Faculty Disclosure Mikayla Spangler, PharmD, BCPS Dr. Spangler has listed no financial...
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Transcript of Faculty Disclosure Mikayla Spangler, PharmD, BCPS Dr. Spangler has listed no financial...
Faculty Disclosure
Mikayla Spangler, PharmD, BCPS
Dr. Spangler has listed no financial interest/arrangement that would be
considered a conflict of interest.
Weight Loss in Diabetes-
It IS Possible!Mikayla Spangler, Pharm.D.,
BCPS
Objective
Identify medications used for diabetes that may aid in weight loss
Special focus on incretin mimetics and amylin analog
Overview of Diabetes Medications
Class Affect on Weight
Insulin Sulfonylureas Thiazolidinediones Dipeptidyl peptidase-4 inhibitors
Biguanides Incretin mimetics Amylin analog
New Agents with Weight Loss
Glucagon-Like Peptide-1 (GLP-1) receptor agonists
2005: exenatide (Byetta©)2010: liraglutide (Victoza©)
Amylin analog2004: pramlintide (Symlin©)
GLP-1 AGONISTS
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
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
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
¤
¤
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
¤
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
¤¤
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
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.
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
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
‡
3 Year Open-Label Extension
Open-Label Extension of Phase 3 AMIGO trialsShowed continued weight loss at 3 yearsTotal weight loss: -5.3 kg
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
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
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.
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.
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]
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.
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]
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.
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.
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.
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.
AMYLIN ANALOG
Amylin Analog Modes of Action
Pancreas Amylin
Stomach
Food Intake
─
Gastric Emptying
─Liver
PostprandialGlucagon
─
Glucose Production
Glucose Uptake
PlasmaGlucose
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
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
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.
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
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.
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
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.
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.
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.
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