The Emerging Role of the Kidney and SGLT2 Inhibition for Patients with Type 2 Diabetes

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1 Silvio E. Inzucchi, MD The Emerging Role of the Kidney and SGLT2 Inhibition for Patients with Type 2 Diabetes Professor of Medicine Clinical Director Section of Endocrinology Yale University New Haven, Connecticut Sponsored by Integrity Continuing Education, Inc. Practitioner s Supported Edge is a by registered an educational service mark grant of Integrity from Continuing AstraZeneca. Education, Inc. 213 Integrity Continuing Education, Inc. Learning Objectives Implement evidence-based guidelines for the detection and diagnosis of prediabetes and T2DM Describe the role of the kidney in glucose homeostasis and the pathophysiology of T2DM Describe treatment t t strategies t that t target t the kidney to reduce hyperglycemia in T2DM, eg, SGLT2 inhibition Apply evidence-based and individualized management strategies for patients with T2DM Prevalence and Burden of Diabetes in the United States Affects ~26 million individuals 7th leading cause of death in 212 Disease sequelae include: Kidney failure, lower-limb amputations, blindness, neuropathy, cardiovascular disease, and stroke Diabetes diagnosis continues to increase, in large part, because of obesity epidemic Estimated that ~3% of adults will have diabetes by 25 T2DM, type 2 diabetes mellitus; SGLT2, soduim-glucose transport protein. 3 Centers for Disease Control and Prevention. Diabetes Report Card 212. American Diabetes Association. Diabetes Care. 213;36: American Diabetes Association. Diabetes Care. 214;37 (suppl 1):S ADA Guidelines for Diabetes Screening Diagnostic Criteria Adults: With body mass index (BMI) >25 and additional risk factors Without risk factors >45 years Children and adolescents who are overweight and have 2 additional risk factors for diabetes Individuals who test normal should follow up every 3 years BMI, body mass index. 5 American Diabetes Association. Diabetes Care. 214;37 (suppl 1):S Prediabetes Test Prediabetic Range FPG mg/dl (IFG) 2-hour plasma glucose (75-g OGTT) mg/dl (IGT) A1c 5.7%-6.4% Note: For all 3 tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range. Overt Diabetes Test Threshold for Diabetes FPG 126 mg/dl 2-hour plasma glucose (75-g OGTT) 2 mg/dl A1c 6.5% Note: In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing. OGTT, oral glucose tolerance test; IFG, impaired fasting glucose. American Diabetes Association. Diabetes Care. 214;37(suppl 1):S14-S8. 6 1

2 Impact of Diabetes: Macro- and Microvascular Complications Coronary artery disease 5% of people with T2DM die of coronary artery disease Peripheral arterial disease 2-fold increase in lower-limb amputations Cerebrovascular disease 15%-4% increased risk of stroke Neuropathy Affects up to 5% of patients with diabetes Retinopathy After 15 years, ~1% of patients with diabetes develop severe visual impairment Nephropathy 1%-2% of people with T2DM die of kidney failure Pathophysiological Disturbances in T2DM: The Ominous Octet Decreased incretin effect Decreased insulin secretion Increased glucagon secretion Increased HGP HYPERGLYCEMIA Neurotransmitter dysfunction Increased lipolysis Increased glucose reabsorption Decreased glucose uptake Fowler MJ. Clin Diabetes. 28;26:6. 7 HGP, hepatic glucose production. DeFronzo RA. Diabetes. 29;58: Factors Contributing to Loss of β-cell Function Loss of Muscle Cell Sensitivity to Insulin Decreased incretin effect Amyloid (IAPP) deposition Glucose toxicity Age Beta Cell Failure Genetics (TCF 7L2) Lipotoxicity FFA Insulin resistance Glucose uptake by 7 the muscle after a 6 meal is decreased, 5 resulting in postprandial p 4 hyperglycemia 3 min mg/kg 2 1 Control Splanchnic Adipose Muscle Brain T2DM Summary of glucose metabolism during euglycemic insulin (+ 1 μl/ml)-clamp studies performed in 38 normal-weight T2DM subjects and in 33 age-matched controls. FFA, free fatty acid; IAPP, islet amyloid polypeptide. DeFronzo RA. Diabetes. 29;58: DeFronzo RA. Diabetes. 1988;37: Loss of Liver Sensitivity to Insulin The Role of the Kidney in Glucose Homeostasis Basal HGP (mg/kg min) P<.1 Control T2DM r=.85, P< Ba asal HGP (mg g/kg min) Under normal conditions, the kidney is involved in maintaining glucose homeostasis via 3 different mechanisms: Release of glucose into circulation via gluconeogenesis Uptake of glucose to meet its own energy needs Reabsorption of glucose from the glomerular filtrate Control T2DM FPG (mg/dl) FPG, fasting plasma glucose. DeFronzo RA. Diabetes. 29;58: Gerich JE. Diabet Med. 21;27: Stumvoll M, et al. J Clin Invest. 1995;96:

3 Glucose Reabsorption in the Kidney by SGLT2 Renal Mechanisms Regulating Glucose Homeostasis Are Altered in T2DM There is an increase in: Threshold for glucosuria Maximum glucose reabsorption Renal glucose production Glucose reabsorption into the serum GLUT, glucose transporter; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; S1, segment 1; S2, segment 2; S3, segment 3 Gerich JE. Diabet Med. 21;27: Whaley JM, et al. Diabetes Metab Syndr Obes. 212;5: Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 213;6: Meyer C and Gerich JE. Curr Diab Rep. 22;2: Gerich JE. Diabet Med. 21;27: Managing Patients with T2DM Recommended Targets for Patients with T2DM Current guidelines stress importance of: Glycemic control to prevent microvascular complications Individualized care to reach treatment goals Management of comorbidities (eg, obesity, hypertension, and dyslipidemia) Lifestyle modifications and individualized pharmacologic interventions A1c Blood pressure (BP) Lipids (LDL-C) ADA <7.% (individualized!) AACE <6.5% 14/8 mm Hg /8 mm Hg <1 mg/dl (<7 mg/dl if overt CVD) <1 mg/dl (<7 mg/dl if overt CVD) Garber AJ, et al. Endocr Pract. 213;19: American Diabetes Association. Diabetes Care. 214;37 (suppl 1):S ADA, American Diabetes Association; AACE, American Association of Clinical Endocrinologists; LDL-C, low-density lipoprotein cholesterol. Garber AJ, et al. Endocr Pract. 213;19: ADA. Diabetes Care. 214;37(suppl 1):S14-S A Multipronged Approach to Pharmacologic Treatment Successful treatment of T2DM usually encompasses a combination of therapeutic strategies to address known underlying pathogenic abnormalities A wide range of pharmacologic therapies are available that target these underlying metabolic/hormonal disorders Recommendations for Lifestyle Modifications Reduce total body weight Primary strategy for preventing the onset of overt T2DM Increase daily physical activity (walking recommended) Limit alcohol consumption to 2 drinks per day Stop smoking Fonseca VA. Clin Ther. 214;36(4): Fonseca VA, Haggar MA. Nat Rev Endocrinol. 214;1: DeFronzo RA. Diabetes. 29;58: DeFronzo RA. Am J Med. 21;123:S Garber AJ, et al. Endocr Pract. 213;19: American Diabetes Association. Diabetes Care. 214;37 (suppl 1):S

4 Recommendations for Dietary Modifications Reduce total daily calorie intake Reduce sodium intake (<2,3 mg/day) Reduce simple carbohydrates/sugars and high-fat foods (eliminate trans fats) Limit saturated fat (<7% of calories, <2-3 g/day) Limit cholesterol (<2 mg/day) Increase water-soluble fiber (1-25 g/day) Increase unsaturated fat and marine-based omega-3s Systems Targeted by Available Pharmacologic Therapies Sulfonylureas Meglitinides GLP-1 agonists DPP-4 inhibitor Amylin analogs Metformin GLP-1 agonists DPP-4 inhibitors Bile acid sequestrants Alpha-glucosidase inhibitors GLP-1 agonists Thiazolidinediones SGLT2 inhibitors Thiazolidinediones 19 Garber AJ, et al. Endocr Pract. 213;19: DeFronzo RA. Diabetes. 29;58: ADA-EASD Position Statement on T2DM Therapies, 212 Case Study 1: Tom, 52-year-old Male Inzucchi SE, et al. Diabetes Care. 212;35: Video 23 Case Study #1: Tom, 52-year-old Male Physical exam: Height: 5 1 Weight: 232 lb BMI: 33.3 BP: 148/82 mm Hg No significant changes from 6 months ago Current medication: Metformin extended release 15 mg/day with evening meal Dietary review: Daily fast food in AM and lunch time Continues to eat many other processed foods Activity review (since last checkup): Exercises 3 minutes, 5 times per week, at moderate level Has trouble maintaining exercise regimen and controlling diet 24 4

5 Case Study #1: Tom, 52-year-old Male Laboratory Results & Diagnosis CBC, renal, liver, and lipid panels normal Glycemic panel: Reference (6 months ago) Current (confirmed on repeat test) A1C 74% 7.4% 76% 7.6% FPG 13 mg/dl 142 mg/dl Diagnosis: T2DM uncontrolled by metformin alone Case Study #1: Discussion What additional treatment might you consider for Tom at this time? Sulfonylurea? TZD? Incretin based therapy? (DPP-4 inhibitor, GLP-1 agonist) SGLT2 inhibitor? other? Based on Tom s case, what are your other recommendations? Increase physical activity? Establish a weight loss goal? Additional dietary modifications? CBC, complete blood cell count Available Therapies for the Treatment of T2DM Available Therapies for the Treatment of T2DM Therapeutic Class Mechanism of Action Reported Adverse Effects Therapeutic Class Mechanism of Action Reported Adverse Effects Metformin Reduces hepatic gluconeogenesis; increases hepatic insulin sensitivity; increases GLP-1 secretion by L cells in the GI tract Gastric distress DPP-4 inhibitors Prolong the effects of GLP-1 by blocking the enzyme (dipeptidyl peptidase-4) responsible for its inactivation; low risk for hypoglycemia, good safety profile, weight neutral Nasopharyngitis, upper respiratory tract infection, headache Bind to ATP-sensitive e potassium (KATP) channel of Sulfonylureas pancreatic β cells, inducing channel closure; stimulate insulin secretion TZDs Insulins Selective agonists for peroxisome proliferatoractivated receptor gamma (PPAR-γ; regulates transcription of genes involved in lipid and carbohydrate metabolism); decrease insulin resistance and preserve β-cell function Varied pharmacologic profiles of the synthetic insulins provide a range of options that differ in onset, peak, and duration of action; generally, insulins may be categorized as short-, intermediate-, or long-acting Hypoglycemia and weight gain Weight gain, edema, and decreased bone density in women Weight gain and mild hypoglycemia 27 GLP-1 receptor agonists SGLT2 inhibitors Mimic GLP-1 effects (stimulate glucose-dependent insulin secretion, slow gastric emptying, suppress postprandial glucagon secretion, increase satiety); preserve β-cell function (exenatide); promote weight loss Induce glucosuria by blocking SGLT2-mediated renal reabsorption of glucose in the S1 segment of the proximal convoluted tubule Nausea, vomiting UTIs, genital infections; intravascular volume depletion; nocturia 28 Mechanism of Action of SGLT2 Inhibitors Therapeutic Benefits Associated With SGLT2 Inhibition Lumen Glucose SGLT2 S1 proximal tubule GLUT2 Blood vessel Downstream tubular transport mechanisms Complete reabsorption of glucose When blood glucose levels are within the normal range, virtually all of the filtered glucose is reabsorbed by the kidney, primarily via SGLT2 and GLUT2 in the S1 segment of the proximal convoluted tubule. Whaley JM, et al. Diabetes Metab Syndr Obes. 212;5: Lumen Glucose SGLT2 S1 proximal tubule GLUT2 Blood vessel Downstream tubular transport mechanisms Urinary glucose excretion SGLT2 inhibitors block glucose reabsorption and result in glucosuria Reduces A1c, FPG, and PPG by an insulin-independent mechanism Weight loss due to renal glucose (4 calories per gram of glucose excreted) Reduces BP Improves insulin sensitivity and insulin secretion (ie, correction of glucotoxicity) PPG, postprandial glucose. Gerich JE. Diabet Med. 21;27: Plosker GL. Drugs. 212;72: Whaley JM, et al. Diabetes Metab Syndr Obes. 212;5: Mudaliar S, et al. Diabetes Technol Ther. 214;16: DeFronzo A., et al. J Clin Invest. 214; 124(2):

6 SGLT2 Inhibitors Currently Approved for the Treatment of T2DM Canagliflozin (CANA) Monotherapy: Sustained Reductions in A1c & Body Weight at 1 Year Approved SGLT2 Inhibitors* Recommendations for Initiation of Treatment and Dosing.2 Canagliflozin (1 or 3 mg qd) Therapy should not be initiated if egfr <45 ml/min/1.73m 2 Patients should be initiated at the lower dose Dose may be increased for patients requiring better glycemic control if well tolerated and egfr >6 ml/min/1.73m 2 Patients should be discontinued if egfr falls <45 ml/min/1.73m 2 % Change in HbA 1c CANA 1 mg (-.81%) CANA 3 mg (-1.11%) Dapagliflozin (5 or 1 mg qd) Empagliflozin (1 or 25 mg qd) Therapy should not be initiated if egfr <6 ml/min/1.73m 2 Patients should be initiated at the lower dose Dose may be increased for patients requiring better glycemic control if tolerated Patients should be discontinued if egfr falls persistently <6 ml/min/1.73m 2 Therapy should not be initiated if egfr <45 ml/min/1.73m 2 Patients should be initiated at the lower dose Dose may be increased for patients requiring better glycemic control if well tolerated Patients should be discontinued if egfr falls persistently <45 ml/min/1.73 m 2 qd, once per day; egfr, estimated glomerular filtration rate; FDA, US Food and Drug Administration. 31 % Change in Body Weight Time (weeks) Time (weeks) Stenlof K, et al. Curr Med Res Opin. 214;3: CANA 1 mg (Mean change: -2.8 kg) CANA 3 mg (Mean change: -3.9 kg) 32 CANA Monotherapy: Effects on Cardiovascular Risk Factors CANA Reduces A1c Levels in Patients with Inadequate Glycemic Control Outcome Measure CANA 1 mg CANA 3 mg Difference versus placebo (95% CI) Systolic BP 3.7 ( 5.9, 1.6)* 5.4 ( 7.6, 3.3)* Diastolic BP 1.6 ( 2.9,.2) 2. ( 3.4,.7) Triglycerides 5.4 ( 14.9, 4.1) 1.2 ( 19.6,.7) LDL-C 2. ( 3.2, 7.1) 6.1 (.9, 11.3) HDL-C 6.8 (2.9, 1.6)* 6.1 (2.3, 9.9) LDL-C/HDL-C 4. ( 9.1, 1.2).9 ( 4.3, 6.1) Non HDL-C.1 ( 4.2, 4.1) 1.9 ( 2.3, 6.1) t 26 Weeks (%) Change in A1c at MONOTHERAPY ADD ON WITH MET + SU ADD ON WITH MET + PIO Monotherapy 1 Add on with MET + SU 2 Add on with MET + PIO CANA 1 mg CANA 3 mg *P<.1; P<.1. MET, metformin; PIO, pioglitazone. CI, confidence interval. Stenlof K, et al. Diabetes Obes Metab. 213;15: Stenlof K, et al. Diabetes Obes Metab. 213;15: Wilding JP, et al. Int J Clin Pract. 213;67: Forst T, et al. Diabetes Obes Metab. 214;16(5): CANA Reduces Body Weight in Patients with Inadequate Glycemic Control Commonly Reported Adverse Events (AEs) with CANA y Weight s (%) Change in Body at 26 Weeks Monotherapy MONOTHERAPY Add ADD ON on with WITH MET MET + + SU 2 Add ADD ON on with WITH MET + PIO PIO Stenlof K, et al. Diabetes Obes Metab. 213;15: Wilding JP, et al. Int J Clin Pract. 213;67: Forst T, et al. Diabetes Obes Metab. 214;16(5): CANA 1 mg CANA 3 mg Hypoglycemia: incidence is low Urinary tract and genital mycotic infections: CANA 1 mgcana 3 mg Female genital mycotic infections 3.2% 1.4% 11.4% Male genital mycotic infections.6% 4.2% 3.7% Urinary tract infections 4.% 5.9% 4.3% Osmotic diuresis and volume depletion AEs Polyuria is uncommon: 4.2% (1 mg) and 3.7% (3 mg) vs.8% (placebo); symptoms are mild and transient Diuretic effect may reduce intravascular volume leading to orthostatic or postural hypotension Volume depletion may result in symptoms such as dizziness or fainting (most common in the first 3 months of therapy) AEs similar at 26 and 52 weeks Bode B, et al. Hosp Pract. 213;41(2): Stenlof K, et al. Diabetes Obes Metab. 213;15(4): Nicolle LE, etal. Postgrad Med. 214;126:7-17. Nyirjesy P, et al. Curr Med Res Opin Epub ahead of print. 36 6

7 DAPA as Add-on Therapy Lowers Mean A1c DAPA Added to Metformin Results in Sustained A1c Reduction at 12 Weeks Change in A1c at 24 Weeks (%) Monotherapy 1 ADD ON Add-on WITH ADD ON Add-on WITH ADD ON Add-on WITH ADD ON Add WITH on MONOTHERAPY MET GLIM PIO SITA with MET 2 with GLIM 3 with PIO 4 with SITA DAPA 5 mg DAPA 1 mg (%) ge % HbA1c Chang Week 24 Week 5 Week Time (weeks) Change From Baseline at Week 12.2, PBO.48, P=.8 DAPA 2.5 mg.58, P<.1 DAPA 5 mg.78, P<.1 DAPA 1 mg GLIM, glimepiride; SITA, sitagliptin. 1. Ferrannini E, et al. Diabetes Care. 21;33: Bailey CJ, et al. Lancet. 21;375: Strojek K, et al. Diabetes Obes Metab. 211;13: Rosenstock J, et al. Diabetes Care. 212;35: Jabbour SA, et al. Diabetes Care. 214;37: PBO, placebo. Bailey CJ, et al. BMC Med. 213;11: Pooled Trial Data for UTIs with DAPA (N=12) Empagliflozin (EMPA) Monotherapy Lowers A1c Levels Rates of UTI for DAPA vs placebo (3.7%) were: 2.5 mg: 3.6% 5 mg: 5.7% 1 mg: 4.3% Discontinuations due to UTI were uncommon Most UTIs were mild to moderate and responded to standard antimicrobial treatment n HbA 1c (%) Adjusted Mean PBO EMPA 25 mg qd EMPA 1 mg qd SITA 1 mg qd Weeks N=675 patients 18 years with A1c of 7%-1%. Johnsson KM, et al. J Diabetes Complications. 213;27: Roden M, et al. Lancet Diabetes Endocrinol. 213;1: EMPA Monotherapy Reduces Body Weight EMPA as Add-on Therapy Reduces Mean A1c Levels at 24 Weeks 1. P<.1 P<.1 P=.355 Add-on ADD ON with WITH SU 1 Add ADD ON on with WITH PIO 2 hange From Weight (kg) Adjusted Mean C Baseline Body W P<.1.5 P< PBO (N=228) EMPA 25 mg qd (N=224) EMPA 1 mg qd (N=224) SITA 1 mg qd (N=223) c (%) Change in A1c EMPA 1 mg EMPA 25 mg Roden M, et al. Lancet Diabetes Endocrinol. 213;1: Haring HU, et al. Diabetes Care. 213;36: Kovacs CS, et al. Diabetes Obes Metab Epub ahead of print. 42 7

8 Common AEs Reported with EMPA UTIs (4.% vs 2.8% with placebo) Pollakiuria* (2.5% vs 1.4% with placebo) Genital infections (4.% vs no reports with placebo) Case Study 2: Jan, 65-year-old Female *Abnormally frequent urination 43 Rosenstock J, et al. Diabetes Obes Metab. 213;15: Case Study #2: Jan, 65-year year-old Female Current Exam Video Physical exam (BP higher vs last visit): Height: 5 5 Weight: 195 lb BMI: 31 BP: 15/81 Current medications: Insulin glargine 5 IU/day Metformin extended release 2 mg/day with evening meal Dietary review (no change since last visit): Consumes mostly high-fat and high-carbohydrate diet Activity review: Limited physical activity due to arthritis of the knees Case Study #2: Jan, 65-year year-old Female Current Laboratory Results Diabetes Panel Today 3 Months Ago 6 Months Ago A1c 8.2% 7.8% 7.6% FPG 155 mg/dl 142 mg/dl 138 mg/dl Lipid Panel Today 3 Months Ago 6 Months Ago Total Cholesterol 24 mg/dl 245 mg/dl 25 mg/dl LDL 13 mg/dl 144 mg/dl 15 mg/dl HDL 39 mg/dl 37 mg/dl 36 mg/dl Triglycerides 25 mg/dl 28 mg/dl 21 mg/dl Case Study #2: Discussion What adjustments should be made to Jan s treatment plan? Increase metformin dose to maximum daily dose? Add a second oral medication? If so, which? Increase insulin dose? Revisit glipizide? Add a TZD? Incretin based drug? (DPP-4 inhibitor, GLP-1 agonist) SGLT2 inhibitor?

9 CANA Improves A1c and Body Weight in Patients Inadequately Controlled with Insulin Patient population N=29 subjects with T2DM not well controlled on insulin and 1 oral antihyperglycemic agent Treatment groups: CANA - 1 mg qd or 3 mg bid Duration of study was 28 days Outcomes A1c and body weight decreased in subjects administered CANA DAPA for Patients Inadequately Controlled with High Doses of Insulin Patient population: N=88 T2DM patients 18-8 years of age Receiving insulin 3 IU/day ± 2 oral antidiabetic drugs A1c 7.5%-1.5% Treatment groups: DAPA 2.5, 5, or 1 mg qd Duration of study: 24 weeks 1 /14-week extension 2 bid, twice per day. Devineni D, et al. Diabetes Obes Metab. 212;14(6): Wilding JP, et al. Ann Intern Med. 212;156(6): Wilding JP, et al. Diabetes Obes Metab. 214;16: DAPA Lowers A1c in Patients Not Well Controlled with Insulin (2 Years) DAPA Lowers Body Weight in Patients Not Well Controlled with Insulin HbA1c Change in Mean INS, insulin (%) PBO + INS N=193 DAPA 2.5 mg + INS N=22 DAPA 5/1 mg + INS N=211 ST Period LT Period 1 LT Period 2 DAPA 1 mg + INS N= Study Week y Weight (kg) Change in Total Body PBO INS N=193 DAPA 2.5 mg + INS N=22 DAPA 5/1 mg + INS N=211 DAPA 1 mg + INS N=194 ST Period LT Period 1 LT Period Study Week Wilding JP, et al. Diabetes Obes Metab. 214;16: Wilding JP, et al. Diabetes Obes Metab. 214;16: Daily Insulin Dose Over 2 Years Was Maintained in Patients Treated with DAPA Potential Benefits of SGLT2 Inhibition for Patients with T2DM nsulin Dose (IU) Change in Mean Daily In PBO INS N=193 ST Period DAPA 2.5 mg + INS N=22 Wilding JP, et al. Diabetes Obes Metab. 214;16: DAPA 5/1 mg + INS N=211 LT Period 1 LT Period 2 DAPA 1 mg + INS N= Study Week 53 Corrects a novel pathophysiologic defect Promotes weight loss Reduces blood pressure Improves glycemic control, o reduces body weight, has insulin sparing effect, and possibly reduces CV risk No hypoglycemia CV, cardiovascular. Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 213;6: DeFronzo RA, et al. Diabetes Obes Metab. 212;14:5-14. Reduces glycated hemoglobin Complements action of other antidiabetic agents Reversal of glucotoxicity

10 Summary Prompt diagnosis and intervention is critical to effectively treat hyperglycemia associated with T2DM SGLT2 inhibition is a novel therapeutic strategy that targets hyperglycemia by blocking glucose reabsorption in the kidney SGLT2 inhibitors are Associated with low hypoglycemic risk and other side effects Effective alone and in combination with other oral therapies or insulin Optimal management of T2DM requires an individualized approach Questions and Answers Thank You! Back Up General Risk Factors for Diabetes Metabolic Risk Factors for Diabetes Physical inactivity Increased caloric intake (obesity) First-degree relative with diabetes Race/ethnicity it Delivery of a baby weighing >9 lb or diagnosed with gestational diabetes mellitus Clinical conditions associated with insulin resistance (eg, severe obesity, metabolic syndrome, acanthosis nigricans) Polycystic ovarian syndrome A1c >5.7%, IGT, or IFG on previous testing Hypertension (>14/9 mm Hg or on therapy for hypertension) HDL cholesterol level 35 mg/dl (.9 mmol/l) and/or a ti triglyceride id level l 25 mg/dl (2.82 mmol/l) History of cardiovascular disease American Diabetes Association. Diabetes Care. 214;37(suppl 1):S14-S8. 59 American Diabetes Association. Diabetes Care. 214;37(suppl 1):S14-S8. 6 1

11 β-cell Failure Progressive β-cell failure is a core pathophysiological defect in T2DM β cells initially exhibit a compensatory increase in insulin production in response to insulin resistance β-cell failure eventually follows Evidence suggests considerable β-cell loss prior to the onset of overt T2DM Individuals with impaired IGT exhibit over 8% loss of β-cell function Prediabetic patients (IGT and IFG) have lost significant β cells (range = 1%-3% or more) Abdul-Ghani MA, et al. Diabetes Care. 26;29: Gastaldelli A, et al. Diabetologia. 24;47: Butler AE, et al. Diabetes. 23;52: Loss of Liver and Muscle Cell Sensitivity to Insulin Liver Excess glucose production in the liver is the primary cause of fasting hyperglycemia Suppression of hepatic glucose production in response to insulin is impaired i with T2DM Hepatic glucose production in T2DM individuals fails to suppress normally following a meal Muscle Glucose uptake after a meal is decreased, resulting in postprandial hyperglycemia DeFronzo RA, Ferrannini E. Diabetes Metab Rev. 1987;3: Magnusson I, et al. J Clin Invest. 1992;9: DeFronzo RA. Diabetes. 29;58: Adipocyte Dysfunction in T2DM Alterations in the Incretin System Resistance to the suppressive effect of insulin on lipolysis results in chronically elevated plasma FFA Elevated plasma FFA stimulates hepatic gluconeogenesis, causes hepatic/muscle insulin resistance, and decreases insulin secretion Excessive production of adipocytokines that are insulin resistance-inducing, inflammatory, and atheroscleroticprovoking Inadequate production of adipocytokines that are insulinsensitizing (eg, adiponectin) Decrease insulin-stimulated glucose uptake 63 DeFronzo RA. Diabetes. 29;58: Secretion of GIP and GLP-1, which stimulate insulin secretion, are normal or slightly reduced in T2DM Insulin secretion in response to GIP and GLP-1 stimulation is markedly decreased in T2DM Suppression of glucagon secretion by GLP-1 1is decreased and contributes to elevated plasma glucagon levels in T2DM Reduced insulin secretion and enhanced glucagon secretion contribute to the impaired suppression of postprandial hepatic glucose production GIP, gastric inhibitory polypeptide, also called glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide DeFronzo RA. Diabetes. 29;58: Genetic Model for SGLT2 Inhibition: Familial Renal Glucosuria Characterized by glucosuria without hyperglycemia or proximal tubular dysfunction Mutations in the SLC5A2 gene, which encodes SGLT2 Considered to be a benign condition Phlorizin: A Naturally Occurring SGLT2 Inhibitor Shown to have antihyperglycemic effects in animal studies by inducing glucosuria Is no longer used due to poor selectivity, poor absorption in the intestine, and tendency to be rapidly hydrolyzed Calado J, et al. Kidney Int. 211;79(suppl 12):S Santer R, Calado J. Clin J Am Soc Nephrol. 21;5: Santer R, Calado J. Clin J Am Soc Nephrol. 21;5:

12 Synthetic SGLT2 Inhibitors Synthetic SGLT2 inhibitors have better absorption in the gastrointestinal tract Resistant to hydrolysis by gastrointestinal enzymes (β-glucosidase) High selectivity it for SGLT2 vs SGLT1 SGLT2 Inhibition in Clinical Trials SGLT2 inhibition in clinical trials has demonstrated lowering of: FPG 2-hour PPG A1c Body weight Blood pressure Triglycerides Increase HDL-cholesterol 67 Ferrannini E, Solini A. Nat Rev Endocrinol. 212;8: Canagliflozin Improves Glycemic Control Canagliflozin Monotherapy Decreases A1c in Treatment-Naïve Patients Monotherapy Combination therapy with other oral antihyperglycemic agents Metformin SUs Metformin and SUs Metformin and pioglitazone Combination therapy with insulin (with and without additional oral agents) ba1c (%) Mean (±SE) Hb PBO CANA 1 mg CANA 3 mg Time Point (weeks) 69 Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 213;6: SE, standard error. Stenlof K, et al. Diabetes Obes Metab. 213;15: Canagliflozin Monotherapy Decreases Weight in Treatment-Naïve Patients Canagliflozin in Patients Inadequately Controlled with Other Oral Antidiabetics e (±SE) in Baseline LS Mean % Change Body Weight From 1 PBO LS Mean % Change.6% (.5 kg) CANA 1 mg 2 2.8% 3 ( 2.5 kg) CANA 3 mg 3.9% 4 ( 3.4 kg) Time Point (weeks) P<.1 P<.1 Patient Population Treatment Groups Duration Receiving metformin + SU therapy N=469 Receiving metformin + pioglitazone N=342 CANA - 1 or 3 mg qd CANA - 1 or 3 mg qd 26 weeks 26 weeks Baseline (kg): =87.5; CANA 1 mg=85.9; CANA 3 mg=86.9. LS, least squares. Stenlof K, et al. Diabetes Obes Metab. 213;15: Forst T, et al. Diabetes Obes Metab Wilding JP, et al. Int J Clin Pract. 213;67:

13 L Canagliflozin Is Comparable With Glimepiride as an Add-on Therapy Patient population: Receiving metformin 18-8 years A1c = 7.%-9.5% N=145 Treatment t groups: CANA 1 or 3 mg qd Glimepiride titrated to 6 or 8 mg qd Duration of study: 52 weeks Cefalu WT, et al. Lancet. 213;382: HbA 1c (%) Mean (SE) Glimepiride Canagliflozin 1 mg Canagliflozin 3 mg Weeks 73 Canagliflozin Improves Glycemic Control and Promotes Weight Loss Compared with Sitagliptin Patient population: Receiving metformin + SU N=755 Treatment groups: CANA 3 mg qd SITA 1 mg qd Duration of study: 52 weeks Schernthaner G, et al. Diabetes Care. 213;36: SITA mg Baseline (%) CANA 3 mg 8.1 Baseline (mmol/mol) LS Mean Change.6.66%.37% ( 7.2 mmol/mmol) (95% CI:.5,.25).8 4. mmol/mol 1.3% 1. (95% CI: 5.5, 2.7) ( 11.3 mmol/mmol) 1.2 LS Mean Change (±SE) in A1C From Baseline (%) Time Point (weeks) SITA 1 mg CANA 3 mg Baseline (%) LS Mean 1. Change.5.3% (.1 kg) % ( 2.3 kg) Time Point (weeks) LS Mean Change (±SE) in Body Weight From Baseline (%) 2.8% ( 2.4 kg) P<.1 74 Dapagliflozin Improves Glycemic Control and Other Parameters Dapagliflozin Monotherapy Studies Monotherapy Combination therapy with other oral antihyperglycemic agents Metformin SUs Pioglitazone Metformin and SUs Metformin and sitagliptin Combination therapy with insulin (with and without additional oral agents) Patient Population Treatment Groups Duration Drug-naïve T2DM years DAPA - 2.5, 5, or 1 mg qd 24 weeks A1c 7.% % 1% N=485 Drug-naïve T2DM years DAPA - 1, 2.5, or 5 mg qd 24 weeks A1c 7.% 1% N= Bailey CJ, et al. Diabetes Obes Metab. 212;14: Ferrannini E, et al. Diabetes Care. 21;33: Effects of Dapagliflozin Monotherapy in Treatment-Naïve Patients (n=75) 2.5 mg (n=65) Dapagliflozin 5 mg (n=64) 1 mg (n=7) A1c (%) * -.89 FPG (mg/dl) * Weight (kg) Systolic BP (mm Hg) Diastolic BP (mm Hg) Treatment with Empagliflozin Effectively Lowers Hyperglycemia Drug naïve Add-on to monotherapy with: Metformin Pioglitazone Add-on to dual therapy with: Metformin and SUs Metformin and pioglitazone Metformin and linagliptin Combination therapy with insulin (with and without additional oral agents) * P<.1; P< Ferrannini E, et al. Diabetes Care. 21;33: Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 213;6:

14 Empagliflozin for Patients Inadequately Controlled with Combination Therapy Patient Population Treatment Groups Duration Receiving metformin and pioglitazone 18 years A1c 7%-1% Receiving metformin and SU 18 years A1c 7%-1% N=661 EMPA - 1 or 25 mg qd EMPA - 1 or 25 mg qd 24 weeks 24 weeks Faculty Disclosures Consulting: Boehringer Ingelheim, Bristol-Myers Squibb/AstraZeneca, Eisai, Lexicon, Merck Data Safety Monitoring Boards: Intarcia, Novo-Nordisk Research: Takeda (providing study drug and placebo for an NIH trial) Haring HU, et al. Diabetes Care. 213;36: Kovacs CS, et al. Diabetes Obes Metab Rosenstock J, et al. Diabetes Obes Metab Current Unmet Needs in T2DM Care The ABCD & E s of Diabetes Management Improve patient screening and risk assessment Utilize: Evidence-based treatment regimens to normalize HbA1c Antidiabetic medications that are weight neutral or promote weight loss and do not cause hypoglycemia Reduce disease sequelae (kidney failure, blindness, MI, stroke) associated with T2DM Individualize care of patients with T2DM Provide self-management strategies through patient education Hb1Ac, glycated hemoglobin; MI, myocardial infarction. 81 Body weight Complications Age Duration of disease Optimal T2DM Management Expense Education Etiology Pozzilli P, et al. Diabetes Metab Res Rev. 21;26: Recommended Lipid Targets for Patients at Risk for CVD Available Therapies for the Treatment of T2DM (cont d) High CVD Risk* Highest CVD Risk Therapeutic Class Mechanism of Action Reported Adverse Effects LDL-C (mg/dl) <1 <7 Non HDL-C (mg/dl) <13 <1 Triglycerides (mg/dl) <15 <15 Total cholesterol/hdl-c <3.5 <3. Apo B (mg/dl) <9 <8 LDL-P (nmol/l) <12 <1 *High risk: diabetes mellitus without CVD. Highest risk: diabetes mellitus + CVD. CVD, cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; Apo B, apolipoprotein B; LDL-P, low-density lipoprotein particle. Garber AJ, et al. Endocr Pract. 213;19: Meglinitides Bind to ATP-sensitive potassium (KATP) channel of β cells (distinct site from those bound by SUs) Inhibit complex polysaccharide carbohydrate conversion Alpha- into monosaccharides; delay carbohydrate absorption glucosidase from the small intestine; lower postprandial blood glucose inhibitors and insulin levels Amylin analogs Slow gastric emptying; prevent inappropriate postprandial secretion of glucagon; increase satiety and promote weight loss; adverse effects include nausea and anorexia Increase endogenous levels of the incretin glucagon-like Bile acid peptide-1 (GLP-1); lower serum glucose levels modestly; sequestrants lower serum LDL-C levels SU, sulfonylurea; GI, gastrointestinal; UTI, urinary tract infection. Hypoglycemia, weight gain Flatulence, diarrhea Gastric distress Gastric distress 84 14

15 Systems Targeted by Available Pharmacologic Therapies Dapagliflozin (DAPA) for Patients Inadequately Controlled with Other Oral Agents Sulfonylureas Meglitinides GLP-1 agonists DPP-4 inhibitors Thiazolidinediones Amylin analogs Metformin GLP-1 agonists DPP-4 inhibitors Bile acid sequestrants Alpha-glucosidase inhibitors GLP-1 agonists Thiazolidinediones SGLT2 inhibitors Thiazolidinediones Patient Population Treatment Groups Duration Receiving metformin years A1c 7.% 1% N=546 DAPA 2.5, 5, or 1 mg daily (qd) Receiving glimepiride >18 years DAPA - 2.5, 5 or 1 mg qd A1c 7%-1% N=597 Receiving pioglitazone >18 years A1c 7.%-1.5% N=48 Receiving sitagliptin + metformin >18 years N=432 DAPA - 5 or 1 mg qd DAPA - 1 mg qd 24 and 12 weeks 24 weeks 24 and 48 weeks 24 weeks DeFronzo RA. Diabetes. 29;58: Bailey CJ, et al. Lancet. 21;375: Bailey CJ, et al. BMC Med. 213;11:43. Jabbour SA, et al. Diabetes Care. 214;37: Rosenstock J, et al. Diabetes Care. 212;35: Strojek K, et al. Diabetes Obes Metab. 211;13: DAPA as Add-on Therapy Reduces Body Weight DAPA Added to Metformin Results in Sustained Weight Reduction at 12 Weeks y Weight at s (%) Change in Body 24 Weeks ADD ON Add-on WITH ADD ON Add-on WITH ADD ON Add-on WITH ADD ON Add-on WITH 1 with MET MET 1 2 with GLIM GLIM 2 3 with PIO PIO 3 4 with SITA SITA DAPA 5 mg DAPA 1 mg 2.14 ght (kg) Baseline Body Weig Change From Week 24 Week 5 Week Time (weeks) Change From Baseline at Week , PBO 1.1, P<.1 DAPA 2.5 mg 1.7, P<.1 DAPA 5 mg 1.74, P<.1 DAPA 1 mg 1. Ferrannini E, et al. Diabetes Care. 21;33: Jabbour SA, et al. Diabetes Care. 214;37: Rosenstock J, et al. Diabetes Care. 212;35: Strojek K, et al. Diabetes Obes Metab. 211;13: Bailey CJ, et al. BMC Med. 213;11: The ABCD & E s of Diabetes Management Complications Duration of disease Expense Body weight Age Optimal T2DM Management Education Etiology Pozzilli P, et al. Diabetes Metab Res Rev. 21;26: