pramlintide & weight - denver, colorado & weight diane m karl md the endocrine clinic &...

Pramlintide & Weight

Diane M Karl MD

The Endocrine Clinic &

Oregon Health & Science University

Portland, Oregon

Conflict of Interest

• Speakers Bureau: Amylin Pharmaceuticals

• Consultant: sanofi-aventis

• Grant support: Amylin Pharmaceuticals, sanofi-aventis

Lecture outline

• Amylin/pramlintide physiology

– Early clinical trials & weight

• Limitations of prandial insulin

• Recent studies

– T2DM

– Non-diabetes

amylin insulin

Amylin: the hormone

• Amylin

– Reported in 1987

– 37-amino acid peptide

– Co-located and co-secreted with insulin

from pancreatic ß-cells

Unger and Foster. Williams Textbook of Endocrinology, 1992.

Insulin and Amylin Co-secreted

Amylin

Insulin

Without Diabetes

n = 6

Plasma insulin

(pM)

Plasma

amylin

(pM)

30

25

20

15

10

5

7 am Midnight5 pm12 noon

Time

600

400

200

0

Meal Meal Meal

Koda et al, Diabetes. 1995; 44 (s1): 23BA.

Weyer et al. Curr Pharm Des. 2001;7:1353-1373

Amylin binding sites in the brain

area

postremanucleus

accumbens

dorsal

raphe

Beaumont K et al. Mol Pharm. 1993; 44:493-497

Amylin: A Neuroendocrine Hormone

Amylin Receptor Identified

CC

N N

Muff R, et al. Endocrinology. 1999; 140: 2924-2927.

Insulin and Amylin:

Complementary Hormones

Plasma Glucose

Glucagon

Tissues

Glucose Disposal

Liver

Gastric Emptying

+Insulin

–

Amylin

Brain

–

–

Pancreas

Satiety –

Bhavsar et al, Physiology and Behavior. 1998; 64(4): 557-561.

Amylin Reduces Food Intake In Animals

0 0.1 1 10 1000

20

40

60

80

100

120

140

160

Intraperitoneal amylin dose (µg/kg)

Food Intake

(% of control)

Amylin Is Deficient in Diabetes

Time after Sustacal® meal (min)

0

5

10

15

20

-30 0 30 60 90 120 150 180

Without Diabetes

Type 1

Plasma amylin

(pM)

Fineman et al, Diabetologia. 1996; 39 (S1): A149.

Kruger et al. Diabetes Educ. 1999; 1999:389-398.

Insulin-Using Type 2

Meal

Human amylinPramlintide

(25, 28, 29 Pro-h-amylin)

Pramlintide: Synthetic Amylin Analog

• Specifically engineered to overcome human amylin tendency

to :

– Aggregate, adhere to surfaces

– Form insoluble particles and amyloid fibrils

• Potency equal to or greater than human amylin

Reduced food intake

with pramlintide

Chapman et al. Diabetologia 2005;48:838-848

T2DM, n=11 (crossover)

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Change in % HbA1c Change in Weight (lb)

-3

-2

-1

0

1

2

3

4

5

6

Change in Insulin Use (%)

-4

-3

-2

-1

0

1

2

Pramlintide Therapy in Type 2 Diabetes

Pre-registration trials

Placebo + Insulin (N=284)

Pramlintide Recommended Dose + Insulin (N=292)

Baseline: 9.3 9.1

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

All Patients, Recommended Dose

Data on file, Amylin Pharmaceuticals, Inc.

Pramlintide Therapy in Type 1 Diabetes

Pre-registration trials

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0Week 4 Week 13 Week 26

-3

-2

-1

0

1

2

3

4

5

6

7Week 4 Week 13 Week 26

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0

0.5

1.0

1.5

2.0

2.5

Week 4 Week 13 Week 26

Placebo + Insulin (N=538)

Pramlintide Recommended Doses + Insulin (N=716)

Baseline: 9.0 8.9

Change in % HbA1c Change in Weight (lb)Change in Insulin Use (%)

All Patients, Recommended Doses

Data on file, Amylin Pharmaceuticals, Inc.

Pramlintide + Insulin in T1DM Weight Effect by BMI

*

-4

-2

0

2

4

*

BMI 23 kg/m2

BMI 23-27 kg/m2

BMI 27 kg/m2

Insulin + Placebo

Insulin + Pramlintide (60 µg TID)

Weight Change from Baseline at Week 26

lbs n=23

n=26

n=35

n=33

n=46

n=40

-6

Data on file, Amylin Pharmaceuticals Inc.

Limitations of prandial insulin

Treating to Target in Type 2 Diabetes (4T) Study

Study Design

N=708 T2DM patientsTaking metformin + sulfonylureaMean age 62, median duration DM 9 yearsMean BMI 29.8 kg/m2

Mean A1c 8.5%

Randomized to add insulin as:Basal insulin (detemir) 1 or 2x dailyPremixed insulin (aspart/protamine-aspart) 2x dailyPrandial insulin (aspart) 3x daily

Titration of dose by computerized system to:72-99 mg/dL FPG and pre-prandial90-126 mg/dL post-prandial

1 year follow-up on assigned treatment; 3 year follow-up after patients with A1c >6.5% at 1 year had each regimen intensified

Holman RR et al. N Engl J Med 2007;357:1716-30 Holman RR et al. N Engl J Med 2009;361:1736-47

4T Study1-year results

Basal 1-2x Premixed 2x Prandial 3x

A1c % 7.6 7.3 7.2

∆ weight kg +1.9 +4.7 +5.7

Hypoglycemia* 2.3 5.7 12.0

Holman RR et al. N Engl J Med 2007;357:1716-30

* Mean number of events confirmed <56 mg/dL or severe per patient per year

4T Study3-year results

Basal 1-2x Premixed 2x Prandial 3x

A1c % 6.9 7.1 6.8

∆ weight kg +3.6 +5.7 +6.4

Hypoglycemia* 1.7 3.0 5.7


* Mean number of events confirmed <56 mg/dL or severe per patient per year

A1c over 3 years in 4T

Biphasic

±prandial

Prandial

±basal

Basal

±prandial

Overall

6.9%

(6.8 to 7.1)

Median±95% confidence interval


Body weight over 3 years in 4T

Median±95% confidence interval

Biphasic

±prandial

Prandial

±basal

Basal

±prandial


DCCTWeight Gain

Purnell, et al. JAMA. 1998;280:140-146

Conventionally Treated Group

Intensively Treated Group30

25

20

15

10

5

0

-5

1 2 3 4

Quartile of Weight Gain

Mean change weight

(kg)

Additional pramlintide studies

Currently approved indication:Pramlintide plus prandial insulin

Approaches under investigation:Pramlintide with basal insulin

Pramlintide vs placebo

Pramlintide vs prandial aspart

Pramlintide in obesity without diabetes

Three studies of pramlintide added to insulin

Concurrent Rx Basal-bolus Basal insulin Basal insulin

insulin±OAD ±OAD ±OAD

Study treatment P 120 mcg P 60/120 mcg P 60/120 mcg

vs baseline vs PLBO vs rapid insulin

Duration of Rx (wk) 24 16 24

N of subjects 166 211 112

BMI (kg/m2) 39 35 36

Duration of DM (yr) 13 11 9

A1c baseline (%)8.3 8.5 8.2

A1c ∆ (%) -0.56 -0.34 +0.2

Wt ∆ (kg) -2.8 -2.3 -4.4

INSTEAD“Clinical

Practice”

Pramlintide added to basal-bolus therapy -- 155 study 6-month open-label clinical experience

130

150

170

190

210

230

acB pcB acL pcL acD pcD hs

*

*

*

*

*

* *

Glucose

mg/dLMean+ SE

Baseline

6 Months

A1c 8.3%

7-point self-monitored glucose profiles

*P <0.05

A1c -0.6%

Wt -2.8 kg

Insulin -6.4%

Karl D et al. Diab Tech Ther 2007;9: 191-9








BMI (kg/m2) 39 35 36


A1c baseline (%)8.3 8.5 8.2

A1c ∆ (%) -0.56 -0.34 +0.2

Wt ∆ (kg) -2.8 -2.3 -4.4

INSTEAD“Clinical

Practice”

Pramlintide added to basal insulin -- 156 study

4-months treatment compared with placebo

100

125

150

175

200

225

250

Baseline

Week 16

Breakfast Lunch Dinner Bedtime

Placebo

* *

* *

Glucose

mg/dL

Baseline

Week 16

Breakfast Lunch Dinner Bedtime

Pramlintide

*Mean ± SE

*P<0.005

Mean ± SE

*P<0.01

7-point self-monitored glucose profiles

Riddle M et al. Diabetes Care 2007;30:2794-99

Pramlintide added to titrated basal insulin


ITT LOCF *p <0.05

0 4 8 12 16-1.0

-0.8

-0.6

-0.4

-0.2

-0.0

*

*

-0.3% ± 0.1

Pramlintide + glargine

A1c %Mean + SE

Weeks

Baseline A1c

8.5 ± 0.1%

8.5 ± 0.1%

Placebo + glargine

Change of A1c

Riddle M et al. Diabetes Care 2007;30: 2794-99



0 4 8 12 16-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

Weeks

*** ***

*** ***

***

-2.3 ± 0. 4 kg ITT LOCF ***p <0.001

Baseline weights

103 ± 1.8 kg

103 ± 1.7 kg

kilogramsMean + SE

Pramlintide + glargine

Placebo + glargine

Change of weight









BMI (kg/m2) 39 35 36


A1c baseline (%)8.3 8.5 8.2

A1c ∆ (%) -0.56 -0.34 +0.2

Wt ∆ (kg) -2.8 -2.3 -4.4

INSTEAD“Clinical

Practice”

Baseline Characteristics INSTEAD trial

Data are mean ± SD, except where indicated

PRAM n=56 RAI n=56

Sex (Male / Female; %) 61 / 39 66 / 34

Age (y) 55 ± 11 54 ± 10

Duration of diabetes (y) 10 ± 7 9 ± 6

Body weight (kg) 108 ± 22 103 ± 18

BMI (kg/m2) 36 ± 6 36 ± 6

A1C (%) 8.2 ± 0.8 8.3 ± 0.8

FPG (mg/dL) 155 ± 40 164 ± 50

Prior OAD use (MET / SFU / TZD; %) 79 / 70 / 38 77 / 61 / 39

Prior insulin use (Yes; %) 48 43

Baseline insulin use (U/day) 20 ± 10 24 ± 12



6-months treatment compared with rapid-acting insulin

0 4 8 12 16 20 24

20

40

60

80

100

RAIInitiation

RAI basalPRAM

RAI total

0 4 8 12 16 20 246.0

6.5

7.0

7.5

8.0

8.5

9.0 RAI

PRAM

%

4 8 12 16 20 24-2

-1

0

1

2

3

4

5

6

*************

Change

From

Baseline

(kg)

0 4 8 12 16 20 24105

125

145

165

FPG

(mg/dL)

FPG A1C

Weight Insulin Use

Time (weeks)Time (weeks)

Riddle MC et al. Diabetes Care 2009;32:1577-82

RAI

PRAM

RAI

PRAM

mg/dl

∆ kg

units/day

Pramlintide in non diabetes?

Reduced food intake in animal studies

Reduced food intake in buffet cross-over

Pramlintide Dose-Escalation Study Design• Randomized, double-blind, placebo-controlled, multicenter study in obese subjects:

– Without type 2 diabetes (N = 160)

– With type 2 diabetes, treated with diet and exercise or metformin (N = 44)

• Study treatment: 16 weeks

– Pramlintide was initiated at 60 µg TID and escalated in 30-µg increments as

tolerated up to 240 µg TID

– No lifestyle intervention

• Follow-up: 8 weeks

– Subjects were monitored for 8 weeks following treatment discontinuation

Aronne L, et al. J Clin Endocrinol Metab 2007;92:2977-2983.

Pbo Lead-In

(1 wk)

Escalation

(4 wk)

Maintenance (12 wk)

Pramlintide or Placebo 120, 180 or 240 mg TID

Follow-Up (8 wk)

(No Pramlintide)

-1 0 4 16 24Time (wk)

Pramlintide Elicited Reductions in Body Weight

Regardless of Presence or Absence of Diabetes

Placebo

Pramlintide

Mean±SE at Wk 16; **P<0.01; ***P<0.001 compared to placebo;

Evaluable N = 145; Mixed effects model N = 204

0 2 4 8 12 16 24 16-5

0

0 2 4 8 12 16 24 16

-4

-3

-2

-1

1

-5

0

Time (wk)

Escal Maintenance Follow-up

*

***

*

*

***

**

Mixed effectsmodelEvaluable

0 2 4 8 12 16 24 16-5

0

0 2 4 8 12 16 24 16

-4

-3

-2

-1

1

-5

0

Time (wk)


***

***

***

******

*

***


With Type 2Without Type 2

∆ kg ∆ kg

Aronne et al. J Clin Endocrinol Metab 2007;92:2977-2983.

Cumulative Incidence of Nausea (ITT) Weight Effect by Nausea Occurrence

Placebo (n = 67)

Pramlintide (n = 137)

Pramlintide – nausea

Pramlintide – no nausea

Pramlintide Reduced Body Weight Independent

of Nausea

0 1 2 3 4 5 6 7 8 9 1011 12131415160

10

20

30

40

50 Escalation Maintenance

PlaceboLead-In

Week of Study

Evaluable: Nausea n = 37; No nausea n = 60

Mixed effects model Nausea n = 52; No nausea n = 85

0 2 4 8 12 16 24 16-5

0

0 2 4 8 12 16 24 16

-4

-3

-2

-1

1

-5

0

Time (wk)



∆ kg

Aronne et al. J Clin Endocrinol Metab 2007;92:2977-2983.

%

with

nausea

Study Design – Main Study and Extension• 4-mo double-blind main study:

– Randomized, placebo-controlled, dose-ranging, multicenter study in obese

subjects (N = 408)

– Three SC injections of study medication per day, 15 min prior to major meals

– Pramlintide BID regimen included placebo 15 min prior to midday meal

– All subjects participated in structured lifestyle intervention (LSI) encompassing

diet, exercise and behavior modification (LEARN®)

• 8-mo single-blind extension:

– All subjects (N = 209) continued with their pre-existing regimens during the

placebo- controlled extension

– Throughout extension LSI was geared towards weight maintenance

0 4 12Month

Weight loss LSI

Placebo

Lead-In

Extension - Weight maintenance LSI

240 µg BID

360 µg BID

Placebo TID

360 µg TID

8

Double-blind Study Single-blind Extension

Smith S.R., et. al. Diabetes Care 2008; 31:1816-1823.

240 µg TID

120 µg TID

120 µg BID

Pramlintide in obese non-diabetic subjects

in conjunction with life-style intervention

Mean ± SE; *P<0.05; **P<0.01 compared to placebo; Significance is indicated only at 4-mo and 12-mo.

0 4 8 12 12

0

0 4 8 12 12

-11

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

1

0

ITT-LOCFEvaluable

*

**

*

Double-blind study Single-blind extension

Number of Subjects

Placebo

120 µg BID

240 µg BID

360 µg BID

36

38

32

39

36

38

32

39

17

24

17

21

17

25

16

21

17

24

17

21

27

28

25

32

Placebo

120 mg

240 mg

360 mg

Time (mo)

0 4 8 12 12

0

0 4 8 12 12

-11

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

1

0

**

*

**

**

*

***

*

ITT-LOCFEvaluable

Double-blind study Single-blind extension

Number of Subjects

Placebo

120 µg TID

240 µg TID

360 µg TID

36

38

45

42

36

38

45

42

17

25

23

18

17

25

23

18

17

25

23

17

27

29

30

38

Time (mo)

Smith et al. Diabetes Care. 2008;31:1816-1823

BID dosing TID dosing

∆ kg ∆ kg

Proportion of Evaluable Subjects Achieving

≥5% and ≥10% Weight Loss by Month 12

*P<0.05 compared to placebo

0

10

20

30

40

50

60

70

80

90

100

Pbo 120 120 240 240 360 360

* **

18%25%

44%41%

57%57%65%

BID TID BID TID BID TID

0

10

20

30

40

50

60

70

80

90

100

12%8%

40%

24%22%

43%35%

BID TID BID TID BID TID

≥10% Weight Loss≥5% Weight Loss

Smith et al. Diabetes Care. 2008;31:1816-1823

Pbo 120 120 240 240 360 360

Summary

• The amylin analog pramlintide used in conjunction

with meal-time insulin can improve glucose control,

often in association with weight loss

• Limitations of relying on prandial insulin for glucose

control include weight gain and hypoglycemia

• Studies using pramlintide in T2DM added to basal

insulin and in obese non-diabetic individuals suggest

possible benefits which deserve further study

Thank you for your attention!

pramlintide & weight - denver, colorado & weight diane m karl md the endocrine clinic &...

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