minimally invasive surgery symposium gut hormones and the medical management of diabesity donna h....

Minimally Invasive Surgery SymposiumGut Hormones and the Medical

Management of Diabesity

Donna H. Ryan, MDPennington Biomedical Research CenterBaton Rouge, LA

[email protected]

Outline Physiologic abnormalities in T2DM Incretins in normal physiology and T2DM Therapeutic approaches targeting

incretins

β-Cell mass in Type 2 diabetes

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

ND IFG T2DM ND T2DM

b-C

ell

volu

me

(%)

Obese Lean

-50%-50%

-63%-63%

Butler et al. Diabetes. 2003ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus

Excessive hepatic glucose production in Excessive hepatic glucose production in Type 2 diabetesType 2 diabetes

Plasma glucose concentration

Fasting & Fasting & postprandial postprandial

hyperglycaemiahyperglycaemia

Insulin; IR

GlucagonHepaticglucoseoutput

IR=insulin resistance


incretins

What is the Incretin Effect?

Time

Insu

lin

(pM

)G

luco

se

(mM

)1000

500

10

5

IVGlucose Oral

Incretineffect

The amplification of insulin secretion caused by gut hormones.

In healthy subjects ~ 70 % less insulin is secreted with an OGTT compared to IVGTT.

Postprandial GLP-1 levels are decreased in people with IGT and Type 2 diabetes

Toft-Nielsen et al. J Clin Endocrinol Metab. 2001

20

15

10

5

00 60 120 180 240

Time (min)

GLP

-1 (

pm

ol/l)

* * * **

**

*

Meal

NGT

T2DM

IGT

*P<0.05 T2DM vs NGT

IGT=impaired glucose tolerance; NGT=normal glucose tolerance

Glucagon like peptide Produced by L cells in

proximal and distal gut Stimulates glucose

dependent insulin release Reduces gastric emptying Reduces body weight Inhibits glucagon secretion

in glucose dependent manner

Enhances B cell proliferation and survival

Glucose-dependent insulinotropic polypeptide Produced by K cells in

duodenum Stimulates glucose

dependent insulin release Minimal effect on gastric

emptying No effect on body weight Stimulates glucagon

secretion ? Enhances B cell

proliferation and survival

What are the Incretin Hormones?GLP-1 and GIP

Incretin Function in T2DM Secretion of GLP-1 impaired Beta Cell sensitivity to GLP-1 decreased Secretion of GIP slightly impaired Effect of GIP abolished or grossly impaired

Normalisation of diurnal plasma glucose Normalisation of diurnal plasma glucose concentrations by continuous IV GLP-1 infusionconcentrations by continuous IV GLP-1 infusion(1.2 pmol/kg/min)(1.2 pmol/kg/min)

Rachman et al. Diabetologia. 1997

T2DM

T2DM + GLP-1

Controls

00600 1000 1400 1600

Glu

cose

(m

mol/l)

16

Clock time (hours)

Breakfast Lunch Snack

12

8

4

02002200

Nauck MA et al. Diabetologia. 1993;36:741-744

Data are mean±SE; *P<0.05

PlaceboGLP-1

Glucose-Dependent Actions of GLP-1in Patients With Type 2 Diabetes

350

300

250

200

150

100

50

0

Insulin (pmol/L)

* ** * *

** *

GLP-1/PBO infusion

Time (min)

-30 0 60 120 180 240 240

25

20

15

10

5

0

Glucagon (pmol/L)

Time (min)

-30 0 60 120 180

**

* *

GLP-1/PBO infusion17.5

15.0

12.5

10.0

7.5

5.0

2.5

0.0

*

Glucose (mmol/L)

GLP-1/PBO infusion

***

**

*

-30 0 60 120 180 240

Time (min)

Restores Islet-Cell Physiology

GLP-1 Inhibits Human Islet Cell Apoptosis and Preserves Islet Morphology

Day 1

GLP-1 treated cellsControl

Day 3

Day 5

Islets treated with GLP-1 are able to maintain their integrity for a longer period of time. Farilla L et al. Endocrinology. 2003;144(12):5149−5158. Permission required.

Restoration of Pancreatic Islet Beta Cells by Restoring GLP-1 Levels

Diabetic miceDiabetic mice + DPP-4 InhibitorLean control mice

Green: Insulin-producing β-cellRed: Glucagon-producing α-cell

Adapted from Zhang BB et al. Poster presentation at the 64th Scientific Session of the ADA, Orlando, Florida, USA, June 2004.

Diabetic mice received 10 weeks of treatment with MK-0431 analog.DPP-4 = Dipeptidyl peptidase-4

Decreasedhepatic glucose output

Increased peripheral glucose uptakeGI tract Pancreas

Incretins Regulate Glucose Homeostasis Through Effects on Islets

Glucagon in glucose-

dependent way from αα

cells (GLP-1)

α cells

Insulinin glucose-dependent way

from β cells(GLP-1 and GIP)

β cells

Ingestion of food

Adapted from Brubaker PL, Drucker DJ. Endocrinology. 2004;145:2653-2659;Zander M et al. Lancet. 2002;359:824-830; Ahrén B. Curr Diab Rep. 2003;3:365-372; Buse JB et al. In Larsen PR et al, eds.: Williams Textbook of Endocrinology. 10th ed. Philadelphia, PA: Saunders; 2003:1427-1483.

InactiveGLP-1 (9-36)

and GIP (3-42)

↓ GLUCAGON

INSULIN

DPP-4 inhibitor

X

Bloodglucose control

Release of incretin gut hormones

Active GLP-1 and

GIP

Bloodglucose control

GLP-1 agonist


incretins

GLP-1 enhancement

Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003

GLP-1 secretion is impaired in Type 2 diabetes

Natural GLP-1 has extremely short half-life

Add GLP-1 analogues with longer half-life:

• exenatide

• liraglutide

Injectables

Block DPP-4, the enzyme that degrades GLP-1:• sitagliptin• vildagliptin• saxagliptin

Oral agents

GLP-1 Receptor Agonists – February 2010Company Compound Status of development Formulation

Eli Lilly/Amylin Byetta (exenatide) Launched Twice-daily

Novo Nordisk Victoza (liraglutide) Approved 1/25/10 Once-daily

Eli Lilly/Amylin exenatide LAR Phase III/Expected 2010 Once-weekly

Sanofi-aventis lixisenatide (AVE0010) Phase III/Expected 2011 Once-daily

GlaxoSmithKline Syncria (albiglutide) Phase III/Expected 2011 Once-weekly

Roche/Ipsen taspoglutide (R1583) Phase IIb-III/Expected 2011 Once-weekly

Eli Lilly LY2189265 Phase II/III Once-weekly

ConjuChem CJC-1134 Phase II Once-weekly

Eli Lilly LY2428757 Phase II Once-weekly

Sanofi-aventis AVE0010(ZP10) Phase II Once-weekly

Novo Nordisk NN9535 Phase II Once-weekly

DPP-4 Inhibitors – February 2010

Company Compound Status of development

Merck Januvia (sitagliptin, MK-0431) Launched 2006

Novartis Galvus (vildagliptin, LAF-237) Launched EU 2008

BMS/AstraZeneca Onglyza (saxagliptin) Launched August 2009

Takeda alogliptin (SYR-322) Filed US 2008

Boehringer-Ingelheim Ondero (BI-1356) Phase III

Phenomix/Forest Lab. dutogliptin (PHX1149) Phase III

Glenmark melogliptin (GRC 8200) Phase IIb

Mitsubishi Tanabe Pharma TA-6666 Phase II

Mitsubishi Tanabe Pharma MP-513 Phase II

Amgen/Servier AMG 222/ALS 2-0426 Phase II

Pfizer PF 00734200 Phase II

Takeda SYR-472 Phase II

Abbott Laboratories ABT-279 Phase II

Incretin mimetics and DPP-4 inhibitors:major differences

Properties/effect Incretin mimetics DPP-4 inhibitors

Mechanism of stimulation of insulin secretion exclusively through GLP-1 effect

Yes Unknown

Restitution of insulin secretion (2 phases) Yes (exenatide) Yes

Hypoglycaemia No No

Maintained counter-regulation by glucagon in hypoglycaemia

Yes Not tested

Inhibition of gastric emptying Yes Marginal

Effect on body weight Weight loss Weight neutral

Side effects Nausea None observed

Administration Subcutaneous Oral

Gallwitz. Eur Endocr Dis. 2006

Exendin-4

Chen & Drucker, J Biol Chem 1997

GlyHis

Val Ala

Glu

Glu

Glu

Gly

Glu

Gly

Leu

Thr Phe Thr

Phe

Ser

LysSer

AspLeu

GlnMet

Leu Lys

GluArg

AsnIle Trp Gly ProSer

SerGlyPro AlaProSer ProH2N-

His Ala

Ala Ala

Ala

Glu

Glu

Gly

Gly

Gly

Glu

Thr Phe Thr

Phe

Ser

Ser

Ser

Asp

Val

TyrLeu

Leu Val

GlnLys

ArgIle Trp Ala Gly

Glu

C-16 fatty acid (palmitoyl)

• Based on human GLP-1 (7-37)• 97% homologous with GLP-1• Resistant to DPP-4• Full agonist at the GLP-1 receptor

• Non-covalent binding to albumin, self-association, slow release from injection site gives prolonged survival time– t½ 12 hr after sc injection

• From saliva of the Gila Monster

• 53% homologous with GLP-1

• Insensitive to DPP-4

• Full agonist at the GLP-1 receptor

• Metabolically stable – t½ 4-5 hr after sc injection

Liraglutide

Knudsen et al, J Med Chem 2000

Conserved Substituted Additional (relative to human GLP-1 7-37)

Exenatide Lowers Postprandial Glucose Large Phase 3 Clinical Studies – Combined (Evaluable)

Placebo BID (N = 44) Exenatide 5 mcg BID (N = 42) Exenatide 10 mcg BID (N = 52)

Time (min)

Prior to Treatment Glucose (mg/dL)

1000 60 120 180

150

200

250

300Placebo

Meal

Mean (SE); Evaluable meal tolerance test cohortsData on file, Amylin Pharmaceuticals, Inc.

Week 30Glucose (mg/dL)

0 60 120 180

Exenatide or PlaceboMeal

-30 -30

N=217; mean (-SE); P<0.0001 from baseline to 30 weeks and baseline to 3 years.Klonoff DC et al. Curr Med Res Opin. 2007;24:275-286.

Exenatide Sustained A1C Reduction:3-Year Completers

0 26 52 78 104 130 1564

5

6

7

8

9

10

Time (weeks)

Baseline A1C8.2%

Placebo-controlled Open-label uncontrolled

-1.1 ± 0.1%

% achieving A1C ≤7%

A1

C (

%)

-1.0 ± 0.1%

46%54%

Changes in body weight over time with exenatide

Mean w

eig

ht

change

(kg

± S

EM

)

Time (week)

Placebo-ControlledTrials

0 10 20 30 40 50 60 70 80 90-5

-4

-3

-2

-1

0

Placebo 10-μg exenatide bd5 μg bd 10-μg exenatide bd10 μg bd 10-μg

exenatide bdOpen-Label Extension(All subjects: 10 μg bd)

N=92; completer cohort; 82-week data; weight change was a secondary endpoint. Baseline weight: placebo=98 kg, 5 μg=98 kg, 10 μg=100 kg. Ratner et al. Diabetes Obes Metab. 2006;

Data on file, Amylin Pharmaceuticals, Inc.

0

5

10

15

20

25

30

35

0-4 >4-8 >8-12 >12-16 >16-20 >20-24 >24-28 >28

Time (week)

% I

ncid

ence

of

naus

ea

Intent-to-treat 30-week data; N=1446Data on file, Amylin Pharmaceuticals, Inc

Incidence of nausea with exenatide inlarge phase 3 clinical studies

Placebo5-μg exenatide bd10-μg exenatide bdDose increased from 5 μg to 10 μg at week 4

26 Week LEAD-6 Trial of Liraglutide vs Exenatide

Liraglutide is GLP-1 analog with a single amino acid substitution and a fatty acid to slow absorption – 97% homology

Half life 13 h. Dose 1.8 mg/d Exenatide has 57% homology Liraglutide lowered HgbA1, FPG and

HOMA-B more than exenatide. Weight loss about 2 kg

Buse J Lancet 2009;May 23

Comparison of Liraglutide and Exenatide in the LEAD-6 Study

0 4 8 12 16 20 24 28-6

-4

-2

0

2 ExenatideLiraglutide

Weeks of Treatment

Wei

gh

t L

oss

(kg

)

Buse J et al Lancet 2009;

Inadequately controlled T2D were treated with exenatide (n=231) 10 mg/d or liraglutide (n-233) 1.8 mg/d for 26 weeks. Liraglutide reduced HbA1c and fasting glucose more than exenatide

24 Week Study of Liraglutide in Obesity

20 week multi-center clinical trial with 564 obese subjects randomized to placebo, orlistat or 4 doses of liraglutide

75 subjects had prediabetes Screening and 2 week run-in prior to

randomization followed by 20 weeks of therapy

Effect of Liraglutide and Orlistaton Body Weight

-5 0 5 10 15 20-10

-8

-6

-4

-2

0Placebo1.2 mg/d1.8 mg/d2.4 mg/d3.0 mg/dOrlistat

Ran

dom

izat

ion

Scr

eeni

ng

Weeks from Randomization

Wei

gh

t L

oss

(kg

)

Finer N Diabetes 2009;

Time will tell… Liraglutide is once daily, exenatide is twice

daily, with once weekly due soon. Both liraglutide and exenatide are

associated with nausea, vomiting and diarrhea.

Will liraglutide have the side effect of pancreatitis that is seen with exenatide?

Sitagliptin improves both fasting and post-meal glucose in monotherapy vs placebo

*Least-squares (LS) mean difference from placebo after 24 weeks Aschner et al. Diabetes Care. 2006

Fasting Glucose

Pla

sma g

luco

se (

mm

ol/l)

Time (weeks)

0 6 123 18 24

Placebo (n=247)Sitagliptin 100 mg (n=234)

FPG* = -1.0 mmol/l (P<0.001)

Post-meal Glucose

Time (minutes)

Pla

sma g

luco

se (

mm

ol/l)

in 2-hr PPG* = -2.6 mmol/l (P<0.001)

0 60 120 0 60 120

8

10

12

14

16

Placebo (n=204)Sitagliptin (n=201)

Baseline24 weeks

Baseline24 weeks

9.0

9.5

8.5

10.0

10.5

8.0

Difference in 24-hourmean glucose: -1.8 mmol/l(-32.8 mg/dl), P<0.001

Brazg et al. Diabetes Obes Metab. 2007

Sitagliptin added to metformin improves 24-hour glucose profile in Type 2 diabetes

Glu

cose

(m

mol/l)

8:00 Day 1

13:00 19:00 0:00Day 2

7:30

6

7

8

9

10

13

11

12

Dose 17:30

Dose 218:30

Breakfast Lunch Dinner

Placebo + metformin (n=13)Sitagliptin 50 mg bd + metformin (n=15)

Time

Sitagliptin once daily lowers HbA1c when added to metformin or pioglitazone

*Placebo-subtracted difference in LS meansCharbonnel et al. Diabetes Care. 2006; Rosenstock et al. Clin Ther. 2006

in HbA1c vs Pbo* = -0.65%

(P<0.001)

in HbA1c vs Pbo* = -0.70% (P<0.001)

Placebo (n=224)Sitagliptin 100 mg (n=453)

Add-on to Pioglitazone Study

Placebo (n=174)Sitagliptin 100 mg (n=163)7.0

7.2

7.4

7.6

7.8

8.0

8.2

0 6 12 18 24Time (weeks)

Hb

A1c (%

)

Add-on to Metformin Study

7.0

7.2

7.4

7.6

7.8

8.0

8.2

0 6 12 18 24Time (weeks)

Hb

A1c (%

)

Safety and tolerability profile: once-daily sitagliptin vs glipizide

between groups = –2.5 kg (P<0.001)

Change in body weight

86

88

90

92

94

0 12 24 38 52Time (weeks)

Body w

eig

ht

(kg)

Sitagliptin 100 mg (n=382)Glipizide (n=411)

4.9%

32%

0

10

20

30

40

50Hypoglycaemia

P<0.001

Week 52In

cid

ence

(%

)

Glipizide (n=584)Sitagliptin 100 mg (n=588)

Stein. ADA. 2006. Late-breaking clinical presentation; Nauck et al. Diabetes Obes Metab. 2007

Adapted from Herman, et al. J Clin End Met. 2006; 91:4612.

Study Drug

10 2 3 4 5 6

0

5

10

15

20

OGTT

Sitagliptin 200 mg (n=54)


Placebo (n=55)

Act

ive

GLP

-1 (

pM/L

)Plasma Levels of Active GLP-1After Sitagliptin Administration

Time (h)

7

Sitagliptin Once Daily Shows Similar Glycemic Efficacy to Glipizide When Added to Metformin

Sitagliptin 100 mg qd (n=382)

Glipizide (n=411)

Mean C

hange in H

bA

1c Mean change from baseline (for both

groups)*: - 0.67%

6.0

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

8.0

8.2

8.4

0 12 24 38 52

Time (weeks)

*per-protocol analysis; -0.51% and -0.56% for sitagliptin and glipizide in LOCF analysis Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205

Hypoglycemia

0

10

20

30

40

50

Week 52

Inci

denc

e (%

)

Glipizide (n=584)


Sitagliptin Once Daily Shows Better Safety and Tolerability Profile Compared to Glipizide (52 Weeks)

p<0.001

Sitagliptin 100 mg qd (n=382)

Glipizide (n=411)

between groups = –2.5 kg (p<0.001)

32%

4.9%

Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205

Change in Body Weight

86

88

90

92

94

0 12 24 38 52

Time (weeks)

Bo

dy

we

igh

t (k

g)

DPP IV inhibitors – the down side DPP IV is important in the immune system

regulation. DPP IV has been reported to be a tumor

suppressor Rare reports of Stevens-Johnsons

Syndrome with sitagliptin

Mean HbA1c of patients

7

6

9

8

10

Hb

A1

c, %

OAD monotherapy

Diet andexercise

OAD combination

OAD up-titration

OAD plus multiple daily

insulininjections

OAD plus basal insulin

Traditional stepwise approach

Earlier Use of Combination Therapy may Improve Treatment of Diabetes

Early combination approach

Duration of DiabetesTime

OAD=oral anti-hyperglycaemic drug.Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355 and Campbell IW. Br J Cardiol. 2000;7:625–631.

Reprinted from Primary Care, 26, Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes. Implications for clinical practice, 771–789, © 1999, with permission from Elsevier.

Development and Progression of Type 2 Diabetes and Related Complications*

*Conceptual representation.

Insulin levelInsulin level

Insulin resistanceInsulin resistance

Hepatic glucose Hepatic glucose productionproduction

PostprandialPostprandial glucoseglucose

Fasting plasma Fasting plasma glucoseglucose

BBetaeta-cell function-cell function

Progression of Type 2 Diabetes Mellitus

Impaired Glucose Tolerance

Diabetes Diagnosis

Frank Diabetes

4–7 years

Development of Macrovascular ComplicationsDevelopment of Microvascular Complications

*

Thank you

[email protected]

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