Improving Patient Outcomes with Individualized Therapy in the Management of Type 2 Diabetes

Improving Patient Outcomes with Individualized Therapy in the Management of Type 2 Diabetes Timothy S. Reid, M.D. Mercy Diabetes Center Janesville, WI Duality Statement Dr. Reid is a Speaker and Consultant for the following organizations: Novo Nordisk Lilly Sanofi Janssen 1

Diabetes Mellitus in the US 29.1 million Americans have diabetes (2012) 9.3% of the population 86 million Americans age 20 and older have prediabetes 7 th leading cause of death in US 8.1 million Americans with Diabetes are undiagnosed In seniors (age 65 and older) the prevalence is 25.9% 1.4 million new diagnosis annually American Diabetes Association: www.diabetes.org/diabetes basics/statistics/ (Accessed 9/7/2016) Oral Antihyperglycemic Agents empagliflozin alogliptin metformin repaglinide glyburide glimepiride dapagliflozin miglitol Are you feeling confused with all of the choices bromocriptine in diabetes medications? pioglitazone saxagliptin linagliptin sitagliptin glipizide acarbose colesevelam rosiglitazone nateglinide canagliflozin 2

HTN and Diabetes Drug Classes in the US over the past 90 Years Number of Medication Classes 12 11 10 9 8 7 6 5 4 3 2 1 Diuretics Adrenergic neuronal blockers Sulfonylureas Vasodialators Peripheral -1 Blockers ACE Inhibitors Central -2 Agonists (Phenformin) Withdrawn 1978 Amylinomimetics Calcium Channel Blockers -blockers Angiotensin II Receptor Blockers Thiazolidinediones Renin Inhibitors -glucosidase Inhibitors Biguanides GLP-1 Receptor Agonists Meglitinides Dopamine Agonists Bile Acid Sequestrants DPP-4 Receptor Antagonists SGLT-2 Inhibitors 1920 s 1950 s 1960 s 1970 s 1980 s 1990 s 2000 s 2010 s Spheres of Concern Hypoglycemia CV Risk Reduction Renal/UTI/Genital Patient Weight Economic Gastrointestinal 3

Do Patients Come to You: Excited? Happy? Committed? Hopeful? Fearful? Hesitant? Dreading? What can we do to improve this? When Patients Come to You: The Words We Use Can Have a Mighty Impact. Our Body Language Tells More Than Our Words. 4

When Patients Come to You: Leave Some Hope With The Patient. Never Say Never. Work With The Patient s Priorities Healthy eating, wt. control, increased physical activity & diabetes education American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes 2015. Diabetes Care 2015;38(Suppl. 1):S41 S48. Diabetes Self Management Education improved diabetes knowledge improved self care behavior improved clinical outcomes lower A1C lower self reported weight improved quality of life healthy coping lower costs American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes 2015. Diabetes Care 2015;38(Suppl. 1):S20 S21. 5

Approaches to Glycemic Treatment Pharmacological Therapy for Type 2 DM is preferred if tolerated and not contraindicated Consider if symptomatic or blood sugars high Advance therapy q3 months if not at goal Patient centered approach to therapy T2DM is progressive. therapy will eventually be needed in most cases American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes 2015. Diabetes Care 2015;38(Suppl. 1):S41 S48. Healthy eating, wt. control, increased physical activity & diabetes education Efficacy Hypo Risk.. Weight.... Side Effects... Cost. High Efficacy Low Hypoglycemic Risk Weight Neutral Lactic Acidosis/GI intolerance Low Cost If A1c target not achieved after ~3 months of monotherapy, proceed to 2 drug combination (order not meant to denote any specific preference choice dependent on a variety of patient and disease specific factors). American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes 2015. Diabetes Care 2015;38(Suppl. 1):S41 S48. 6

Healthy eating, wt. control, increased physical activity & diabetes education Efficacy Hypo Risk.. Weight.... Side Effects... Cost. High Efficacy Low Hypoglycemic Risk Weight Neutral Lactic Acidosis/GI intolerance Low Cost If A1c target not achieved after ~3 months of monotherapy, proceed to 2 drug combination (order not meant to denote any specific preference choice dependent on a variety of patient and disease specific factors). Efficacy Hypo Risk.. Weight.... Side Effects... Cost. Sulfonylurea Thiazolidinedione DPP 4 Inhibitor SGLT 2 Inhibitor GLP 1 Receptor High.. high. Intermediate.. Intermediate.. high.. Agonist Moderate risk. low Risk.. Low risk.. Low risk Low risk gain... Gain. neutral.. losing losing.. hypoglycemia. Edema,CHF,Fx s Low rare GU, dehydration. GI.. Low. high high high (basal) Highest High risk gain hypoglycemia variable If A1c target not achieved after ~3 months of dual therapy, proceed to 3 drug combination (order not meant to denote any specific preference choice dependent on a variety of patient and disease specific factors). American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes 2015. Diabetes Care 2015;38(Suppl. 1):S41 S48. Healthy eating, wt. control, increased physical activity & diabetes education Efficacy Hypo Risk.. Weight.... Side Effects... Cost. High Efficacy Low Hypoglycemic Risk Weight Neutral Lactic Acidosis/GI intolerance Low Cost If A1c target not achieved after ~3 months of monotherapy, proceed to 2 drug combination (order not meant to denote any specific preference choice dependent on a variety of patient and disease specific factors). Efficacy. Hypo Risk. Weight.. Side Effects. Cost Sulfonylurea Thiazolidinedione DPP 4 Inhibitor SGLT 2 Inhibitor GLP 1 Receptor High.. high. Intermediate.. Intermediate.. high.. Agonist Moderate risk. low Risk.. Low risk.. Low risk Low risk gain... Gain. neutral.. losing losing.. hypoglycemia. Edema,CHF,Fx s rare GU, dehydration. GI.. Low. Low Cost high high high (basal) Highest High risk gain hypoglycemia variable American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes 2015. Diabetes Care 2015;38(Suppl. 1):S41 S48. If A1c target not achieved after ~3 months of dual therapy, proceed to 3 drug combination (order not meant to denote any specific preference choice dependent on a variety of patient and disease specific factors). Sulfonylurea Thiazolidinedione DPP 4 Inhibitor SGLT 2 Inhibitor GLP 1 Receptor Agonist (basal) If A1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on GLP RA, add basal insuin; or (3) on optimally titrated basal insulin, add or mealtime insulin. In refractory patients, consider adding or SGLT 2i: 7

Things Patients Never Say: Doc, My I Diabetes Algorithm is Off. My seldom Grandmother Can LDL Cholesterol You use Fix my It? insulin. and Hurts Uncle I don t had a exercise horrible and painful I eat death odd as hours. a result Can of their diabetes Life as you I know and fix me? I it am is over..right? afraid this will happen to me. New Therapeutic Classes 9 classes of oral medication 4 classes of subcutaneous medications New Concentrated s /GLP 1 Combinations New classes coming.. 9

Where Diabetes Medications Work GLP 1 GLP 1 GLP 1 GLP 1 GLP 1 DeFronzo RA. Diabetes. 2009;58 (4): 773-795. Where Diabetes Medications Work GLP 1 GLP 1 GLP 1 GLP 1 GLP 1 DeFronzo RA. Diabetes. 2009;58 (4): 773-795. 10

Class Generic Name Trade Name α glucosidase Inhibitor acarobose, miglitol Precose, Glyset amylinomimetics amylin Symlin biguanides metformin Glucophage, Riomet Bile Acid Sequestrants colesevelam WelChol Dopamine Agonists bromocriptine Cycloset DPP 4i GLP 1 Agonists alogliptin, linagliptin saxagliptin, sitagliptin albiglutide, dulaglutide exenatide, liraglutide Nesina, Tradjenta Onglyza, Januvia Tanzeum, Trulicity, Byetta Victoza Glucagon glucagon Glucagon meglitinides SGLT 2i Sulfonylureas insulin (various) nateglinide, repaglinide canagliflozin, dapagliflozin, empagliflozin glimepiride, glipizide glyburide Humulin, Novolin, Humalog, Novolog, Apidra, Lantus, Levemir Starlix, Prandin Invokana, Farxiga, Jardiance Amaryl, Glucotrol, Diabeta, Micronase Thiazolidinediones pioglitazone, rosiglitazone asdf Actos, Avandia Oral Diabetes Medications Secretion Hepatic Glucose Production Pancreatic Glucagon Secretion Peripheral Glucose Uptake GI CHO Absorption Renal Reabsorp-tion of Glucose β-cell Function -Glucosidase Inhibitor Biguanide Bromocriptine Colesevelam Unknown Unknown DPP-4 Inhibitor Improve * Glinide SGLT-2 Inhibitor Improve National Diabetes Education Program. Available at: http://www.ndep.nih.gov/media/drug_tables_supplement.pdf Accessed August 10, 2010. Nathan DM, et al. Diabetes Care. 2009;32:193 203. Rodbard HW, et al. Endocr Pract. 2009;15(6):540 559. Januvia [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc.; 2010. Onglyza [prescribing information]. Princeton, NJ: Bristol Myers Squibb Co.; 2009. Welchol [prescribing information]. Parsippany, NJ: Daiichi Sankyo Inc.; 2011.. Cycloset [prescribing information]. San Diego, CA: Santarus, Inc.; 2010. * In vitro and rodent data; preliminary human data 11

Multiple Sites of Actions of Incretins Hormone that stimulates insulin secretion in response to oral carbohydrate intake GLP 1 GIP This action impacts multiple sites of glucose regulation Suppression of glucagon at the pancreatic cell Stimulates insulin release at the pancreatic cell Promotes satiety and reduce appetite in CNS Slows gastric emptying nactivates native GLP 1 Works quickly Current Stable of GLP 1 agonists Twice Daily Exenatide Lixisenatide (FDA Approved 7/28/2016) 1 Once Daily Liraglutide Once Weekly Albiglutide Dulaglutide Exenatide LAR Semaglutide (oral) (Investigational) 1. FDA Press Release: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm513602.htm (Accessed 9/18/2016) 13

Current Stable of GLP 1 agonists Generic Name Albiglutide Exenatide IR Exenatide LAR Dulaglutide Liraglutide Lixisenatide Dosage Expected A1c Reduction Fasting BGM Reduction 30 mg/wk 0.7% 16 mg/dl 50 mg/wk 0.9% 25 mg/dl % Patients Reaching <7% A1c 5 mcg/bid 0.7% 17 mg/dl 48% 10 mcg BID 0.9% 19 mg/dl 53% 2 mg subq weekly 1.6% 25 mg/dl 58% 0.75 mg/weekly 0.7% 26 mg/dl 1.5 mg/weekly 0.8% 29 mg/dl 1.2 mg/d 0.8% 15 mg/dl 1.8 mg/d 1.1% 26 mg/dl 10 mcg/d Transition Dose 20 mcg/d 0.83% 15.84 mg/dl 44% https://www.gsksource.com/pharma/content/dam/glaxosmithkline/us/en/prescribing_information/tanzeum/pdf/tanzeum PI MG IFU COMBINED.PDF http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021773s9s11s18s22s25lbl.pdf Current Stable of GLP 1 agonists Generic Name Albiglutide (Tanzeum) Exenatide IR (Byetta) Exenatide LAR (Bydureon) Dulaglutide (Trulicity) Liraglutide (Victoza) Lixisenatide (Adlyxin) Dosage Expected A1c Reduction Fasting BGM Reduction 30 mg/wk 0.7% 16 mg/dl 50 mg/wk 0.9% 25 mg/dl % Patients Reaching <7% A1c 5 mcg/bid 0.7% 17 mg/dl 48% 10 mcg BID 0.9% 19 mg/dl 53% 2 mg subq weekly 1.6% 25 mg/dl 58% 0.75 mg/weekly 0.7% 26 mg/dl 1.5 mg/weekly 0.8% 29 mg/dl 1.2 mg/d 0.8% 15 mg/dl 1.8 mg/d 1.1% 26 mg/dl 10 mcg/d Transition Dose 20 mcg/d 0.83% 15.84 mg/dl 44% https://www.gsksource.com/pharma/content/dam/glaxosmithkline/us/en/prescribing_information/tanzeum/pdf/tanzeum PI MG IFU COMBINED.PDF http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021773s9s11s18s22s25lbl.pdf 14

Risks: GLP 1 s and Safety GI upset: Nausea, Vomiting, Diarrhea Pancreatitis Renal Impairment Medullary Thyroid Carcinoma (Rats and Mice) Hypersensitivity Hypoglycemia (esp. with insulin and sulfonylureas) GLP 1 s and Safety Choosing the Right Patient: Exclusions Personal Hx of Pancreatitis or high risk of developing pancreatitis Gastroparesis Severe Renal Disease Personal or Family Hx of Medullary Thyroid Carcinoma Personal or Family Hx of MEN 2 (thyroid, parathyroid and adrenal tumors) 15

Current Basal s 16

How Do You Approach The Discussion? is a 4 letter word Patients: Can be injection adverse Fearful of losing control of life and scheduling Fearful of the End of the Road The Unknown Use All of Your Resources Healthy eating, wt. control, increased physical activity & diabetes education Efficacy Hypo Risk.. Weight.... Side Effects... Cost. High Efficacy Low Hypoglycemic Risk Weight Neutral Lactic Acidosis/GI intolerance Low Cost If A1c target not achieved after ~3 months of monotherapy, proceed to 2 drug combination (order not meant to denote any specific preference choice dependent on a variety of patient and disease specific factors). Efficacy. Hypo Risk. Weight.. Side Effects. Cost Sulfonylurea Thiazolidinedione DPP 4 Inhibitor SGLT 2 Inhibitor GLP 1 Receptor High.. high. Intermediate.. Intermediate.. high.. Agonist Moderate risk. low Risk.. Low risk.. Low risk Low risk gain... Gain. neutral.. losing losing.. hypoglycemia. Edema,CHF,Fx s rare GU, dehydration. GI.. Low. Low Cost high high high (basal) Highest High risk gain hypoglycemia variable American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes 2015. Diabetes Care 2015;38(Suppl. 1):S41 S48. If A1c target not achieved after ~3 months of dual therapy, proceed to 3 drug combination (order not meant to denote any specific preference choice dependent on a variety of patient and disease specific factors). Sulfonylurea Thiazolidinedione DPP 4 Inhibitor SGLT 2 Inhibitor GLP 1 Receptor Agonist (basal) If A1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on GLP RA, add basal insuin; or (3) on optimally titrated basal insulin, add or mealtime insulin. In refractory patients, consider adding or SGLT 2i: (basal) Mealtime or 17

Current Basal s Once Daily Degludec 1 U 100 U 200 Detemir 2 U 100 Glargine 3,4 U 100 U 300 Twice Daily Detemir 2 U 100 (NPH 5 ) U 100 1. http://www.novo pi.com/tresiba.pdf (Accessed 9/30/2016) 2. http://www.novo pi.com/levemir.pdf (Accessed 9/30/2016) 3. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021081s034lbl.pdf (Accessed 9/30/2016) 4. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206538lbl.pdf (Accessed 9/30/2016) 5. http://pi.lilly.com/us/humulin N USPI.pdf (Accessed 9/30/2016) Current Basal s Generic Name Concentration Expected A1c Reduction Fasting BGM Reduction Degludec 1 U 100 0.7% 16 mg/dl U 200 0.9% 25 mg/dl Detemir 2 U 100 2.0% 69 mg/dl Glargine U 100 3 0.46% 49 mg/dl U 300 4 0.9% 29 mg/dl (NPH) (typically twice daily dosing) 5 U 100 1. http://www.novo pi.com/tresiba.pdf (Accessed 9/30/2016) 2. http://www.novo pi.com/levemir.pdf (Accessed 9/30/2016) 3. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021081s034lbl.pdf (Accessed 9/30/2016) 4. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206538lbl.pdf (Accessed 9/30/2016) 5. http://pi.lilly.com/us/humulin N USPI.pdf (Accessed 9/30/2016) 18

Current Basal s Generic Name Degludec 1 (Tresiba) Detemir 2 (Levemir) Glargine (Lantus, Toujeo) Concentration Expected A1c Reduction Fasting BGM Reduction U 100 0.7% 16 mg/dl U 200 0.9% 25 mg/dl U 100 2.0% 69 mg/dl U 100 3 0.46% 49 mg/dl U 300 4 0.9% 29 mg/dl (NPH) (typically twice daily dosing) 5 (Novolin, Humulin) U 100 1. http://www.novo pi.com/tresiba.pdf (Accessed 9/30/2016) 2. http://www.novo pi.com/levemir.pdf (Accessed 9/30/2016) 3. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021081s034lbl.pdf (Accessed 9/30/2016) 4. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206538lbl.pdf (Accessed 9/30/2016) 5. http://pi.lilly.com/us/humulin N USPI.pdf (Accessed 9/30/2016) s in General Robust blood sugar reduction A1c reductions 1.5 3.5% Few toxicities Hypersensitivities typically related to excipients Hypoglycemia requires monitoring and management Antibodies clinical significance? Lipodystrophy Edema Few Drug:Drug interactions Most are changes in blood sugars, high or low Delivery Vial/Syringe Pens Pumps Inhalation 19

Safety and Basal Hypoglycemia Especially when combined with secretogogues ( s, glinides) Hypersensitivity Weight Gain Pen Sharing! Inappropriate Dosing Mixing s Mis Dosing Why the New s? Flatter Action Curves Prolonged Activity Smaller Depot Suggestion of improved nocturnal hypoglycemia 20

Confirmed Nocturnal or Severe Nocturnal Hypoglycemic Events (Weeks 9 to 6 months) Gla 300 % (Events/pt yr) Gla 100 %(Events/pt yr) Relative Risk [95%CI] Based on % pts. Edition 1 Edition 2 Edition 3 36.1 (2.97) 21.6 (1.94) 16 (NS) 45.8 (4.05) 27.9 (3.19) 17 (NS) 0.79 [0.67,0.93]* 0.77 [0.61,0.99]* 0.89 [0.66,1.20] *Significant vs. Gla 100 % = percentage of patients experiencing 1 event, NS = not shown http://www.pbm.va.gov/pbm/clinicalguidance/drugmonographs/_glargine_300u_per_ml_toujeo.pdf (Accessed 10/1/2016) Confirmed Nocturnal Hypoglycemic (Meta analysis): Degludec End of Trial Rate Ratio IDeg vs. GLA [95%CI] Dose Titration Period Maintenance Period T2D Pooled Studies 0.68 [0.57, 0.82]* 0.81 [0.64,1.02] 0.62 [0.49, 0.78]* T1D Pooled Studies 0.83 [0.69, 1.00] 0.88 [0.72, 1.08] 0.75 [0.60, 0.94]* T2D and T1D Pooled Studies 0.75 [0.65, 0.85]* 0.86 [0.74, 1.00] 0.68 [0.58, 0.80]* *Significant vs. Gla 100 http://www.pbm.va.gov/pbm/clinicalguidance/drugmonographs/_degludec_tresiba_monograph.pdf (Accessed 10/1/2016) Russel Jones, et al. Nutrition Metab Cardiovasc Dis; 2015. 21

10/28/2016 Healthy eating, wt. control, increased physical activity & diabetes education High Efficacy Low Hypoglycemic Risk Weight Neutral Lactic Acidosis/GI intolerance Low Cost Efficacy Hypo Risk.. Weight.... Side Effects... Cost. If A1c target not achieved after ~3 months of monotherapy, proceed to 2 drug combination (order not meant to denote any specific preference choice dependent on a variety of patient and disease specific factors). Efficacy. Hypo Risk. Weight.. Side Effects. Cost Sulfonylurea High.. Moderate risk. gain... hypoglycemia. Low. Thiazolidinedione high. low Risk.. Gain. Edema,CHF,Fx s Low Cost DPP 4 Inhibitor Intermediate.. Low risk.. neutral.. rare high SGLT 2 Inhibitor Intermediate.. Low risk losing GU, dehydration. high GLP 1 Receptor Agonist high.. Low risk losing.. GI.. high (basal) Highest High risk gain hypoglycemia variable If A1c target not achieved after ~3 months of dual therapy, proceed to 3 drug combination (order not meant to denote any specific preference choice dependent on a variety of patient and disease specific factors). American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes 2015. Diabetes Care 2015;38(Suppl. 1):S41 S48. Sulfonylurea Thiazolidinedione DPP 4 Inhibitor SGLT 2 Inhibitor GLP 1 Receptor Agonist (basal) If A1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on GLP RA, add basal insuin; or (3) on optimally titrated basal insulin, add or mealtime insulin. In refractory patients, consider adding or SGLT 2i: (basal) Mealtime or 22

Rationale for Basal /GLP 1 Balanced Approach to Fasting and Prandial glucose coverage Replace insulin for fasting/underlying glycemic control Up regulating native gut metabolism to glucose stimulation Easier for patient than MDI insulin management Overall reduced risk of hypoglycemia vs. MDI Where Diabetes Medications Work GLP 1 GLP 1 GLP 1 GLP 1 GLP 1 DeFronzo RA. Diabetes. 2009. 58 (4): 773-795. 23

Effect of Glargine Up Titration vs. Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial Baseline A1c = 8.4% 767 Pts Screened 557 Randomized Baseline A1c = 8.2% 278 Received Degludec/liraglutide 279 Received insulin glargine metformin 250 participants completed 265 participants completed A1c = 1.81% Wt = 1.4kg Hypoglycemia 2.23 episodes/pt. year A1c <7% = 71.6% A1c = 1.13% Wt = 1.8kg Hypoglycemia 5.05 episodes/pt. year A1c <7% = 24.6% 26 Week Study Period Randomized, open label, treat to target Lingvay I, Manghi F et. al. Effect of Glargine UP titration vs Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes. JAMA. 2016;315:898 907. Effect of Glargine Up Titration vs. Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial Lingvay I, et al. Effect of Glargine Up titration vs Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes. JAMA. 2016;315(9):898 907. 24

Effect of Glargine Up Titration vs. Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial Lingvay I, et al. Effect of Glargine Up titration vs Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes. JAMA. 2016;315(9):898 907. Effect of Glargine Up Titration vs. Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial Lingvay I, et al. Effect of Glargine Up titration vs Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes. JAMA. 2016;315(9):898 907. 25

Prandial Options to Advance Basal Glargine Therapy: Testing Lixisenatide Plus Basal Versus Glulisine Either as Basal Plus or Basal Bolus in Type 2 Diabetes: The GetGoal Duo 2 Trial Glargine Lixisenatide / A1c 7.2% Symptomatic Hypoglycemia = 107 Glargine Optimization A1c improved from 8.5 to 7.9% Glargine Glulisine Daily / metformin Glargine Glulisine 3x daily / metformin A1c 7.2% Symptomatic Hypoglycemia = 140 (P = 0.01 vs. Lixi) A1c 7.0% Symptomatic Hypoglycemia = 154 (P = 0.0001 vs. Lixi) 12 Weeks 26 Weeks 26

Dulaglutide Glargine: AWARD 9 Trial Presented at 76 th American Diabetes Association Scientific Sessions A1c reduction Fasting Blood Sugar (mg/dl) Weight Change (kg) Dulaglutide 1.5 mg glargine 1.44% 44.63 1.91 Placebo glargine 0.67% 27.90 0.50 Pozzilli P. Improved Glycemic Control and Weight Loss with Once Weekly Dulaglutide vs. Placebo, Both Added to Titrated Daily Glargine in Type 2 Diabetes Paitients (AWARD 9). Presented at the 2016 American Diabetes Association Scientific Session June 10 14 th, 2016. Advancing Basal Replacement in Type 2 Diabetes Inadequately Controlled with Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP 1 Receptor Agonist, Versus Thrice Daily Prandial Lispro (Harmony 6) 26 week Study: Randomized, open label, active controlled trial Once weekly albiglutide vs thrice daily insulin lispro added to titrated once daily glargine Oral agents metformin and or pioglitazone could be continued Rosenstock J. et al. Advancing Basal Replacement in Type 2 Diabetes Inadequately Controlled with Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP 1 Receptor Agonist, Versus Thrice Daily Prandial Lispro. Diabetes Care 2014;37:2317 2337. 27

Advancing Basal Replacement in Type 2 Diabetes Inadequately Controlled with Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP 1 Receptor Agonist, Versus Thrice Daily Prandial Lispro (Harmony 6) ± pioglitazone and Glargine Optimization Albiglutide 30/50 mg plus glargine/oad s 285 pts 3x daily prandial Lispro glargine/oad s 281 pts A1c = 0.82% Weight Change = 0.7kg Hypoglycemia = 0.9 events/pt/yr A1c = 0.66% Weight Change = 0.8kg Hypoglycemia = 2.3 events/pt/yr 4 8 Weeks 26 Weeks 8 Week Follow up Rosenstock J. et al. Advancing Basal Replacement in Type 2 Diabetes Inadequately Controlled with Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP 1 Receptor Agonist, Versus Thrice Daily Prandial Lispro. Diabetes Care 2014;37:2317 2337. Advancing Basal Replacement in Type 2 Diabetes Inadequately Controlled with Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP 1 Receptor Agonist, Versus Thrice Daily Prandial Lispro (Harmony 6) Rosenstock J. et al. Advancing Basal Replacement in Type 2 Diabetes Inadequately Controlled with Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP 1 Receptor Agonist, Versus Thrice Daily Prandial Lispro. Diabetes Care 2014;37:2317 2337. 28

Basal /GLP 1 Powerful new approach to patients with T2DM Effective A1c reduction Less hypoglycemia exposure Potential for weight loss Basal /GLP 1 Agonist Patient Profile Patient with T2DM Has tried a number of oral agents/basal insulin Possibly at hypoglycemic risk No Hx of pancreatitis/mtc/men 2 Renal Status acceptable/stable No Hx of gastroparesis/severe GI disturbance 29

Summary: Type 2 Diabetes Mellitus has grown to epidemic proportions The landscape of diabetes medications continues to expand Opportunities for improved control of the disease state with fewer side effects and the potential for reduction of CV risk are growing Combination therapy with newer agents that provide powerful synergy for our patients has the potential to change the landscape of Type 2 Diabetes management. 30