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Incretins: Expanding Role in Treatment Strategies Pediatric Type 1 Diabetics (n=8) Insulin dose reduced 20% with exenatide dosing – mixed meal 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 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS • Comorbidities Metformin: CVD benefit (UKPDS) - Coronary Disease Avoid hypoglycemia - Heart Failure ? SUs & ischemic preconditioning - Renal disease - Liver dysfunction ? Pioglitazone & CVD events ? Effects of incretin-based therapies - Hypoglycemia 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 Vagal Afferents Cardiovascular Outcome Trials Leptin Incretins TECOS - sitagliptin Exenatide – Bydureon, Byetta EXSCEL – weekly Insulin Liraglutide - Victoza exenatide Visceral Fat Cell LEADER – liraglutide Amylin DPP-IV ELIXAInhibitors – lixisenitide Sitagliptin – Januvia SAVOR saxagliptin Glucagon Linagliptin – -Tradjenta PYY3-36 GI Tract GLP-1 GIP Glicentin Oxyntomodulin Saxagliptin - Onglyza CCK Islet Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914 Cardiovascular RR ACCORD:Mortality Hazard Ratios for PostRandomization Prescription of Glycemia Medications Adjusted for Baseline Participant Characteristics ACCORD Study Group. Presented at the ADA Scientific Sessions, San Francisco, June 2008 Peptide Therapeutics: Incretins (GLP-1 and GIP) Exenatide vs. Non-Exenatide – Cardiovascular Events ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS • Comorbidities Metformin: CVD benefit (UKPDS) - Coronary Disease Avoid hypoglycemia - Heart Failure ? SUs & ischemic preconditioning ? Pioglitazone & CVD events - Renal disease - Liver dysfunction ? Effects of incretin-based therapies - Hypoglycemia Glyburide (and older) – Should never be used Glimepiride or Glipizide if any SU Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] 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] 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 + + DPP-4 Inhibitor + Metformin + GLP-1 receptor agonist + SU† SU† TZD More complex insulin strategies 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 Hypoglycemia Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] T2DM– Treatment Strategies Islet b-cell Decreased Incretin Effect Impaired TZDs Insulin Secretion TZDs Increased Lipolysis Islet a-cell TZDs Increased Glucagon Secretion Increased Glucose Reabsorption TZDs TZDs Increased HGP Neurotransmitter Dysfunction TZDs Decreased Glucose Uptake PROactive: Pioglitazone Reduced “Hard” Coronary Heart Disease Endpoints Time to Fatal/Nonfatal MI (Excluding Silent MI) Kaplan-Meier Event Rate 0.10 Pioglitazone (65/1230) Placebo (88/1215) 0.08 0.06 –28% 0.04 0.02 0.00 Pioglitazone vs Placebo: HR 0.63 (95% CI 0.41–0.97); p=0.035 0.06 Kaplan-Meier Event Rate Pioglitazone vs Placebo: HR 0.72 (95% CI 0.52–0.99); p=0.045 Time to Acute Coronary Syndrome Pioglitazone (35/1230) Placebo (54/1215) 0.05 0.04 –37% 0.03 0.02 0.01 0.00 0 6 12 18 24 30 36 Time from Randomization (Months) Prespecified Analysis 0 6 12 18 24 30 36 Time from Randomization (Months) Post Hoc Exploratory Analysis 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. Slide Source: Lipids Online Slide Library www.lipidsonline.org Type 2 Diabetes: Benefits vs Risks of TZDs Type 2 Diabetes: Benefits vs Risks of TZDs But???? Actos causes Bladder Cancer!!!...Right? 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 Insulin # (multiple daily doses) T2DM Anti-hyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] The Ominous Octet – Treatment Strategies Islet b-cell Decreased Incretin Effect Impaired Insulin Insulin Secretion Insulin Increased Lipolysis Islet a-cell Insulin Increased Glucagon Secretion Increased Glucose Reabsorption Insulin Insulin Increased HGP Neurotransmitter Dysfunction Insulin Decreased Glucose Uptake New Basal Insulins: insulin degludec molecular structure DesB30 LysB29(Nε-γ-glu-hexadecandioyl) human insulin s G I V E Q C C T S A chain Degludec s I (Tresiba) C S L Y Q L E N Y C N s s s s F V N Q H L C G S H L V E A L Y L V C G E R G F B chain F Y T P K T desB30 Insulin NH O L-g-Glu O HO O N H Hexadecandioyl OH O Multi-hexamer formation after injection [ Phenol; Zn2+] Insulin degludec in pen Injection site Long multi-hexamer chains assemble Jonassen I et al. Diabetes. 2010;59(suppl 1):A11 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) Following injection Subcutaneous depot [Zn2+ Insulin degludec multi-hexamers - zinc As zinc slowly diffuses out of the multi-hexamers, insulin degludec monomers are formed Monomers are absorbed from the depot into the circulation Jonassen I et al. Diabetes. 2010;59(suppl 1):A11 ] Clamp profile in type 2 diabetes: ultralong, flat and consistent Glucose infusion rate (mg/(kg*min)) Treatment 5 4 3 2 1 0 Nosek L et al. ADA 2011;49-LB (NN1250-1987) Nosek L. EASD 2011; 093-P #1055 (NN1250-1987) IDeg 100 U/mL 0.8 U/kg IDeg 100 U/mL 0.6 U/kg IDeg 100 U/mL 0.4 U/kg Consistently lower within-subject variability over time for insulin degludec 220 IDeg Day-to-day variability (CV%) 200 180 160 140 120 100 80 60 40 20 0 Area under the GIR curve (time interval, hours) Heise et al. Diabetes 2011;60(Suppl. 1):A263c Consistently lower within-subject variability over time for insulin degludec 220 IDeg IGlar Day-to-day variability (CV%) 200 180 160 140 120 100 80 60 40 20 0 Area under the GIR curve (time interval, hours) Heise et al. Diabetes 2011;60(Suppl. 1):A263c Study design ONCE LONG (3579) IDeg OD+ metformin ±DPP-4 (n=773) Insulin-naïve patients with type 2 diabetes (n=1030) Inclusion criteria • Type 2 diabetes ≥6 months • Insulin naïve treated with metformin ± SU, DPP-4 or acarbose for ≥3 months IGlar OD + metformin ±DPP-4 (n=257) 52 weeks 0 Randomized 3:1 (IDeg OD:IGlar OD) Open label • HbA1C 7.0–10.0% • BMI ≤40 kg/m2 • Age ≥18 years DPP-4: dipeptidyl peptidase-4 inhibitor SU: sulphonylurea OD: once-daily NN1250-3579; IDeg OD vs IGlar OD in T2DM. Nocturnal confirmed hypoglycemia ONCE LONG (3579) IDeg OD (n=766) IGlar OD (n=257) 36% lower rate with IDeg OD p<0.05 SAS Comparisons: Estimates adjusted for multiple covariates NN1250-3579; IDeg OD vs IGlar OD in T2DM. Pre-specified hypoglycemia meta-analyses Type 1 & type 2 diabetes Maintenance period Reduction in confirmed hypoglycemia with degludec (all IDeg vs. IGlar studies, maintenance period) Nocturnal T1 and T2 32%* T2 basal only 49%* Overall T1 and T2 16%* T2 basal only 28%* *statistically significant improvement http://www.novonordisk.com/images/investors/investor_presentations/2011/CMD2011/04_Diabetes_treatment_tomorrow_CMD2011.pdf’ Treatment Strategies for Type 2 Diabetes (My Approach – T2DM + Metabolic Syndrome) Islet b-cell Decreased Incretin Exercise Effect Exercise GLP-1 Impaired TZDs GLP-1 Insulin Secretion Islet a-cell Insulin GLP-1 Insulin Increased Lipolysis TZDs Insulin TZDs Increased Glucose Reabsorption Increased Glucagon Secretion Exercise Metformin TZDs GLP-1 Increased HGP Insulin Exercise GLP-1 TZDs Insulin Neurotransmitter Dysfunction Exercise TZDs Insulin Decreased Glucose Uptake 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] Energy Balance and Body Weight: Simple Right? Energy In (Caloric Intake) Body Weight Energy Out (Metabolism) Evolving Treatment Strategies: The Complexity of Energy Homeostasis Brain Ghrelin Visfatin Resistin Hind Brain Hypothalmus Stomach Adiponectin Vagal Afferents The Science of Willpower Leptin PYY3-36 GI Tract Insulin Amylin GLP-1 Visceral Fat Cell GIP Glucagon Glicentin Oxyntomodulin CCK Islet Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914