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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 Islet b-cell Impaired Insulin Secretion Insulin Metformin Increased HGP HGP=hepatic glucose production. SUs Insulin Decreased Glucose Uptake Advances in Therapy, but Falling Short of Goals 10 Pre-DCCT 9.0% NHANES 1999-2000 9 HbA1c (%) 2003: ADA eliminated HbA1c 2008:HbA ACCORD, 2005: 1c goal “action point” ofADA <8% added from ADVANCE, VADT, and of <6% for “individual guidelines UKPDS 80 published patients” to guidelines 1997: ADA1998: lowered T2DM UKPDS results diagnosis from published FPG ≥140 mg/dLto ≥126 mg/dL NHANES 2003-2004 7.8 8 7 General ADA Target: <7% 7.2 7.7 NHANES 1988-1994 6 SU / Insulin Metformin (1995) 7.5 NHANES 2001-2002 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. Future 6.0% ? Type 2 Diabetes Evolving Treatment Strategies Mortality HR = 1.22 (95% CI =1.01-1.46) p = 0.04 intensive standard Advances in Therapy, but Falling Short of Goals 10 NHANES 1999-2000 9 HbA1c (%) 2009: ADA added “less stringent” HbA1c goal for patients with significant comorbidities or risk of hypoglycemia, or short life expectancy NHANES Pre-DCCT 9.0% 7.8 2003-2004 8 7 General ADA Target: <7% 7.2 7.7 NHANES 1988-1994 6 SU / Insulin Metformin (1995) 7.5 NHANES 2001-2002 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. Future 6.0% ? Group Intensive A1C Targets < 6% Intensification Thresholds A1C > 50% of SMBG Results/4 Days > 5.9% Fasting > 100 (5.6) OR 2 Hr PP > 140 (7.8) Rx was reduced in the presence of significant hypoglycemia. Even if the A1C is <6.0 Mortality Primary outcome (composite nonfatal MI, nonfatal stroke, CVD death) Diabetes Management Strategies Making Sense of ACCORD Mortality vs Treatment A1c Death Rate vs Drop in A1c No drop in A1c = higher death rate 10 x more 10 x less Pathogenesis of Type 2 Diabetes Islet b-cell Impaired Insulin Secretion Increased HGP HGP=hepatic glucose production. Decreased Glucose Uptake The Ominous Octet Islet b-cell Decreased Incretin Effect Impaired Insulin Secretion Increased Lipolysis Islet a-cell Increased Glucose Reabsorption Increased Glucagon Secretion Increased HGP Neurotransmitter Dysfunction Decreased Glucose Uptake Type 2 Diabetes: A Heterogeneous Disorder 20-30% of population 70-80% of population Functional b-cell Insulin resistance Metabolic syndrome Failing b-cell Insulin resistance Hyperglycemia Nephropathy CVD Cancer Retinopathy Heine RJ, Spijkerman AM. 2006. Neuropathy DIABETES/OBESITY Management Strategies Insulin Resistance Insulin Supply Metabolic Syndrome Energy Storage Beta Cell Dysfunction Hyperglycemia Relative Function 100 (%) Prevention! Damage Control! Insulin Resistance Intensive managment of Less intensive Insulin resistance Macrovascular Risk/ Cancer Risk goals glycemic β cell dysfunction β cell function Avoid hypoglycemia CVD risks β cell mass -20 -10 0 10 20 Years of Diabetes/Metabolic Syndrome 30 Adapted from IDC, Minneapolis, MN History of Diabetes Therapy: What More Could We Possibly Want? Glucagon R antangonists 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 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) 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] Approach to management of hyperglycemia: more less stringent stringent Figure 1 Patient attitude and expected treatment efforts highly motivated, adherent, excellent self-care capacities Risks potentially associated with hypoglycemia, other adverse events low Disease duration newly diagnosed Life expectancy long Important comorbidities absent few / mild severe Established vascular complications absent few / mild severe Resources, support system readily available less motivated, non-adherent, poor self-care capacities high long-standing short limited 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) Healthy eating, weight control, increased physical activity Initial drug monotherapy Metformin high low risk neutral/loss GI / lactic acidosis low If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference): Efficacy (! HbA1c) Hypoglycemia Weight Side effects Costs Metformin Two drug combinations* Efficacy (! HbA1c) Hypoglycemia Weight Major side effect(s) Costs + Metformin + Metformin + Metformin + Metformin + Sulfonylurea† Thiazolidinedione DPP-4 Inhibitor GLP-1 receptor agonist Insulin (usually basal) high moderate risk gain hypoglycemia ‡ low high low risk gain edema, HF, fx’s‡ high intermediate low risk neutral rare‡ high high low risk loss GI‡ high highest high risk gain hypoglycemia ‡ variable If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference): Metformin Three drug combinations + Sulfonylurea† + Metformin + Thiazolidinedione + Metformin + DPP-4 Inhibitor + + GLP-1 receptor agonist + SU† SU† TZD Metformin Metformin + Insulin (usually basal) + SU† TZD or DPP-4-i or DPP-4-i or TZD or TZD or DPP-4-i or GLP-1-RA or GLP-1-RA or Insulin § or Insulin § or GLP-1-RA or Insulin § or Insulin § If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents: More complex insulin strategies Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] Insulin # (multiple daily doses) 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] Healthy eating, weight control, increased physical activity Initial drug monotherapy Metformin high low risk neutral/loss GI / lactic acidosis low If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference): Efficacy (! HbA1c) Hypoglycemia Weight Side effects Costs Metformin Two drug combinations* Efficacy (! HbA1c) Hypoglycemia Weight Major side effect(s) Costs + + + Metformin + Metformin + Thiazolidinedione DPP-4 Inhibitor GLP-1 receptor agonist Insulin (usually basal) high moderate risk gain hypoglycemia ‡ low high low risk gain edema, HF, fx’s‡ high intermediate low risk neutral rare‡ high high low risk loss GI‡ high highest high risk gain hypoglycemia ‡ variable + Sulfonylurea† + Metformin + Thiazolidinedione + Metformin + DPP-4 Inhibitor + Metformin + GLP-1 receptor agonist + SU† SU† TZD More complex insulin strategies Metformin Sulfonylurea† Metformin Three drug combinations Metformin Metformin + Insulin (usually basal) + SU† TZD or DPP-4-i or DPP-4-i or TZD or TZD or DPP-4-i or GLP-1-RA or GLP-1-RA or Insulin § or Insulin § or GLP-1-RA or Insulin § or Insulin § Insulin # (multiple daily doses) Adapted Recommendations: When Goal is to Avoid Weight Gain Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] Peptide Therapeutics: Incretins (GLP-1 and GIP) Brain Ghrelin Visfatin Resistin Hind Brain Hypothalmus Stomach Adiponectin Incretins (injectables) Exenatide – Bydureon, Byetta Liraglutide Insulin - Victoza Leptin Amylin DPP-IV Inhibitors Visceral Fat Cell (orals) Sitagliptin – Januvia Glucagon Linagliptin – Tradjenta Saxagliptin - Onglyza Vagal Afferents PYY3-36 GI Tract GLP-1 GIP Glicentin Oxyntomodulin CCK Islet Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914 Incretins: GLP-1 Agonists vs. DPP-IV Inhibitors Differential Effects: Glycemic Control Energy Balance Pharmacology vs Physiology DPP-IV – increases endogenous GLP-1 GLP-1 agonist – super physiologic effect …Not quite that simple T2DM – Treatment Strategies Islet b-cell GLP-1 > DPP-IV Decreased Incretin Effect GLP-1 > DPP IV (A1c, FPG, b-cell function) Impaired Insulin Secretion Increased Lipolysis Islet a-cell Increased Glucose Reabsorption Increased Glucagon Secretion Increased HGP Neurotransmitter Dysfunction Decreased Glucose Uptake Incretins (Exenatide): Sustained Efficacy- Improved Beta Cell Function Buse et.al., Oct 2012, EASD, Berlin T2DM – Treatment Strategies Islet b-cell GLP-1 > DPP-IV Decreased Incretin Effect GLP-1 > DPP IV (A1c, FPG, b-cell function) Impaired Insulin Secretion Increased Lipolysis Islet a-cell Increased Glucose Reabsorption Increased Glucagon Secretion GLP-1 (weight loss) Increased HGP Neurotransmitter Dysfunction Decreased Glucose Uptake Incretin Therapy Effect on Energy Homeostasis T2DM– Treatment Strategies Islet b-cell GLP-1 > DPP-IV Decreased Incretin Effect GLP-1 > DPP IV (A1c, FPG, b-cell function) Impaired Insulin Secretion Increased Lipolysis Islet a-cell GLP-1 > DPP IV (Glucagon inhibition, FPG, Prandial control) Increased Glucose Reabsorption Increased Glucagon Secretion GLP-1 > DPP IV (glucagon inhibition, FPG, Prandial control) GLP-1 (weight loss) Increased HGP Neurotransmitter Dysfunction Decreased Glucose Uptake