‘Emerging Insulin-Independent Approaches for the Management of Type 2 Diabetes’

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. Introduction • 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.

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

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

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

6. Diagnosis Standard Therapies Metformin Depends on a sufficient residual insulin secretion Lifestyle changes + Metformin for everybody Metformin (if tolerated) is widely accepted as the 1st-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 Courtesy of Bernard Charbonnel, MD

7. Standard Therapies Sulfonylureas and Glinides • 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 The generally recommended 2nd line drug (for cost-effectiveness reasons) Courtesy of Bernard Charbonnel, MD

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

9. Incretin-based Therapies • DPP-4 inhibitors • Sitagliptin • Vildagliptin • Saxagliptin • Linagliptin • In development • Alogliptin* • GLP-1 receptor agonists • Exenatide • Liraglutide * Licensed in Japan 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. Kidney and Glucose Homeostasis • The Kidney • Produces glucose • Uses glucose • Filters glucose • Reabsorbs glucose Courtesy of Clifford Bailey, PhD

12. Location of Sodium Glucose Transporters in the Kidney S1 & S2 segment SGLT2 (> 90% glucose reabsorbed) S3 segment SGLT1 (remaining 10% glucose reabsorbed) Glucose Glucose Glucose Glucose GLUT2 Glucose SGLT2 Glucose Na+ GLUT1 Glucose Na+ Na+ Na+ SGLT1 K+ 2Na+ Na+ K+ Lumen Epithelium lining proximal tubule K+ K+ Blood S1 & S2 segment proximal renal tubule Blood Lumen Epithelium lining proximal tubule S3 segment proximal renal tubule Adapted from Bailey CJ, Day C. Br J Diabetes Vasc Dis. 2010;10:193-199.

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

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

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

16. Dapagliflozin – Sustained Effects on HbA1c and Body Weight Subjects with T2D with Inadequate Glycaemic Control on Metformin HbA1c (%) Body weight (kg) Mean change from baseline Mean change from baseline N = 75 N = 65 N = 64 N = 70 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? Type 2 Diabetes: the Usual Step-by-step Approach Yes: on the top of insulin when large doses of insulin fail Injections Step 3 Yes: in triple oral therapy (when you want to avoid injections) Lifestyle changes Two oral agents Yes: in dual therapy in some obese or hypertensive patients, mainly when DPP4-inhibitors fail Step 2 One oral agent Step 1 No in monotherapy Diabetes progression Courtesy of Bernard Charbonnel, MD

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

22. When Basal Insulin Is Not Enough Start with basal insulin 1st step for everybody Titration If HbA1c 7.5%*, despite titration *or an individualized target Add SGLT2-inhibitor Intensify insulin The usual option A very promising option Intensification of insulin therapy usually consists of additional prandial injections • Weight loss • A reduced risk of hypos • Reduced doses of insulin • Weight gain • Hypos • Large doses of insulin often needed Courtesy of Bernard Charbonnel, MD

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. General Take-Home Messages • 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