Improving Outcomes with SGLT2 Cotransporter Inhibitors in Challenging T2DM Patients Part 4 of 4

Incorporating SGLT2 Inhibitors into Practice: Updates from EASD Mark W. Stolar, MD Associate Professor Clinical Medicine, General Internal Medicine and Geriatrics Feinberg School of Medicine Northwestern University Chicago, IL

or Special Populations SGLT2 Inhibitors: Use in Challenging or Special Populations Non-insulin dependent mechanism of action allows for use in low insulin secreting or high insulin resistance type 2 diabetics Safety/efficacy in older adults and /or renally impaired patients Effects on weight, blood pressure and lipids

Determining A1C Targets Decision-Making Elements in Determining A1C Targets MORE STRINGENT LESS STRINGENT Patient attitude and expected treatment efforts Highly motivated, adherent, excellent self-care capacities Less motivated, non-adherent, poor self-care capacities High Long-standing Short Severe Severe Limited Risks potentially associated with Low hypoglycemia, other adverse events Disease duration Newly diagnosed Life expectancy Long Important comorbidities Absent Established vascular complications Absent Resources, support system Readily available Hypothetical patient. Examples are for illustrative purposes only. Adapted from Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379.

Determining A1C Targets Decision-Making Elements in Determining A1C Targets MORE STRINGENT LESS STRINGENT Patient attitude and expected treatment efforts Highly motivated, adherent, excellent self-care capacities Less motivated, non-adherent, poor self-care capacities High Long-standing Short Severe Severe Limited Risks potentially associated with Low hypoglycemia, other adverse events Disease duration Newly diagnosed Life expectancy Long Important comorbidities Absent Established vascular complications Absent Resources, support system Readily available Hypothetical patient. Examples are for illustrative purposes only. Adapted from Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379.

Determining A1C Targets Decision-Making Elements in Determining A1C Targets MORE STRINGENT LESS STRINGENT Patient attitude and expected treatment efforts Highly motivated, adherent, excellent self-care capacities Less motivated, non-adherent, poor self-care capacities High Long-standing Short Severe Severe Limited Risks potentially associated with Low hypoglycemia, other adverse events Disease duration Newly diagnosed Life expectancy Long Important comorbidities Absent Established vascular complications Absent Resources, support system Readily available Hypothetical patient. Examples are for illustrative purposes only. Adapted from Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379.

Ominous Octet Reprinted with permission from DeFronzo RA. Diabetes. 2009;58:773-795.

Increased hepatic glucose production Reduced peripheral glucose uptake Reduced pancreatic insulin secretion Insulin resistance Hyperglycemia Inhibition of glucose reabsorption from renal tubules Urinary glucose disposal Reduce fasting plasma glucose Improve glucose tolerance A1C reduction Urinary calorie loss/ Weight Loss Adapted from Idris I, et al. Diab Obes Metab. 2009;11:79-88.

Efficacy of SGLT2 Inhibitors in Older Adults

Efficacy of Canagliflozin in Older Adults: A1C and Weight Subjects <65 years old Subjects ≥65 years old Efficacy Parameters*,† Placebo (n=509) Canagliflozin 100 mg (n=674) Canagliflozin 300 mg (n=685) Placebo (n = 137) Canagliflozin 100 mg (n=159) Canagliflozin 300 mg (n=149) A1C change, % -0.15 (0.04) -0.89 (0.03) -1.08 (0.03) -0.05 (0.07) -0.69 (0.07) -0.88 (0.07) difference vs -0.74 (0.05) -0.93 (0.05) -0.64 (0.10) -0.82 (0.10) placebo Body weight % change -0.06 (0.2) -2.8 (0.1) -3.4 (0.1) -0.6 (0.3) -2.9 (0.3) -3.8 (0.3) -2.2 (0.2) -2.9 (0.2) -2.3 (0.4) -3.2 (0.4) Pooled data from 4 randomized, placebo-controlled, 26-week studies (N=2,313) Sinclair A, et al. Presented at the 49th EASD Annual Meeting; Barcelona, Spain; Sept, 2013. Abstract 955.

Efficacy of Canagliflozin in Older Subjects: Lipid and BP effects Subjects <65 years old Subjects ≥65 years old Efficacy Parameters*,† Placebo (n=509) Canagliflozin 100 mg (n=674) Canagliflozin 300 mg (n=685) Placebo (n=137) Canagliflozin 100 mg (n=159) Canagliflozin 300 mg (n=149) Triglycerides % change‡ 9.1 (2.2) 3.7 (2.0) 0.6 (2.0) 2.6 (3.0) -2.4 (2.8) -2.5 (2.9) difference vs placebo -5.4 (2.9) -8.5 (2.9) -5.2 (4.2) LDL-C % change‡ 1.5 (1.4) 6.3 (1.2) 9.8 (1.2) 0.7 (2.1) 3.5 (1.9) 6.8 (2.0) 4.8 (1.8) 8.3 (1.8) 2.8 (2.9) 6.1 (2.9) HDL-C % change‡ 4.0 (0.8) 9.2 (0.7) 10.2 (0.7) 3.7 (1.4) 9,7 (1.3) 10.7 (1.4) 5.2 (1.1) 6.2 (1.1) 6.0 (1.9) 7.1 (1.9) LDL-C/HDL-C % change‡ -0.5 (1.4) -0.7 (1.2) 1.3 (1.2) -1.4 (2.3) -4.2 (2.2) -1.2 (2.3) -0.2 (1.8) 1.8 (1.8) -2.8 (3.2) 0.2 (3.2) Non-LDL-C % change‡ 1.1 (1.0) 2.6 (0.9) 4.7 (0.9) -0.5 (1.8) 0.8 (1.7) 2.9 (1.8) 1.4 (1.4) 3.6 (1.4) 1.4 (2.5) 3.4 (2.6) Systolic BP change, mm Hg -0.3 (0.5) -4.2 (0.4) -4,.8 (0.4) -0.8 (1.1) -4.6 (1.0) -5.9 (1.0) -3.9 (0.6) -4.5 (0.6) -3.9 (1.4) -5.1 (1.5) Pooled data from 4 randomized, placebo-controlled, 26-week studies (N=2,313) Sinclair A, et al. Presented at the 49th EASD Annual Meeting; Barcelona, Spain; Sept 2013 Abstract 955.

Patients with Chronic Kidney Disease

Diabetes Therapy in the Setting of Impaired Renal Function Metformin not indicated based on eGFR Sulfonylureas should be used cautiously if at all due to hypoglycemic risk TZD drugs are safe, but risk of edema increased with low eGFR DPP-4 inhibitors may require dosage adjustment GLP-1 receptor agonists may require dosage adjustment Insulin clearance is decreased, and risk of hypoglycemia is increased SGLT2 inhibitors safe, but efficacy may be decreased

Efficacy and Safety of Canagliflozin in Patients with T2DM and Chronic Kidney Disease: A1C and Weight Parameter Canagliflozin 100 mg Canagliflozin 300 mg Placebo A1C change, % -0.19 (0.10) -0.33 (0.10) 0.07 (0.10) Difference vs placebo -0.27 (-0.53, 0.001) -0.41 (-0.68, -0.14) % of subjects reaching A1C <7.0% 23.6 (4.5) 28.1 (4.8) 18.4 (4.2) 5.2 (-7.9, 18.3) 9.7 (-3,8, 23.2) FPG change, mmol/L -0.1 (0.3) -0.3 (0.3) 0.5 (0.3) -0.7 (-1.5, 0.2) -0.8 (-1.7, 0.1) Body weight % change -1.3 (0.4) -1.0 (0.4) 0.1 (0.4) -1.5 (-2.6, -0.4) -1.1 (-2.2, 0.0) Nieto J, et al. Presented at the 49th EASD Annual Meeting; Barcelona, Spain; Sept 2013. Abstract 951.

Lipid and Blood Pressure Effects Efficacy and Safety of Canagliflozin in Patients with T2DM and Chronic Kidney Disease: Lipid and Blood Pressure Effects Parameter Canagliflozin 100 mg 300 mg Placebo Systolic blood pressure change, mm Hg -5.5 (1.5) -6.7 (1.5) -0.01 (1.5) Difference vs placebo -5.5 (-9.3, -1.7) -6.7 (-10.5, -2.9) Diastolic blood pressure change, mm Hg -2.0 (1.0) -2.4 (1.0) -1.4 (1.0) -0.7 (-3.1, 1.8) -1.0 (-3.5, 1.5) Triglycerides % change 12.4 (4.8) 9.1 (4.7) 9.9 (4.9) 2.5 (-9.9, 14.9) -0.8 (-13.0, 11.4) HDL-C % change 3.3 (1.9) 4.1 (1.8) 1.3 (1.9) 1.9 (-2.9, 6.8) 2.8 (-1.9, 7.6) LDL-C % change 6.4 (3.8) 2.5 (3.7) 9.4 (3.9) -3.0 (-12.7, 6.8) -6.9 (-16.6, 2.8) LDL-C/HDL-C % change 4.7 (4.1) -1.2 (4.0) 9.0 (4.2) -4.3 (-14.9, 6.3) -10.2 (-20.7, 0.4) Non-HDL-C % change 6.7 (2.9) 3.5 (2.8) 6.4 (3.0) -0.3 (-7.9, 7.3) -2.9(-10.3, 4.6) Nieto J, et al. Presented at the 49th EASD Annual Meeting; Barcelona, Spain; Sept 2013. Abstract 951.

Change in A1C with Canagliflozin in Subjects with T2DM and Stage 3 Chronic Kidney Disease Pooled analysis in patients with T2DM from placebo-controlled studies with eGFR >30 and <60 mL/min/1.73m2 (n=1,085) and in subgroups with eGFR >45 and <60 (n=721) or > 30 and <45 (n=364). Data presented as Least Squares Mean (SE) change from baseline using ANCOVA and placebo-subtracted Least Squares mean (95% CI) values. † Mean baseline age 67 years; A1C 8.1%; eGFR 48.2; body weight 91 kg. ‡ Mean baseline age 66 years; A1C 8.1%; eGFR 53.3; body weight 90 kg; §Mean baseline age 66 years; A1C 8.1%; eGFR 38.2; body weight 92 kg. ¥ P < 0.001 vs placebo. P values reported for prespecified comparisons only. Woo V, et al. Presented at American Diabetes 2013 Scientific Sessions; Chicago, IL; June 2013. Abstract 73-LB.

Patients with Renal Impairment Recommended Dosing in Patients with Renal Impairment Canagliflozin Dapagliflozin Increase dose to 300 mg daily if eGFR >60 mL/min/1.73 m2 eGFR 45 to < 60 mL/min/1.73 m2: Limit dose to 100 mg daily Do not initiate or discontinue if eGFR < 45 mL/min/1.73 m2 Do not initiate or discontinue if eGFR < 60 mL/min/1.73 m2 Canagliflozin [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2013. Dapagliflozin [package insert].Princeton, NJ: Bristol-Myers Squibb Company; 2014.

Changes in Lipid Profiles with SGLT2 Inhibitors

Changes in Lipid Profiles of Patients on Dapagliflozin Plasma lipid changes from baseline (%, 95% CI) in pooled DAPA studies at 24 weeks Placebo (n=1393) Dapagliflozin 5 mg (n=1145) Dapagliflozin 10 mg (n=1193) TC - n 989 888 834 BL mean 5.06 mmol/L 5.04 mmol/L 5.07 mmol/L Mean change -0.4% +1.1% +1.4% (95% CI) (-1.4, +0.6) (0.0, +2.2) (+0.2, +2.6) HDL-C 990 889 1.15 mmol/L 1.16 mmol/L 1.17 mmol/L Mean Change +3.8% +6.5% +5.5% (+2.8, +4.8) (+5.3, +7.8) (+4.3, +6.7) LDL-C 985 884 828 2.97 mmol/L 2.93 mmol/L 2.95 mmol/L -1.9% +0.6% +2.7% (-3.5, -0.3) (-1.2, +2.4) (+0.8, +4.7) TG 984 886 831 2.12 mmol/L 2.15 mmol/L 2.19 mmol/L -0.7% -3.2% -5.4% (3.0, +1.7) (-5.8, -0.6) (-7.9, -2.8) FFA 838 732 694 BL 0.56 meq/L 0.58 meq/L mean -5.7% -0.5% +1.2% (8.9, -2.5) (-3.7, +2.8) (-2.4, +5.0) 12 phase 2b/3 double-blind, controlled trials for up to 24 weeks were analyzed. (n=3,731) Hardy E, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. Sept 2013. Abstract 947.

Weight Loss and Blood Pressure Effects

Dapagliflozin-induced Weight Loss Affects 24 Week A1C and Blood Pressure Levels ∆ BW, kg -5 -4 -3 -2 -1 Effect of other variables 14% 17% Added benefit of weight loss during dapagliflozin treatment that contributes to overall changes in A1C and to changes in blood pressure after 24 weeks of treatment -1 37% -2 Effect of ∆ In BW 49% ∆ SBP, mm Hg -3 46% -4 Non-BW ∆ related -5 37% treatment effect -6 Dapagliflozin 10 mg Placebo -7 Sjöström CD, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. Sept 2013. Abstract 181.

and Weight Loss–Associated Mechanisms Canagliflozin Lowers A1C Through Weight Loss–Independent and Weight Loss–Associated Mechanisms Relationship between changes in A1C and body weight at week 26* 0.2 -0.2 -0.4 -0.6 -0. -1.0 -1.2 -1.4 Placebo Canagliflozin 100 mg Canagliflozin 300 mg ∆ A1C (%) Weight loss- independent Weight loss- associated Most (85%) of the A1C-lowering effect of canagliflozin is independent of weight loss -10 -5 0 5 ∆ body weight (%) Across all 3 treatment groups, subjects with greater weight loss had greater reductions in A1C, and the slope associated weight loss for A1C was similar across all 3 groups. Each 1% reduction in BW was associated with a 0.045% reduction in A1C. *Solid symbols represent mean changes within each decile of weight change, and open symbols are mean changes in the entire treatment group. Pooled analysis of 4 previously reported, randomized, double-blind, 26-week, phase 3 studies (N=2,250). Wilding L, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. Sept 2013. Abstract 946. Reproduced with the permission of Janssen Research & Development, LLC

and Weight Loss–Associated Mechanisms Canagliflozin Lowers A1C Through Weight Loss–Independent and Weight Loss–Associated Mechanisms Relationship between changes in systolic blood pressure and body weight at Week 26* 6 4 2 -2 -4. -6 -8 -10 Placebo Canagliflozin 100 mg Canagliflozin 300 mg ∆ SBP (mm Hg) Weight loss contributes to ~40% of the SBP-lowering effect of canagliflozin -10 -5 0 5 ∆ body weight (%) In each treatment group, subjects with greater weight loss had greater reductions in systolic blood pressure, with similar slopes associated with weight loss observed across all 3 groups. Each 1% reduction in body weight was associated with a 0.62% mm Hg reduction in systolic blood pressure. *Solid symbols represent mean changes within each decile of weight change, and open symbols are mean changes in the entire treatment group. Pooled analysis of 4 previously reported, randomized, double-blind, 26-week, phase 3 studies (N=2,250). Wilding L, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. Sept 2013. Abstract 946. Reproduced with the permission of Janssen Research & Development, LLC

Effects of Dapagliflozin on Body Weight Placebo + Metformin Dapagliflozin 10 mg + Metformin 0.5 1.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0 Change in total body weight (kg)* LOCF Difference from placebo -2.08 kg (95%CI -2.84, -1.31) P<0.0001 0 4 Sample size per time point 8 16 Study Week 24 Baseline value (kg) Placebo 91 90 88 86 90.9 Dapagliflozin 89 85 83 92.1 Dapagliflozin reduces total body weight predominantly by reducing fat mass, visceral adipose tissue and SC adipose tissue volume. Reprinted with permission from Bolinder J, et al. J Clin Endocrinol Metab. 2012.97(3):1020–1031.

Effects of Dapagliflozin on Regional Adipose Tissue Distribution Mean change from baseline in VAT and SAT volume with treatment at 24 wk Placebo + Metformin n=42; n=37 Dapagliflozin 10 mg + Metformin n=37; n=30 200 Change in adipose tissue volume (cm3) -39.2 -121.4 -200 -297.5‡ -400 -306.4§ -600 -800 Visceral AT Subcutaneous AT Dapagliflozin reduces total body weight predominantly by reducing fat mass, visceral adipose tissue and SC adipose tissue volume. ‡, VAT, -258.4 cm3 (95 CI = -448.1 to -68.6; nominal P = 0.0084); §, SAT, -184.9 cm3 (95% CI = -359 to -10.1; nominal P = 0.0385). Reprinted with permission from Bolinder J, et al. J Clin Endocrinol Metab. 2012.97(3):1020–1031.

Summary SGLT2 inhibitors are effective therapies in challenging patient populations Efficacy of these therapies is reduced in older adults and renally impaired patients, but safety is maintained Beneficial effects on weight and blood pressure are consistently seen, but clinical impact remains to be determined Minor changes in LDL-C, but not HDL-C or triglycerides, are observed – Minor changes in non-HDL-C with canagliflozin Cardiovascular outcome studies are in progress