1. Treatment Strategies for Diabetes and Obesity: Update 2013 Christopher Sorli, MD/PhD, FACE Chair, Department of Diabetes, Endocrinology and Metabolism Billings Clinic Billings, MT

2. Pathogenesis of Type 2 Diabetes HGP=hepatic glucose production. Islet  -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake Metformin SUs Insulin

3. NHANES1988-1994 Advances in Therapy, but Falling Short of Goals 5 6 7 8 9 10  1980s 1990s 2000s  HbA 1c (%) SU / Insulin Metformin (1995) TZDs (1999) Incretins (2004) Pre-DCCT9.0% 7.7NHANES1999-2000 7.8 NHANES2001-2002 7.5 NHANES2003-2004 7.2 Future 6.0% ? 1997: ADA lowered T2DM diagnosis from FPG ≥140 mg/dLto ≥126 mg/dL 2003: ADA eliminated HbA 1c “action point” of <8% from guidelines SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes. Koro CE, et al. Diabetes Care. 2004;27:17-20; Hoerger TJ, et al. Diabetes Care. 2008;31:81-86. 2005: ADA added HbA 1c goal of <6% for “individual patients” to guidelines General ADA Target: <7% 1998: UKPDS results published 2008: ACCORD, ADVANCE, VADT, and UKPDS 80 published

4. Type 2 Diabetes Evolving Treatment Strategies

5. Mortality intensive standard HR = 1.22 (95% CI =1.01-1.46) p = 0.04

6. NHANES1988-1994 Advances in Therapy, but Falling Short of Goals 5 6 7 8 9 10  1980s 1990s 2000s  HbA 1c (%) SU / Insulin Metformin (1995) TZDs (1999) Incretins (2004) Pre-DCCT9.0% 7.7NHANES1999-2000 7.8 NHANES2001-2002 7.5 NHANES2003-2004 7.2 Future 6.0% ? SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes. Koro CE, et al. Diabetes Care. 2004;27:17-20; Hoerger TJ, et al. Diabetes Care. 2008;31:81-86. General ADA Target: <7% 2009: ADA added “less stringent” HbA 1c goal for patients with significant comorbidities or risk of hypoglycemia, or short life expectancy

7. Group A 1 C Targets Intensification Thresholds A1CA1C> 50% of SMBG Results/4 Days Intensive < 6%> 5.9% Fasting > 100 (5.6) OR 2 Hr PP > 140 (7.8) Even if the A 1 C is <6.0 Rx was reduced in the presence of significant hypoglycemia.

8. Mortality Primary outcome (composite nonfatal MI, nonfatal stroke, CVD death)

9. Diabetes Management Strategies Making Sense of ACCORD Mortality vs Treatment A1c 10 x less 10 x more Death Rate vs Drop in A1c No drop in A1c = higher death rate

10. Pathogenesis of Type 2 Diabetes HGP=hepatic glucose production. Islet  -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake

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

12. Metabolic syndromeHyperglycemia Failing  -cell Functional  -cell Heine RJ, Spijkerman AM. 2006. Insulin resistance Type 2 Diabetes: A Heterogeneous Disorder CVD Cancer Retinopathy Neuropathy Nephropathy 70-80% of population 20-30% of population

13. DIABETES/OBESITY Management Strategies Insulin Resistance Metabolic Syndrome Energy Storage Insulin Supply Beta Cell Dysfunction Hyperglycemia Insulin Resistance β cell function Years of Diabetes/Metabolic Syndrome Relative Function 100 (%) -20-100102030 β cell mass Adapted from IDC, Minneapolis, MN Macrovascular Risk/ Cancer Risk Prevention! Intensive managment of Insulin resistance β cell dysfunction CVD risks Damage Control! Less intensive glycemic goals Avoid hypoglycemia

14. History of Diabetes Therapy: What More Could We Possibly Want? Animal Insulin 19221950’s1982-851995199620012003200520072009 Sulfonylurea Human Insulin Metformin Lispro Glitazones Glinides Aspart Exenatide Pramlintide Detemir Sitagliptin Bromocriptine Saxagliptin 2013 Liraglutide SGLT-2 inhib 11-β-HSD1 inhib The End of Protocol Driven Therapy Weekly Exenatide Degludec Glucagon R antangonists

15. Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

16. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Glycemic targets  HbA1c < 7.0% (mean PG  150-160 mg/dl [8.3-8.9 mmol/l]) - Pre-prandial PG <130 mg/dl (7.2 mmol/l) - Post-prandial PG <180 mg/dl (10.0 mmol/l) - Individualization is key:  Tighter targets (6.0 - 6.5%) - younger, healthier  Looser targets (7.5 - 8.0% + ) - older, comorbidities, hypoglycemia prone, etc. - Avoidance of hypoglycemia PG = plasma glucose Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

17. Figure 1 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)

18. Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

19. 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]

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

21. 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 Incretins (injectables) Exenatide – Bydureon, Byetta Liraglutide - Victoza DPP-IV Inhibitors (orals) Sitagliptin – Januvia Linagliptin – Tradjenta Saxagliptin - Onglyza Incretins (injectables) Exenatide – Bydureon, Byetta Liraglutide - Victoza DPP-IV Inhibitors (orals) Sitagliptin – Januvia Linagliptin – Tradjenta Saxagliptin - Onglyza

22. Incretins: GLP-1 Agonists vs. DPP-IV Inhibitors Pharmacology vs Physiology DPP-IV – increases endogenous GLP-1 GLP-1 agonist – super physiologic effect …Not quite that simple Differential Effects: Glycemic Control Energy Balance

23. T2DM – Treatment Strategies Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect GLP-1 > DPP IV (A1c, FPG,  -cell function) GLP-1 > DPP-IV

24. Incretins (Exenatide): Sustained Efficacy- Improved Beta Cell Function Buse et.al., Oct 2012, EASD, Berlin

25. T2DM – Treatment Strategies Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect GLP-1 > DPP IV (A1c, FPG,  -cell function) GLP-1 (weight loss) GLP-1 > DPP-IV

26. Incretin Therapy Effect on Energy Homeostasis

29. T2DM– Treatment Strategies Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect GLP-1 > DPP IV (A1c, FPG,  -cell function) GLP-1 (weight loss) GLP-1 > DPP-IV GLP-1 > DPP IV (glucagon inhibition, FPG, Prandial control) GLP-1 > DPP IV (Glucagon inhibition, FPG, Prandial control)