CANA 100 mg Canagliflozin Canagliflozin 1. Lavalle-González FJ, Januszewicz A, et al. (2013). Diabetologia 2013; 56(12):

44 LS mean change (±SE) from baseline (%) CHANGE IN HBA 1C (LOCF) CANTATA D2 (DIA3015) Add-on to MET + SU vs Sitagliptin SITA 100 mg CANA 300 mg Baseline (%) LS mean change 0.66% 1.03% 0.37% (95% CI: 0.50, 0.25) Time point (wk) LOCF, last observation carried forward ; SITA, sitagliptin; CANA, canagliflozin; LS, least squares; SE, standard error; CI, confidence interval. Schernthaner G. et al. Poster presented at the 4 th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy), 2012;Nov.8-11; Barcelona, Spain, (P70). Schernthaner G et al. Diabetes Care Apr 5. [Epub ahead of print]

45 LS mean % change (±SE) from baseline PERCENT CHANGE IN BODY WEIGHT (LOCF) CANTATA D2 (DIA3015) Add-on to MET + SU vs Sitagliptin Baseline (kg) SITA 100 mg CANA 300 mg LS mean % change 0.3% (0.1 kg) % ( 2.4 kg) P < % ( 2.3 kg) Time point (wk) LOCF, last observation carried forward; SITA, sitagliptin; CANA, canagliflozin; LS, least squares; SE, standard error. Schernthaner G. et al. Poster presented at the 4 th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy), 2012;Nov.8-11; Barcelona, Spain, (P70).Schernthaner G et al. Diabetes Care Apr 5. [Epub ahead of print]

46 CANVAS: ADD-ON TO BASAL INSULIN Change in Insulin Dose Change in insulin dose defined as an increase or decrease of >15% from baseline for 7 consecutive days Post-baseline mean daily insulin dose (prior to glycemic rescue) was unchanged for 93% of PBO-treated subjects 85% of subjects treated with CANA 100 mg 86% of subjects treated with CANA 300 mg Majority of those receiving CANA had a decrease in insulin dose, whereas all of those receiving PBO had an increase. Daily insulin dose from baseline Mean daily insulin dose at Week 18 CANA 100 mg -3.2 IU 53.3 IU CANA 300 mg -2.4 IU 58.4 IU Placebo +1.1 IU 60.4 IU

47 LS mean change (±SE) from baseline (%) CHANGE IN HBA1C PBO CANA 100 mg CANA 300 mg Baseline (%) LS mean change 0.10% Difference vs PBO % (95% CI: 1.07, 0.65) % 0.79% 0.89% (95% CI: 1.09, 0.69) A higher proportion of subjects achieved A1C <7.0% with CANA 100 and 300 mg versus PBO (16%, 29%, and 6%, respectively) while required per protocol to remain on stable basal insulin therapy. LS, least squares; SE, standard error. Time point (wk) Rosenstock J et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun ; Chicago, Illinois, (P1084).

48 LS mean % change (±SE) from baseline PERCENT CHANGE IN BODY WEIGHT Baseline (kg) PBO CANA 100 mg CANA 300 mg Time point (wk) LS mean % change 0.0% (0.0 kg) 1.8% ( 1.9 kg) 2.7% ( 2.7 kg) Difference vs PBO 1.8% (95% CI: 2.7, 0.9) ( 1.9 kg [95% CI: 2.9, 1.0]) 2.7% (95% CI: 3.6, 1.8) ( 2.8 kg [95% CI: 3.7, 1.9]) Rosenstock J et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun ; Chicago, Illinois, (P1084).

49 Additional benefits of weight loss and blood pressure reduction Glycaemic control Insulin-independent Approach to Treat hyperglycemia low incidence for hypoglycaemia Weight loss Blood pressure reduction

50 F. Zaccardi, D. R. Webb, Z. Z. Htike, D. Youssef, K. Khunti& M. J. Davies Diabetes, Obesity and metabolism May 2016 doi: /dom.12670

51 Efficacy outcomes HbA1c(%) reduction compared to placebo (38 RCTs) 0,0% Mean baseline A1c 8.1% -0,1% -0,2% Dapa 5mg -0,3% -0,4% -0,5% -0,6% -0,6% -0,7% -0,7% -0,8% -0,9% Empa 10mg Dapa 10mg -0,6% Empa 25mg -0,7% Cana 100mg -0,8% -0,9% -1,0% Compared to placebo, all SGLT2 inhibitors : The highest dose of CANA reduced HbA1c, FPG, and SBP to a greater extent compared to DAPA and EMPA at any dose Cana 300mg F. Zaccardi, D. R. Webb, Z. Z. Htike, D. Youssef, K. Khunti& M. J. Davies Diabetes, Obesity and metabolism May 2016 doi: /dom.12670

52 Cardiovascular outcomes of gliflozin The multicentre trial to evaluate the effect of Dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI 58) April 2019 / Canagliflozin cardiovascular assessment study (CANVAS) June 2017 / 4411 are the two large scale studies which are currently ongoing and assessing the impact of SGLT 2 inhibitors on the CV risk for MACE

53 Canagliflozin CANVAS Study Study design Aim: To assess CV safety of canagliflozin in adult patients with T2DM and elevated CV risk 1:1:1 randomization to Cana 100 mg, Cana 300 mg or PBO Due to report in 2017 Patient population 4330 T2DM patients History of prior CV event or 2 risk factors for a CV event Study endpoints Primary: Major adverse cardiovascular events, including CV death, nonfatal myocardial infarction (MI), and nonfatal stroke Secondary: Progression of albumin in the urine, standard measure of fasting insulin secretion The data from this study will be combined with the data from CANVAS-R study in a pre-specified meta-analysis of CV safety outcomes to satisfy US FDA post-marketing requirements for canagliflozin

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55 3-point MACE and 4-point MACE Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/ / (0.74, 0.99)* CV death 172/ / (0.49, 0.77) < Non-fatal MI 213/ / (0.70, 1.09) Non-fatal stroke 150/ / (0.92, 1.67) point MACE 599/ / (0.78, 1.01)* ,25 0,50 1,00 2,00 Favours empagliflozin Favours placebo Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI This article was published on September 17, 2015, at NEJM.org

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57 CV RISK FACTOR CHANGES WITH CANAGLIFLOZIN Changes in fasting lipids Increases in HDL-C No change in LDL-C/HDL-C ratio Decreases in TG Increases in LDL-C Smaller increases in non-hdl-c, Apo B, LDL particle number Decreases in systolic and diastolic blood pressure Improved glycemic control Decrease in body weight

58 Estimated % of subjects with an event KAPLAN-MEIER PLOT OF TIME TO FIRST FEMALE GENITAL MYCOTIC INFECTION Population 2: 8 placebo and active controlled trials (mean treatment duration>64 weeks) All non-cana CANA 100 mg CANA 300 mg Time (weeks) All non-cana CANA 100 mg CANA 300 mg 1,338 1,312 1,250 1,209 1, ,289 1,217 1,143 1,087 1, ,319 1,243 1,153 1,101 1,

59 Safety and Tolerability Profile -No detrimental effect on renal function over 2 years - Improvement in the albuminuria category

60 Change in egfr (ml/min/1.73m 2 ) Effect of canagliflozin and glimepiride on egfr ml/min ( ) 1.5 ml/min ( ) Glimepiride Canagliflozin 100 mg Canagliflozin 300 mg Time (weeks) Least square mean Heerspink et.al. J Am Soc Nephrol 28: 2016

61 Change in UACR (%) Change in UACR (%) Effect of canagliflozin and glimepiride on albuminuria Overall population UACR 30 mg/g Glimepiride Canagliflozin 100 mg Canagliflozin 300 mg Glimepiride Canagliflozin 100 mg Canagliflozin 300 mg Least square Time (weeks) mean Time (weeks) Least square mean Heerspink et.al. J Am Soc Nephrol 28: 2016

62 SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis - When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis - SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion -Phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels. - Volume depletion S I Taylor, JCEM, Published Online: June 18, 2015

63 Bone Fractures: No meaningful changes in mineral homeostasis (phosphate, Ca, Vit D, Mg) No SGLT2 receptors in bone CANVAS (CANA 4.0% vs PBO 2.6%) In pooled non-canvas studies (CANA 1.7% vs non- CANA 1.5%) May be mediated by falls related to volume depletion Caution in high risk patients - older - history/risk of CVD - moderate renal impairment - higher baseline diuretic use Alba M et al. Curr Med Res Opin May 6:1-11

64 CANAGLIFLOZIN DOSE RECOMMENDATIONS Important Safety Information INVOKANA (canagliflozin) Tablets, International Package Insert (US Indication), 24 JAN 2014, Version 04, Based on CCDS dated 09 JAN 2014

65 SGLT 2 Inhibition: Meeting Unmet Needs in Diabetes Care Reduces HbA 1c Lowers TRIG Increases HDL Promotes Weight Loss Reduces Blood Pressure Improves Glycemic Control and CVRFs No Hypoglycemia Complements Action of Other Antidiabetic Agents Reversal of Glucotoxicity

66 THANK YOU