Coventry Diabetes PLT Meeting

Jim McMorran

Diabetes GPSI

Coventry PCT

• Inhaled Insulin.

• DPP IV inhibitors/GLP1 analogues.

• Rimonabant (Acomplia).

• Insulin pumps.

• Islet cell transplants.

• Non-invasive monitoring.

What’s New

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

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.

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

INCRETINS AND THEIR ROLE AS A TREATMENT

TARGET IN TYPE 2 DIABETES

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

The incretin effect

Nauck et al. Diabetologia 1986;29:46–52, *p ≤ 0.05. n=8 healthy volunteers

IR-i

nsu

lin (

mU

/l)

80

60

40

20

–10 –5 60 120 1800

** * * * * *

Time (min)

Incretineffect

Insulin response

Pla

sma g

luco

se (

mm

ol/l)

–10 –5 60 120 180

10

Time (min)

5

0

15Plasma 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

Pla

sma g

luco

se (

mg/d

l)

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

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

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

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

Gastric emptying

Acid secretion

GLP-1GLP-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

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

Pla

sma g

luco

se (

mm

ol/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

Pla

sma g

luco

se (

mg/d

l)

360

450

GLP-1 controls blood glucose and weight in type 2 diabetes

Pla

sma g

luco

se (

mm

ol/l)

0

5

10

15

20

25

0 1 2 3 4 5 6 7 8

Hours post-injection

Week 0

Week 1 GLP-1

Week 6 GLP-1

Weig

ht

change (

kg)

p = 0.013 absolute valuesp = 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

Pla

sma g

luco

se (

mg/d

l)

360

450

Native GLP-1 is rapidly degraded by DPP-IV

Human ileum, GLP-1 producingL-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

7

37

9

Lys

DPP-IV

His Ala Thr Thr SerPheGlu Gly AspVal

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly Arg

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)

Inta

ct G

LP-1

(pm

ol/l)

Time (min)

–5 5 15 35 450

500

1000

25

t½ = 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

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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%

Gila Monster

•Exenatide

–Synthetic version of salivary protein found in the Gila monster

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

Exenatide Reduced HbA1C and Weight: Large Phase 3 Clinical Studies –

Combined

ITT 30-wk data; N = 1446; Mean (SE); *P<0.005; Weight was a secondary endpointData on file, Amylin Pharmaceuticals, Inc.

Placebo BID 5 µg Exenatide BID10 µg Exenatide BID

-1.5

-1

-0.5

0

-0.9 *

-0.6 *

0.1

H

bA

1C (

%)

-0.5

W

eig

ht

(kg

)

-2

-1.5

-1

-0.5

0

-0.7

-1.4 *

-1.9 *

0.5

Effect on weight (liraglutide in combination with metformin

Mean c

hang

e in b

ody w

eig

ht

from

base

line (

%)

Time (weeks)

-3

-2

-1

0

1

2

0 1 2 3 4 5

Adapted from: Nauck et al. Diabetes 2004;52(suppl 2):A83. n=number randomised Study 1499

Mean c

hang

e in b

ody

weig

ht

from

base

line (

%) 2

1

0

-1

-2

-3

p = 0.40p < 0.0001

p < 0.0001

p = 0.83

p = 0.29

23

Liraglutide + metformin (n=36)Metformin + glimepiride (n=36)

Liraglutide (n=36)Metformin (n=36)

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 al1 1/135 (0.7%) 4/26 (15%) – –

Feinglos et al2 5/176 (3%) – 2/34 (6%) -

Nauck et al3 0/36 (0%) – 0/36 (0%) 0/36 (0%)

Symptoms only

Madsbad et al1 7/135 (5%) 5/26 (19%) – –

Feinglos et al2 12/176 (7%) – 2/34 (6%) -

Nauck et al3 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

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• No major hypoglycaemic events were reported

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

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