Houston, TX. March 12th, 2015

Transcription

1 March 12th, 215 George R. Brown Conven on Center Houston, TX P F Dace L. Trence, MD, FACE Professor, Department of Medicine Director, Endocrine Fellowship Program Director, Diabetes Care Center University of Washington Medical Center Sea le, Washington Felice Caldarella, MD, FACE, CDE, FACP Endocrinologist, Hunterdon Medical Center Diabetes and Endocrine Associates of Hunterdon Flemington, New Jersey

2 Session 5: Combining GLP-1 Receptor Agonists with Basal : Realizing the Potential in Type 2 Diabetes Learning Objectives 1. Implement ADA recommendations for A1C, fasting plasma glucose, and post-prandial glucose targets in the management of patients with type 2 diabetes 2. Assess the clinical profiles of GLP1 receptor agonists and the advantages and disadvantages of prandial insulin 3. Describe the clinical rationale and expected benefits of using antidiabetic therapies with complementary mechanisms of action in the treatment of patients with type 2 diabetes 4. Utilize appropriate strategies to select and intensify antidiabetic therapy to achieve PPG control in patients with type 2 diabetes on basal insulin Faculty Dace L. Trence, MD, FACE Director, Diabetes Care Center Professor, Division of Metabolism, Endocrinology and Nutrition University of Washington Medical Center Seattle, Washington Dr Dace Trence is currently director of the diabetes care center and professor of medicine at the University of Washington Medical Center, Seattle. She is also the University of Washington endocrine fellowship program director and director of endocrine days; a medical education program for endocrinologists practicing in the Pacific Northwest. She currently serves on the American Association of Clinical Endocrinologists (AACE) board of directors, chairing the AACE publications committee and co-chairing AACE CME committee. She has been on the editorial boards of several journals including Clinical Diabetes. She has had articles published in JCEM, JAMA, Diabetes Care and is a coauthor of Optimizing Diabetes Care for the Practitioner. Her current interests include improving educational processes in diabetes self management and clinical training of health care professionals. Felice Caldarella, MD, FACE, CDE, FACP Endocrinologist Hunterdon Medical Center Diabetes and Endocrine Associates of Hunterdon Flemington, New Jersey Dr Felice Caldarella is a graduate of New York University and received his medical degree from SUNY Upstate Medical University. He completed his residency at Brown University, Rhode Island. Dr Caldarella went on to receive subspecialty training in endocrinology, diabetes and metabolism at University of Medicine and Dentistry of New Jersey. He is board certified in endocrinology, diabetes and metabolism. He is a fellow of the American College of Endocrinology and a fellow of the American College of Physicians. He is also a certified diabetes educator. Dr Caldarella was recognized as a New Jersey top doctor in 211. Dr Caldarella supervises the medically supervised weight loss program at the Center for Advanced Weight Loss. Faculty Financial Disclosure Statements The presenting faculty reported the following: Dr Trence has ownership interest as a Stockholder with Sanofi and Medtronic. Dr Caldarella has served on the speaker's bureau for NoroNordisk, Salix, and Takeda. Education Partner Financial Disclosure Statement The content collaborators at Horizon CME have no relationships to disclose. Session 5

3 Acronym List Acronym Definition ASP insulin aspart BG blood glucose DET insulin detemir DPP-4I dipeptidyl peptidase 4 inhibitor FPG fasting plasma glucose GIP glucose dependent insulinotropic polypeptide GLAR insulin glargine GLP-1 RA glucagon like peptide 1 receptor agonist GLU insulin glulisine MET metformin NPH neutral protamine Hagedorn NSHE nonsevere hypoglycemic events OAD oral antidiabetic drugs OHA oral hypoglycemic agents PG plasma glucose PPG postprandial glucose SGLT-2 sodium glucose transporter 2 SMBG self monitoring of blood glucose SU sulfonylurea T1DM type 1 diabetes T2D/T2DM type 2 diabetes TZD thiazoladinedione Suggested Reading List Rodbard HW, Blonde L, Braithwaite SS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2;13 (Suppl 1):1-. American Diabetes Association. Approaches to Glycemic Treatment. Diabetes Care. 215;3(Suppl 1):S41-S4. Balena R, Hensley IE, Miller S, Barnett AH. Combination therapy with GLP-1 receptor agonists and basal insulin: a systematic review of the literature. Diabetes Obes Metab. 213;15(): Giugliano D, Maiorino MI, Bellastella G, Chiodini P, Esposito K. Treatment regimens with insulin analogues and haemoglobin A1c target of <% in type 2 diabetes: a systematic review. Diabetes Res Clin Pract. 211;2(1):1-1. Monnier L, Colette C, Dunseath GJ, Owens DR. The loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes. Diabetes Care. 2;3(2):23-2. Riddle M, Umpierrez G, DiGenio A, Zhou R, Rosenstock J. Contributions of basal and postprandial hyperglycemia over a wide range of A1C levels before and after treatment intensification in type 2 diabetes. Diabetes Care. 211;34(12): Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 4). UK Prospective Diabetes Study (UKPDS) Group. JAMA:1;21(21): Raccah D, Haak TJ, Huet D, et al. Comparison of stepwise addition of prandial insulin to a basal-bolus regimen when basal insulin is insufficient for glycaemic control in type 2 diabetes: results of the OSIRIS study. Diabetes Metab. 212;3(): Session 5

4 SESSION 5 2 3:15pm Combining GLP-1 Receptor Agonists with Basal : Realizing the Potential in Type 2 Diabetes SPEAKERS Dace Trence, MD, FACE Felice Caldarella, MD, FACE, CDE, FACP Presenter Disclosure Information The following relationships exist related to this presentation: Dr. Trence has ownership interest as a Stockholder with Sanofi and Medtronic. Dr. Caldarella has served on the speaker's bureau for NoroNordisk, Salix, and Takeda. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Objectives Combining GLP-1 Receptor Agonists with Basal : Realizing the Potential in Type 2 Diabetes Dace Trence, MD, FACE Director, Diabetes Care Center Professor, Division of Metabolism, Endocrinology and Nutrition University of Washington Medical Center Seattle, WA Felice Caldarella, MD, FACE, CDE Endocrinologist Hunterdon Medical Center Diabetes and Endocrine Associates of Hunterdon Flemington, NJ Implement ADA recommendations for A1C, fasting plasma glucose, and post-prandial glucose targets in the management of patients with type 2 diabetes Assess the clinical profiles of GLP-1 receptor agonists and the advantages and disadvantages of prandial insulin Describe the clinical rationale and expected benefits of using antidiabetic therapies with complementary mechanisms of action in the treatment of patients with type 2 diabetes Utilize appropriate strategies to select and intensify antidiabetic therapy to achieve PPG control in patients with type 2 diabetes on basal insulin Patient Case Susan B. is a 4 year old woman diagnosed with type 2 diabetes mellitus 5 yrs ago and has required progression from metformin to added glimepiride. No complications to date of retinopathy, nephropathy, neuropathy. She is trying to diet and exercise, but back pain has become more chronic and is limiting physical exertion. Medical history: Hypothyroidism, T2DM, chronic back pain, and hypercholesterolemia Meds: Atorvastatin, irbesartan, levothyroxine, metformin 1 mg BID, glimepiride 4 mg QD, IBU PRN. P. Exam: 13/ mm Hg, Weight 2 lb, BMI 3. Lab: A1c.%, Cr. mg/dl, LDL-chol Normoglycemia and Recommended Glycemic Targets in T2DM Glucose Control Healthy Individuals 1-3 A1C, % <. Preprandial PG, mg/dl Peak postprandial PG, mg/dl ADA AACE Individualized Target <. <. most pts <.5 healthy pts Individualized Target.-. <.5 most pts <1-13 <11 <14 <1 a <14 b a Peak postprandial capillary plasma glucose; b 2-hour postprandial glucose concentration; Patients with known CVD or multiple co-morbidities. PG = plasma glucose; ADA = American Diabetes Association. 1. ADA. Clinical Practice Recommendations 215. Diabetes Care 215;3(Suppl. 1):S33 S4. 2.ADA. Standards of Medical Care in Diabetes-214. Diabetes Care. 214;3(1 Suppl):S14-S. 3. ADA. Diabetes Care. 21;24: Garber AJ, et al. Endocr Pract. 213;1: Handelsman Y, et al. Endocr Pract. 211;1(Suppl 2):1-53.

5 When to Consider in Type 2 Diabetes Patients with symptomatic hyperglycemia When combination oral/injectable agents become inadequate (A1C >.-.5%) High FPG or high PPG Unacceptable side effects of other agents Special circumstances (e.g., steroids, infection, pregnancy), hepatic and renal disease Patient with hyperglycemia in the hospital Severely uncontrolled diabetes FPG = fasting plasma glucose; PPG = postprandial glucose. Defined as fasting glucose >25 mg/dl, random glucose > 3 mg/dl, A1C >1%, ketonuria, or symptomatic (polyuria, polydipsia, and weight loss) by ADA 2 Consensus Statement. After glucose controlled, oral agents can be added and insulin withdrawn if preferred. Nathan DM, et al. Diabetes Care. 2; volume 32, Inzucchi SE, et al. Diabetes Care. 212;35(): ADA Diabetes Care. 214:3(Suppl 1):S14-S. Glycemic Control Declines over Time with Traditional Monotherapy Patients (%) with A1c <% Most patients on traditional therapies will require another agent to maintain long-term glycemic control % 34% 13% 3 yr yr yr 3 yr yr yr Adequately Controlled and Treated with Metformin Adequately Controlled and Treated with Sulfonylureas Overweight drug-naïve patients. Normal weight and overweight drug-naïve patients. Turner RC, et al. JAMA. 1;21:25 Patients (%) with A1c <% % 34% 24% UKPDS: Progressive Deterioration in Glycemic Control over Time HbA1C Level 1 beta-cell Function Basal Therapy Concept and Physiology Median A1c (%) Conventional Intensive B-cell Function (%) Time from Randomization (y) Years from Diagnosis UKPDS Group. Lancet. 1;352:3-53. Holman RR. Diabetes Res Clin Pract. 1;4(suppl):S21-S25. Postprandial Hyperglycemia Persists after Basal Therapy 14 patients with baseline A1c.5% on diet, oral agents, or insulin. Mealtime hyperglycemia persisted after 3 months of intensive treatment. Pharmacokinetic Profile of Current Basal s Glucose (mg/dl) A1c >% (n=44) A1c % (n=12) Plasma Levels Intermediate (NPH insulin) Long ( detemir) Long ( glargine) Hours Woerle HJ, et al. Diabetes Res Clin Pract. 2;:2-5. : 2: 4: : : 1: 12: 14: 1: 1: 2: 22: 24: Time (h) NPH = neutral protamine Hagedorn Adapted from Hirsh IB. NEJM. 25; 352: Flood TM. J Fam Pract. 2;5(suppl 1):S1-S12.

6 A Simple Approach to Starting Basal Comparison of Analogue Basal and NPH Added to Oral Therapy: FPG and A1C 5 patients previously treated with 1-2 OHAs and HbA1c >.5% Bedtime or morning long-acting insulin OR Bedtime intermediate-acting insulin Daily dose: 1 units or.1-.2 units/kg/day Mean Daily Dose Glargine: 4 Units NPH: 42 Units Glargine NPH Check FBG daily Increase dose by 2-4 units every 3 days until FPG is -13 mg/dl In the event of hypoglycemia or FPG level < mg/dl: Reduce bedtime insulin dose by 4 units, or by 1-2% FPG (mmol/l) 1 HbA1c (%) 1 Continue regimen and check A1C every 3 months Time (weeks) Time (weeks) FPG = fasting plasma glucose Nathan DM, et al. Diabetes Care. 2;32: ADA. Diabetes Care. 215;3(suppl 1):S41-S4. OHA = oral hypoglycemic agent Riddle M, et al. Diabetes Care. 23;2:3-. Comparison of Analogue Basal and NPH Added to Oral Therapy: Hypoglycemia Symptomatic Hypoglycemia by Time of Day Effective Dose Titration of Consistently Reduces A1C to Target Clinical Trials of Analogue Glargine Patients (%) with 1 Hypoglycemia Episode Basal Glargine NPH 2 4 B L D Time of Day (hr) 2 HbA1c Treat-to- Target 1 Baseline Study Endpoint LANMET 2 APOLLO 3 LAPTOP Triple Therapy 5.. INITIATE p<.5 vs. insulin glargine; hypoglycemia is defined as PG 2 mg/dl. B = Breakfast; L = Lunch; D = Dinner. Riddle M, et al. Diabetes Care. 23;2: Riddle M, et al. Diabetes Care. 23;2: Yki-Jarvinen H, et al. Diabetologia. 2;4: Bretzel RG, et al. Diabetes. 2;55(Suppl). Abstract 32-OR. 4. Janka H, et al. Diabetes Care. 25;2: Rosenstock J, et al. Diabetes Care. 2;2: Yki-Jarvinen H, et al. Diabetes Care. 2; 55. Abstract 125-OR. Combined Effects of Metformin with Therapy in Type 2 Diabetes Regimens with Analogues and A1C <% in T2DM Patients Subject (n) Duration (mo) dose at end (U) HbA1c at end (%) Weight gain (kg) Yki-Järvinen et al [2] + Metformin Avilés-Santa et al [2] + Metformin Strowig et al [3] + Metformin Wulffelé et al [31] + Metformin trials, with 1,5 patients HbA1c <% was achieved in 41.4% (5% CI, %) First insulin treatment, lower insulin and use of 2 oral drugs were predictors of response Hypoglycemia ranged from to 4.1 events/patient/ 3 days Weight gain ~1.5 kg All of the studies compared subjects on insulin versus metformin and insulin. All found less weight gain, a lower insulin dosage, and mostly HbA1c, HbA1c-hemoglobin A1c. Sasali A and Leahy JL. Curr Diab Rep. 23;3:3-35. Giugliano D, et al. Diabetes Res Clin Pract. 211;2(1):1-1.

7 Patient Case Cont d Susan B. was started on basal insulin at 1 units hs. What if Basal Is Not Enough? Two weeks later she calls to report that her fasting glucoses are now in the mg/dl range. You advise a 3 unit increase in the insulin dose, fasting glucose one month later is at mg/dl months later, she notes that blood sugars have been up and down. She has had several lows that have been embarrassing, as they have occurred at physical therapy sessions started for back pain. And she is concerned that she has gained 5 lbs You order a blinded 3-day continuous glucose monitor Glucose (mg/dl) Patient Case: Glucose Readings Continued Mon Feb 2 Tue Feb 3 Wed Feb 4 Thu Feb 5 Average 12:a 2:a 4:a :a :a 1:a 12:p 2:p 4:p :p :p 1:p 12:a Courtesy of Dace Trence, MD. 14 Glucose Concentration (mmol/l) Stepwise Glycemic Deterioration in T2DM Fasting (nocturnal period) 2 Breakfast Morning Period Monnier, et al. Diabetes Care. 2;3: Time (h) Postprandial (daytime period) Diabetes Duration (yrs) Basal and Postprandial Contributions to Hyperglycemia by A1C Range Pooled baseline data from Treat-to-Target design studies 1 T2DM patients on diet ± OAD Mean A1c.%, FPG 1. mmol/l (14 mg/dl) -point ambulatory SMBG profiles (ac, 2hr-pc, and hs) Calculations assume hyperglycemia is >5. mmol/l (1 mg/dl) % 24% <. % 22% % 21% Baseline A1c Ranges On oral therapy, fasting hyperglycemia dominates over a wide range of A1c Riddle M, et al. Diabetes Care. 211:34: % 21% % 2%.5 Basal Hyperglycemia Postprandial Hyperglycemia Matching Treatment to Disease Progression Using a Stepwise Approach Basal Plus: Once-daily basal insulin glargine or detemir plus once-daily rapid-acting insulin Basal Add Basal and Titrate Raccah D, et al. Diabetes Metab Res Rev. 2;23:25-4. Basal Bolus Add Prandial before Each Meal Basal Plus Add Prandial at Main Meal Lifestyle Changes plus Metformin (± other agents) Progressive Deterioration of -cell Function

8 Steps in Transition from Basal to Basal-Bolus Therapy in T2DM Intensification: OSIRIS Study Design Above target: A1c >.% FPG >11 mg/dl STEP 1 Basal Weekly titration based on FPG All oral agents continued Above target STEP 2 Add insulin Main Meal Above target STEP 3 Add insulin Next Largest Meal Above target A1c <.%, FPG <11 mg/dl STEP 4 Add insulin Last Meal Maintain treatment regimen with monitoring of FPG and A1c Karl DM. Curr Diab Rep. 24: American Association of Clinical Endocrinologists. Endocr Pract. 2;13(suppl 1):3-. Poorly controlled on basal insulin + MET (N=11) N=14 Switched to GLAR for A1C months a >.% and N=1 FPG <12 mg/dl (n=4) N=123 Group 1:GLAR + MET + 3xGLU Group 2: GLAR + MET + 1, 2, or 3xGLU Group 3: GLAR + MET + SU + 1, 2, or 3xGLU Randomization and 12 Month F/U a Oral antidiabetic agents were continued. GLAR = insulin glargine; GLU = insulin glulisine; MET = metformin; SU = sulfonylurea. Raccah D, et al. Diabetes Metab. 212;3():5-14. Mean in A1C (%) OSIRIS Study: Change in A1C and Weight Change in A1C from Randomization to Endpoint Randomization GLAR = insulin glargine; GLU = insulin glulisine; MET = metformin; SU = sulfonylurea. Raccah D, et al. Diabetes Metab. 212;3():5-14. Weight (kg) Group 1: GLAR + MET + 3xGLU Group 2: GLAR + MET + 1, 2, or 3xGLU Group 3: GLAR + MET + SU + 1,2, or 3xGLU Change in Body Weight (kg) 2.3 p= Intensification: STEP-WISE Study Design Poorly controlled on basal insulin + 1 to 3 OADs (N=345) Switched to IDet for 12 weeks R SimpleSTEP a (N=15) A1c.% (n=2) ExtraSTEP b (N=14) IDet + OADs + 1, 2, or 3xIAsp IDet + OADs + 1, 2, or 3 IAsp SU discontinued; a SimpleSTEP = sequential addition of IAsp to meal(s) perceived by the patient as being the largest of the day, with titrations based on the premeal plasma glucose concentration; b ExtraSTEP = sequential addition of IAsp to meal(s) with the highest measured PPG increase, with titrations based on the PPG level. IDet = insulin detemir; IAsp = insulin aspart; SU = sulfonylurea; PPG = postprandial glucose. Meneghini L, et al. Endocr Pract. 211;1(5):2-3. STEP-WISE Study: Change in A1C HbA1c (%) Period 1 Period 2 Period Weeks ExtraSTEP a SimpleSTEP b a SimpleSTEP = sequential addition of IAsp to meal(s) perceived by the patient as being the largest of the day, with titrations based on the premeal plasma glucose concentration; b ExtraSTEP = sequential addition of IAsp to meal(s) with the highest measured PPG increase, with titrations based on the PPG level. Meneghini L, et al. Endocr Pract. 211;1(5): Regimens with Analogues and A1C <% in Type 2 Diabetes Patients Systematic review of RCT 4 trials, 5 arms, 3,5 patients with a primary outcome of A1C <% in patients with T2DM Basal insulin (n=1,5): 41.4% Biphasic insulin (n=,23): 4.5% Prandial insulin (n=1,5): 3.% Basal-bolus insulin (n=2,114): 53.% Incidence of hypoglycemia ranged from to 4.1 events/patient/3 days Weight gain ranged from 1.5 kg for basal to 3 kg for biphasic insulin. Giugliano D, et al. Diabetes Res Clin Pract. 211;2(1):1-1.

9 Basal Bolus Regimen: Percent of Patients with A1C <% 12 trials, with 2114 patients A1c <% was achieved in 53.% Hypoglycemic events (mean/patient/3 days):. ( ) Mean weight gain ~2.5 kg Mean final insulin dose:. U/kg Escalation from basal to basalbolus increases success rate in an additional ~12% to 14% of patients HbA1c <% is achieve in ~54% of patients Study Basal Bolus Regimen (first author, year, reference) Proportion of Patients with HbA1c <% Hollander, 2 (44) Hollander, 2 (44) Rosenstock, 2 (4) Bergenstal, 2 (4) Bergenstal, 2 (4) Lankisch, 2 (4) Lankisch, 2 (4) Liebl, 2 (5) Riddle, 2 (53) Raskin, 2 (5) Raskin, 2 (5) Fritsche, 2 (5) Pooled Estimate (5% CI) 53.% (43.5%-4.%) Adding Prandial to Basal Advantages Treats postprandial hyperglycemia Increases success rate in achieving A1c <% Disadvantages Increases weight gain Increases hypoglycemia risk Less convenient with multiple injections Increases success rate only by an additional 12% to 14% Giugliano D, et al. Diabetes Res Clin Pract. 211;2(1):1-1. How Often Does Hypoglycemia Occur in Diabetes? Daily to about 1/wk 1/mo to several times/mo Only a few times/y or very rarely Hypoglycemia Frequency of NSHE (%) T1DM 12 Frequency of NSHE (%) T2DM 4.2 NSHE = nonsevere hypoglycemic events. Survey 4 US patients with T1DM (n=2) and with T2DM (n=2). Brod M, et al. Value Health. 211;14:5-1. Risk of Hypoglycemia Increases as Therapy Intensifies Percentage of Patients Reporting 1 Hypoglycaemic Event per Year (%) Diet Alone For all therapies, the significance of differences between levels is p<.1 Metformin SU = sulfonylurea. Wright AD, et al. J Diabetes Complicat. 2;2:35-41 (UKPDS 3). 1.. SU 21.2 Basal Only 32. Basal + Bolus HRQoL Decrement All Hypoglycemia Negatively Affects Quality of Life in Patients with T2DM Alvarez-Guisasola 1 (N=1; 3% with events) a a a HRQoL Decrement Marrett 2 (N=14; 3% with events) a Hypoglycemia Severity Hypoglycemia Severity Hypoglycemia is also associated with lower treatment satisfaction, poorer adherence, and greater resource utlization 3 a p<.5 vs. no reported hypoglycemia. 1. Alvarez-Guisasola F, et al. Health Qual Life Outcomes. 21;:. 2. Marrett E, et al. BMC Res Notes. 211;4: Williams S, et al. Diabetes Res Clin Pract. 211;1: a -.13 a -.21 a

10 Severe Hypoglycemia Is Associated with Increased Risk of Mortality and CV Events Advance Trial Results 1 Macrovascular events 3.45 ( ); P<.1 Death any cause 3.3 ( ); P<.1 Death CV cause 3. ( ); P<.1 Death non-cv cause 2. (1.-4.); P<.1.1 VADT Results 2 Macrovascular events 1. ( ); P=.4 Death any cause.3 ( ); P=.1 Death CV cause 3.3 ( ); P=.11.1 Decreased Risk 1. Zoungas S, et al. ADVANCE Collaborative Group. N Engl J Med. 21;33: Duckworth W, et al. VADT Investigators. VA Diabetes Trial (VADT) update. ADA th Scientific Sessions. 21: =. 1 1 Hazard Ratio 1 1 Increased Risk in Combination with GLP-1 Receptor Agonists Dace Trence, MD, FACE Director, Diabetes Care Center Professor, Division of Metabolism, Endocrinology and Nutrition University of Washington Medical Center Seattle, WA After food ingestion GLP-1 and GIP is secreted from L-cells of the jejunum and ileum That in turn. Incretin Physiology Secretion of GLP-1 Stimulates glucosedependent insulin secretion from -cells Suppresses glucagon secretion from -cells Slows gastric emptying Reduces food intake Degraded by DPP-4 enzyme Secretion of GIP Increases glucosedependent insulin release Degraded by DPP-4 enzyme GLP-1 = glucagon-like peptide-1; GIP = glucose-dependent insulinotropic polypeptide. Drucker DJ. Curr Pharm Des. 21;: Drucker DJ. Mol Endocrinol. 23 Feb;1(2):11-1. Drucker DJ, Nauck MA. Lancet. 2;3:1-15. Nauck MA. Am J Med. 2;122(Suppl 1):S3-S1. GLP-1 Receptor Agonists (GLP-1 RA) A1c reduction ~.%-2.% Multiple mechanisms of action insulin secretion glucagon release food intake Slows gastric emptying Advantages No hypoglycemia Weight loss some CV risk factors (i.e., lipids, BP, hs-crp) PPG (mainly short-acting agents) Disadvantages GI side effects (nausea, vomiting, diarrhea) Injectable heart rate hs-crp = high sensitivity C-reactive protein; BP = blood pressure; PPG = postprandial glucose. Drucker DJ, Nauck MA. Lancet. 2;3(54):1-15. Baggio LL, Drucker DJ. Gastroenterology. 2;132(): American Diabetes Association. Diabetes Care. 215;3(suppl 1):S41-S4. Pharmacokinetic Profile of GLP-1 RAs Short-acting GLP-1 RA vs. Basal : Changes in A1C and Weight Over Time Drug Dosing Half-life Duration of Action Exenatide 5-1 mcg SC twice daily 2.4 hours Short Lixisenatide 1-2 mcg SC daily 2-4 hours Short Albiglutide 3-5 mg SC once weekly - days Long Dulaglutide.5 mg SC once weekly 5 days Long Exenatide ER 2 mg SC once weekly 2.4 hours Long Liraglutide.-1. mg SC once daily 13 hours Long Available in Europe. Not FDA approved. Pinelli NR and Hurren KM. The Annals of Pharmacotherapy. 211;45(-):5-. American Diabetes Association. Diabetes Care. 215;3(suppl 1):S41-S4. US FDA. Drugs@FDA Website. data.fda.gov/scripts/cder/drugsatfda/. EU EMA. Medicines@EMA Website. Change in Body Weight (lbs) Glargine + 4. lbs Exenatide lbs p< Weeks Heine RJ, et al. Ann Intern Med. 25;143:55-5. A1C (%) ITT sample shown Mean ± SE shown Exenatide 1 mcg BID Glargine (dose 25 U/day) 12 2 Weeks

11 Postprandial Glucose Effect of Short- and Long-acting GLP-1 RAs: EXN vs. LIRA EXN preferentially affects PPG compared to Liraglutide. EXN reduced PPG significantly more after breakfast and dinner than LIRA, p<.1 14 Self-Measured Plasma Glucose (mmol/l) Before BF BF + min Before Lunch Lunch + min Time Before Dinner Dinner + min Bedtime LIRA Baseline LIRA Week 2 EXN Baseline EXN Week 2 p<.1. PPG = postprandial glucose; BF = breakfast; EXN = exenatide; LIRA = liraglutide. Buse JB, Rosenstock J, Sesti G, et al. Lancet. 2;34:3-4. PPG Effect of Short- and Long-acting GLP-1 RAs: LIXI vs. LIRA Mean Change from Premeal Plasma Glucose (mg/dl) 3-3 Lixisenatide (Baseline) Liraglutide (Baseline) Meal Lixisenatide (Day 2) Liraglutide (Day 2) p< Time after Study Drug Administration GLP-1 Agonist LIXI = lixisenatide; PPG = postprandial glucose. Not FDA approved. Adapted from Kapitza C, et al. IDF 211:Poster D-4. Patients (%) Proportion of Patients with 2-h PPG <14 mg/dl at Day Lixisenatide Liraglutide (n=5) (n=) Why Combine GLP-1 RAs with Basal Potential Benefits of Combining GLP-1 RAs with Basal GLP-1 RA No risk of hypoglycemia Associated with weight loss Mainly controls PPG especially with short-acting agents Glucose depend mechanism of action Basal Increased risk of hypoglycemia Associated with weight gain Controls fasting glucose supplementation and individualized dosing Minimize weight gain Minimize hypoglycemia risk Treat postprandial glucose excursions Reduce or eliminate the need for prandial insulin Reduce insulin requirements PPG = postprandial glucose. Cohen ND, et al. Med J Aust. 213;1(4):24-. American Diabetes Association. Diabetes Care. 215;3 (suppl 1):S41-S4. Cohen ND, et al. Med J Aust. 213;1(4):24-. Adding Prandial vs. GLP-1 RAs When Basal Is Not Enough Basal Bolus Add Prandial before Each Meal Basal Plus Add Prandial at Main Meal Basal Add Basal and Titrate Basal plus GLP-1 RAs Lifestyle Changes plus Metformin (± other agents) Exenatide BID Added to Basal : Efficacy and Safety Change in HbA1c (%) Adults with T2DM and HbA1c =.1% to 1.5% receiving glargine ± metformin ± pioglitazone were randomized to exenatide (1 mcg twice a day) or placebo for 3 weeks Efficacy Glargine + PBO (n=123) Glargine + EXN (n=13) Week Outcome PBO EXN BID only 1 reported event of major hypoglycemia (PBO group) p- value Hypoglycemia Discontinuation due to Adverse 1 <.1 Events (% of pts) p<.1; BID = twice daily; PBO = placebo; EXN = exenatide. Buse JB, et al. Ann Intern Med. 211;154(2):

12 Glucose Level (mmol/l) Exenatide BID Added to Basal : Effect on PPG Adults with T2DM and HbA1c =.1% to 1.5% receiving glargine ± metformin ± pioglitazone were randomized to exenatide (1 mcg twice a day) or placebo for 3 weeks SMBG Changes Glargine + EXN (Baseline) Glargine + PBO (Baseline) Glargine + EXN (3 wk) Glargine + PBO (3 wk) 1 Fasting Morning Midday Midday Evening Evening 3 2-hr PP Premeal 2-hr PP Premeal 2-hr PP Hours p<.1; p<.1; BID = twice daily; PBO = placebo; EXN = exenatide; PPG = postprandial glucose; PP = postprandial; SMBG = self monitored blood glucose. Buse JB, et al. Ann Intern Med. 211;154(2): Exenatide BID Added to Basal Effect on Dose and Weight Dose (U/day) Glargine + EXN (n=13) 2 Glargine + PBO (n=123) Change in Body Weight (kg) Glargine + Placebo Glargine + Exenatide p< Week Baseline insulin doses = 4.5 and 4 U/day in EXN BID and PBO groups, respectively. Respective increases = 13 and 2 IU/day. EXN = exenatide; PBO = placebo. Buse JB, et al. Ann Intern Med. 211;154: Lixisenatide Added to Basal in T2DM over 24 Weeks: Efficacy Lixisenatide Added to Basal in T2DM over 24 Weeks: Weight & Hypoglycemia Change in HbA1c (%) A1C P<.1 LS Mean Change (mg/dl) hour PPG P<.1 Change in Weight (kg) Weight Change -.3. Hypoglycemia (Events/pt-yr) Hypoglycemia With SU Without SU Lixisenatide + + SU (n =153) Placebo + + SU (n = 15) Not FDA approved. PPG = postprandial glucose; SU = sulfonylurea. Seino Y, et al. Diabetes Obes Metab. 212;14:1-1. Lixisenatide + + SU (n =153) Placebo + + SU (n = 15) Not FDA approved. PPG = postprandial glucose; SU = sulfonylurea. Seino Y, et al. Diabetes Obes Metab. 212;14:1-1. GLP-1 RAs Added to Basal : Comparison with Prandial A1C (%) Added to GLAR (3 wk, N=3) EXN BID -1.1 Noninferior LIS TID -1.1 Outcome EXN BID LIS TID Weight (kg) (P<.5) Minor hypo (E/Y) Nocturnal hypo (E/Y) Nausea (%) 32 2 Added to DEG (2 wk, N=1) 2,a Outcome LIRA QD ASP QD Weight (kg) -2.. (P<.5) Minor hypo (E/Y) 1..2 (P<.5) Nocturnal hypo (E/Y).2. (P<.5) Nausea (%) LIRA>ASP, first 2 wk Consider lowering basal insulin dose to decrease hypoglycemia risk with GLP-1 RAs 3 a degludec is not FDA approved. DEG = insulin degludec; EPY = events per patient-year; EXN BID = exenatide twice daily; E/Y = events per year; GLAR = insulin glargine; ASP = insulin aspart; LIS = insulin lispro; LIRA = liraglutide; QD = once daily; TID = three times daily. 1. Dimant M, et al. ADA 3rd Scientific Sessions. 213;-OR. 2. Mathieu C, et al. ADA 3rd Scientific Sessions. 213; US FDA. Drugs@FDA. A1C (%) LIRA QD -. P=.24 ASP QD -.4 Combining GLP-1 RAs and Basal GLP-1 RA Added to Basal 1 Basal Added to GLP- 1 RA 1 Outcome EXN BID PBO ISET + LIRA LIRA A1C (%) -1. a a. Weight (%) -1. a a -.5 Minor hypoglycemia (%) b 25 2,2 1.3 GLP-1RAs and basal insulin combined c improve glycemic control relative to either class alone, regardless of order of addition. 1-4 Consider lowering basal insulin dose to decrease hypoglycemia risk with GLP-1 RAs 3 a p<.5; b 1 major hypoglycemic event occurred in the PBO group of the GLP-1 RA added to basal in study; c EXN BID and LIRA, but not EXN QW, are approved for use with basal, but not prandial insulin. EXN BID = exenatide twice daily; IDET = insulin detemir; LIRA = liraglutide; PBO = placebo; TDD = total daily dose. 1. Buse JB, et al. Ann Intern Med. 211;154: DeVries J, et al. Diabetes Care. 212;35: Pawaskar M, et al. Endocr Pract. 212;1: Li CJ, et al. Cardiovasc Diabetol. 212;11: US FDA. Drugs@FDA.

13 Liraglutide Added to Basal in T2DM over 3 Weeks: Effects on A1c and Weight A1C (%) After MET + LIRA Run-in Efficacy MET + LIRA + DET (n=12) At 3 Weeks Weight (kg) MET + LIRA (n=11) Weight Change After MET + LIRA Run-in At 3 Weeks Minor Hypoglycemia (EPY) MET + LIRA (OBS) (n=4) HbA1c GLP-1 RAs in Combination with in T2DM Systematic Review Results reported as available from RCTs and 15 clinical practice or observational studies including at least 3 patients with T2DM 1 GLP-1 RA Added to Added to GLP-1 RA GLP-1 RA + (sequence not specified) Body Weight (kg) Dose (Units) No major hypoglycemia in any group during weeks Transient nausea in 21% during weeks -12, 4% during weeks Baseline Endpoint 1 Baseline Endpoint 3 Baseline Endpoint Rosenstock J, et al. Diabetes. 211;(Suppl 1):A. Abstract 2-OR. Each line in the graph represents a study. Balena R, et al. Diabetes Obes Metab. 213;15(): Adding Rapid-Acting or GLP-1 RA to Basal : Outcomes in a Community Setting Percentage of Patients with >1 Healthcare Visit Adding Rapid-Acting or GLP-1 RA to Basal : Outcomes in a Community Setting Mean All Healthcare Costs (USD) Percentage of Patients with 1 Healthcare Visit (%) Basal + GLP-1 Basal + RAI p< Any Hospitalization Dalal, et al. Endocr Pract. 215;21:-. p= ED Visits p= Office Visits p< Endocrinologist Visits Mean All-cause Healthcare Costs (U.S. $) 25, 2, 15, 1, 5, = $2,4 p=.2 1,413 2,21 Total Cost = $2,51 p<.1 3,423 5,44 Inpatient Cost Basal + GLP-1 Basal + RAI = $1,2 p<.1 Outpatient Cost Health Care Costs at 1-year Follow-up (matched analysis): All-cause and Diabetes-related ED = emergency department. Dalal, et al. Endocr Pract. 215;21:-. 5,22,44 = $ p=.2 52 ED Cost = $1,411 p<.1,4,33 Pharmacy Cost Basal and GLP-1 RA Combination Fixed-Ratio Formulation of Glargine/Lixisenatide GLARG 2 U/LIXI 1 µg (Administered via single pen device) Emerging Fixed Dosed Combinations of GLP-1 RAs and Basal Poorly controlled T2DM pts on MET (N=323) naive R Mean baseline A1c.% (n=11) Glargine (N=14) 24 week follow-up Primary outcome: A1C reduction Not FDA approved. GLARG = insulin glargine; LIXI = lixisenatide. Rosenstock J, et al. ADA 214:Presentation No. 241.

14 Fixed-Ratio Formulation of Glargine/Lixisenatide in T2DM over 24 Wks Fixed-Ratio Formulation of Glargine/Lixisenatide in T2DM over 24 Wks Change in HbA1c (%) A1C -1.4 LS mean difference: -.1, P=.13 LS Mean Change (mg/dl) hour PPG LS mean difference: -5, P<.1 Change in Weight (kg) Weight Change -..4 LS mean difference: P<.1 No difference in hypoglycemic events between the two groups. No severe hypoglycemic events GLARG 2 U/LIXI 1 µg (n =11) GLARG (n = 14) Not FDA approved; Superiority. PPG = postprandial plasma glucose; GLARG = insulin glargine; LIXI = lixisenatide. Rosenstock J, et al. ADA 214:Presentation No GLARG 2 U/LIXI 1 µg (n =11) GLARG (n = 14) Not FDA approved ;GLARG = insulin glargine; LIXI = lixisenatide. Rosenstock J, et al. ADA 214:Presentation No A1C (%) Fixed-Ratio Combination of Degludec and Liraglutide DEG 1 U/LIRA.3 mg DEG LIRA 13 T2DM patients on MET + PIO; 2 week open-label trial Patients achieving A1C <% DEG 1 U/LIRA.3 mg: 1% DEG: 5% LIRA: % DEG 1 U/LIRA.3 mg vs. DEG Weight change: kg; P<.1 Hypoglycemia: RR.; P<.2 DEG 1 U/LIRA.3 mg vs. LIRA Weight change: 2.44 kg; P<.1 Hypoglycemia: RR.; P<.1 Patient Case Cont d Susan B. was started on exenatide BID. Over the next months her A1c improved to.2%. She has not experienced any episodes of hypoglycemia and has loss 4 lbs of weight. She is extremely happy and thanks you for helping her get control of her diabetes. Not FDA approved. DEG = insulin degludec; LIRA = liraglutide; MET = metformin; PIO = pioglitazone; RR = risk ratio. Gough SC, et al. Lancet Diabetes Endocrinol. 214;2(11):5-3. Summary + DPP-4 inhibitor combination therapy in T2DM improves glycemic control, reduces hypoglycemia, and is typically considered weight-neutral + GLP-1 RA combination therapy in T2DM improves glycemic control, reduces hypoglycemia, and can induce weight loss + GLP-1 RA combination therapy is being very actively investigated in T1DM and T2DM