1. Therapy of Type 2 Diabetes Mellitus: UPDATE Glycemic Goals in the Care of Patients with Type 2 Diabetes- 2013 ADA and AACE Guidelines: Room For Improvement (Be HAPPY/ Avoid Burnout, While Caring for Patients with DM) Stan Schwartz MD, FACP, FACE Affiliate, Main Line Health System Clinical Associate Professor of Medicine, Emeritus, U of Pa. Part 4

2. Metformin  Advantages  Improves insulin resistance in liver  High initial response rate  Effective, 2%  HbA 1c (1% with extended-release metformin)  No initial weight gain or modest weight loss (UKPDS)  Advantageous lipid profile  No hypoglycemia when used alone or with TZD, incretins  Potential to delay or prevent DM and progression, but secondary failure is = SU  Decreases MIs (39% UKPDS obese subgroup,retrospective analysis)  Decreases AGEs, improved endothelial dysfunction  Potential decrease in some cancer risk  Cheap

3. Metformin  Disadvantages  GI side effects on initiation  Hold after radiologic studies using intravascular iodinated contrast media until Cr stable  Risk of lactic acidosis: Don’t use if… Cr >1.4 female, >1.5 male Cr Clearance 70), blood levels increase Cr Clearance <40, lactic acidosis cases seen Impaired hepatic function (CHF not a contr-indication any more) Rarely order metformin as admit to hospital

4. Pioglitazone  ADVANTAGES-  Improves insulin resistance (fat/muscle), decreases insulin conc., improves endothelial dysfunction, dysfibrinolysis, BP, decreased microalbumin, improved beta-cell function, treats PCOS and steatohepatitis Lipids (GLIA study) Advantage to pio - decrease TG, decreased # of buoyant LDL particles, decrease non-HDL chol. May use in renal insufficiency  No hypoglycemia used alone or with metformin, incretin mimetics  Potential to delay or prevent DM and progression; lower secondary failure rate than SU/met  Pio decreased prospective composite endpoint (MI,CVA, death) 16% in PROactive trial (Can’t assume class effect), dec. risk second MI/ ACS, decreased risk second stroke 47%

5. Pioglitazone in Dysmetabolic Syndrome, Prediabetes, Type 2 Diabetes  Safety  No liver toxicity  Increased distal fractures in women  Edema-renal sodium and total body water retention - can be prevented/minimized (patient selection, NAS diet) - treated with spironolactone, amilioride, triamterene  Weight gain not an obligatory side effect- studies- portion control/ education freq.  Bone loss in women = risk/benefit evaluation for each patient  CHF not a cardiac issue except more susceptible with diastolic dysfunction –function of renal sodium and total body water retention -Can be prevented/reduced- low salt diet/ patient selection; ranolazine

6. No !!! Increased Risk Bladdder Cancer at 8 years in K-P Prospective Study All Analyses Cross 1.0 line Independent of duration of use, total dose

7. Natural History of Type 2 Diabetes Insulin Secretion IR phenotype Atherosclerosis obesity hypertension  HDL,  TG, HYPERINSULINEMIA Endothelial dysfunction PCO,ED Envir.+ Other Disease Obesity (visceral) Poor Diet Inactivity Insulin Resistance Risk of Dev. Complications ETOH BP Smoking Eye Nerve Kidney  Beta Cell Secretion Genes Blindness Amputation CRF Disability MI CVA Amp Age 0-1515-40+15-50+25-70+ Macrovascular Complications IGT – OMINOUS OCTET Type II DM 8 mechanisms of hyperglycemia Microvascular Complications DEATH pp>7.8

9. Incretins Gut-derived hormones, secreted in response to nutrient ingestion, that potentiate insulin secretion from islet  -cells Stimulation of insulin secretion is glucose-dependent. Incretins only work when glucose levels are above basal levels- THUS, NO HYPOGLYCEMIA if not on secreatogogue or insulin Two predominant incretins –glucagon-like peptide-1 (GLP-1) –glucose-dependent insulinotropic peptide ([GIP] also known as gastric inhibitory peptide) Holst JJ et al. Diabetes. 2004;53(suppl 3):s197-s204; Meier JJ et al. Diabetes Metab Res Rev. 2005;21:91-117.

10. GLUT2 Glucose ATP Pyruvate K+K+ Potassium channel Insulin [Ca 2+ ] Glucose Independent Triggering cAMP ATP AC Amplifying- Glucose Dependent + Pancreatic Beta Cell GK GLP-1 Glucose-Stimulated Secretion of Insulin Calcium channel SUR GIP + 3 1 Glucose metabolism TCA Cycle* 2 AC = adenylyl cyclase ATP = adenosine triphosphate cAMP = cyclic adenosine monophosphate GK = glucokinase GLUT2 = glucose transporters SUR = sulfonylurea receptor *TCA = Tricarboxylic acid (Kreb’s cycle) Hinke SA et al. J Physiol. 2004;558:369–380. Henquin JC. Diabetes. 2000;49:1751–1760. Henquin JC. Diabetes. 2004;53:S48–S58. Gillison, Tranplantation 1991;52:890 corticosteroids PKA Calmodulin inhibitors (Transplant meds )

11. GLP-1 Actions Extend Beyond the Pancreas: Address 6 of 8 Aspects of the Ominous Octet + Improves Cardiac Function Adapted from Drucker DJ. Cell Metab. 2006;3:153-165., Brownlee EASD,2007 Insulin synthesis INC. PDX-1  -cell proliferation  -cell apoptosis Gastric emptying Neuroprotection Appetite Cardio-protection Cardiac output Heart Stomach Brain Pancreas Liver Muscle Production of glucose Insulin secretion: glucose-Dependent Glucagon secretion Insulin sensitivity 9-37, dec. ox. stress GLP-1 1,2 3 4 5 6

12. Location and Impact of GLP-1/Receptors in the Cardiovascular System Cardiomyocytes Endocardium Endothelium Smooth Muscle Cells T Lymphocytes/Macrophages Koska J, et al. Diabetes Care. 2010;33(5):1028-30. Basu A, et al. Am J Physiol Endocrinol Metab 2007;293(5);1289-1296. Zhao T, et al. J Pharmacol Exp Ther. 2006;317(3):1106–1113. Nikolaidis, et al. Circulation. 2004;110(8):955–961. Nikolaidis LA, et al. Am J Physiol Heart Circ Physiol. 2005;289(6):H2401–H2408. Nikolaidis LA, et al. Circulation. 2004;109(8):962–965. Sokos GG, et al. J Card Fail. 2006;12(9):694–699. Watts GF, Chan DC. Diabetes 2013;62(2);336-338. GLP-1 agonists improve endothelial function and reduce BP Reduce inflammation Improve function in post-MI LV dysfunction and CHF Reduces Apo 48 synthesis and non-HDL fraction

13. Mechanism of Incretins Release of active incretins GLP-1 and GIP  Blood glucose in fasting and postprandial states Ingestion of food  Glucagon (GLP-1)  Hepatic glucose production GI tract DPP-4 enzyme Inactive GLP-1 X DPP-4 inhibitor  Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels  in response to a meal.  Incretin Mimetics are resistant to DPP-4 inactivation  Insulin (GLP-1and GIP) Glucose- dependent Glucose dependent Pancreas Inactive GIP GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide. S e c t i o n 12, 12.2 Concentrations of the active intact hormones are increased by DPP-4 inhibition, thereby increasing and prolonging the actions of these hormones. Beta cells Alpha cells  Glucose uptake by peripheral tissue Incretin Mimetic