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Coventry Diabetes PLT Meeting Jim McMorran Diabetes GPSI Coventry PCT.

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Presentation on theme: "Coventry Diabetes PLT Meeting Jim McMorran Diabetes GPSI Coventry PCT."— Presentation transcript:

1 Coventry Diabetes PLT Meeting Jim McMorran Diabetes GPSI Coventry PCT

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

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

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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 in hindbrain/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 Nauck et al. Diabetologia 1986;29:46–52, *p ≤ 0.05. n=8 healthy volunteers IR-insulin (mU/l) 80 60 40 20 –10–560120180 0 * * * * * * * Time (min) Incretin effect Insulin response Plasma glucose (mmol/l) –10–560120180 10 Time (min) 5 0 15 Plasma glucose Oral glucose load (50 g/400 ml) Isoglycaemic glucose infusion Insulin response is greater following oral glucose than i.v glucose, despite similar plasma glucose concentration 9 90 0 180 270 Plasma glucose (mg/dl)

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  -cell function 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. insulin release glucose sensitivity glucokinase insulin biosynthesis GLUT2  -cell 11  -cell

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

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

14 Gastric emptying Acid secretion GLP-1 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. Satiety Food intake Learning and memory ( animal models ) GLP-1: effects on the gastrointestinal and central nervous systems 14

15 Blood glucose lowering is safe and effective with GLP-1 Adapted from: Toft-Nielsen et al. J Clin Endocrinol Metab 2001;86:3853–3860. Open circles are mean ± 1 SD. *50 mg/dl Plasma glucose (mmol/l) Patients reaching a stable glucose level (fluctuations ≤ 0.2 mmol/l) Fasting plasma glucose Nadir plasma glucose 0 5 10 15 25 20 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 Hypoglycaemia threshold 2.8 mmol/l * 15 90 0 180 270 Plasma glucose (mg/dl) 360 450

16 GLP-1 controls blood glucose and weight in type 2 diabetes Plasma glucose (mmol/l) 0 5 10 15 20 25 012345678 Hours post-injection Week 0 Week 1 GLP-1 Week 6 GLP-1 Weight change (kg) p = 0.013 absolute values p = 0.16 change in weight –3.0 –2.5 –2.0 –1.5 –1.0 –0.5 0.0 GLP-1 (n=10) Saline (n=9) Adapted from: Zander et al. Lancet 2002;359:824–830. Data are mean ± SE. 8-hour BG profiles (GLP-1 patients, n=10) Weight Continuous subcutaneous infusion of GLP-1 or saline for 6 weeks 16 90 0 180 270 Plasma glucose (mg/dl) 360 450

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

18 7 37 9 Lys DPP-IV HisAlaThr Ser PheGluGly Asp Val Ser TyrLeuGluGlyAla GlnLys Phe Glu IleAlaTrp LeuGly ValGlyArg Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88:220–224. Type 2 diabetes (n=6) Healthy individuals (n=6) i.v. bolus GLP-1 (15 nmol/l) Intact GLP-1 (pmol/l) Time (min) –55153545 0 500 1000 25 t ½ = 1.5–2.1 minutes (i.v. bolus 2.5–25.0 nmol/l) Enzymatic cleavage High clearance (4–9 l/min) Native GLP-1 has limited clinical value because of its short half-life 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 HbA 1C and Weight: Large Phase 3 Clinical Studies – Combined ITT 30-wk data; N = 1446; Mean (SE); *P<0.005; Weight was a secondary endpoint Data on file, Amylin Pharmaceuticals, Inc. Placebo BID 5 µg Exenatide BID 10 µg Exenatide BID -1.5 -1 -0.5 0 -0.9 * -0.6 * 0.1  HbA 1C (%) -0.5  Weight (kg) -2 -1.5 -0.5 0 -0.7 -1.4 * -1.9 * 0.5

23 Effect on weight (liraglutide in combination with metformin Mean change in body weight from baseline (%) Time (weeks) -3 -2 0 1 2 01234 5 Adapted from: Nauck et al. Diabetes 2004;52(suppl 2):A83. n=number randomised Study 1499 Mean change in body weight from baseline (%) 2 1 0 -2 -3 p = 0.40 p < 0.0001 p = 0.83 p = 0.29 23 Liraglutide + metformin (n=36) Metformin + glimepiride (n=36) Liraglutide (n=36) Metformin (n=36)

24 Liraglutide and hypoglycaemic risk Liraglutide (0.045–2 mg OD) Glimepiride (1–4 mg) Metformin (1000 mg bid) Liraglutide (0.5–2 mg OD) + Metformin (1000 mg bid) Minor events (< 2.8 mmol/l [50 mg/dl]) Madsbad et al 1 1/135 (0.7%)4/26 (15%)–– Feinglos et al 2 5/176 (3%)–2/34 (6%)- Nauck et al 3 0/36 (0%)– Symptoms only Madsbad et al 1 7/135 (5%)5/26 (19%)–– Feinglos et al 2 12/176 (7%)–2/34 (6%)- Nauck et al 3 0/36 (0%)–0/36 (%)1/36 (3%) 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 Number of patients reporting events in three trials Study 1310, 2072, 1499 24 No major hypoglycaemic events were reported

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


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