1. ‘Emerging Insulin-Independent Approaches for the Management of Type 2 Diabetes’ Chair: Clifford J. Bailey, PhD Professor of Clinical Science Head of Diabetes Research Life and Health Sciences Aston University Birmingham, United Kingdom Bernard Charbonnel, MD Professor of Endocrinology and Metabolic Diseases Head of Internal Medicine, Endocrinology and Diabetes University of Nantes Nantes, France Ele Ferrannini, MD Professor of Internal Medicine, Chief, Metabolism Unit National Research Council Institute of Clinical Physiology University of Pisa Pisa, Italy Michael Nauck, MD, PhD Professor of Internal Medicine Head, Specialist Clinic for Diabetes and Metabolic Diseases Diabetes Centre Bad Lauterberg, Germany

2. The role of the kidney in the physiological regulation of glucose homeostasis has come into focus. Latest development efforts for novel antidiabetic therapies have concentrated on insulin-independent mechanisms like the sodium-glucose co-transporter 2 (SGLT2) inhibitors. The emerging profile of the most advanced compounds in this novel class points towards likely clinical benefits but also potential risks and issues to be addressed. We will attempt to formulate where these novel drugs may fit into future treatment algorithms and which patients may benefit the most. Introduction

3. Development and Progression of Type 2 Diabetes: Multiple Intervention Targets Image courtesy of Clifford Bailey, PhD IGT = Impaired Glucose Tolerance Normal Hyperglycaemia Fasting glucose Glucose tolerance Insulin action Insulin secretion Abnormal glucose tolerance β-cell failure Insulin resistance β-cell compensation IGT T2DM Blood glucose Insulin Glucagon

4. Type 2 Diabetes: Current Therapy Options Insulin Resistance β-Cell Dysfunction Carbohydrate Digestion Loss of β-Cell Mass Treatments for Obesity Metformin TZDs Insulin α-glucosidase inhibitors Diet, Exercise Treat lipids + BP Orlistat, Pramlintide Bromocriptine Colesevelam α-Cell Dysfunction Sulphonylureas Meglitinides GLP-1 agonists DPP4 inhibitors Image courtesy of Clifford Bailey, PhD

5. Available Medications Used to Get the HbA1c Target (in 2011) 1.Metformin 2.Sulfonylureas/Glinides 3.TZDs (Pioglitazone) 4.α-glucosidase-inhibitors 5.DPP4-inhibitors 6.GLP1-agonists 7.Insulins 8.Coming-up : SGLT2-inhibitors Courtesy of Bernard Charbonnel, MD injections Oral agents

6. Standard Therapies Metformin Diagnosis Metformin (if tolerated) is widely accepted as the 1 st -line drug for type 2 diabetes An insulin-sensitizer fits with the early physiopathological features of the disease Decreases HbA1c by >1% Absence of weight gain and hypoglycaemia Possible cardiovascular protective effect Possible protective effect against cancer Safe : low level of serious side effects Inexpensive Lifestyle changes + Metformin for everybody Depends on a sufficient residual insulin secretion Courtesy of Bernard Charbonnel, MD

7. Standard Therapies Sulfonylureas and Glinides The generally recommended 2 nd line drug (for cost-effectiveness reasons) Inexpensive Rapid response Poor durability Risk of hypoglycemia Weight gain Perhaps excess risk for cancers No evidence of a CV benefit Depends on a sufficient residual insulin secretion Courtesy of Bernard Charbonnel, MD

8. Standard Therapies TZDs (Pioglitazone) A good 2 nd or 3 rd line option in selected patients with: marked insulin resistance and high cardio-vascular risk, especially: –Post-MI (if no heart failure) –Post-stroke –Chronic kidney disease The most powerful on the long- term : good durability No hypos A likely CV benefit in high CV risk patients But various adverse effects In whom the benefits are likely to exceed the risks Depends on a sufficient residual insulin secretion Courtesy of Bernard Charbonnel, MD

9. DPP-4 inhibitors Sitagliptin Vildagliptin Saxagliptin Linagliptin In development Alogliptin* * Licensed in Japan Incretin-based Therapies GLP-1 receptor agonists Exenatide Liraglutide Courtesy of Clifford Bailey, PhD

10. Glucotoxicity High glucose levels are toxic for two main pathogenetic defects of type 2 diabetes – Beta-cell function – Insulin action in peripheral tissues High chronic hyperglycaemia damages vascular tissues resulting in – Microvascular complications – Macroangiopathy of diabetes

11. The Kidney Produces glucose Uses glucose Filters glucose Reabsorbs glucose Kidney and Glucose Homeostasis Courtesy of Clifford Bailey, PhD

12. S1 & S2 segment SGLT2 (> 90% glucose reabsorbed) S1 & S2 segment proximal renal tubule S3 segment proximal renal tubule S3 segment SGLT1 (remaining 10% glucose reabsorbed) Glucose SGLT2 Glucose Na + K+K+ K+K+ Glucose Epithelium lining proximal tubule Lumen Blood GlucoseGLUT2 Lumen Blood SGLT1 Glucose 2Na + K+K+ K+K+ Na + Glucose Epithelium lining proximal tubule Glucose GLUT1 Location of Sodium Glucose Transporters in the Kidney Adapted from Bailey CJ, Day C. Br J Diabetes Vasc Dis. 2010;10:193-199.

13. Sodium-Glucose Co-transporter-2 Inhibitors Courtesy of Clifford Bailey, PhD. Diet Blood glucose Normally no glucosuria SGLT-1 SGLT-2 - in proximal tubules reabsorbs most of filtered glucose SGLT-1 - also in proximal tubules, normally reabsorbs remaining filtered glucose SGLT2 inhibitors Increase renal glucose elimination Normally all filtered glucose reabsorbed SGLT-2 SGLT-1

14. HbA1c (%) mean change from baseline N = 546 Dapagliflozin Added to Metformin Mean Change in HbA1c (%) and Body Weight (kg) From Bailey et al. Lancet. 2010;375:2223-33. Week 24 (LOCF) change from baseline (n = 137) (n = 135) Weeks Body weight (kg) mean change from baseline Weeks

15. Dapagliflozin Monotherapy & Canagliflozin Add-on to Metformin 12 week  from baseline Body Weight (%) DapagliflozinCanagliflozin From List et al. Diabetes Care. 2009;32:650-657. Rosenstock et al. Diabetes. 2010;59(suppl 1):77-OR Abstract.

16. HbA 1c (%) Mean change from baseline Body weight (kg) Mean change from baseline N = 75N = 65N = 64N = 70 Dapagliflozin – Sustained Effects on HbA 1c and Body Weight Subjects with T2D with Inadequate Glycaemic Control on Metformin Woo et al. Data presented at: World Diabetes Congress; Dubai, UAE; December 4, 2011.

17. Limitations of SGLT2 Inhibitor Therapy Increased risk of genito-urinary infections – Slight excess of UTIs but amenable to treatment, no recurrence – Increase in genital infections, particularly in women or those with history of genital infections Risk of dehydration – Some dehydration in patients with very high glucose levels (  osmotic diuresis) – Very few cases of dehydration reported

18. Additional Benefit - Blood Pressure Reduction Well documented, consistent reduction of systolic blood pressure in clinical trials Probably triggered by osmotic diuresis Clinical value – Reduction in use/dose of anti-hypertensives ? – Cardiovascular risk reduction ?

19. Increased Risk for Cancer ? Bladder Cancer – 9 occurrences of bladder cancer in 5478 dapagliflozin recipients (0.16%) versus 1 in 3156 (0.03%) for control – Of the 10 bladder cancer cases, 6 were associated with haematuria at baseline and 5 of the cases were identified within the first year – Ascertainment bias ? Breast Cancer – 9 breast cancer cases in 2223 (0.4%) dapagliflozin recipients versus 1 in 1053 (0.1%) for control – All breast cancer cases were identified in the first year of treatment No overall imbalance in malignant tumours No carcinogenic or genotoxic activity in preclinical studies

20. SGLT2-inhibitors : For which Patients? At What Stage of the Disease? No in monotherapy Yes: in dual therapy in some obese or hypertensive patients, mainly when DPP4-inhibitors fail Yes: in triple oral therapy (when you want to avoid injections) Type 2 Diabetes: the Usual Step-by-step Approach Lifestyle changes One oral agent Two oral agents Injections Diabetes progression Step 1 Step 2 Step 3 Courtesy of Bernard Charbonnel, MD Yes: on the top of insulin when large doses of insulin fail

21. Type 2 Diabetes Treatment intensification : 3 rd Line When Oral Dual Therapies Are Not Enough HbA1c > 7-7.5 % Metformin + Sulfonylurea/DPP4 Insulin Injections GLP1-agonists Generally recommended Dual oral Courtesy of Clifford Bailey, PhD Especially in obese and/or hypertensive patients, in whom insulin may not be the best option: risk of hypos, need for high doses… An alternative to injections Rather than adding Pioglitazone Metformin + SUs/DPP4 + SGLT2-inhibitor Triple oral therapy

22. 1st step for everybody When Basal Insulin Is Not Enough Start with basal insulin Titration If HbA 1c  7.5%*, despite titration Intensify insulin Add SGLT2- inhibitor *or an individualized target The usual option A very promising option Weight gain Hypos Large doses of insulin often needed Weight loss A reduced risk of hypos Reduced doses of insulin Courtesy of Bernard Charbonnel, MD Intensification of insulin therapy usually consists of additional prandial injections

23. Further Considerations - Diabetic Patient Groups for SGLT2 Inhibitor Treatment Caution in Elderly patients at risk of dehydration Diabetic women with history of infections Compromised renal function – Eg, stage 3 or 4 of chronic kidney disease Potential in type 1 diabetes ? Reduce dose of insulin Reduce frequency of hypoglycaemia

24. Type 2 diabetes is progressive and difficult to control Tight glycaemic control is essential to reduce the burden of complications Insulin-dependent therapies address beta-cell failure and insulin resistance, but are limited by disease progression Insulin-independent therapies - such as SGLT2 inhibition - enable glucose-lowering and weight loss without increased propensity for hypoglycaemia General Take-Home Messages