1. Page 1: Baker IDI Update on therapies for type 2 diabetes

2. Page 2: Baker IDI Treatment algorithms for type 2 diabetes

3. Page 3: Baker IDI BasalPremixed Basal Bolus insulin Sulphonylurea AcarboseDPP-4 inhibitor #Glitazone*Insulin Lifestyle Modification diet modification weight control physical activity Metformin Management Algorithm for Blood Glucose Control in Type 2 Diabetes in Australia The algorithm includes only therapeutic agents available through the PBS. If HbA1c >7% consider intensifying treatment provided hypoglycaemia is not a problem. # Authorised only as dual therapy with metformin or sulphonylurea where combination metformin and sulphonylurea is contraindicated or not tolerated. * Rosiglitazone is not authorised for triple therapy or for use with insulin (from February 1, 2009) but is approved only as dual therapy with metformin or sulphonylurea where combination metformin and sulphonylurea is contraindicated or not tolerated.

4. Targets for type 2 diabetes in Australia Glycaemic control –HbA1c <7.0% Blood pressure* –<130/80 mmHg –<125/75 mmHg in the presence of proteinuria Lipids* –LDL >2.5 mmol/l – consider statin –TG >2.0 mmol/l – consider fibrate Aspirin for those with prior CVD, and those with other CVD risk factors * NHMRC 2005

5. ADA/EASD algorithm 2009 a Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide. b Insufficient clinical use to be confident regarding safety. Nathan et al. Diabetes Care 2009 32:193-203

6. Stepwise Use of Medication Monotherapy Combination OHA Insulin + OHA HbA1c > 7.0% Metformin Sulphonylurea Metformin Sulphonylurea 2 or more of: Metformin Sulphonylurea Acarbose Glitazone Glinide GLP1 DPPIV 2 or more of: Metformin Sulphonylurea Acarbose Glitazone Glinide GLP1 DPPIV Metformin Sulphonylurea Glitazone Metformin Sulphonylurea Glitazone

7. Thiazoledinediones – Australian PBS restrictions Dual therapy, ie. rosiglitazone or pioglitazone, when SU or metformin contra-indicated or causes adverse event Triple oral therapy NOW pioglitazone only! Can be combined with insulin NOW pioglitazone only! HbA1c must be >7.0% at initiation Precautions: fluid retention, bone loss, (?coronary events with rosigltazone)

8. Page 8: Baker IDI Insulin initiation in type 2 diabetes

9. 2468 Hours after Injection 0.5 2.5 Hours after injection 2468 Insulin Action Regular Insulin (Actrapid,Humulin R) Humalog NovoRapid Apidra Hours after injection 1012 Quick-acting insulins

10. 2468 Hours after Injection 0.5 2.5 Blood Insulin Level 41216 Hours after injection 8 Blood Insulin Level 2024 Protaphane Humulin NPH Lantus Levemir Long-acting insulins

11. Page 11: Baker IDI BasalPremixed Basal Bolus insulin Sulphonylurea AcarboseDPP-4 inhibitor #Glitazone*Insulin Lifestyle Modification diet modification weight control physical activity Metformin Management Algorithm for Blood Glucose Control in Type 2 Diabetes in Australia The algorithm includes only therapeutic agents available through the PBS. If HbA1c >7% consider intensifying treatment provided hypoglycaemia is not a problem. # Authorised only as dual therapy with metformin or sulphonylurea where combination metformin and sulphonylurea is contraindicated or not tolerated. * Rosiglitazone is not authorised for triple therapy or for use with insulin (from February 1, 2009) but is approved only as dual therapy with metformin or sulphonylurea where combination metformin and sulphonylurea is contraindicated or not tolerated.

12. Consensus statement EASD ADA 2008

13. Page 13: Baker IDI Insulin initiation trials

14. Diabetes Care 2003, Riddle et al.

17. Minor hypoglycaemia 43% vs. 16% BiAsp vs. Glargine Diabetes Care 2005, Raskin et al.

21. Page 21: Baker IDI Why new treatments? What’s wrong with the old treatments?

22. Page 22: Baker IDI New treatments - why new treatments? Beta cell preservation –Prevent relentless progression of type 2 diabetes Hypoglycaemia ? harmful CV morbidity and mortality –ACCORD and other CV outcome trials –Glitazone controversies Weight loss as a priority –Recognized as a major factor in morbidity

23. Page 23: Baker IDI Incretins GLP 1 analogues Exenatide Liraglutide Once weekly GLP – 1 analogues DPP 4 inhibitors Sitagliptin

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25. The Incretin Effect Demonstrates the Response to Oral vs IV Glucose Mean ± SE; N = 6; *p .05; 0 1 -0 2 = glucose infusion time. Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63:492-498. Copyright 1986, The Endocrine Society. Venous Plasma Glucose (mmol/L ) Time (min) C-peptide (nmol/L) 11 5.5 0 0101 60120180 0101 60120180 0.0 0.5 1.0 1.5 2.0 Time (min) 0202 0202 Incretin Effect Oral Glucose IV Glucose * * * * * * *

26. The Incretin Effect Is Reduced in Patients With Type 2 Diabetes 0 20 40 60 80 Insulin (mU/L) 0306090120150180 Time (min) * * * * * * * 0 20 40 60 80 0306090120150180 Time (min) * * * *p≤.05 compared with respective value after oral load. Nauck MA, et al. Diabetologia. 1986;29:46-52. Reprinted with permission from Springer-Verlag © 1986. Patients With Type 2 Diabetes Control Subjects Intravenous Glucose Oral Glucose

27. GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins Promotes satiety and reduces appetite Beta cells: Enhances glucose- dependent insulin secretion Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169. Liver: ↓ Glucagon reduces hepatic glucose output Alpha cells: ↓ Postprandial glucagon secretion Stomach: Helps regulate gastric emptying

28. 28 Exenatide (Exendin-4) Synthetic version of salivary protein found in the Gila monster Approximately 50% identity with human GLP-1  Binds to known human GLP-1 receptors on  cells in vitro  Resistant to DPP-4 inactivation Development of Exenatide: An Incretin Mimetic Adapted from Nielsen LL, et al. Regulatory Peptides. 2004;117:77-88. With permission from Elsevier for English use only.; Drucker DJ. Diabetes Care. 2003;26:2929-2940.; Ahrén B. Best Pract Res Clin Endocrinol Metab. 2007;21:517-533. Site of DPP-4 Inactivation H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G P S S G A P P P S – NH 2 H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R – NH 2 Exenatide GLP-1 Human

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31. Page 31: Baker IDI Exenatide once weekly Once weekly vs bd exenatide, 30 week study Patients were drug naive or treated with 1 or more oral glucose- lowering therapies (~15% diet/exercise, ~45% 1 OAD, ~40% 2 OADs). Starting HbA1c 8.3±1.0% HbA1c decreased in both groups, 1.9%±0.08 vs 1.5%± 0.08 (P=0.002) in once weekly vs bd 22 week extension study LAR for all patients after first 30 weeks At 52 weeks decrease HbA1c by 2.0% both groups, 4.1 kg wt loss, 80% patients lost weight BP decreased 4-6 mmHg

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33. DPP 4 inhibitors Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913; Ahrén B. Curr Diab Rep. 2003;2:365–372; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441. Ingestion of food β cells α cells Release of gut hormones — incretins * Pancreas Glucose-dependent  Insulin from β cells (GLP-1 and GIP) Glucose uptake by muscles Glucose dependent  Glucagon from α cells (GLP-1) GI tract Active GLP-1 & GIP DPP-4 enzyme Inactive GIP Inactive GLP-1 *Incretins are also released throughout the day at basal levels. Glucose production by liver Blood glucose in fasting and postprandial states 10

34. Clinical experience with sitagliptin Effective for dual, triple therapy and with insulin Low side effect profile Weight neutral No hypoglycaemia in combination with metformin or glitazone Safe and effective in older patients

35. Januvia -PBS restrictions in Australia Dual therapy for combination with metformin or a sulphonylurea agent HbA1c > 7.0% at initiation Treatment with metformin or sulphonylurea as a second agent is either contraindicated or not tolerated (private script $100 per month)

36. Page 36: Baker IDI Other new agents SGLT 2 inhibitors Glucokinase activators Glucagon receptor antagonists