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