Coventry Diabetes PLT Meeting

1. Coventry Diabetes PLT Meeting Jim McMorran Diabetes GPSI Coventry PCT

2. What’s New • Inhaled Insulin. • DPP IV inhibitors/GLP1 analogues. • Rimonabant (Acomplia). • Insulin pumps. • Islet cell transplants. • Non-invasive monitoring.

3. Inhaled Insulin • Huge potential advantages • avoid injections • rapid absorption • systemic distribution • Potential problems with getting insulin into lungs and variable day-day absorption • Technology has solved many of these problems

5. Exubera – Advantages • Not an injection! • Rapid-acting (comparable to humalog or novorapid). • Initial studies suggest that it is at least, if not more “predictable” than existing short-acting analogues. • Equivalent HBA1c reductions to sc insulin in both Type 1 and Type 2 DM (and equivalent or slightly less hypos) • High patient satisfaction in studies.

6. Issues with inhaled insulin • Limited experience • Not licensed in children • ? Needle free • Larger doses required • Concerns when upper airways infection • Not approved by NICE • ?Effect with in lungs • Need 6-12 monthly spirometry • Cannot use in smokers/asthma/COPD • Reduction in FEV1 and DLCO (lung diffusing capacity) • Insulin is potent growth factor

7. INCRETINS AND THEIR ROLE AS A TREATMENT TARGET IN TYPE 2 DIABETES

8. What is GLP-1? • A 31 amino acid peptide • Cleaved from proglucagon in L-cells in the GI-tract (and neurons inhindbrain/hypothalamus) • Secreted in response to meal ingestion (direct luminal and indirect neuronal stimulation) • Member of incretin family (GIP, GLP-1 and others) 8

9. The incretin effect Isoglycaemic glucose infusion Oral glucose load (50 g/400 ml) Plasma glucose Insulin response 80 15 270 60 10 180 Incretineffect IR-insulin (mU/l) 40 Plasma glucose (mmol/l) Plasma glucose (mg/dl) * 5 90 * * * * 20 * * 0 0 0 –10 –5 60 120 180 –10 –5 60 120 180 Time (min) Time (min) • Insulin response is greater following oral glucose than i.v glucose, despite similar plasma glucose concentration Nauck et al. Diabetologia 1986;29:46–52, *p ≤ 0.05. n=8 healthy volunteers 9

10. GLP-1 has multiple desirable effects • Stimulates insulin secretion, glucose-dependently • Stimulates -cell function • Increases -cell mass in animal models • Decreases glucagon secretion, glucose-dependently • Delays gastric emptying, decreases food intake and body weight • Has beneficial cardiovascular effects 10

11. GLP-1 stimulates b-cell function insulin release insulin biosynthesis glucose sensitivity b-cell b-cell GLUT2 glucokinase Improved function Holz et al. Nature 1993;361:362–365. Drucker et al. Proc Natl Acad Sci USA 1987;84:3434–3438. Bulotta et al. J Mol Endocrinol 2002;29:347–360. 11

12. b-cell proliferation GLP-1 stimulates b-cell regeneration and mass in animal models Key Red arrows indicate effect of GLP-1 b-cell neogenesis b-cell b-cell apoptosis b-cell hypertrophy b-cellregeneration and increased mass Farilla et al. Endocrinology 2003;144:5149–5158. Bulotta et al. J Mol Endocrinol 2002;29:347–360.

13. Hepatic glucose output GLP-1: functional pancreatic effects Glucose dependent insulin secretion Somatostatin secretion Glucagon secretion Pancreatic cells: -cell -cell -cell Ørskov et al. Endocrinology 1988;123:2009–2013. Drucker et al. Proc Natl Acad Sci USA 1987;84:3434–3438. 13

14. GLP-1: effects on the gastrointestinal and central nervous systems GLP-1 Learning and memory (animal models) Gastric emptying Satiety Acid secretion Food intake Kieffer, Habener. Endocr Rev 1999;20:876–913. Flint et al. J Clin Invest 1998;101:515–520. Wettergren et al. Dig Dis Sci 1993;38:665–673. During et al. Nat Med 2003;9:1173–1179. 14

15. Blood glucose lowering is safe and effective with GLP-1 Patients reaching a stable glucose level (fluctuations ≤ 0.2 mmol/l) • Protocol • 50 type 2 patients • OAD discontinued for 3 days • Overnight fast • 4-hour GLP-1 i.v. infusion • Interpretations • No non-responders • Strict glucose-dependency • Effective over a broad range 25 450 20 360 270 15 Plasma glucose (mg/dl) Plasma glucose (mmol/l) 180 10 5 90 Hypoglycaemia threshold 2.8 mmol/l* 0 0 Fasting plasma glucose Nadir plasma glucose Adapted from: Toft-Nielsen et al. J Clin Endocrinol Metab 2001;86:3853–3860. Open circles are mean ± 1 SD. *50 mg/dl 15

16. GLP-1 controls blood glucose and weight in type 2 diabetes Continuous subcutaneous infusion of GLP-1 or saline for 6 weeks 8-hour BG profiles (GLP-1 patients, n=10) Weight Saline (n=9) GLP-1 (n=10) Week 0 0.0 25 450 Week 1 GLP-1 –0.5 Week 6 GLP-1 360 20 –1.0 270 15 –1.5 Plasma glucose (mmol/l) Weight change (kg) Plasma glucose (mg/dl) –2.0 10 180 –2.5 90 5 –3.0 0 0 p = 0.013 absolute values 0 1 2 3 4 5 6 7 8 p = 0.16 change in weight Hours post-injection Adapted from: Zander et al. Lancet 2002;359:824–830. Data are mean ± SE. 16

17. Native GLP-1 is rapidly degraded by DPP-IV Human ileum, GLP-1 producing L-cells Capillaries, Di-Peptidyl Peptidase-IV (DPP-IV) Double immunohistochemical staining for DPP-IV (red) and GLP-1 (green) in the human ileum Adapted from: Hansen et al. Endocrinology 1999;140:5356–5363. 17

18. DPP-IV His Ala Glu Gly Thr Phe Thr Ser Asp Val 7 9 Ser Ser Lys Ala Ala Gln Gly Glu Leu Tyr Glu 37 Phe Lys Ile Ala Trp Val Gly Arg Leu Gly Native GLP-1 has limited clinical value because of its short half-life i.v. bolus GLP-1 (15 nmol/l) Healthy individuals (n=6) 1000 Type 2 diabetes (n=6) 500 Intact GLP-1 (pmol/l) 0 –5 5 15 25 35 45 Time (min) Enzymatic cleavage High clearance (4–9 l/min) t½ = 1.5–2.1 minutes (i.v. bolus 2.5–25.0 nmol/l) Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88:220–224. 18

19. GLP-1 analogues • Exenetide • originally isolated from saliva of gila monster • 53% homology with natural GLP-1 • subcutaneous bd injection • 5mg bd or 10mg bd • side effects -> principally gastrointestinal • 50% incidence of nausea on 10mg bd • antibodies to exenetide in 50%

20. Gila Monster • Exenatide • Synthetic version of salivary protein found in the Gila monster

21. GLP-1 analogues • Liraglutide • Maximal action at 9-12 h; half-life 11-15 hours • once daily subcutaneous injection • 97% homology with natural GLP-1 • Mild, transient GI-symptoms • no liraglutide antibodies

22. Exenatide Reduced HbA1C and Weight: Large Phase 3 Clinical Studies – Combined Placebo BID 5 µg Exenatide BID10 µg Exenatide BID 0.5 -0.5 0.1 0 0 -0.5  Weight (kg) -0.5  HbA1C (%) -0.7 -1 -0.6 * -1 -0.9 * -1.5 -1.4 * -1.5 -2 -1.9 * ITT 30-wk data; N = 1446; Mean (SE); *P<0.005; Weight was a secondary endpointData on file, Amylin Pharmaceuticals, Inc.

23. Metformin (n=36) Metformin + glimepiride (n=36) Liraglutide (n=36) Liraglutide + metformin (n=36) Effect on weight (liraglutide in combination with metformin p = 0.29 2 p = 0.40 2 p < 0.0001 1 1 0 0 Mean change in body weight from baseline (%) Mean change in body weight from baseline (%) -1 -1 -2 -2 -3 -3 p < 0.0001 5 0 1 2 3 4 p = 0.83 Time (weeks) Study 1499 Adapted from: Nauck et al. Diabetes 2004;52(suppl 2):A83. n=number randomised 23

24. Liraglutide and hypoglycaemic risk Number of patients reporting events in three trials • No major hypoglycaemic events were reported 1. Madsbad et al. Diabetes Care 2004;27:1335-42 (12 weeks). n randomised=193.2. Saad et al. Diabetologia 2002;45 (Suppl 2)A44. Feinglos et al. Submitted 2004 (12 weeks). n randomised=210. 3. Nauck et al. Diabetes 2004;52(suppl 2):A83 (5 weeks). n randomised=144 Study 1310, 2072, 1499 24

25. DPP-IV Inhibitors (“gliptins”) • Sitagliptin (MK-0431) (Merck) • Vildagliptin (LAF-237) (Novartis) • Saxagliptin (BMS-477118) (BMS) • (NVP-DPP728) (Novartis) • (P93/01) (OSI Pharmaceuticals) • CJC-1134

26. Summary • incretin analogues are a novel treatment modality for T2 diabetes • administration via injection • reduce HbA1c by approximately 1% • associated with weight loss • gastrointestinal side effects – principally nausea • low incidence of hypoglycaemia • ? will be used if poor glycaemic control on metformin and another agent