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Treatment Strategies for Diabetes and Obesity: Update 2013

Treatment Strategies for Diabetes and Obesity: Update 2013. Christopher Sorli, MD/PhD, FACE Chair, Department of Diabetes, Endocrinology and Metabolism Billings Clinic Billings, MT. Pathogenesis of Type 2 Diabetes. Impaired Insulin Secretion. Islet b -cell. Increased HGP. SUs.

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Treatment Strategies for Diabetes and Obesity: Update 2013

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  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 Impaired Insulin Secretion Islet b-cell Increased HGP SUs Insulin Insulin Metformin Decreased Glucose Uptake HGP=hepatic glucose production.

  3. Advances in Therapy, but Falling Short of Goals NHANES 1999-2000 NHANES 2003-2004 7.8 7.2 7.5 NHANES 2001-2002 2003: ADA eliminated HbA1c“action point” of <8% from guidelines 2008: ACCORD, ADVANCE, VADT, and UKPDS 80 published 1997: ADA lowered T2DM diagnosis from FPG ≥140 mg/dLto ≥126 mg/dL 2005: ADA added HbA1c goal of <6% for “individual patients” to guidelines 1998: UKPDS results published 10 Pre-DCCT 9.0% 9 8 General ADA Target: <7% HbA1c (%) NHANES 1988-1994 7.7 7 Future 6.0% ? 6 SU / Insulin Metformin (1995) TZDs (1999) Incretins (2004) 5  1980s 1990s 2000s  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.

  4. Type 2 Diabetes Evolving Treatment Strategies

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

  6. Advances in Therapy, but Falling Short of Goals NHANES 1999-2000 NHANES 2003-2004 7.8 7.2 7.5 NHANES 2001-2002 10 2009: ADA added “less stringent” HbA1c goal for patients with significant comorbidities or risk of hypoglycemia, or short life expectancy Pre-DCCT 9.0% 9 8 General ADA Target: <7% HbA1c (%) NHANES 1988-1994 7.7 7 Future 6.0% ? 6 SU / Insulin Metformin (1995) TZDs (1999) Incretins (2004) 5  1980s 1990s 2000s  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.

  7. Design of Intensive Glycemia Intervention Even if the A1C is <6.0 Rx was reduced in the presence of significant hypoglycemia.

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

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

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

  11. The Ominous Octet Impaired Insulin Secretion Islet a-cell Increased Glucagon Secretion Islet b-cell Neurotransmitter Dysfunction DecreasedIncretin Effect Increased Lipolysis Increased Glucose Reabsorption Increased HGP Decreased Glucose Uptake

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

  13. DIABETES/OBESITYManagement Strategies Insulin Resistance Metabolic Syndrome Energy Storage Insulin Supply Beta Cell Dysfunction Hyperglycemia Macrovascular Risk/ Cancer Risk Prevention! Intensive managment of Insulin resistance β cell dysfunction CVD risks Damage Control! Less intensive glycemic goals Avoid hypoglycemia Insulin Resistance RelativeFunction 100 (%) β cell function β cell mass -20 -10 0 10 20 30 Years of Diabetes/Metabolic Syndrome Adapted from IDC, Minneapolis, MN

  14. Glucagon R antangonists History of Diabetes Therapy:What More Could We Possibly Want? Degludec 11-β-HSD1 inhib SGLT-2 inhib Weekly Exenatide Liraglutide Bromocriptine Saxagliptin Sitagliptin The End of Protocol Driven Therapy Detemir Pramlintide Exenatide Aspart Glinides Glitazones Lispro Metformin Human Insulin Sulfonylurea Animal Insulin 1922 1950’s 1982-85 1995 1996 2001 2003 2005 2007 2009 2013

  15. Management of Hyperglycemia in Type 2Diabetes: A Patient-Centered ApproachPosition 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. 19April 2012 [Epub ahead of print]

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

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

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

  21. Adiponectin Visfatin Resistin Glucagon Ghrelin Brain Stomach Vagal Afferents Glicentin GI Tract Hind Brain Oxyntomodulin Hypothalmus Islet CCK Visceral Fat Cell Peptide Therapeutics:Incretins (GLP-1 and GIP) Incretins (injectables) Exenatide – Bydureon, Byetta Liraglutide - Victoza DPP-IV Inhibitors (orals) Sitagliptin – Januvia Linagliptin – Tradjenta Saxagliptin - Onglyza Leptin PYY3-36 Insulin GLP-1 Amylin GIP Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914

  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 Impaired Insulin Secretion Islet a-cell Increased Glucagon Secretion Islet b-cell Neurotransmitter Dysfunction GLP-1 > DPP-IV DecreasedIncretin Effect GLP-1 > DPP IV (A1c, FPG, b-cell function) Increased Lipolysis Increased Glucose Reabsorption Increased HGP Decreased Glucose Uptake

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

  25. T2DM – Treatment Strategies Impaired Insulin Secretion Islet a-cell Increased Glucagon Secretion Islet b-cell Neurotransmitter Dysfunction GLP-1 > DPP-IV DecreasedIncretin Effect GLP-1 > DPP IV (A1c, FPG, b-cell function) Increased Lipolysis Increased Glucose Reabsorption GLP-1 (weight loss) Increased HGP Decreased Glucose Uptake

  26. Incretin TherapyEffect on Energy Homeostasis

  27. T2DM– Treatment Strategies Impaired Insulin Secretion Islet a-cell Increased Glucagon Secretion Islet b-cell Neurotransmitter Dysfunction GLP-1 > DPP-IV DecreasedIncretin Effect GLP-1 > DPP IV (A1c, FPG, b-cell function) Increased Lipolysis GLP-1 > DPP IV (Glucagon inhibition, FPG, Prandial control) Increased Glucose Reabsorption GLP-1 > DPP IV (glucagon inhibition, FPG, Prandial control) GLP-1 (weight loss) Increased HGP Decreased Glucose Uptake

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