The Role of SGLT-2 Inhibitors in the Management of Patients with Type 2 Diabetes Lawrence Blonde, MD Director, Ochsner Diabetes Clinical Research Unit, Department of Endocrinology, Diabetes, and Metabolic Diseases Ochsner Medical Center, New Orleans, LA

Disclosures: Lawrence Blonde, MD Clinical research: Boehringer Ingelheim , Eli Lilly, Johnson & Johnson, Novo Nordisk, Roche, Sanofi-aventis Advisor or consultant: Amylin, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Halozyme Therapeutics, Johnson & Johnson, MannKind Corporation, Merck, Novo Nordisk, Orexigen Therapeutics, Roche, Sanofi-aventis, Santarus, VeroScience Speaker/speakers bureau: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Merck, Novo Nordisk, Santarus, VeroScience

The Role of SGLT-2 Inhibitors in the Management of Patients with Type 2 Diabetes This CME activity is supported by an educational grant from:

The Role of SGLT-2 Inhibitors in the Management of Patients with Type 2 Diabetes Please complete the questionnaire/evaluation form located in your program books.

Case Presentation 48-year-old African American man with 12 month history of type 2 diabetes Hypertension for past 6 years treated with lisinopril 10 mg daily Most recent blood pressure was 138/84 mm Hg Increased LDL-C treated with simvastatin 40 mg qd; Most recent LDL-C 98 mg/dL Diabetes treated with lifestyle intervention (increased physical activity, medical nutritional therapy) and metformin 1000 mg bid Weight 240 pounds, height 6’ (BMI = 32.5) A1C = 7.5 %

Natural History of T2D and β-cell Function Bergenstal R, et al. Endocrinology. Philadelphia, PA: WB Saunders Co;2001:821-835.

Ominous Octet DeFronzo RA. Diabetes. 2009;58:773-795.

Survival as a Function of A1C in Patients Type 2 Diabetes: A Retrospective Cohort Study* Oral Agents Insulin +/- Oral Agents Currie CJ, et al. Lancet. 2010;6(375):481-9. *28,000 patients 50 years and older

ABCs of Type 2 Diabetes: AACE/ACE 2011 and ADA 2011 Target Treatment Goals AACE/ACE 2011 ADA 2011 A1C ≤ 6.5% < 7.0% Blood pressure <130/80 mm Hg Cholesterol (lipids) LDL-C < 100 mg/dL (< 70 mg/dL for patients with diabetes and coronary artery disease) HDL-C > 40 mg/dL in men; > 50 mg/dL in women Triglycerides <150 mg/dL HDL-C > 40 mg/dL in men; > 50 mg/dL in women; Triglycerides < 150 mg/dL *In individuals with overt cardiovascluar disease, a lower LDL-cholesterol goal of <70 mg/dL (1.8 mmol/L), using high-dose of a statin, is an option. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13(suppl 1):1-68. "Standards of Medical Care in Diabetes—2011." Diabetes Care 34(Supplement 1): S11-S61. Handelsman Y, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for Developing a Diabetes Mellitus Comprehensive Care Plan. Endocr Pract. 2011;17(Suppl 2):1-53. Standards of Medical Care in Diabetes—2011. Diabetes Care. 34(Supplement 1): S11-S61.

Target Treatment Goals Glycemic Control Recommendations for Type 2 Diabetes: AACE/ACE 2011 and ADA 2011 Target Treatment Goals AACE/ACE 2011 ADA 2011 A1C ≤ 6.5% < 7.0% Fasting glucose Fasting plasma glucose: < 110 mg/dL Preprandial capillary plasma glucose: 70 – 130 mg/dL Postprandial glucose 2-hr postprandial glucose: < 140 mg/dL Peak postprandial capillary plasma glucose: < 180 mg/dL *In individuals with overt cardiovascluar disease, a lower LDL-cholesterol goal of <70 mg/dL (1.8 mmol/L), using high-dose of a statin, is an option. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13(suppl 1):1-68. "Standards of Medical Care in Diabetes—2011." Diabetes Care 34(Supplement 1): S11-S61. Handelsman Y, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for Developing a Diabetes Mellitus Comprehensive Care Plan. Endocr Pract. 2011;17(Suppl 2):1-53. Standards of Medical Care in Diabetes—2011. Diabetes Care. 34(Supplement 1): S11-S61.

ADA/AHA/ACC Consensus Recommendations From ACCORD, ADVANCE, & VA Diabetes Trials A1C goal for non-pregnant adults in general = < 7.0% Lowering A1C to ≈7.0% has been shown to reduce microvascular and neuropathic complications For selected individual patients, lower A1C goals may be recommended if goal can be achieved without significant hypoglycemia or other adverse events, eg, patients with Short duration of diabetes Long life expectancy No significant cardiovascular disease For some patients, less stringent A1C goals may be appropriate, eg, patients with History of severe hypoglycemia Limited life expectancy Advanced microvascular or macrovascular complications Extensive co-morbid conditions Long-standing diabetes where goals have not been achieved despite optimal Rx Skyler J, et al. Diabetes Care. 2009;32:187–192.

Challenges in Type 2 Diabetes Large number of patients Diabetes affects 25.8 million people (8.3 % of the US population) DIAGNOSED- 18.8 million people UNDIAGNOSED- 7.0 million people PREDIABETES – 79 million people Progressive worsening of insulin secretory deficit requiring increased number of antihyperglycemic medications over time Risk for hypoglycemia with some therapies Risk for weight gain with some therapies Difficulty controlling postprandial glucose and glucose fluctuations Preventing and managing complications and co-morbidities Difficulty attaining and sustaining optimal long-term glycemic control CDC 2010. National Diabetes Fact Sheet. US Department of Health and Human Services. Cefalu, WT. Am J Med. 2012;343(1):21-26.

This is the new landing page of Diabetes HealthSense on the NDEP website. When you arrive at Diabetes HealthSense, you’ll be directed to a series of options on the left-hand side of the page. The user can select from these options to view and explore the resources within HealthSense that match the criteria you’ve specified. The resources available include more than 140 tools and programs that have been reviewed by a team of behavior change experts who determined the resources’ potential effectiveness and whether or not they should be included in HealthSense. NDEP’s new video series of real people with diabetes talking about how they manage their diabetes, the struggles they’ve faced, and how they’ve overcome them are available on the Diabetes HealthSense landing page. I will be sharing clips from these later in the presentation. Below the video player is a list of selected resources for patients that address coping with stress and emotions, healthy eating, being active, and managing your weight. For patients who need help getting started or who are feeling overwhelmed, this is a good place to get started. http://ndep.nih.gov/resources/diabetes-healthsense/

ADA/EASD Writing Goup Consensus Algorithm *Validation based on clinical trials and clinical judgment †Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide Nathan DM, et al. Diabetes Care. 2009:32:193-203.

AACE/ACE Diabetes Algorithm for Glycemic Control American Association of Clinical Endocrinologists. AACE/ACE Diabetes Algorithm for Glycemic Control. Available at https://www.aace.com/publications. Accessed January 2012.

Summary of Key Benefits and Risks of Medications Metformin DPP-4 Inhibitor GLP-1 Agonist Sulfonylurea Glinide TZD Colesevelam AGI Insulin Pramlintide Benefits PPG - lowering Mild Moderate Moderate to Marked FPG - lowering Neutral Nonalcoholic fatty liver disease (NAFLD) Risks Hypoglycemia Moderate to Severe GI Symptoms Risk of use with renal insufficiency Severe Reduce Dosage Contraindicated if liver failure or predisposition to lactic acidosis Heart failure/Edema Contra-indicted in CHF Mild/ Moderate Unless with TZD Contra-indicted in class 1, 4 CHF Weight Gain Benefit Mild to Moderate Fractures Drug-Drug Interactions American Association of Clinical Endocrinologists. AACE/ACE Diabetes Algorithm for Glycemic Control. Available at https://www.aace.com/publications. Accessed January 2012.

Unmet Needs With Conventional Antihyperglycemic Therapies Many therapies are associated with weight gain Insulin and non incretin oral insulin secretagogue therapies are associated with significant risk for hypoglycemia Other AEs with some therapies include GI side effects and edema Many therapies fail to adequately control postprandial hyperglycemia Therapies often fail to maintain long-term glycemic control Blonde L. Am J Manag Care. 2007;13:S36-S40. Blonde L, et al. J Manag Care Pharm. 2006;12(suppl):S2-S12. Blonde L, Rosenstock J, Triplitt C. What are incretins, and how will they influence the management of type 2 diabetes? J Manag Care Pharm. 2006;12(suppl):S2-S12. Blonde L. State of diabetes care in the United States. Am J Manag Care. 2007;13:S36-S40. 17

Unmet Needs Type 2 DM Control is Not Durable 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (months) Bloomgarden, ZT. Diabtes Care. 2007;30(1):174-180.

New Classes Presently in Development Long-acting GLP-1 receptor agonists Ranolazine Dual & Pan PPAR agonists 11 Hydroxysteroid Dehydrogenase (HSD)- 1 inhibitors Fructose 1,6-bisphosphatase inhibitors Glucokinase activators G protein-coupled Receptor (GPR)- 40 & -119 agonists Protein Tyrosine Phosphatase (PTB)- 1b inhibitors Camitine- Palmitoyltransferase (CPT)- 1 inhibitors Acetyl COA Carboxylase (ACC)- 1 & -2 inhibitors Glucagon receptor antagonists Salicylate derivatives Immunomodulatory drugs Sodium- Glucose Cotransporter (SGLT) {-1} & -2 inhibitors

The Kidneys Play an Important Role in Glucose Control Normal Renal Glucose Physiology 180 g of glucose is filtered each day Virtually all glucose reabsorbed in the proximal tubules & reenters the circulation SGLT2 reabsorbs about 90% of the glucose SGLT1 reabsorbs about 10% of the glucose Virtually no glucose excreted in urine Mather, A & Pollock, C. Kidney International. 2011;79:S1-S6.

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

Targeting the Kidney Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.

Renal Glucose Transport Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9:551-559.

Altered Renal Glucose Control in Diabetes Gluconeogenesis is increased in postprandial and postabsorptive states in patients with Type 2 DM Renal contribution to hyperglycemia 3-fold increase relative to patients without diabetes Glucose reabsorption Increased SGLT-2 expression and activity in renal epithelial cells from patients with diabetes vs. normoglycemic individuals Marsenic O. Am J Kidney Dis. 2009;53:875-883. Bakris GL, et al. Kidney Int. 2009;75(12):1272-1277. Rahmoune H, et al. Diabetes. 2005;54(12):3427-3434.

Rationale for SGLT2 Inhibitors SGLT2 is a low-affinity, high capacity glucose transporter located in the proximal tubule and is responsible for 90% of glucose reabsorption Mutation in SGLT2 transporter linked to hereditary renal glycosuria, a relatively benign condition in humans Selective SGLT2 inhibitors have a novel & unique mechanism of action reducing blood glucose levels by increasing renal excretion of glucose Decreased glycemia will decrease glucose toxicity leading to further improvements in glucose control Selective SGLT2 inhibition, would also cause urine loss of the calories from glucose, potentially leading to weight loss Brooks AM, Thacker SM. Ann Pharmacother. 2009;42(7):1286-1293.

Effects of SGLT2 Inhibitors Inhibition of renal tubular Na+- glucose cotransporter reversal of hyperglycemia reversal of “glucotoxicity” Insulin sensitivity in muscle GLUT4 translocation Insulin signaling Insulin sensitivity in liver Glucose-6-phosphatase Gluconeogenesis Decreased Cori Cycle PEP carboxykinase Improved beta cell function DeFronzo RA, et al. Diabetes Obes Metab. 2012;14(1):5-14.

SGLT2 Inhibitors in Phase 3 Development Empagliflozin Canagliflozin Dapagliflozin Ipragliflozin

Empagliflozin: Change in A1C Randomized, double-blind, 12 week trial comparing empagliflozin and open-label metformin * * * *P˂.001 vs. placebo †500 mg BID for four weeks, then 1000 mg BID or the maximum tolerate dose Ferrannini E, et al. Abstract 877. EASD 2010.

Empagliflozin: Change in Plasma Glucose in the Fasting State Randomized, double-blind, 12 week trial comparing empagliflozin and open-label metformin * * * *P˂.001 vs. placebo †500 mg BID for four weeks, then 1000 mg BID or the maximum tolerate dose Ferrannini E, et al. Abstract 877. EASD 2010.

Empagliflozin Safety Summary In Phase 2b study Reported adverse events were comparable among treatment groups Most frequently reported AEs Frequent urination, thirst, and nasopharyngitis Urinary tract infection frequency was low (1.2%) and comparable to placebo (1.2%) and metformin (1.2%) Incidence of genital infection was low: mycosis (0.8%) and pruritis (1.2%) with Empagliflozin versus none with metformin or placebo Rates of hypoglycemia were similar between groups Ferrannini E, et al. Abstract 877. EASD 2010.

Metformin + Canagliflozin Dose-Ranging Study Mean Baseline A1C (%) 7.71 8.01 7.81 7.57 7.70 7.71 7.62 * * * * * * Rosenstock J, et al. Abstract 77-OR. ADA 2010. *P˂.001 vs. placebo calculated using LS means

Canagliflozin SGLT2 Inhibition for Type 2 Diabetes: Metformin + Canagliflozin Dose-Ranging Study Mean Baseline Weight (kg) 85.5 87.5 87.7 87.7 87.8 86.3 87 * * * * * * * Rosenstock J, et al. Abstract 77-OR. ADA 2010. *P˂.001 vs. placebo calculated using LS means

Canagliflozin Trials Symptomatic genital infections in 3-8% canagliflozin arms 2% placebo 2% SITA Urinary tract infections in 3-9% canagliflozin arms 6% placebo Hypoglycemia in 0-6% canagliflozin arms 5% SITA Rosenstock J, et al. Abstract 77-OR. ADA 2010.

Changes from Baseline in A1C in Phase 3 Dapagliflozin Studies Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224; Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233.

Changes from Baseline in Fasting Plasma Glucose in Phase 3 Dapagliflozin Studies 5 -5 mg/dL -10 -15 -20 -25 -30 Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224; Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233.

Changes from Baseline in Body Weight in Phase 3 Dapagliflozin Studies Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224; Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233.

Monotherapy Study: Summary and Conclusion In treatment-naïve patient with newly-diagnosed Type 2 DM, dapagliflozin monotherapy resulted in Clinically meaningful decreased in A1C and fasting plasma glucose with a near absence of hypoglycemia Favorable effects on weight and blood pressure In the exploratory evening dose cohort, changes from baseline in A1C, fasting plasma glucose, and body weight at week 24 were similar to those seen in the main patient cohort In the high A1C (QAM) exploratory cohort, dapagliflozin elicited a considerable improvement in glycemia Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224.

Monotherapy Study: Summary and Conclusion Increased incidence of urinary tract and genital infections with dapagliflozin treatment: Events suggestive of urinary tract infection were 4%, 4.6%, 12.5%, and 5.7% for placebo, DAPA 2.5mg, 5mg, and 10mg groups, respectively Events suggestive of genital infections were 1.3%, 7.7%, 7.8%, and 12.9% for placebo, DAPA 2.5mg, 5mg, and 10mg groups, respectively Hypoglycemic events occurred in 2.7%, 1.5%, 0%, and 2.9% in patients in placebo, DAPA 2.5mg, 5mg, and 10mg groups, respectively Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224.

Dapagliflozin as Add-on Therapy: Summary and Conclusions Add-on to metformin in patients inadequately controlled with metformin alone Favorable safety parameters and tolerability Improved glycemic control Lowers weight Not associated with risk for hypoglycemia Adverse events occurred in similar proportions Events suggestive of urinary tract infection were 8%, 4%, 7%, and 8% for placebo, DAPA 2.5mg, 5mg, and 10mg groups, respectively Events suggestive of genital infection were 5%, 8%, 13%, and 9% for placebo, DAPA 2.5mg, 5mg, and 10 mg groups respectively Hypoglycemic events occurred in 3%, 2%, 4%, and 4% of patients in placebo, DAPA 2.5mg, 5mg, and 10 mg groups respectively Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233.

Dapagliflozin as Add-on Therapy: Summary and Conclusions Add-on to glimepiride in patients poorly controlled sulfonylurea therapy Significantly improved mean A1C Reduced weight Well-tolerated Adverse events were similar across all treatment groups Events suggestive of urinary tract infection were 6.2%, 3.9%, 6.9%, and 5.3% for placebo, DAPA 2.5mg, 5mg, and 10mg groups, respectively Events suggestive of genital infection were 0.7%, 3.9%, 6.2%, and 6.6% for placebo, DAPA 2.5mg, 5mg, and 10 mg groups respectively Hypoglycemic events occurred in 4.8%, 7.1%, 6.9%, and 7.9% in patients for placebo, DAPA 2.5mg, 5mg, and 10 mg groups respectively Strojek K, et al. Abstract 870. EASD 2010

Dapagliflozin as Add-on Therapy: Summary and Conclusions Add-on to insulin in patients poorly controlled with insulin Sustained effectiveness and stable tolerability Less likely to D.C or require insulin up-titration due to poor glycemic control versus placebo Increased frequency of weight loss and reduced frequency of peripheral edema over time Adverse events and discontinuations were balanced across groups Actively solicited signs and symptoms suggestive of urinary tract (UTI) and genital infections (GI) were higher with dapagliflozin vs. placebo Events suggestive of urinary tract infection occurred in 8.4% DAPA vs 4.1% placebo Events suggestive of genital infection occurred in 7.2% DAPA vs 2.0% placebo Wilding JPH, et al. Abstract 78-OR. ADA 2010

Dapagliflozin* vs. Glipizide as Add-on Therapy to Metformin: 2 Years Treatment Change in A1c ≥ 1 Hypoglycemic Episode Change in Total Body Weight Dapagliflozin + Metformin (n=315) -0.32% (-0.42, -0.21) 4.2% -3.70 kg (-4.16, -3.24) Glipizide + metformin (n=309) -0.14% (-0.25, -0.03) 45.8% + 1.36 (0.88, 1.84) Urinary tract infection: 13.5% for dapagliflozin; 9.1% for glipizide Genital infection: 14.8% for dapagliflozin ; 2.9% for glipizide Nauck MA, et al. Diabetes Care. 2011;34:2015-2022. *The FDA has not approved this medication for use.

Dapagliflozin as Add-on to Metformin: 2 Year Extension Study Δ from BL (SE) Placebo DAPA 2.5mg DAPA 5mg DAPA 10mg A1c, % 0.2 (0.11) -0.48 (-.1) -0.58 (0.1) -0.78 (0.09) FPG, mg/dl -10.4 (3.6) -19.3 (3.2) -26.5 (2.8) -24.5 (2.7) Body weight, kg -0.7 (0.5) -2.2 (0.5) -3.4 (0.4) -2.8 (0.4) % Pts with ≥ 1 hypoglycemic event 5.8 3.6 5.1 5.2 Events suggestive of urinary tract infection Dapagliflozin 2.5 mg: 8.0%, 5 mg: 8.8%, 10 mg: 13.3% Placebo: 8.0% Dapagliflozin 2.5 mg: 11.7%, 5 mg: 14.6%, 10 mg: 12.6% Placebo: 5.1% Events primarily mild or moderate in intensity and responded to standard treatment Bailey CJ et al. Abstract 988-P. ADA 2011.

Safety: Malignancies Bladder cancer incidence rate: 0.16% patients (n=5,478) treated with dapagliflozin vs 0.03% patients (n-3,156) in placebo group (p = 0.15) Breast cancer incidence rate: 0.4% patients (n=2,223) treated with dapagliflozin vs 0.09% patients (n=1,053) in placebo group (p = 0.27) Jones D. Nat Rev Drug Discov. 2011;10(9):645-646.

Ipragliflozin: Phase 2 Studies Phase 2, Randomized, Placebo-controlled Study (28 days) Treatment (n=61) Change in A1c FPG(mmol/L) Change in Total Body Weight AE’s Ipragliflozin 50mg QD (n=12) -0.73% (p<0.003) -3.35 (p<0.001) Ipragliflozin (n=48) -3.2 kg to -4.2kg vs. Placebo (n=12) 1.8kg Constipation, nausea, xerosis, and headache Ipragliflozin 100mg QD (n=12) -0.61% (p<0.015) -2.72 (p<0.004) Ipragliflozin 200mg QD (n=12) -0.84% (p<0.001 -3.92 (p<0.001) Ipragliflozin 300mg QD (n=12) -3.61 (p<0.001) Ipragliflozin as add-on Therapy to Metformin Phase 2, Double-blind, Placebo-controlled, Dose Finding Study (12 weeks) Treatment (n=272) (95% CI) FPG (mg/dL) Ipragliflozin 12.5mg (n=69) -0.53% (-0.71; -0.36) -8.5 (-16.1; -0.9) -0.9 ± 2.3 Urinary tract infections and genital tract infections in ipragliflozin groups were no different from placebo group. Hypoglycemia was similar between placebo and treatment groups. Ipragliflozin 50mg (n=66) -0.66% (-0.84, -0.47) -14.3 (-22.0; -6.6) -2.1 ± 2.0 Ipragliflozin 150mg (n=66) -0.72% (-0.90; -0.54) -24.3 (-32.1; -16.5) -2.1 ± 2.4 Ipragliflozin 300mg (n=71) -0.79% (-0.97; -0.62) -27.8 (35.3; -20.3) -2.3 ± 2.5 Schwartz S, et al. Safety, Pharmacokinetic, And Pharmacodynamic Profiles Of Ipragliflozin (ASP1941), A Novel And Selective Inhibitor Of Sodium-dependent Glucose Co-transporter 2, In Patients With Type 2 Diabetes Mellitus. Diabetes Technology & Therapeutics. 2011; 13(12): 1219-1227. Wilding J, et al. Efficacy and safety of ipragliflozin in type 2 diabetes patients inadequately controlled on metformin: a dose-finding study. Abst D-0741. IDF 2011.

BRIGHTEN Trial: Ipragliflozin Phase 3, Double-blind, Placebo-controlled Study-16 weeks (n=129) Ipragliflozin treatment group 50mg QD (n=62) Ipragliflozin achieved a mean decrease of 1.23% in A1c compared with placebo (p<0.001) FPG was reduced by 45.8mg/dL compared with placebo (p<0.001) Total body weight was reduced by 1.47kg compared with placebo (p<0.001) Similar adverse events occurring in about half the patients in both cohorts. 1 case if hypoglycemia and 2 cases of genital infections in ipragliflozin group Kashiwagi, A. et al. Ipragliflozin improved glycemic control with additional benefits of reductions of body weight and blood pressure in Japanese patients with type 2 diabetes mellitus: BRIGHTEN Study. Abst 149. EASD 2011

Case Presentation 1 48-year-old African American man with 12 month history of type 2 diabetes Hypertension for past 6 years treated with Lisinopril 10 mg daily; most recent blood pressure was 138/84 mm Hg Increased LDL-C treated with simvastatin 40 mg qd; most recent LDL-C 98 mg/dL Diabetes treated with metformin 1000 mg bid and lifestyle intervention (increased physical activity, medical nutritional therapy) Weight 240 pounds, height 6’ (BMI = 32.5) A1C = 7.5 %

Case Presentation 2 64-year-old Latina with 8 year history of type 2 diabetes Hypertension for past 6 years treated with Olmesartan 10 mg and HCTZ 12 mg daily most recent blood pressure was 142/86 mm Hg Increased LDL-C treated with simvastatin 40 mg qd; most recent LDL-C 98 mg/dL Diabetes treated with metformin XR 1500 mg QD; insulin glargine 30 U QHS and lifestyle intervention (increased physical activity, medical nutritional therapy) Weight 160 pounds, height 5’ 2” (BMI = 29.3) A1C = 7.5 %; FPG

Perspectives on SGLT2 Inhibition Potential advantages Insulin Independence Weight loss (75g urine glucose = 300kcal/day) Low risk of hypoglycemia Blood pressure lowering? Concerns Polyuria Electrolyte disturbances Bacterial urinary tract infections Fungal genital infections Malignancies