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  1. Media Briefing Friday, April 15th 10:00 am – Media briefing begins Short five to seven minute presentations from physicians Speaker #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

  2. SUPPRESSING DIABETES Type 1 diabetes (T1DM) is caused by, insulin deficiency PLUS glucagon excess,but only the formeris treated. We propose to treat the other half of the disorder, the glucagon excess to reduce will eliminate glucose volatility and its clinical consequences.

  3. 0 ~40-80 U/ml ~2000 U/ml ~40-80 U/ml 100 U/ml 0 ~40-80 U/ml 20 U/ml 0 Insulin EXOGENOUS INSULIN TARGET TISSUES OF ENDOGENOUS INSULIN Insulin Concentration X a-cells Liver Adipocytes Skeletal muscle

  4. Leptin Suppresses Hyperglucagonemia of Double Dose Streptozotocin Diabetes Plasma Glucagon (pg/ml) p<0.01 800 600 400 200 0 Nondiabetic Untreated diabetic Ad Leptin diabetic N=4 N=4 N=5

  5. GLYCEMIC STABILITY IS RESTORED BY SUPPRESSING GLUCAGON AND LOWERING INSULIN (0.2U insulin at 10 AM and 5 PM) 700 Insulin Dose 0.2 U b.i.d. I=4ng/ml G=140pg/ml 600 500 400 mg/dl 300 200 G=52pg/ml 100 Leptin + Low Dose Insulin (0.02 U b.i.d.) I=0.7ng/ml 0 I=16ng/ml G=55pg/ml 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Days

  6. Insulin Monotherapy Relics of the Roaring 20’s Dust Bin of History

  7. Antidiabetic Efficacy of Glucagon Suppression in Diabetic Animals and Humans HORMONE TYPE DIABETES EFFICACY Animals Humans Excellent Excellent T1DM Somatostatin Leptin Lipodystrophic Excellent Excellent Leptin T1DM Excellent ?

  8. 800 600 400 200 0 0 2 4 6 Weeks Glucagon: Role in the Hyperglycemia of Diabetes Blood Glucose Levels in Insulin- Deficient Mice: GnR-/- (■)vs Wild Type (●) STREPTOZOTOCIN ALLOXAN 800 Wild Type Wild Type 600 400 mg/dl mg/dl GnR-/- GnR-/- 200 0 0 2 4 6 Weeks GnR-/- mice provided by Dr. M. Charron

  9. OGTT IN GLUCAGON RECEPTOR NULL MICE BEFORE AND AFTER STZ DESTRUCTION OF β-CELLS C-peptide During OGTT Glucose During OGTT Insulin During OGTT 1.6 400 400 C-peptide (pM) BEFORE STZ Gcgr (-/-) 1.2 300 BEFORE STZ 300 Glucose (mg/dl) AFTER STZ Insulin (ng/ml) 0.8 200 200 Stz Gcgr (-/-) 0.4 100 100 AFTER STZ 0 0 0 0 50 100 150 20 0 50 100 150 0 50 100 150 20 20 Time (min) Time (min) Time (min)

  10. Questions

  11. 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

  12. Lipodystrophy (LD) is a rare, debilitating chronic disease with large unmet medical need Rare and severe metabolic/endocrine disorder • 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 Often severe metabolic abnormalities • 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 Large unmet medical need • No therapies indicated specifically for the treatment of the metabolic abnormalities associated with lipodystrophy Prevalence: ~ a few thousand patients worldwide Oral EA. Rev Endo Metab Disord. 2003;4:61-77; Chan JL, et al. Endocr Pract. 2010 ;16:310-323

  13. Study 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.)

  14. Efficacy of metreleptin in patients with diabetes and/or hypertriglyceridemia at baseline Baseline Triglycerides ≥ 200 mg/dL N = 41 (75%) Baseline A1C ≥ 7% N = 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/dL TG = 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.)

  15. Safety 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.)

  16. Questions? Rare and severe metabolic/endocrine disorder • 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 Often severe metabolic abnormalities • 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 Large unmet medical need • No therapies indicated specifically for the treatment of the metabolic abnormalities associated with lipodystrophy Prevalence: ~ a few thousand patients worldwide Oral EA. Rev Endo Metab Disord. 2003;4:61-77; Chan JL, et al. Endocr Pract. 2010 ;16:310-323

  17. AACE Medical Guidelines for Clinical Practice for Developing a Diabetes Mellitus Comprehensive Care Plan Dan Einhorn, MD, FACP, FACE – President, AACE Yehuda Handelsman, MD, FACP, FACE, FNLA – Chair, DM Guideline

  18. American Association of Clinical Endocrinologists (AACE) Medical Guidelines for Clinical Practice for Developing a Diabetes Mellitus Comprehensive Care Plan President :Daniel Einhorn, MD, FACP, FACE WRITING COMMITTEE chairpersons Yehuda Handelsman, MD, FACP, FACE, FNLA Jeffrey I. Mechanick, MD, FACP, FACE, FACN Lawrence Blonde, MD, FACP, FACE George Grunberger, MD. FACP, FACE

  19. 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

  20. Type 2 Diabetes: A Progressive Disease Type 2 Diabetes Normal IGT Disability Death Complications Clinical disease Prediabetes state Complications 79,000,000 26,000,000 Primary Secondary Tertiary prevention prevention prevention Garber AJ, Handelsman Y, Einhorn D, et al. Endocr Pract. 2008;14:933-46. http://www.cdc.gov/media/releases/2011/p0126_diabetes

  21. Diabetes Complications Macrovascular Microvascular Cerebrovascular disease Diabetic eye disease (retinopathy, cataracts macular edema) Heart disease and hypertension Autonomic Neuropathy Erectile dysfunction Renal disease Peripheral vascular disease Peripheral Neuropathy Ulcers and amputation Foot problems

  22. Prevalence of Diabetes Macrovascular and Microvascular Complications ‡ † * Macrovascular Microvascular *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. 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.

  23. Risk of Complications in Type 2 Diabetes Any End Point Related to Diabetes* 5 4 3 2 Hazard Ratio P<.0001 1 0 5.5 6.5 7.5 8.5 9.5 HbA 1c 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.

  24. 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

  25. 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

  26. Glycemic Control and Beyond a comprehensive approach to managing diabetes • “… although glycemiccontrol- 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 managingObesity and all CV risk factors- HTN, Lipids & Coagulation achieving improved clinical outcomes in people with diabetes.”

  27. AACE 2011 Diagnosis of Diabetes & Pre DM * Requires testing FG or GTT ** Confirm with Glucose when possible ENDOCRINE PRACTICE Vol 16 No. 2 March/April 2010 155-6

  28. 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

  29. 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

  30. Comprehensive Diabetes Care: Treatment Goals Individualized Goals

  31. Glycemic Goals for Pregnant Women

  32. Comprehensive Diabetes Care: Treatment Goals, cont’d.

  33. 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

  34. THANK YOU QUESTIONS