leveraging weight loss in the treatment of type 2 diabetes part 4 of 4
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Leveraging Weight Loss in the Treatment of Type 2 Diabetes
Part 4 of 4
Amylin Insulin
Amylin the Hormone
• 37-amino acid peptide• Colocated and cosecreted with insulin from
pancreatic cells • Deficient in diabetes
Unger RH, et al. Williams Textbook of Endocrinology. 8th ed. 1992;1273-1275.Photographs reprinted with permission of Elsevier.
Pramlintide
• Synthetic analog of the -cell hormone, amylin
• Pramlintide limits postprandial glucose excursions through at least 3 mechanisms of action
– Slows gastric emptying
– Decreases postprandial hypersecretion of glucagon
– Increases satiety, leading to decreased caloric intake and potential weight loss
Chapman I, et al. Diabetologia. 2005;48:838-848. Fineman M, et al. Horm Metab Res. 2002;34:504-508.Kong M-F, et al. Diabetologia. 1998;41:577-583. Kruger DF, et al. Drugs. 2004;64:1419-1432.
Effect of Pramlintide Adjunctive Therapy on Weight in Individuals With Type 2 Diabetes
0 39 5226-2.0
13
-1.5
-1.0
-1.5
1.5
1.0
0.5
0.0
Placebo
Weeks
Ch
ang
e in
Wei
gh
tF
rom
Bas
elin
e (k
g)
*P<.05 vs placebo.
Hollander PA, et al. Diabetes Care. 2003;26:784-790.Pramlintide [prescribing information]. http://www.fda.gov/cdev/foi/label/2005/021332lbl.pdf.Symlin® [package insert]. San Diego, CA: Amlyn Pharmaceuticals; 2007.
*
*
-0.3% ± 0.1
∆ A
1C (
%)
Time (weeks)
0 4 8 12 16-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
Time (weeks)
† †
† †
†
-2.3 ± 0. 4 kg
∆ B
od
y W
eig
ht
(kg
)
Placebo + Insulin GlarginePramlintide + Insulin Glargine
Baseline A1C8.5 ± 0.1%8.5 ± 0.1%
Baseline Weight.103 ± 1.8 kg103 ± 1.7 kg
Mean±SE; ITT LOCF: Placebo (n=106); Pramlintide (n=105); *P<.05 vs placebo; †P<.001 vs placebo.Riddle M, et al. Diabetes Care. 2007;30:2794-2799.
0 4 8 12 16-1.0
-0.8
-0.6
-0.4
-0.2
-0.0
Pramlintide Lowers A1C and Weight in Individuals With T2DM on Basal Insulin
Multihormonal Control of Body Weight:Role of Fat-, Gut-, and Islet-Derived Signals
Leptin (r-met human)(AC164594)
Pramlintide(AC137)
PYY3-36 (synthetic)(AC162352)
Clinical-Stage Compounds
Adapted from Badman MK, et al. Science. 2005;307:1909-1914.
Weeks
Leptin
-20
-15
-10
-5
0
% ∆
Bo
dy
Wei
gh
t(v
ehic
le c
orr
ecte
d)
-250 1 2 3
Fen/phen1
Roux-en-Y2
Vehicle
Amylin
Amylin+Leptin
½ Dose:Amylin+Leptin+PYY3-36
DIO = diet-induced obese; Continuous infusion of peptides at full doses (osmotic minipump).1. Weintraub M, et al. Clin Pharmacol Ther. 1992;51(5):602-601. 2. Stylopoulos N, et al. Surg Endosc. 2005;19:942-946. 3. Roth JD, et al. Proc Natl Acad Sci U S A. 2008;105:7257-7262. 4. Roth J, et al. Obesity. 2006;14(suppl 9):A57-A58. Abstract 177-P.
Means of Achieving Greater Weight Loss: Integrated Therapy With 3 Neurohormones in DIO Rats
Bariatric Surgery: Gastrorestrictive Procedures
Vertical-Banded Gastroplasty
Gastric Bypass(Roux-en-Y)
Gastric Banding
Out of Favor Gold StandardCommonly Used
American Society for Bariatric Surgery. http://www.asbs.org. Accessed May 30, 2003. Mun EC, et al. Gastroenterology. 2001;120:669-681. Philadelphia, PA. Elsevier; 2003:275-298. Pratt JSA, et al. In: Office Management of Obesity.
Diabetes Remits After Adjustable Gastric Banding
• Unblinded, randomized, controlled trial of 60 individuals with type 2 diabetes diagnosed within preceding 2 years
• Diabetes remission defined by A1C <6.2%, taking no diabetes medications
Surgery Control P Value
Weight (kg)
-21.110.5 -1.55.4 <.001
A1C (%) -1.811.24 0.381.26 <.001
TG (mg/dL) -71.792.9 -2.1120.6 .02
HDL-C(mg/dL)
12.69.8 2.66.1 <.001
% Achieving Remission of Diabetes
Dixon JB, et al. JAMA. 2008;299:316-323.
73
13
0
20
40
60
80
100
Surgery Conventional
Bariatric Surgery: Diabetes• Compared to 2 year data, about half of those in remission
after surgery will need treatment for diabetes at 10-year follow-up1
• In a 10-year follow-up study of all individuals2
– gastric bypass associated with 40% lower mortality– 56% reduction in death from coronary artery disease– 92% lower death rate from “diabetes”
1. Sjostrom L, et al. N Engl J Med. 2004;351:2683-2693.
2. Adams TD, et al. N Engl J Med. 2007;357:753-761.
National Survey Cites Need for New Medical Options for Controlling Type 2 Diabetes• Survey of 636 patients with diabetes and 409 primary care physicians
in United States• Both groups said they lack the tools to successfully manage diabetes
over time– 88% of patients and 92% of physicians expressed need for better
treatment options• 60% of patients are at least somewhat dissatisfied with the weight
gain due to their current diabetes medication• Both physicians and patients desire new antihyperglycemic therapies
that minimize side effects of hypoglycemia and weight gain• Physicians may overestimate patients’ fear of needles
– 87% of physicians report patients fear needles– 36% of patients expressed such fear
http://www.devicespace.com/news_story.aspx?NewsEntitld=2264. Accessed April 9, 2008.
Bo
dy
We
igh
t (l
b)
200
220
240
260
280
300
320
Adapted from Kendall DM, et al. © 2004 International Diabetes Center, Minneapolis, MN. All rights reserved.
Years
DiabetesDiagnosis
Onset
Prediabetes (IFG, IGT)Metabolic Syndrome
Fasting Glucose
Postmeal Glucose
Glu
co
se
(m
g/d
L)
50
100
150
200
250
300
350
Obesity, Inactivity,Genetics
Re
lati
ve
Fu
nc
tio
n
-10 -5 0 5 10 15 20 25 30
Insulin Resistance
Insulin Response
0
50
100
150
200
250
-15
Progressive -Cell Defect (glucose specific)
Amylin Response
Oral Agents/Incretin Enhancers
Basal Insulin
Basal/Bolus Insulin
Amylin Replacement
Natural History of Type 2 Diabetes and Obesity
• Weight gain from diabetes medications– Worsens cardiovascular risk factors
• Especially blood pressure– Is unacceptable for patients
• Will not choose therapy known to cause weight gain• May discourage patients from taking medications
• Is avoidable with several antihyperglycemic therapies– Metformin– Sitagliptin– Exenatide– Pramlintide
• Data from bariatric surgery is promising
Summary
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