Media Briefing

Friday, April 15th 10:00 am – Media briefing begins

Short five to seven minute presentations from physiciansSpeaker #1 – Roger Unger, MD, FACE will provide a brief presentation on his abstract

research: Laying the basis for translational trials, results from models systems studies: Making Type 1 Diabetes Metabolically Nondiabetic

Speaker #2 – Christian Weyer, MD will provide a brief presentation on his abstract research: Clinical Effects of Leptin Replacement in Lipodystrophy Patients

Speaker #3 & #4 – Daniel Einhorn, MD, FACP, FACE, AACE President and Yehuda Handelsman, MD, FACP, FACE, FNLA, AACE President Elect will present the new AACE Diabetes Guidelines

10:25 am – Floor opens to questions from the media 10:30 am – Media Briefing adjourns

SUPPRESSING DIABETES

Type 1 diabetes (T1DM) is caused by,insulin deficiency PLUS glucagon excess, but

only the former is treated.

We propose to treat the other half of thedisorder, the glucagon excess to reduce will eliminate

glucose volatility and its clinical consequences.

Insulin Concentration

-cells

Liver

~2000 U/ml

100 U/ml

20 U/ml

Skeletal muscle

Adipocytes

TARGET TISSUES OF ENDOGENOUS INSULIN

Insulin

~40-80 U/ml

~40-80 U/ml

~40-80 U/ml

EXOGENOUS INSULIN

X 0

0

0

Leptin Suppresses Hyperglucagonemia of Double Dose Streptozotocin Diabetes

Plasma Glucagon (pg/ml)

0

200

400

600

800

Untreateddiabetic

Ad Leptindiabetic

Nondiabetic

p<0.01

N=4N=4 N=5

0

100

200

300

400

500

600

700

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

mg/

dl

Days

GLYCEMIC STABILITY IS RESTORED BY SUPPRESSING GLUCAGON AND

LOWERING INSULIN (0.2U insulin at 10 AM and 5 PM)

Leptin + Low Dose Insulin (0.02 U b.i.d.)

Insulin Dose 0.2 U b.i.d.G=140pg/ml

G=55pg/ml

G=52pg/ml

I=4ng/ml

I=16ng/ml

I=0.7ng/ml

Relics of the Roaring 20’s

Insulin Monotherapy

Dust Binof

History

Antidiabetic Efficacy of GlucagonSuppression in Diabetic Animals and Humans

HORMONE TYPE DIABETES EFFICACY

Somatostatin

Leptin

Leptin

T1DM

Lipodystrophic

T1DM

Excellent

Excellent

Excellent

Excellent

Excellent

?

Animals Humans

0 2 4 60

200

400

600

800

Weeks

mg

/dl

Blood Glucose Levels in Insulin-Deficient Mice: GnR-/- (■) vs Wild Type (●)

STREPTOZOTOCIN

0 2 4 60

200

400

600

800

Weeks

ALLOXAN

mg

/dl

GnR-/- mice provided by Dr. M. Charron

Glucagon: Role in theHyperglycemia of Diabetes

Wild Type Wild Type

GnR-/- GnR-/-

Glucose During OGTT

100

200

300

400

Glu

co

se

(m

g/d

l)OGTT IN GLUCAGON RECEPTOR NULL MICE BEFORE AND AFTER STZ DESTRUCTION OF β-CELLS

0 50 100 150Time (min)

200

BEFORE STZ

AFTER STZ

Insulin During OGTT

0

0.4

0.8

1.2

1.6

0 50 100 150Time (min)

Insu

lin (

ng

/ml)

20

BEFORE STZ

AFTER STZ

Gcgr (-/-)

Stz Gcgr (-/-)

C-peptide During OGTT

0 50 100 150Time (min)

20

100

200

300

400

0

12

QuestionsQuestions

13

Clinical Effects of Leptin Replacement in Lipodystrophy Patients

Clinical Effects of Leptin Replacement in Lipodystrophy Patients

Christian Weyer1, Jean L. Chan1, Karen Lutz1, Wenying Huang1,Elaine Cochran2, Phillip Gorden2

1Amylin Pharmaceuticals, Inc, San Diego, CA, USA

2National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

15

Lipodystrophy (LD) is a rare, debilitating chronic disease with large unmet medical needLipodystrophy (LD) is a rare, debilitating chronic disease with large unmet medical need

Oral EA. Rev Endo Metab Disord. 2003;4:61-77; Chan JL, et al. Endocr Pract. 2010 ;16:310-323

• Characterized by loss of adipose (fat) tissue

• Concomitant deficiency of leptin (fat-cell hormone)

• Accumulation of excess fat in blood, liver, muscle

• Patients typically affected in childhood or adolescence

Rare and severe metabolic/endocrine disorder

• Severe insulin resistance

• Diabetes, often uncontrolled by current medications

• Severe hypertriglyceridemia (high levels of triglycerides in the bloodstream)

• Excess fat accumulation in the liver

• Multiple other co-morbidities

Often severe metabolic abnormalities

• No therapies indicated specifically for the treatment of the metabolic abnormalities associated with lipodystrophy

Large unmet medical need

Prevalence: ~ a few thousand patients worldwide

16

Study introductionStudy introduction

• New analysis of NIH study examining the clinical effects of leptin replacement, with metreleptin, in patients with lipodystrophy

• Long-term study that has been ongoing for > 10 years• Dr. Phillip Gorden (NIH) is Principal Investigator• Includes > 50 patients from the U.S. and other countries• Results (not including the new analysis) published in multiple journals, such

as NEJM, JCI, JCEM, Diabetes

• New analysis:• 55 patients

—Largest lipodystrophy cohort reported to-date• Median follow-up of 2.5 y (up to 9 y)

—Longest follow-up reported to-date

NIH open-label study of metreleptin treatment, N=55 patients with metreleptin exposure ranging from 3 months to 9 years (Data on File, Amylin Pharmaceuticals, Inc.)

17

0 4 8 12 16 20 24 28 32 366.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

41 31 31 27 16 14

Number of Patients

Time (months)

Mea

n (

SE

) H

bA

1c (

%)

0 4 8 12 16 20 24 28 32 360

100

200

300

400

500

600

41 30 30 29 17 13

Number of Patients

Time (months)M

edia

n T

rig

lyce

rid

es (

mg

/dL

)

Efficacy of metreleptin in patients with diabetes and/or hypertriglyceridemia at baselineEfficacy of metreleptin in patients with diabetes and/or hypertriglyceridemia at baseline

Baseline A1C ≥ 7%N = 41 (75%)

Baseline Triglycerides ≥ 200 mg/dLN = 41 (75%)

• Mean ± SE A1C reduction from baseline at Year 3: -2.6 ± 0.6%

• Median (min, max) TG reduction from baseline at Year 3: -374 (-7141, 465) mg/dLTG = triglycerides; NIH open-label study of metreleptin treatment, N = 55 ITT patients with metreleptin exposure ranging from 3 months to 9 years (Data on File, Amylin Pharmaceuticals, Inc.)

18

Safety observationsSafety observations

Adverse events were generally consistent with known co-morbid conditions of lipodystrophy (pancreatitis, proteinuria, autoimmune/chronic hepatitis) or expected pharmacological effects of metreleptin (weight loss or insulin-induced hypoglycemia in the setting of improved insulin sensitivity)

NIH open-label study of metreleptin treatment, N=55 patients with metreleptin exposure ranging from 3 months to 9 years (Data on File, Amylin Pharmaceuticals, Inc.)

19

Questions?Questions?

Oral EA. Rev Endo Metab Disord. 2003;4:61-77; Chan JL, et al. Endocr Pract. 2010 ;16:310-323

• Characterized by loss of adipose (fat) tissue

• Concomitant deficiency of leptin (fat-cell hormone)

• Accumulation of excess fat in blood, liver, muscle

• Patients typically affected in childhood or adolescence

Rare and severe metabolic/endocrine disorder

• Severe insulin resistance

• Diabetes, often uncontrolled by current medications

• Severe hypertriglyceridemia (high levels of triglycerides in the bloodstream)

• Excess fat accumulation in the liver

• Multiple other co-morbidities

Often severe metabolic abnormalities

• No therapies indicated specifically for the treatment of the metabolic abnormalities associated with lipodystrophy

Large unmet medical need

Prevalence: ~ a few thousand patients worldwide

20

AACE Medical Guidelines for Clinical Practice for Developing a

Diabetes Mellitus Comprehensive Care Plan

Dan Einhorn, MD, FACP, FACE – President, AACEYehuda Handelsman, MD, FACP, FACE, FNLA – Chair, DM Guideline

American Association of Clinical Endocrinologists (AACE) Medical

Guidelines for Clinical Practice for Developing a Diabetes Mellitus

Comprehensive Care Plan

WRITING COMMITTEEchairpersons

Yehuda Handelsman, MD, FACP, FACE, FNLA

Jeffrey I. Mechanick, MD, FACP, FACE, FACN

Lawrence Blonde, MD, FACP, FACE

George Grunberger, MD. FACP, FACE

President :Daniel Einhorn, MD, FACP, FACE

AACE Medical Guidelines for Clinical Practice for Developing a Diabetes Mellitus Comprehensive Care PlanPrimary Writers

Zachary T. Bloomgarden, MD, FACE

George A. Bray, MD, MACP, MACE

Sam Dagogo-Jack, MD, FACE

Jaime Davidson, MD, FACP, FACE

Daniel Einhorn, MD, FACP, FACE

Om Ganda, MD, FACE

Alan J. Garber, MD, PhD, FACE

Irl B. Hirsch, MD

Edward S. Horton, MD, FACE

Faramarz Ismail-Beigi, MD, PhD

Paul S. Jellinger, MD, MACE Kenneth L. Jones, MD, AACE Lois Jovanovic, MD, MACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Etie S. Moghissi, MD, FACP,

FACE Eric A. Orzeck, MD, FACP,

FACE Arthur Vinik, MD Kathryn Wynn, MD

Reviewers: Alan J Garber MD, PhD, FACE, Daniel L. Hurley, MD, FACE Farhad Zangeneh MD, FACP, FACE

Prediabetes state

Normal IGT

Clinical disease

Type 2Diabetes

Disability Death

Complications

Complications

Primary Secondary Tertiaryprevention prevention prevention

Type 2 Diabetes: A Progressive Disease

79,000,000 26,000,000

Garber AJ, Handelsman Y, Einhorn D, et al. Endocr Pract. 2008;14:933-46.

http://www.cdc.gov/media/releases/2011/p0126_diabetes

Macrovascular Microvascular

Cerebrovascular disease

Heart disease and hypertension

Ulcers and amputation

Diabetic eye disease(retinopathy, cataracts

macular edema)

Renal disease

Peripheral Neuropathy

Foot problems

Peripheral vascular disease

Diabetes Complications

Erectile dysfunction

Autonomic Neuropathy

9.8 9.5 9.17.9

6.6

27.8

22.9

18.9

1.8 1.7 2.1 1.1 1.8

6.1

10

0

10

20

30

Heart attack Chest pain Coronaryheart

disease

Congestiveheart failure

Stroke Chronickidneydisease

Footproblems

Eye damage

Perc

enta

ge w

ith c

ompl

icat

ions

Diagnosed diabetes

Normal blood sugar levels

Prevalence of Diabetes Macrovascular and Microvascular Complications

Macrovascular Microvascular

American Association of Clinical Endocrinologists. State of Diabetes Complications in America Report. Available at: http://www.aace.com/newsroom/press/2007/images/DiabetesComplicationsReport_FINAL.pdf. Accessed April 18, 2007.

*†

‡

*In NHANES, “chronic kidney disease" refers to people with microalbuminuria (albumin:creatinine ratio >30 µg/mg).†In the NHANES analysis, "foot problems" includes foot/toe amputations, foot lesions, and numbness in the feet.‡"Eye damage" includes a positive response by NHANES participants to the question, "Have you been told diabetes has affected your eyes/had retinopathy?" Retinopathy is damage to the eye's retina. In NHANES, people without diagnosed diabetes were not asked this question, therefore, prevalence information for nondiabetics is not available.

Risk of Complications in Type 2 Diabetes

0

1

2

3

4

5

5.5 6.5 7.5 8.5 9.5

HbA1c

Hazard RatioP<.0001

21% risk decrease per 1% decrement in HbA1c

*Reference category (hazard ratio 1.0) is HbA1c <6% with log linear scales. Data adjusted for age at diagnosis of diabetes, sex, ethnic group, smoking, presence of albuminuria, systolic blood pressure, high and low density LDL and triglycerides.

Adapted from Stratton IM, et al. (UKPDS 35). BMJ. 2000;321:405-412.

Any End Point Related to Diabetes*

AACE 2011 DM GL- New and/or Unique

Easy to follow Questions and answers format-

Evidence-based answers to real life questions

Modified diagnostic criteria for diabetes

New diagnostic Criteria for Gestational Diabetes

Diabetes Comprehensive Care Plan (DCCP)- beyond hyperglycemia presented

AACE 2011 DM GL- New and/or Unique Individualized goals and define personalized

treatment plans

Obesity in DM- management: Lifestyle, Medical & New GI surgical recommendations

Use of newer technologies- insulin pumps and Continuous Glucose Monitoring

Less familiar topics: sleep and breathing disturbances depression & Diabetes,

Special populations: Pre Diabetes, Children, Gestational Diabetes & pregnant women, In Hospital

Glycemic Control and Beyond a comprehensive approach to

managing diabetes

“… although glycemic control- hemoglobin A1c [A1C],

postprandial glucose excursions [PPG], fasting

plasma glucose [FPG]- parameters have an impact

on coronary heart disease (CVD) risk, mortality, a

comprehensive approach managing Obesity and all

CV risk factors- HTN, Lipids & Coagulation achieving

improved clinical outcomes in people with diabetes.”

NORMAL IFG or IGT High Risk for DM

DIABETES

FPG < 100 mg/dl IFG FPG > 100 - 125

mg/dl

FPG > 126 mg/dl

2-h PG < 140 mg/dl

IGT2-h PG > 140 -

199 mg/dl

2-h PG > 200 mgRandom PG >

200 + symptoms

A1C 5.5% to 6.4% For

screening *

≥ 6.5%Secondary **

AACE 2011 Diagnosis of Diabetes & Pre DM

ENDOCRINE PRACTICE Vol 16 No. 2 March/April 2010 155-6

* Requires testing FG or GTT ** Confirm with Glucose when possible

Diagnosis of Gestational Diabetes

Screening

75-g OGTT (100g), 24–28 weeks of gestation

in the AM, overnight fast of at least 8 h.

(The 50g & 1hr test [140] is no more recommended)

Diagnosis

• Fasting - 92 mg/dl ( 5.1 mmol/l) ( 95)

• 1 hr- 180 mg/dl (10.0 mmol/l) (180)

2 hr- 153 mg/dl ( 8.5 mmol/l) (155)

DIABETES CARE, VOLUME 34, SUPPLEMENT 1, JANUARY 2011 S15

How Can Diabetes Be Prevented?

People with pre-diabetes should modify

lifestyle, including

Lose 5-10% of body weight if

overweight or obese

Moderate physical activity (e.g.,

walking) at least 150 min/week   Medications- metformin, precose and perhaps

thiazolidinediones (TZDs)- should be considered

Comprehensive Diabetes Care: Treatment Goals Individualized Goals

Parameter Treatment Goal for Non-Pregnant Adults

Glucose

A1C (%) Individualize based on co-morbidities, duration of disease, hypoglycemia risk, life expectancy≤ 6.5% for most; If can be done safely.< 6% (5%) As close to normal for New, young relative healthy; provided safely.> 7% Less stringent for “less healthy” – multiple co morbidities, labile, short life expectency

FPG (mg/dL) < 110 mg/dL

2- hour PPG (mg/dL) <140 mg/dL

Inpatient hyperglycemia 140-180 mg/dL

Glycemic Goals for Pregnant WomenStatus Goal

Gestational Diabetes

Prepandial ≤95 mg/dL

Postprandial one hour postmeal ≤140 mg/dL or two hour post meal ≤120 mg/dL

Pre-existing DM (either T1DM or T2DM) who become pregnant

A1C ≤6.0%

Preprandial, bedtime and overnight

60-99 mg/dL

Peak postprnadial 100 –129 mg/dL

Comprehensive Diabetes Care: Treatment Goals, cont’d. Parameter Treatment Goal

Lipids (mg/dL)

LDL-C ≤ 70 highest risk; <100 high risk

non-HDL-C < 100 highest risk; <130 high risk

HDL-C > 40 in men; > 50 in women

Triglycerides < 150

Blood Pressure (mm Hg)

Systolic 130

Diastolic 80

Anticoagulant Therapy

Aspirin For secondary CVD prevention or primary prevention for very high risk patients

Surgery for Obesity in Patients with T2DM

• BMI > 30 kg/m2

− laparoscopic-assisted gastric banding in or Roux-en-Y gastric bypass – As approved by FDA

• BMI > 35 kg/m2

− Roux-en-Y gastric bypass to achieve at least short-term weight reduction Patients with T2DM who undergo Roux-en-Y gastric

bypass must have meticulous metabolic postoperative follow-up because of a risk of vitamin and mineral deficiencies and hypoglycemia

THANK YOU QUESTIONS