faculty disclosure mikayla spangler, pharmd, bcps dr. spangler has listed no financial...
TRANSCRIPT
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Faculty Disclosure
Mikayla Spangler, PharmD, BCPS
Dr. Spangler has listed no financial interest/arrangement that would be
considered a conflict of interest.
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Weight Loss in Diabetes-
It IS Possible!Mikayla Spangler, Pharm.D.,
BCPS
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Objective
Identify medications used for diabetes that may aid in weight loss
Special focus on incretin mimetics and amylin analog
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Overview of Diabetes Medications
Class Affect on Weight
Insulin Sulfonylureas Thiazolidinediones Dipeptidyl peptidase-4 inhibitors
Biguanides Incretin mimetics Amylin analog
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New Agents with Weight Loss
Glucagon-Like Peptide-1 (GLP-1) receptor agonists
2005: exenatide (Byetta©)2010: liraglutide (Victoza©)
Amylin analog2004: pramlintide (Symlin©)
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GLP-1 AGONISTS
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GLP-1 Modes of Action in Humans
Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Larsson H, et al. Acta Physiol Scand. 1997;160:413-422; Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Drucker DJ. Diabetes. 1998;47:159-169.
Stomach: regulates gastric
emptying
Brain: promotes satiety and reduces food intake
Liver: reduces hepaticglucose output-cells: enhances
glucose-dependent insulin
secretion
-cells: reduces postprandial
glucagon secretion
GLP-1: secreted by intestinal L-cells in response to food
intake
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Exenatide
Developed from the saliva of the Gila monster
50% homology with human GLP-1
Only approved with oral antidiabetic agentsWeight loss data from 3 AMIGO trials
AMIGO 1Metformin + placebo v. metformin + exenatide
AMIGO 2Sulfonylurea + placebo v. sulfonylurea + exenatide
AMIGO 3Metformin + sulfonylurea + placebo v. metformin + sulfonylurea + exenatide
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AMIGO 1
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
Exenatide 5 mcg BIDExenatide 10 mcg BIDPlacebo
Weight change (kg) at 30 weeks
Data from DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100 ¤ P<0.05 v. placebo
¤
¤
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AMIGO 2
-2
-1.5
-1
-0.5
0
0.5
1
Exenatide 5 mcg BIDExenatide 10 mcg BIDPlacebo
Weight change (kg) at 30 weeks
Data from Buse JB, et al. Diabetes Care. 2004;27:2628-2635 ¤ P<0.05 v. placebo
¤
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AMIGO 3
Series1
-2
-1.5
-1
-0.5
0
0.5
1
Exenatide 5 mcg BIDExenatide 10 mcg BIDPlacebo
Weight change (kg) at 30 weeks
Data from Kendall DM, et al. Diabetes Care. 2005;28:1083-1091 ¤ P<0.05 v. placebo
¤¤
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Thiazolidinedione (TZD) Trial
-2.5
-2
-1.5
-1
-0.5
0
0.5
Exenatide 10 mcg BIDPlacebo
Weight change (kg) at 16 weeks
Data from Zinman B, et al. Ann Intern Med. 2007;146:477-485 Ж P<0.001 v. placebo
Ж
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Other Trials
Other studies with metformin + sulfonylurea + exenatide or insulin
Study 3- Crossover study with metformin or sulfonylurea had -2.2 kg difference in wt. with exenatide vs. titrated insulin glargine (p<0.001)
Wt. Change (kg)
P value
Study 1Exenatide 10 mcg BID -2.3 P<0.000
1Titrated insulin glargine +1.8
Study 2Exenatide 10 mcg BID -2.5 P<0.001
Titrated premix insulin analog
+2.9
Data from Heine R, et al. Ann Intern Med 2005;143:559-69; Nauck M, et al. Diabetologia 2007;50:259-67; Barnett AH, et al. Clin Ther 2007;29:2333-48.
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Other Trials
Wt. Change (kg)
P value
Study 4Exenatide 10 mcg BID -2.7 P<0.001
Insulin glargine +3
Study 5Exenatide -3.6 P<0.000
1Insulin glargine +1
Data from Davies M, et al. DOM 2009;11:1153-62; Bunck M, et al. Diabetes Care 2009;32:762-8
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Drug Naïve Trial
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
Exenatide 5 mcg BIDExenatide 10 mcg BIDPlacebo
Weight change (kg) at 24 weeks
‡P<0.007 v. placeboData from Moretto TJ, et al. Clin Ther. 2008;30:1448-1460
‡
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3 Year Open-Label Extension
Open-Label Extension of Phase 3 AMIGO trialsShowed continued weight loss at 3 yearsTotal weight loss: -5.3 kg
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Liraglutide
Analog of human GLP-197% homology
Only approved with oral antidiabetic agentsWeight loss data from 6 LEAD trials
LEAD 1 glimepiride + rosiglitazone or placebo or liraglutide
LEAD 2 metformin + glimepiride or placebo or liraglutide
LEAD 3 glimepiride v. liraglutide
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Liraglutide
LEAD trials (cont.)LEAD 4
metformin + rosiglitazone + placebo v. metformin + rosiglitazone + liraglutide
LEAD 5 metformin + glimepiride + placebo v. metformin + glimepiride + insulin glargine or metformin + glimepiride + liraglutide
LEAD 6Metformin or sulfonylurea or both + exenatide or liraglutide
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LEAD 1
-1
0
1
2
3
4
5
Liraglutide 0.6 mgLiraglutide 1.2 mgLiraglutide 1.8 mgPlaceboRosiglitazone
¤ P<0.05 v. placebo§ P< 0.0001 v. rosiglitazone
¤ §
¤ §
¤
Weight Change (lb) at 26 weeks
Data from Marre M, et al. Diabet Med. 2009; 26:268-278.
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LEAD 2
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
Liraglutide 0.6 mgLiraglutide 1.2 mgLiraglutide 1.8 mgPlaceboGlimepiride
Ж P<0.001 v. placebo § P<0.0001 v. glimepiride
Ж §
§
Ж §Weight Change (lb) at 26 weeks
Data from Nauck MA, et al. Diabetes Care. 2009; 32:84-90.
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LEAD 2 Open Label Extension
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
liraglutide 0.6 mgliraglutide 1.2 mgliraglutide 1.8 mgglimepiride
§ P<0.0001 v. glimepiride
Weight Change (lb) at 2 years
§
§ §
Data from Frid A, et al. Diabetologia. 2009;52(Suppl 1):8. [abstract]
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LEAD 3
-6
-5
-4
-3
-2
-1
0
1
2
3
Liraglutide 1.2 mgLiraglutide 1.8 mgGlimepiride
§ §
§ P<0.0001 v. glimepiride
Weight Change (lb) at 1 year
Data from Garber A, et al. Lancet. 2009; 373:473-481.
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LEAD 3 Open Label Extension
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
Liraglutide 1.2 mgLiraglutide 1.8 mgGlimepiride
♦ p<0.05 v. glimepiride
Weight Change (lb) at 2 years
♦
♦
Data from Garber AJ, et al. Diabetes. 2009; 58(suppl 1):A42. [Abstract]
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LEAD 4
-5
-4
-3
-2
-1
0
1
2
3
Liraglutide 1.2 mgLiraglutide 1.8 mgPlacebo
»
»
» P<0.0001 v. placebo
Weight change (lb) at 26 weeks
Data from Zinman B, et al. Diabetes Care. 2009; 32:1224-1230.
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LEAD 5
-5
-4
-3
-2
-1
0
1
2
3
4
5
Liraglutide 1.8 mgPlaceboInsulin glargine
» §
» P<0.0001 v. placebo§ P< 0.0001 v. glargine
Weight change (lb) at 26 weeks
Data from Russell-Jones D, et al. Diabetologia. 2009; 52:2046-2055.
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LEAD 6
-7.5
-7
-6.5
-6
-5.5
-5
-4.5
-4
Liraglutide 1.8 mgExenatide 10 mcg
Weight Change (lb) Weeks 26-40
Liraglutide → Liraglutide Exenatide → Liraglutide
-0.9 (p=0.0089) -2 (p<0.0001)
Weight Change (lb) to Week 26
Data from Buse JB, et al. Lancet. 2009; 374:39-47 and Buse J, et al. Diabetes Care. 2010;33:1300-03.
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Liraglutide v. Sitagliptin
-8
-7
-6
-5
-4
-3
-2
-1
0
Liraglutide 1.2 mgLiraglutide 1.8 mgSitagliptin 100 mg
§
§
§ P< 0.0001 v. sitagliptin
Weight change (lb) at 26 weeks
Data from Pratley RE, et al. Lancet. 2010; 375:1447-56.
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AMYLIN ANALOG
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Amylin Analog Modes of Action
Pancreas Amylin
Stomach
Food Intake
─
Gastric Emptying
─Liver
PostprandialGlucagon
─
Glucose Production
Glucose Uptake
PlasmaGlucose
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Pramlintide
Pramlintide made to overcome tendency to self-aggregate as natural amylin doesOnly approved in use with insulin4 long term diabetes type 1 trials and 4 long term diabetes type 2 trialsDiabetes Type 1
All studies with insulin
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Diabetes Type 1 Study 1
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
Pramlintide 30 or 60 mcg QIDPlacebo
P- value not reported
Weight change (kg) at 1 year
Data from Whitehouse F, et al. Diabetes Care. 2002;25:724-730
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Diabetes Type 1 Study 2
-2
-1.5
-1
-0.5
0
0.5
Pramlintide 60 mcg TIDPramlintide 90 mcg BIDPramlintide 90 mcg TIDPlacebo
Weight change (kg) at 26 weeks
P- value not reported
Data from Fineman M, et al. Diabetes. 1999;48(Suppl 1): Abstract 0489.
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Diabetes Type 1 Study 3
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
Pramlintide 60 mcg TIDPramlintide 60 mcg QIDPlacebo
Data from Ratner RE, et al. Diabet Med. 2004;21:1204-1212
¥ P<0.027 v. placeboΦ P<0.04 v. placebo
¥ Φ
Weight change (kg) at 1 year
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Diabetes Type 1 Study 4
-1.5
-1
-0.5
0
0.5
1
1.5
Pramlintide 30-60 mcg TIDPlacebo
Weight change (kg) at 29 weeks » P<0.0001 v.
placebo
»
Data from Edelman S, et al. Diabetes Care. 2006;29;2189-95.
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Pramlintide
Diabetes Type 2Study 1
Insulin (±metformin or sulfonylurea) + placebo OR pramlintide
Study 2Insulin (±metformin or sulfonylurea) + placebo OR pramlintide
Study 3Insulin + placebo OR pramlintide
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Diabetes Type 2 Study 1
-2
-1.5
-1
-0.5
0
0.5
1
Pramlintide 90 mcg BIDPramlintide 120 mcg BIDPlacebo TID
Weight change (kg) at 1 year ¤ P<0.05 v. placebo
¤
Data from Hollander PA, et al. Diabetes Care. 2003;26:784-90.
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Diabetes Type 2 Study 2
-2
-1.5
-1
-0.5
0
0.5
1
1.5
Pramlintide 30 mcg TIDPramlintide 75 mcg TIDPramlintide 150 mcg TIDPlacebo
¤ P<0.05 v. placebo
¤
¤
Weight change (kg) at 1 year
¤
Data from Ratner RE, et al. Diabetes Technol Ther. 2002;4:51-61.
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Diabetes Type 2 Study 3
-2
-1.5
-1
-0.5
0
0.5
1
Pramlintide 90 mcg BIDPramlintide 90 mcg TIDPramlintide 120 mcg BIDPlacebo
Weight change (kg) at 26 weeks
P- value not reported
Data from Gottlieb A, et al. Diabetologia. 1999;42(Suppl 1):A232.
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Summary
Many therapies available to treat diabetes
Only few that promote weight lossNew incretin mimetics and amylin analog promote weight loss significantly more than other therapies