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Coventry Diabetes PLT Meeting

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Presentation on theme: "Coventry Diabetes PLT Meeting"— Presentation transcript:

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

4

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) What is GLP-1? Glucagon-like peptide-1 (GLP-1) is a 30 amino acid peptide. It is an incretin hormone that is secreted from L-cells in the gastrointestinal system in response to calorie intake, causing the glucose dependent secretion of insulin. Incretins are chemical excitants that promote pancreatic sections (glucose-dependent insulinotropic polypeptide [GIP] is another example). 8

9 The incretin effect Time (min) Time (min)
Oral glucose load (50 g/400 ml) Isoglycaemic glucose infusion Plasma glucose Insulin response 15 270 80 60 10 180 Incretin effect IR-insulin (mU/l) Plasma glucose (mmol/l) 40 The incretin effect The effect of incretins on insulin secretion is clearly indicated in this study. Healthy volunteers (n=8) fasted overnight before received an oral glucose load of 50 g/400 ml or an isoglycaemic intravenous glucose infusion for 180 minutes. As can be seen in the left figure, venus plasma was similar with both glucose interventions. However, insulin response was greater following oral glucose ingestion than following intravenous glucose infusion, demonstrating the contribution of incretins on insulin secretion. References Nauck et al. Diabetologia 1986;29:46–52 Plasma glucose (mg/dl) 5 90 * * * 20 * * * * –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 ≤ 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 GLP-1 stimulates -cell function One of the most important functions of GLP-1 is glucose-dependent stimulation of insulin release from -cells. However, GLP-1 also exerts several other functional effects on -cells. For example, GLP-1 appears to be a modulator of insulin biosynthesis (Drucker et al 1987), and, through its actions on the glucose signalling pathway, GLP-1 has been shown to confer glucose sensitivity to glucose-resistant -cells (Holz et al. 1993). GLP-1 has also been shown to stimulate expression of the glucose transporter, GLUT-2, and glucokinase (Bulotta et al. 2002). References 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 GLUT2 glucokinase Improved function Holz et al. Nature 1993;361:362–365. Drucker et al. Proc Natl Acad Sci USA 1987;84:3434– Bulotta et al. J Mol Endocrinol 2002;29:347–360. 11

12 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 proliferation GLP-1 stimulates -cell regeneration and mass Studies have demonstrated that GLP-1 plays an important role in maintaining -cells. In animal studies, GLP-1 increases -cell mass through the stimulation of -cell neogenesis, growth and proliferation. Proliferation results from differentiation and division of existing -cells, while neogenesis occurs through differentiation of insulin-secreting cells from precursor cells in the pancreatic ductal epithelium (Bulotta et al. 2002). Additionally, a recent study using freshly isolated human islets reported a reduction in the number of apoptotic -cells following 5 days of in vitro treatment with GLP-1 (Farilla et al. 2003). These observations of increased -cell mass and decreased apoptosis are of particular interest in the treatment of type 2 diabetes as progressive -cell dysfunction is one of the main pathophysiologies of the disease. References Bulotta et al. J Mol Endocrinol 2002;29:347–360 Farilla et al. Endocrinology 2003;144:5149–5158 b-cell apoptosis b-cell hypertrophy b-cell regeneration and increased mass Farilla et al. Endocrinology 2003;144:5149–5158. Bulotta et al. J Mol Endocrinol 2002;29:347–360.

13 GLP-1: functional pancreatic effects
Glucose dependent insulin secretion Somatostatin secretion GLP-1: functional pancreatic effects GLP-1 has a direct functional effect on pancreatic cells, influencing secretions from alpha-, beta- and delta- cells. One of its most important effects is to increase insulin secretion. Importantly, however, its insulinotropic action is glucose dependent. Consequently, GLP-1 has the capacity to lower blood glucose while protecting against hypoglycaemia. GLP-1 also regulates glucagon secretion, partly via an increase in somatostatin secretion, and partly via a direct effect on the alpha-cell. This reduction in glucagon secretion serves to decrease hepatic glucose output. References Drucker et al. Proc Natl Acad Sci USA 1987;84:3434–3438 Ørskov et al. Endocrinology 1988;123: Hepatic glucose output 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
Learning and memory (animal models) GLP-1: effects on the gastrointestinal and central nervous systems The net effect of GLP-1’s action on the gastrointestinal system is to delay absorption of food. This is caused by several means, including decreased gastric emptying and acid secretion. For example, the infusion of GLP-1 to generate plasma levels similar to those normally observed following meals delays gastric emptying (Wettergren et al. 1993). Combined, these gastrointestinal effects serve to flatten the meal-related increase in glucose. This may be important in the management of type 2 diabetes because elevated postprandial glucose excursions are a key feature of type 2 diabetes. Reducing this excursion should therefore be an aim of diabetes treatment. Prolonged presence of food in the stomach through delayed gastric emptying may also reduce food intake by increasing the feeling of satiety. Additionally, GLP-1 receptors are present in several areas in the brain. The receptors in the brainstem (area postrema and subfornical organ) are believed to be involved in inducing feelings of satiety, regardless of the presence of food in the gastric system. This action therefore provides another means for decreasing food intake. Recently, GLP-1 has also been shown to improve spatial and associative learning following its intracerebroventricular infusion in the rat (During et al. 2003). References Wettergren et al. Dig Dis Sci 1993;38:665–673 Kieffer, Habener. Endocr Rev 1999;20:876–913 During et al. Nat Med 2003;9:1173–1179 Flint et al. J Clin Invest 1998;101:515–520 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 15 Blood glucose lowering is safe and effective with GLP-1 The blood glucose lowering efficacy of exogenously administered GLP-1 was clearly demonstrated in this study. Following the cessation of anti-diabetic medication and an overnight fast, 50 patients with type 2 diabetes received a 4-hour i.v. infusion of GLP-1 (1.2 pmol/kg/min). In all patients, plasma glucose levels during this infusion were reduced. Of the 50 patients, 39 reached a stable nadir (lowest glucose level with fluctuations ≤ 0.2 mmol/l [3.6 mg/dl]), and in all these patients this nadir was above the hypoglycaemia threshold. Eleven patients did not reach a stable nadir; however the mean final plasma glucose level in this subgroup remained above the hypoglycaemia threshold. Thus, GLP-1 effectively lowered glucose level to a level that minimises hypoglycaemia risk. References Toft-Nielsen et al. J Clin Endocrinol Metab 2001;86:3853–3860 270 Plasma glucose (mg/dl) Plasma glucose (mmol/l) 10 180 5 90 Hypoglycaemia threshold 2.8 mmol/l* 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 GLP-1 (n=10) Saline (n=9) Week 0 0.0 25 Week 1 GLP-1 450 Week 6 GLP-1 –0.5 20 360 –1.0 GLP-1 controls blood glucose and weight in type 2 diabetes The ability of GLP-1 to consistently reduce blood glucose over several weeks is shown in this trial. Type 2 diabetes patients (n = 20) were randomly assigned GLP-1 (4.8 pmol/kg/min) or saline as continuous subcutaneous infusion via a portable pump for 6 weeks. At weeks 0, 1 and 6 all patients underwent 8-hour blood glucose monitoring along with other assessments of glycaemic control and insulin activity. At week 6, in patients receiving GLP-1 infusion, fasting and 8-hour mean plasma glucose had significantly decreased relative to baseline by 4.3 and 5.5 mmol/l (77 and 99 mg/dl), respectively (p < for both comparisons). HbA1c decreased by 1.3% points (from 9.2 to 7.9, p = 0.003) and serum fructosamine fell from 349 to 282 μmol/l (p = ). Furthermore, gastric emptying was inhibited, appetite suppressed and body weight decreased by 1.9 kg (p = 0.013) during the 6-week period in patients receiving GLP-1. Insulin sensitivity increased by 77.3% (p = 0.002) and all indices of -cell function improved significantly during GLP-1 treatment. Saline infusion had no significant effect on glycaemic control (as measured by HbA1c and fasting plasma glucose), -cell sensitivity, gastric emptying or bodyweight. In this trial, GLP-1 therefore provided blood glucose control, while improving -cell function and reducing body weight. References Zander et al. Lancet 2002;359:824–830 15 270 Plasma glucose (mmol/l) –1.5 Plasma glucose (mg/dl) Weight change (kg) 10 180 –2.0 –2.5 5 90 –3.0 p = absolute values 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) Native GLP-1 is rapidly degraded by DPP-IV GLP-1 is stored in intestinal L-cells. As active GLP-1 is secreted from these cells, it is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV) resulting in the inactive, N-terminally truncated form, GLP-1-(9-36)amide. More than 50% of plasma GLP-1 appears to be in this inactive form. In this slide, immunohistochemical staining shows the very close proximity of active GLP-1 in the L-cells and DPP-IV in the capillaries within the human ileum. References Hansen et al. Endocrinology 1999;140:5356–5363 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 Native GLP-1 has limited clinical value because of its short half-life
7 37 9 Lys DPP-IV His Ala Thr Ser Phe Glu Gly Asp Val Tyr Leu Gln Ile Trp Arg i.v. bolus GLP-1 (15 nmol/l) Healthy individuals (n=6) 1000 Type 2 diabetes (n=6) Intact GLP-1 (pmol/l) 500 Native GLP-1 has limited clinical value because of its short half-life The rapid degradation of GLP-1 into its inactive form by DPP-IV means that when administered as an i.v. bolus, it has a half-life of just 1.5–2.1 minutes. Combined with rapid clearance, this means that the action of GLP-1 has a very limited time span. References Vilsbøll et al. J Clin Endocrinol Metab 2003;88:220–224 –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 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 BID 10 µg Exenatide BID -0.5 0.5 0.1 DISCUSSION Combined results from the three Phase 3 clinical studies demonstrated that exenatide improved glycaemic control and reduced body weight. Mean HbA1c was (compared to baseline): Increased by +0.1% in the placebo group Reduced by -0.6% for the 5-µg treatment group, and -0.9% for the 10-µg treatment group Mean body weight was (compared to baseline): Reduced by -1.4 pounds (lbs) in the placebo group Reduced by -3.1 lbs for the 5-µg treatment group, and -4.2 lbs for the 10-µg treatment group BACKGROUND Baseline HbA1c: placebo, 8.5%; 5 µg BID, 8.4%; 10 µg BID, 8.5%. Baseline weight: placebo, 218 lbs; 5 µg BID, 213 lbs; 10 µg BID, 216 lbs. Combined pivotals/AMIGOs: Three, 30-week, double-blind, Phase 3 studies Subjects with type 2 diabetes treated with metformin (MET), a sulphonylurea (SFU) or MET + SFU Randomised to placebo (n=483), 5 µg BID (n=480), or 10 µg BID (n=483) plus existing diabetes treatment. Weight change was a secondary endpoint. -0.5 -0.5  Weight (kg)  HbA1C (%) -1 -0.7 -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 endpoint Data on file, Amylin Pharmaceuticals, Inc.

23 Effect on weight (liraglutide in combination with metformin
p = 0.29 2 2 p < p = 0.40 1 1 Mean change in body weight from baseline (%) Mean change in body weight from baseline (%) -1 -1 Liraglutide significantly lowered body weight in combination with metformin This trial compared the effect of four treatment regimens (liraglutide, liraglutide + metformin, metformin, or metformin + glimepiride) on glycaemic control and body weight in 144 patients with type 2 diabetes. Following a 2–6 week run-in period of metformin dose titration (to 1 g BID), patients were randomised to one of the four treatment groups (n = 36 for each group). Body weight decreased from baseline in all groups except the metformin + glimepiride group. After 5 weeks’ treatment, body weight had decreased by approximately 2 kg in both groups receiving liraglutide treatment (liraglutide or metformin + liraglutide) and by approximately 1.5 kg in the metformin monotherapy group. A significant difference in body weight was observed for individuals receiving metformin + liraglutide compared with those receiving metformin + glimepiride (-3.2 %, p < ). Despite the weight loss attained by individuals receiving liraglutide treatment, both liraglutide treatment groups achieved significantly better glycaemic control than individuals receiving metformin monotherapy. Indeed, treatment with metformin + liraglutide resulted in a reduction in fasting serum glucose (3.8 mmol/l [68 mg/dl]) that was significantly greater than all other treatment groups. Thus, liraglutide combines weight control with glycaemic control. References Adapted from Nauck et al. Diabetes 2004;52(suppl 2):A83. -2 -2 -3 -3 p < 1 2 3 4 5 Time (weeks) p = 0.83 Liraglutide + metformin (n=36) Metformin + glimepiride (n=36) Liraglutide (n=36) Metformin (n=36) Adapted from: Nauck et al. Diabetes 2004;52(suppl 2):A83. n=number randomised Study 1499 23

24 Liraglutide and hypoglycaemic risk
Number of patients reporting events in three trials 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 al1 1/135 (0.7%) 4/26 (15%) Feinglos et al2 5/176 (3%) 2/34 (6%) - Nauck et al3 0/36 (0%) Symptoms only 7/135 (5%) 5/26 (19%) 12/176 (7%) 0/36 (%) 1/36 (3%) Liraglutide has a very low risk of hypoglycaemia In two 12-week trials, the incidence of hypoglycaemia during treatment with liraglutide was low (Madsbad et al 2004, Feinglos et al submitted). No major events were reported with liraglutide and minor events were documented in only 0.7–2% of patients. This incidence was similar to that reported with metformin and lower than that reported with glimepiride, despite similar glycaemic control. Additionally, a lower percentage of liraglutide-treated patients reported symptoms-only hypoglycaemia relative to those receiving glimepiride (5 vs. 19%). The percentage of patients reporting symptoms-only hypoglycaemia with liraglutide was similar to metformin (6 vs. 6%). Furthermore, in a 5-week study involving larger doses of liraglutide (0.5–2 mg), there were no reported hypoglycaemic events of any type in patients receiving liraglutide or metformin monotherapy. One patient reported one symptoms-only event during treatment with liraglutide + metformin, and there were three reports of hypoglycaemia (1 minor, 2 symptoms only) in three patients during treatment with glimepiride + metformin (n = 36, data not shown). This low incidence of hypoglycaemia is probably due to the glucose-dependent action of liraglutide. That is, the observation that its insulinotropic action diminishes as blood glucose concentration decreases. It is important that treatments are associated with low levels of hypoglycaemia because hypoglycaemia can restrict glycaemic targets and reduce adherence to treatment. References 1. Madsbad et al. Diabetes Care 2004;27: Saad et al. Diabetologia 2002;45(Suppl 2)A44. Feinglos et al. Submitted Adapted from Nauck et al. Diabetes 2004;52(suppl 2):A83. No major hypoglycaemic events were reported 1. Madsbad et al. Diabetes Care 2004;27: (12 weeks). n randomised= Saad et al. Diabetologia 2002;45 (Suppl 2)A44. Feinglos et al. Submitted 2004 (12 weeks). n randomised= 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 ) (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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