Amylin:The Other β Cell Hormone

John Buse, MD, PhDProfessor of Medicine

Chief, Division of EndocrinologyUNC School of Medicine

Chapel Hill, NC USA

Beaumont K, et al. Mol Pharm. 1993; 44:493-497Muff R, et al. Endocrinology. 1999; 140:2924-2927

AmylinAmylin

Receptor image Adapted from Christopoulos G, et al. Mol Pharmacol. 1999; 56: 235-242

• Peptide hormone – co-localized and co-secreted with insulin– 37 amino acid peptide related to calcitonin, CGRP, adrenomedullin– Amylin gene - chromosome 12

• Neuroendocrine peptide– Receptor identified– Binding sites in CNS

Area postremaDorsal raphaeNucleus accumbens

C C

N N

Amylin Receptor

RAMP1 CTR

Amylin Binding Sites in the Brain

Dorsal Raphe

Nucleus Accumbens Area Postrema

Amylin Is Co-Secreted With InsulinAmylin Is Co-Secreted With Insulin

Plas

ma

Insu

lin (p

M)

25

20

15

10

57 am Midnight5 pm12 noon

Time (24 h)

600

400

200

0

Meal Meal Meal

Plas

ma

Am

ylin

(pM

)

30

InsulinAmylin

Healthy adults; n = 6Data from Kruger D, et al. Diabetes Educ 1999; 25:389-398

Hepatic Glucose Output in Diabetes is Abnormally Increased After Meals

Hepatic Glucose Output in Diabetes is Abnormally Increased After Meals

Time (min)H

epat

ic G

luco

se O

utpu

t (m

mol

/min

)

-15 30 60 90 120 150 180

2.0

1.5

1.0

0.5

Meal *

* *

Type 1 DiabetesSubjects Without Diabetes

Time (min)

Hep

atic

Glu

cose

Out

put

(µm

ol/k

g/m

in)

5

10

15

0 100 200 400300

Meal

Type 2 DiabetesSubjects Without Diabetes

Type 2 Diabetes: P<0.01 AUC 0-120 min; *P<0.05Data from Wahren J, et al. J Clin Invest 1976; 57:987-999Data from Frank JW, et al. Gastroenterology 1995; 109:755-765

Deficient Insulin and Hypersecreted GlucagonDeficient Insulin and Hypersecreted Glucagon

Defects in diabetes:

• Deficient insulin release

• Glucagon not suppressed(postprandially)

• Hyperglycemia

Mea

l

120

60

0

Insulin(µU/mL)

100

120

140

-60 0 60 120 180 240

Time (min)

Glucagon(pg/mL)

360

300

240110

80

Glucose(mg/dL)

Without Diabetes (n=14)Type 2 Diabetes (n=12)

TYPE 2 DIABETESTYPE 2 DIABETES

Data from Muller WA, et al. N Engl J Med 1970; 283:109-115

Plasma Glucose AUC0-30 min(mmol/L/min)

Gastric-Emptying Rate Is an Important Determinant of Postprandial GlycemiaGastric-Emptying Rate Is an Important Determinant of Postprandial Glycemia

% Emptied at 30 min

260

10 20 30 400

240

220

200

180

160

140

Subjects without diabetes ; n = 16r = 0.58; P<0.05Data from Horowitz M, et al. Diabetologia 1993; 36:857-862

Gastric Emptying Is Accelerated in DiabetesGastric Emptying Is Accelerated in Diabetes

Type 1

*

Without DiabetesDiabetes

0

120

180

60

0

20

40

60

80

Type 2

**

Gas

tric

Hal

f-Em

ptyi

ng T

ime

(min

)

Gas

tric

Hal

f-Em

ptyi

ng T

ime

(min

)

Type 2: without diabetes, n = 9; type 2 diabetes, n = 9; *P<0.05Type 1: without diabetes, n = 12; type 1 diabetes, n = 11; **P = 0.0005Data from: Nowak TV, et al. Gastroenterology 1990; 98:A378; Phillips WT, et al. J Nuclear Med 1992; 33:1496-1500

Amylin Is Deficient in DiabetesAmylin Is Deficient in Diabetes

Time After Sustacal® Meal (min)

0

5

10

15

20

-30 0 30 60 90 120 150 180

Meal

Late Stage Type 2

Type 1

Without DiabetesPl

asm

a A

myl

in (p

M)

Without diabetes; n = 27Late-stage type 2; n = 12Type 1; n = 190Data from Kruger D, et al. Diabetes Educ 1999; 25:389-398

Plasma Glucose

Tissues

GlucoseDisposal

Rate ofglucose

appearance

Rate ofglucose

disappearance

Stomach

BrainFoodIntake

—

GastricEmptying

—Liver

GLP-1

Gut

Multihormonal Regulation of GlucoseMultihormonal Regulation of Glucose

PostprandialGlucagon

Pancreas

Insulin

•Insulin helps regulate glucose

disappearance

Amylin

•Amylin helps regulate glucose

appearance

APPEARANCE AND DISAPPEARANCEAPPEARANCE AND DISAPPEARANCE

Model derived from animal studiesAdapted from Edelman S, et al. Diabetes Technol Ther 2002; 4:175-189

PramlintidePramlintide– An analog of amylin that overcomes the tendency of human amylin to:

Aggregate, form insoluble particles Adhere to surfaces

– Pharmacokinetic and pharmacodynamic properties similar to human amylin

Human amylin Pramlintide (analog of amylin)

AmideS S

AY

TNS

GV N

T

T TT

N

AA

A

LI

KS

SC

CQ

RL N

NNF

G

FL

VH

Amide

PP P

YT

NS

GV N

T

T TT

N

AA

A

LI

KS

SC

CQ

RL N

NNF

G

FL

VH

Adapted from Young A, et al. Drug Dev Res 1996; 37:231-248Adapted from Westermark P, et al. Proc Natl Acad Sci 1990; 87: 5036-5040

Pramlintide Reduces Postprandial GlucagonPramlintide Reduces Postprandial Glucagon

Type 1 Diabetes

Time (h)

PlaceboPramlintide

Placebo or 25 µg/h pramlintide infusion-20

0

10

20

30

-10

InsulinSustacal®

0 2 3 4 51

Type 2 Diabetes, Insulin treated

Time (h)

Plas

ma

Glu

cago

n (p

g/m

L)

InsulinSustacal®60

40

30

50

Placebo or 100 µg/h pramlintide infusion

0 1 2 3 4 5Pl

asm

a G

luca

gon

(pg/

mL)

Type 2 diabetes, n = 12; AUC1-4 h: P = 0.005Type 1 diabetes, n = 9; AUC1-5 h: P<0.001; Data from: Fineman M, et al. Metabolism 2002; 51:636-641; Fineman M, et al. Horm Metab Res 2002; 34:504-508

Effect of Pramlintide on Gastric Emptyingin Type 1 Diabetes

Effect of Pramlintide on Gastric Emptyingin Type 1 Diabetes

MeanHalf-Emptying

Time (h)

0

1

2

3

4~1-h delay*

60 µg

*

30 µgPlacebo

Insulin + PlaceboInsulin + PramlintideBreakfast

Single SC pramlintide doses: n = 11, crossover; *P<0.004; 99m Tc labelled pancake; solid component measuredData from Kong MF, et al. Diabetologia 1998; 41:577-583

Pramlintide Reduces Caloric Intakein Type 2 Diabetes

Pramlintide Reduces Caloric Intakein Type 2 Diabetes

0

250

500

750

1000

1250

Protein

CHO

Fat

CHO

Fat

Protein

-202 kcal(-23%)P <0.01

Ad-LibitumCaloric Intake

(kcal)

PlaceboPramlintide

n = 11; subjects given buffet meal Pramlintide (single SC injection, 120 μg)Data from Chapman I, et al. Diabetologia 2005; 48:838-848

Pramlintide Clinical EffectsPramlintide Clinical Effects

-2

-1

0

1

* **

**

**

****

****-4

-2

0

2

4

6

8

-0.8

-0.6

-0.4

-0.2

0

Δ Insulin Use (%)Δ A1C (%) Δ Weight (kg)

Week 4 Week 13 Week 26Week 4 Week 13 Week 26Week 4 Week 13 Week 26

Placebo + Insulin120 μg Pramlintide BID + Insulin

TYPE 2 DIABETES COMBINED PIVOTALSTYPE 2 DIABETES COMBINED PIVOTALS

ITT; Mean (SE); *P<0.01, **P<0.0001 Placebo + insulin, N = 284, Baseline A1C = 9.3%; Pramlintide + insulin, N = 292, Baseline A1C = 9.1%Pramlintide Acetate Prescribing Information, 2005. Data on file, Amylin Pharmaceuticals, Inc.Data from: Hollander P, et al. Diabetes Care 2003;26:784-790; Ratner RE, et al. Diabetes Technol Ther 2002; 4:51-61

Pramlintide Reduces Fasting andPostprandial Glucose

Pramlintide Reduces Fasting andPostprandial Glucose

Baseline6 Months

120

140

160

180

200

220

Glu

cose

(mg/

dL)

pre-bf post-bf pre-lu post-lu pre-di post-di bedtime

**

*

**

* *

TYPE 2 DIABETESTYPE 2 DIABETES

N = 166; *P<0.05; Clinical-Practice Study, 120 μg pramlintidebf, breakfast; lu, lunch; di, dinner

Pramlintide Clinical EffectsPramlintide Clinical Effects

-0.8

-0.6

-0.4

-0.2

0

-4

-2

0

2

4

6

8

-2

-1

0

1

***

***

***

**

*

***

*** ***

Week 4 Week 13 Week 26Week 4 Week 13 Week 26Week 4 Week 13 Week 26

Δ Insulin Use (%)Δ A1C (%) Δ Weight (kg)

Placebo + Insulin30 or 60 μg Pramlintide TID or QID + Insulin

TYPE 1 DIABETES COMBINED PIVOTALSTYPE 1 DIABETES COMBINED PIVOTALS

ITT; Mean (SE); *P<0.05, **P<0.01, ***P<0.0001; Placebo + insulin, N = 538, Baseline A1C = 9.0% ; Pramlintide + insulin, N = 716, Baseline A1C = 8.9%Pramlintide Acetate Prescribing Information, 2005; Data on file, Amylin Pharmaceuticals, Inc.Data from: Whitehouse FW, et al. Diabetes Care 2002; 25:724-730; Ratner R, et al. Diabetic Med 2004; 21:1204-1212

Pramlintide Reduces Fasting andPostprandial Glucose

Pramlintide Reduces Fasting andPostprandial Glucose

120

140

160

180

pre-bf post-bf pre-lu post-lu pre-di post-di bedtime

Glu

cose

(mg/

dL)

Baseline6 Months

**

TYPE 1 DIABETESTYPE 1 DIABETES

N = 265; *P<0.5; Clinical-Practice Study: all pramlintide doses bf, breakfast; lu, lunch; di, dinner

Pramlintide Reduces Postprandial GlucosePramlintide Reduces Postprandial Glucose

Pre-Breakfast Post-Breakfast

100

150

200

250

Mean Glucose (mg/dL)

Time (d)-7 30 60 90 1200 150 200170

Time (d)-7 30 60 90 1200 150 200170

100

150

200

250

Mean Glucose (mg/dL)

PlaceboPramlintide

PlaceboPramlintide

TYPE 1 DIABETESTYPE 1 DIABETES

Placebo, n = 147Pramlintide, n = 148

Study DesignStudy Design

Pramlintide 120 µg + Insulin Glargine

Placebo + Insulin Glargine

0 4 8 12 16

Insulin Glargine Dose Titration (FPG target ≥70 and <100 mg/dL)

Screening

Time (Weeks)

• 16-week, randomized, double-blind, placebo-controlled, multicenter study in patients with type 2 diabetes

• Pramlintide or placebo added to insulin glargine (±OAs)– Administered immediately prior to major meals– Initiated at 60 μg for 3-7 days, then increased to 120 μg as tolerated

Study Visits

Change in A1C From Baseline to Week 16Change in A1C From Baseline to Week 16

Mean±SE; ITT LOCF: Placebo N = 106; Pramlintide N = 105*p <0.05 vs. PlaceboRiddle, et al. Diabetes 2007; 56(Suppl 1):A143-144

0 4 8 12 16-1.0

-0.8

-0.6

-0.4

-0.2

-0.0

**

-0.3% ± 0.1

Baseline A1C

Placebo + Insulin GlarginePramlintide + Insulin Glargine

8.5 ± 0.1%8.5 ± 0.1%

Δ A1C (%)

Time (Weeks)

Change in Glucose FluctuationsChange in Glucose Fluctuations

100

125

150

175

200

225

250

BaselineWeek16

******

***

Mean±SE; ITT observed**p<0.01 and *** p<0.001 vs. Baseline

100

125

150

175

200

225

250

pre-breakfastpost-breakfastpre-lunchpost-lunchpre-dinnerpost-dinnerbedtime

pre-breakfastpost-breakfastpre-lunchpost-lunchpre-dinnerpost-dinnerbedtime

BaselineWeek 16

Pramlintide + Insulin GlarginePlacebo + Insulin Glargine

Blo

od G

luco

se (m

g/dL

)

****** ***

*****

****

***

Change in Body Weight From Baseline to Week 16Change in Body Weight From Baseline to Week 16

0 4 8 12 16-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

Time (Weeks)

*** ***

*** ***

***

-2.3 ± 0. 4 kg

Mean±SE; ITT LOCF: Placebo N=106; Pramlintide N=105***p <0.001 vs. PlaceboRiddle, et al. Diabetes 2007; 56(Suppl 1):A143-144

Placebo + Insulin GlarginePramlintide + Insulin Glargine

Baseline Wt.103 ± 1.8 kg103 ± 1.7 kg

Δ Body Weight (kg)

Proportion of Patients Achieving the Composite Endpoint At Week 16

Proportion of Patients Achieving the Composite Endpoint At Week 16

ITT LOCF: Placebo N=106; Pramlintide N=105; #Patients had to achieve each of the following components: A1C ≤7.0% or ≥0.5%, PPG excursions ≤40 mg/dL, no weight gain, and no severe hypoglycemia ***p < 0.001 vs. PlaceboRiddle, et al. Diabetes 2007; 56(Suppl 1):A143-144

0

25

50

75

100

25%***

7%

Patie

nts

Ach

ievi

ng C

ompo

site

Endp

oint

(%)#

Placebo + Insulin Glargine Pramlintide + Insulin Glargine

ConclusionsConclusions♦ Amylin, a newly discovered islet-hormone, has an

important role in glucose regulation, particularly postprandial hyperglycemia

♦ Synthetic amylin (pramlintide), provides an opportunity to replace this peptide to both improve glycemia and reduce weight.

♦ Careful patient selection, in addition to physicians comfortable with insulin use, are both important for success