1. Incretins: Expanding Role in Treatment Strategies Pediatric Type 1 Diabetics (n=8) Insulin dose reduced 20% with exenatide dosing – mixed meal

2. Incretins (DPP-IV inhibitors): Special Populations: Geriatrics Pharmacology Recommendations Metformin – still first line for most Less effective in many GFR - <30 – no, 30-50 reduce dose Glyburide – never DPP-IV inhibitors - recommended

3. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities -Coronary Disease -Heart Failure -Renal disease -Liver dysfunction -Hypoglycemia  Metformin: CVD benefit (UKPDS)  Avoid hypoglycemia  ? SUs & ischemic preconditioning  ? Pioglitazone &  CVD events  ? Effects of incretin-based therapies Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

4. Stomach Islet GI Tract Brain Hypothalmus Hind Brain Peptide Therapeutics: Incretins (GLP-1 and GIP) Visceral Fat Cell Vagal Afferents Leptin Amylin Insulin GLP-1 Glicentin Oxyntomodulin Ghrelin GIP Adiponectin Visfatin Resistin Glucagon CCK Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914 PYY 3-36 Cardiovascular Incretins Exenatide – Bydureon, Byetta Liraglutide - Victoza DPP-IV Inhibitors Sitagliptin – Januvia Linagliptin – Tradjenta Saxagliptin - Onglyza Incretins Exenatide – Bydureon, Byetta Liraglutide - Victoza DPP-IV Inhibitors Sitagliptin – Januvia Linagliptin – Tradjenta Saxagliptin - Onglyza Cardiovascular Outcome Trials TECOS - sitagliptin EXSCEL – weekly exenatide LEADER – liraglutide ELIXA – lixisenitide SAVOR - saxagliptin

5. ACCORD:Mortality Hazard Ratios for Post- Randomization Prescription of Glycemia Medications Adjusted for Baseline Participant Characteristics ACCORD Study Group. Presented at the ADA Scientific Sessions, San Francisco, June 2008 RR

6. Peptide Therapeutics: Incretins (GLP-1 and GIP) Exenatide vs. Non-Exenatide – Cardiovascular Events

7. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities -Coronary Disease -Heart Failure -Renal disease -Liver dysfunction -Hypoglycemia  Metformin: CVD benefit (UKPDS)  Avoid hypoglycemia  ? SUs & ischemic preconditioning  ? Pioglitazone &  CVD events  ? Effects of incretin-based therapies Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] Glyburide (and older) – Should never be used Glimepiride or Glipizide if any SU

8. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities -Coronary Disease -Heart Failure -Renal disease -Liver dysfunction -Hypoglycemia  Emerging concerns regarding association with increased mortality  Proper drug selection in the hypoglycemia prone Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

9. Adapted Recommendations: When Goal is to Avoid Hypoglycemia Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

10. T2DM– Treatment Strategies Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect TZDs

11. Slide Source: Lipids Online Slide Library www.lipidsonline.org Time to Fatal/Nonfatal MI (Excluding Silent MI) Kaplan-Meier Event Rate Prespecified Analysis 061218243036 Time from Randomization (Months) Time to Acute Coronary Syndrome Kaplan-Meier Event Rate Post Hoc Exploratory Analysis 061218243036 Time from Randomization (Months) – 28% – 37% Reprinted with permission from Erdmann E et al. J Am Coll Cardiol. 2007;49:1772-1780. Copyright © 2007 American College of Cardiology Foundation. All rights reserved. Pioglitazone (65/1230) Placebo (88/1215) Pioglitazone (35/1230) Placebo (54/1215) PROactive: Pioglitazone Reduced “Hard” Coronary Heart Disease Endpoints Pioglitazone vs Placebo: HR 0.72 (95% CI 0.52 – 0.99); p=0.045 Pioglitazone vs Placebo: HR 0.63 (95% CI 0.41 – 0.97); p=0.035

12. Type 2 Diabetes: Benefits vs Risks of TZDs

13. But???? Actos causes Bladder Cancer!!!...Right?

14. T2DM Anti-hyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

15. The Ominous Octet – Treatment Strategies Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect Insulin

16. New Basal Insulins: insulin degludec molecular structure DesB30 LysB29(Nε-γ-glu-hexadecandioyl) human insulin Degludec (Tresiba) s s s F F V V N N Q Q H H L L C C G G S S H H L L V V E E A A L L Y Y L L V V C C G G E E R R G G F F F F Y Y T T P P G G I I V V E E Q Q C C T T S S I I C C S S L L Y Y Q Q L L E E N N Y Y C C N N C C s s s A chain B chain K K Hexadecandioyl L-g-Glu desB30 Insulin T T

17. Multi-hexamer formation after injection Insulin degludec in pen Long multi-hexamer chains assemble [ Phenol; Zn 2+ ] Injection site Jonassen I et al. Diabetes. 2010;59(suppl 1):A11

18. Insulin degludec multi-hexamers Main picture shows elongated IDeg structures in absence of phenol; inset (white box) shows absence of elongated IDeg structures in presence of phenol. Kurtzhals P et al. ADA 2011;32-LB (MoP + NN1250-1993) Kurtzhals P. EASD 2011; 092-P #1049 (MoP + NN1250-1993)

19. Following injection [ Zn2+ ] Insulin degludec multi-hexamers Subcutaneous depot Monomers are absorbed from the depot into the circulation - zinc As zinc slowly diffuses out of the multi-hexamers, insulin degludec monomers are formed Jonassen I et al. Diabetes. 2010;59(suppl 1):A11

20. Clamp profile in type 2 diabetes: ultra- long, flat and consistent Glucose infusion rate (mg/(kg*min)) 5 4 3 2 1 0 Treatment IDeg 100 U/mL 0.4 U/kg IDeg 100 U/mL 0.8 U/kg IDeg 100 U/mL 0.6 U/kg Day 6 Day 7 Nosek L et al. ADA 2011;49-LB (NN1250-1987) Nosek L. EASD 2011; 093-P #1055 (NN1250-1987)

21. Consistently lower within-subject variability over time for insulin degludec Heise et al. Diabetes 2011;60(Suppl. 1):A263c IDeg

22. Consistently lower within-subject variability over time for insulin degludec IDeg IGlar Heise et al. Diabetes 2011;60(Suppl. 1):A263c

23. IDeg OD+ metformin ±DPP-4 (n=773) IGlar OD + metformin ±DPP-4 (n=257) Insulin-naïve patients with type 2 diabetes (n=1030) 0 52 weeks Inclusion criteria Type 2 diabetes ≥6 months Insulin naïve treated with metformin ± SU, DPP-4 or acarbose for ≥3 months HbA 1C 7.0–10.0% BMI ≤40 kg/m 2 Age ≥18 years Study design ONCE LONG (3579) Randomized 3:1 (IDeg OD:IGlar OD) Open label NN1250-3579; IDeg OD vs IGlar OD in T2DM. DPP-4: dipeptidyl peptidase-4 inhibitor SU: sulphonylurea OD: once-daily

24. Nocturnal confirmed hypoglycemia ONCE LONG (3579) 36% lower rate with IDeg OD p<0.05 NN1250-3579; IDeg OD vs IGlar OD in T2DM. IDeg OD (n=766) IGlar OD (n=257) SAS Comparisons: Estimates adjusted for multiple covariates

25. Reduction in confirmed hypoglycemia with degludec (all IDeg vs. IGlar studies, maintenance period) *statistically significant improvement Overall Nocturna l T1 and T2 32%* T2 basal on ly 49%* 16%* T1 and T2 28%* T2 basal only http://www.novonordisk.com/images/investors/investor_presentations/2011/CMD2011/04_Diabetes_treatment_tomorrow_CMD2011.pdf’ Maintenance period Pre-specified hypoglycemia meta-analyses Type 1 & type 2 diabetes

26. Treatment Strategies for Type 2 Diabetes (My Approach – T2DM + Metabolic Syndrome) Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect GLP-1 Insulin Metformin Exercise TZDs

27. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Weight -Majority of T2DM patients overweight / obese -Intensive lifestyle program -Metformin -GLP-1 receptor agonists -? Bariatric surgery -Consider LADA in lean patients Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

28. Energy Balance and Body Weight: Simple Right? Body Weight Energy In (Caloric Intake) Energy Out (Metabolism)

29. Stomach Islet GI Tract Brain Hypothalmus Hind Brain Evolving Treatment Strategies: The Complexity of Energy Homeostasis Visceral Fat Cell Vagal Afferents Leptin Amylin Insulin GLP-1 Glicentin Oxyntomodulin Ghrelin GIP Adiponectin Visfatin Resistin Glucagon CCK Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914 PYY 3-36 The Science of Willpower