SESSION 4 12:30pm 1:45pm

SESSION 4 12:30pm 1:45pm Addressing Renal-Mediated Glucose Homeostasis: Diabetes and the Kidney SPEAKER Davida Kruger, MSN, BC-ADM, APRN Presenter Disclosure Information The following relationships exist related to this presentation: Davida F. Kruger, MSN, APN-BC, BC-ADM, consultant for content development and faculty member, reports the following financial disclosures: Ms. Kruger report having received honoraria for serving on Advisory Boards as a consultant for Dexcom, Takeda Pharmaceutical Company, Abbott Laboratories, Janssen Pharmaceuticals, Eli Lilly, and Novo Nordisk. Ms. Kruger has also reports having received honoraria for her participation as a facultymember on Speakers Bureaus for Valeritas, Janssen Pharmaceuticals, Novo Nordisk, AstraZeneca/Bristol-Myers Squibb Diabetes, and Boehringer Ingelheim. Presenter Disclosure Information Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Closing the Gap in Diabetes Care: Addressing Renal-Mediated Glucose Homeostasis Learning Objectives 1. Recognize the role of the renal system in glucose uptake, reabsorption, and maintenance of glucose homeostasis 2. Explain the mechanism of action of renal glucose transporter inhibitors and their role in attaining glucose homeostasis 3. Review professional guidelines for target goals of therapy and treatment recommendations in specific patient types 4. Identify the safety and efficacy profiles of current and emerging therapies that target renally mediated glucose uptake and reabsorption 5. Implement management strategies that incorporate current and emerging therapies in patients who would benefit from a targeted approach to glycemic control The Basics of Glucose Metabolism 6

Complex Etiology of T2DM Relative Amount Glucose (mg/dl) 350 300 250 200 150 100 50 250 200 150 100 50 0 Prediabetes (IFG, IGT) 15 Diabetes diagnosis Postmeal glucose Insulin resistance Fasting glucose Beta cell failure Insulin level 10 5 0 5 10 15 20 25 30 Onset of Diabetes Years Hyperglycemia can impair islet cell function and exacerbate insulin resistance Role of the Renal System in Glucose Homeostasis IFG, impaired fasting glucose; IGT, impaired glucose tolerance. Bergenstal R, et al. Endocrinology. Philadelphia, PA: WB Saunders Co; 2001:821 835. Jabbour SA, Goldstein BJ. Int J Clin Pract. 2008;62(8):1279 1284. 13 Renal Gluconeogenesis The Kidney s Role in Normal Glucose Homeostasis 1,2 Glucose Release (µmol Kg 1 min 1 ) + Glucose input ~250 g/day: Dietary intake ~180 g/day Glucose production ~70 g/day Gluconeogenesis Glycogenolysis The kidney filters circulating glucose Net balance ~0 g/day 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 Meyer C, et al. J Clin Invest. 1998;102(3):619 624. 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10 F18. 2. Gerich JE. Diabetes Obes Metab. 2000;2:345 350. 20 Sodium-Glucose Co-transporters (SGLTs) and Normal Renal Handling of Glucose Glomerulus Proximal Convoluted Tubule Distal Convoluted Tubule Renally Mediated Glucose Transporters 180 g/day/1.73 m 2 is filtered glucose load 1 SGLT2 transports 90% of filtered glucose out of the tubular lumen 1-4 SGLT1 transports the remaining 10% of filtered glucose 1-4 SGLT1 is the primary SGLT in the small intestine 1,2 Glucose is filtered in the glomerulus SGLT2 Glucose reabsorbed into systemic circulation SGLT1 Loop of Henle Collecting Duct Urine No detectable glucose in urine SGLT, sodium-glucose co-transporter 1. Wright EM et al. J Intern Med. 2007;261(1):32 43. 2. Kanai Y et al. J Clin Invest. 1994;93(1):397 404. 3. You G et al. J Biol Chem. 1995;270(49):29365 29371. 4. Wright EM. Am J Physiol Renal Physiol. 2001;280(1):F10 F18.

Urinary glucose excretion (g/day) SGLT-2 inhibitors Lower Renal Threshold for Glucose Excretion (RT G ) 125 100 75 50 25 0 50 T2DM + Canagliflozin Healthy 180 mg/dl Plasma glucose (mg/dl) T2DM, type 2 diabetes mellitus. Adapted with permission from Abdul Ghani MA, DeFronzo RA. 1.Abdul Ghani MA, DeFronzo RA. Endocr Pract. 2008;14(6):782 790. 2.Nair S, Wilding JP. J Clin Endocrinol Metab. 2010;95(1):34 42. 3.Invokana (canagliflozin) full prescribing information. Available at: http://www.pdr.net/full prescribing information/invokana?druglabelid=3094. RT G 100 150 RT G SGLT-2 inhibitors 200 T2DM 240 mg/dl RT G 250 300 Altered Renal Glucose Control in Diabetes Gluconeogenesis is increased in postprandial and postabsorptive states in patients with type 2 diabetes 1-3 Renal contribution to hyperglycemia 3-fold increase relative to patients without diabetes Glucose reabsorption 1-3 Increased SGLT-2 expression and activity in renal epithelial cells from patients with diabetes vs. normoglycemic individuals Selective SGLT2 inhibitors reduce blood glucose levels 4 Increased renal excretion of glucose Improved glucose control and decreased glucose toxicity Urine loss of glucose calories (leading to weight reduction) 1. Marsenic O. Am J Kidney Dis. 2009;53(5):875 883. 2. Bakris GL, et al. Kidney Int. 2009;75(12):1272 1277. 3. Rahmoune H, et al. Diabetes. 2005;54(12):3427 3434. 4. Brooks AM, Thacker SM. Ann Pharmacother. 2009;42(7):1286 1293. Goal of Pharmacologic SGLT-2 Therapy Lowers plasma glucose levels independent of insulin secretion/action (i.e., beta cell function) No (or very low) risk of hypoglycemia Potential for weight reduction No adverse renal effects in individuals with familial renal glucosuria Professional Guidelines for Patient Management in T2DM Setting Glycemic Targets for Patients With T2DM: ADA/EASD Position Statement Recommendations For most patients, HbA 1c <7.0% is appropriate Individualization is the key Tighter targets for younger, healthier patients Less stringent targets for older patients; those with comorbidities, known CAD, hypoglycemia unawareness, short life expectancy; and/or those who live alone Safety and efficacy trump cost Minimize risk of hypoglycemia Treatment Goals AACE 1 ADA 2 HbA 1c % 6.5 7.0 Fasting/pre meal BG (mg/dl) <110 70 130 Postprandial (mg/dl) <140 <180 Blood pressure (mm Hg) <130/80 <140/80 LDL Cholesterol (mg/dl) <100 (<70) <100 HDL Cholesterol (mg/dl) >40 in men, >50 >50 in women Triglycerides (mg/dl) <150 <150 Peak 2 hours post meal Lower goals recommended for high risk / CVD AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; BG, blood glucose. Inzucchi. SE, et al. Diabetes Care. 2012;35:1364 1379 1. Handelsman Y, et al. Endocr Pract. 2011;17 (Suppl 2):1-53. 2. ADA. Diabetes Care. 2013 ;36 Suppl 1:S11-S66.

Profiles of Antidiabetic Medications Efficacy ( HbA 1c ) With metformin 2 Risk of hypoglycemia With metformin 2 Effect on weight With metformin 2 1. Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364 1379. 2. Garber AJ, et al. Endocr Pract. 2013;19(2):327 336. MET DPP 4i GLP 1 RA TZD Low HbA1c lowering-effect relative to that observed with insulin (highest) Intermediate 1 Intermediate Low MET, metformin; DPP 4i, DPP 4 inhibitor; GLP1 RA, GLP 1 receptor agonist; TZD, thiazolidinedione. 1 Low Reduced Reduced 2 Low Profiles of Antidiabetic Medications (cont.) Efficacy ( HbA 1c ) 2 With metformin 2 Risk of hypoglycemia With metformin 2 Effect on weight With metformin 2 SU GLN Insulin SGLT 2i Moderate to severe Moderate Low Mild HbA1c lowering-effect relative to that observed with insulin (highest) SU, sulfonylurea; GLN, meglitinide; SGLT 2i, sodium glucose linked transporter 2 inhibitors. 1. Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364 1379. 2. Garber AJ, et al. Endocr Pract. 2013;19(2):327 336. Moderate to severe Intermediate 2 Intermediate Reduced Reduced Emerging Therapies in T2DM: SGLT2 Inhibitors The Benefits of SGLT2 Inhibitors Unique Mechanism of Action Inhibition of SGLT2 results in daily urinary excretion of excess glucose ~70 g, providing: 1 Significant reductions in HbA 1c 2,3 Additional benefits of weight reduction and a reduction in blood pressure 2 Reduction of fasting and PPG levels SGLT2 Inhibitors act independently of insulin mechanisms 2 Works regardless of β cell function Complements insulin dependent mechanisms Low propensity for hypoglycemia 1. List JF, et al. Diabetes Care 2009;32:650 657. 2. Bailey CJ, et al. Lancet 2010;375:2223 2233. 3. Bailey CJ, et al. Diabetes. 2011;60(Suppl. 1):71st ADA Scientific Sessions; San Diego, CA. June 24 28, 2011.Poster #988 P. SGLT2 Inhibitors for Use in T2DM Approved SGLT-2 Inhibitors FDA Approved Canagliflozin Dapagliflozin Empagliflozin Investigative Ipragliflozin Tofogliflozin Ertugliflozin Luseogliflozin Canagliflozin 1, dapagliflozin 2, and empagliflozin 3 Approved as adjuncts to diet and exercise to improve glycemic control in adults with T2DM Reduce HbA 1c and promote weight reduction with a low incidence of hypoglycemia 4-7 Complement the action of other antidiabetic agents 2,5 and can be used in any stage of diabetes 1-3 Side effects include urinary tract and genital infections 4 Positive effects on BP (primarily systolic BP) 7 Improve beta cell function 5-7,9 1. Invokana (canagliflozin) full prescribing information. Available at: http://www.pdr.net/full prescribing information/invokana?druglabelid=3094. 2. Farxiga (dapagliflozin) full prescribing information. Available at: http://www.pdr.net/full prescribing information/farxiga?druglabelid=3427. 3. Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 2013;6:453 467. 4. Babu A. Drugs Today (Barc). 2013;49(6):363 376. 5. Henry RR, et al. Int J Clin Pract. 2012;66(5):446 456. 6. Bhartia M, et al. Rev Diabet Stud. 2011;8(3):348 354. 7. Ferrannini E, et al. Diabetes Care. 2010;33(10):2217 2224. 8. Rosenstock J, et al. Diabetes Care. 2012;35(6):1232 1238. 9. Polidori D, et al. Presented at: 72nd ADA Scientific Sessions; June 8 12, 2012; Philadelphia, PA.

Canagliflozin Dosing 1 100 mg/300 mg prior to the 1 st meal of the day Use in patients with compromised renal function 1 100 mg/day if estimated glomerular filtration rate (egfr) 60 ml/min; titrate to 300 mg/day 100-mg/day in patients with egfr of 45-60 ml/min Not for use with egfr <45 ml/min Change in HbA 1c (%) From Baseline Canagliflozin: Changes in HbA 1c From Placebo-Controlled Studies Placebo CANA 100 mg CANA 300 mg P < 0.05 vs. placebo in all studies. Data reported after 26 weeks of therapy except the insulin add on study (18 weeks). 1. Invokana (canagliflozin) full prescribing information. Available at: http://www.pdr.net/full prescribinginformation/invokana?druglabelid=3094. CANA, canagliflozin; PIO, pioglitazone. Invokana (canagliflozin) full prescribing information. Available at: http://www.pdr.net/fullprescribing information/invokana?druglabelid=3094. Change in Weight (%) From Baseline Canagliflozin: Changes in Body Weight From Placebo-Controlled Studies Placebo CANA 100 mg CANA 300 mg P <.05 vs. placebo in all studies. Data reported after 26 weeks of therapy except the insulin add on study (18 weeks). Canagliflozin Pooled Safety Analysis: 26-Week Placebo-Controlled Trials Adverse Reaction Placebo (n = 646) CANA 100 mg (n = 833) CANA 300 mg (n = 834) Female genital mycotic 3.2% 10.4% 11.4% infections Urinary tract infections 4.0% 5.9% 4.3% Increased urination 0.8% 5.3% 4.6% Male genital mycotic 0.6% 4.2% 3.7% infections Vulvovaginal pruritis 0% 1.6% 3.0% The 4 placebo controlled trials included 1 monotherapy trial and 3 add on combination trials with metformin, metformin and a sulfonylurea, or metformin and pioglitazone. Invokana (canagliflozin) full prescribing information. Available at: http://www.pdr.net/fullprescribing information/invokana?druglabelid=3094. Invokana (canagliflozin) full prescribing information. Available at: http://www.pdr.net/fullprescribing information/invokana?druglabelid=3094. Dapagliflozin Dapagliflozin: Changes in HbA 1c Dosing 5 mg/10 mg in the morning, independent of meals Use in patients with compromised renal function 1 No dose adjustment is needed in patients with mild renal impairment (egfr 60 ml/min) Not for use with an egfr <60 ml/min Absolute Change in HbA 1c (%) From Baseline Placebo DAPA 2.5 mg DAPA 5 mg DAPA 10 mg P <.05 vs. placebo. 1. Farxiga (dapagliflozin) full prescribing information. Available at: http://www.pdr.net/full prescribing information/farxiga?druglabelid=3427. DAPA, dapagliflozin. 1. Wilding J, et al. Ann Intern Med. 2012;156(6):405 415. 2. Strojek K, et al. Diabetes Obes Metab. 2011;13(10):928 938. 3. Ferrannini E, et al. Diabetes Care. 2010;33(10):2217 2224. 4. Bailey CJ, et al. Lancet. 2010;375(9733):2223 2233.

Dapagliflozin: Changes in Body Weight Safety of Dapagliflozin: Monotherapy, 1 Add-on to Metformin, 2 and Glimepiride 3 Studies Placebo DAPA 2.5 mg DAPA 5 mg DAPA 10 mg P <.05 for change from baseline. Urinary tract infections Monotherapy 1 Metformin add on 2 Glimepiride add on 3 Genital infections Monotherapy 1 Metformin add on 2 Glimepiride add on 3 Hypoglycemia Monotherapy 1 Metformin add on 2 Glimepiride add on 3 Placebo DAPA 2.5 mg DAPA 5 mg DAPA 10 mg 4% 8% 6.2%% 1.3% 5% 0.7% 2.7% 3% 4.8% 4.6% 4% 3.9% 7.7% 8% 3.9% 1.5% 2% 7.1% 12.5% 7% 6.9% 7.8% 14% 6.2% 0.0% 4% 6.9% 5.7% 8% 5.3% 12.9% 9% 6.6% 2.9% 4% 7.9% 1. Wilding J, et al. Ann Intern Med. 2012;156(6):405 415. 2. Strojek K, et al. Diabetes Obes Metab. 2011;13(10):928 938. 3. Ferrannini E, et al. Diabetes Care. 2010;33(10):2217 2224. 4. Bailey CJ, et al. Lancet. 2010;375(9733):2223 2233. 1. Ferrannini E, et al. Diabetes Care. 2010;33(10):2217 2224. 2. Bailey CJ, et al. Lancet. 2010;375(9733):2223 2233. 3. Strojek K, et al. Diabetes Obes Metab. 2011;13(10):928 938. Safety of Dapagliflozin: Malignancies Incidence rate of bladder cancer 1 : Dapagliflozin: 0.17% of patients (n = 6045) Placebo: 0.03% of patients (n = 3512) Animal studies showed no evidence of cancer 2 Empagliflozin Dosing 10 mg once daily, taken in the morning, with or without food May be increased to 25 mg once daily Use in patients with compromised renal function Assess renal function before initiating therapy and do not initiate empagliflozin if egfr is below 45 ml/min/1.73 m 2 Discontinue if egfr falls persistently below 45 ml/min/1.73 m 2 1. Farxiga (dapagliflozin) full prescribing information. Available at: http://www.pdr.net/full prescribing information/farxiga?druglabelid=3427. 2. Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 2013;6:453 467. 1. Jardiance (empagliflozin) full prescribing information. Available at: http://www.pdr.net/drug summary/jardiance?druglabelid=3597. Accessed October 21, 2014. Empagliflozin: Changes in HbA 1c From Placebo-Controlled Studies Absolute Change in HbA 1c (%) From Baseline Placebo EMPA 10 mg EMPA 25 mg P < P<0.05 vs. placebo. versus placebo in all studies Data reported after 24 weeks of therapy except the insulin add on study (18 weeks). EMPA, empagliflozin Empagliflozin: Changes in Body Weight From Placebo Controlled Studies Placebo EMPA 10 mg EMPA 25 mg P <0.05 for change from baseline. Data reported after 24 weeks of therapy except the insulin add on study (18 weeks). EMPA, empagliflozin Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 2013;6:453 467. Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 2013;6:453 467.

Safety of Empagliflozin: Pooled Data From Placebo-Controlled Studies Reported adverse events comparable among groups Most frequently reported adverse events Urinary tract infection, Female genital mycotic infections, dyslipidemia Urinary tract infection Empagliflozin 10 mg 9.3% Empagliflozin 25 mg 7.6% Placebo 7.6% Female genital mycotic infections Empagliflozin 10 mg 5.4% Empagliflozin 25 mg 6.4% Placebo 1.5% Rates of hypoglycemia similar between groups Systolic blood pressure decreased 4.1 mm Hg (10 mg) to 4.8 mm Hg (25 mg) Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 2013;6:453 467. Label Comparison: Canagliflozin, Dapagliflozin, and Empagliflozin Topic Canagliflozin 1 Dapagliflozin 2 Empagliflozin 3 Indication Adjunct to diet and exercise to improve glycemic control in T2D Same Same Dose and Timing Dosing regarding GFR 100 mg/300 mg prior 1 st meal of day 100 mg/day if GFR >60 ml/min Titrate to 300 mg 100 mg/day if GFR 45 60 ml/min T2D, type 2 diabetes; GFR, glomerular filtration rate 5 mg/10 mg in the morning independent of meals 5 mg if GFR >60 ml/min with titration to 10 mg 10 mg/25 mg in the morning independent of meals Do not initiate if GFR 45 ml/min Discontinue if GFR is persistently < 45 ml/min 1. Invokana (canagliflozin) full prescribing information. Available at: http://www.pdr.net/full prescribinginformation/invokana?druglabelid=3094. 2. Farxiga (dapagliflozin) full prescribing information. Available at: http://www.pdr.net/full prescribing information/farxiga?druglabelid=3427. 3. Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 2013;6:453 467. Label Comparison: Canagliflozin, Dapagliflozin, and Empagliflozin (cont.) Topic Canagliflozin 1 Dapagliflozin 2 Empagliflozin 3 Contraindications Warnings/ Precautions Hypersensitivity reactions Impaired renal function Hypotension with ACEi and ARBS Renal impairment Hypoglycemia with SUs and insulin Hyperkalemia Hypersensitivity Increased LDL C Category C pregnancy rating Same Hypotension Renal impairment Hypoglycemia with SUs and insulin Bladder cancer Hypersensitivity Increased LDL C Category C pregnancy rating Monitor and treat as appropriate ACEi, acetylcholinesterase inhibitor; ARBs angiotensin receptor blockers; SUs, sulfonylureas; LDL-C, low-density lipoprotein cholesterol Same Hypotension with diuretics Renal impairment Hypoglycemia with SUs and insulin Increased LDL C Category C pregnancy rating Summary Management of T2DM may be optimized with combination therapy The kidneys regulate glucose production, uptake, reabsorption, and elimination New agents target SGLT2-mediated increases in renal glucose reabsorption SGLT2 inhibitors Block glucose reabsorption and promote glucosuria Improve glycemic control and lower blood glucose levels to target with a low risk of hypoglycemia Promote weight reduction Class-specific side effect profile 1. Invokana (canagliflozin) full prescribing information. Available at: http://www.pdr.net/full prescribing information/invokana?druglabelid=3094. 2. Farxiga (dapagliflozin) full prescribing information. Available at: http://www.pdr.net/full prescribing information/farxiga?druglabelid=3427. 3. Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 2013;6:453 467.