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
Holman RR et al. N Engl J Med 2009;361:1736-47
* 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
Holman RR et al. N Engl J Med 2009;361:1736-47
Body weight over 3 years in 4T
Median±95% confidence interval
Biphasic
±prandial
Prandial
±basal
Basal
±prandial
Holman RR et al. N Engl J Med 2009;361:1736-47
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
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 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
4-months treatment compared with placebo
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
Pramlintide added to titrated basal insulin
4-months treatment compared with placebo
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
Riddle M et al. Diabetes Care 2007;30: 2794-99
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”
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
Riddle M et al. Diabetes Care 2009;32: 1577-82
Pramlintide added to titrated basal insulin
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)
Escal Maintenance Follow-up
***
***
***
******
*
***
Mixed effectsmodelEvaluable
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)
Escal Maintenance Follow-up
Mixed effectsmodelEvaluable
∆ 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!