Faculty FACULTY DISCLOSURES. - Advisor/Consultant Boehringer Ingelheim, Sanofi Aventis, Daiichi Sankyo, Lilly, Novo Nordisk, Takeda, Janssen

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1 Getting Comfortable with Injectable Therapies for Diabetes: A Two-Way Discussion Getting Comfortable with Injectable Therapies for Diabetes: A Two-Way Discussion Emerging Challenges In Primary Care: 2014! Part 1 Rationale for Injectable Therapies for Diabetes: Breaking the Barrier Faculty Robert S. Busch, MD, FACE Managing Partner of The Endocrine Group, LLP, Albany, NY Louis Kuritzky, MD Clinical Assistant Professor Department of Community Health & Family Medicine University of Florida, Gainesville, FL Anne Peters, MD Director, USC Clinical Diabetes Programs Professor, Keck School of Medicine University of Southern California Los Angeles, CA Mark Stolar, MD Associate Professor of Clinical Medicine Feinberg School of Medicine Northwestern University, Chicago, IL FACULTY DISCLOSURES ² Robert S. Busch, MD, FACE - Speaker Astra Zeneca, Novo Nordisk; Advisory Board Merck, Janssen ² Louis Kuritzky, MD - Advisor/Consultant Boehringer Ingelheim, Sanofi Aventis, Daiichi Sankyo, Lilly, Novo Nordisk, Takeda, Janssen ² Anne Peters, MD - Advisory Committee Abbott Diabetes Care, Becton Dickinson, Bristol Myers Squibb/Astra-Zeneca, Janssen, Lilly, Medtronic Minimed, Novo Nordisk, Sanofi; Speaker s Bureau - Bristol Myers Squibb/Astra-Zeneca, Novo Nordisk; Medical Research Medtronic Minimed; Editorial Contributor - Medscape ² Mark Stolar, MD - Speaker/Advisory Committee Takeda, Vivus, Bristol Myers Squibb/AZ 2 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-1

2 LEARNING OBJECTIVES After participating in this educational activity, clinicians should be better able to: 1 Identify the barriers between physicians and patients to discussing and initiating injectable therapies for diabetes 2 Discuss the role of incretin based therapies in the management of type 2 diabetes with a focus on injectable glp-1 analogues 3 Describe how best to initiate, utilize and intensify insulin therapy in patients with diabetes 4 Recognize the role of combining glp-1 analogues with insulin to individualize care, achieve glycemic and metabolic targets and minimize hypoglycemia 5 Hear from and listen to patients with diabetes and understand their perspectives 3 PRE-TEST QUESTION 1 On a scale of 1 to 5, please rate how confident you would be in the diagnosis and management of a patient with diabetes. 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 4 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-2

3 PRE-TEST QUESTION 2 Which of the following is incorrect about barriers to successful diabetes management? 1. Patients feel needing to start insulin is a personal failure 2. Health care providers feel patient motivation is the biggest barrier to successful diabetes care 3. The quality of the patient provider relationship has not been shown to impact outcomes in diabetes care 4. Physicians and patients have divergent views on natural history of diabetes vs diabetes getting worse 5. Nurses play an essential role in meeting psychosocial needs in the diabetic patient 5 PRE-TEST QUESTION 3 What are the fundamental differences between oral and injectable incretin based therapies? 1. Significant differences in weight loss 2. Significant differences in glycemic control 3. Significant differences in blood pressure 4. Significant differences in pancreatitis risk 5. 1,2 and 3 6. All of the above 6 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-3

4 Combination of injectable Glp-1 analogues with insulin results in which of the following compared to mixed insulin regimens? 1. Significantly less hypoglycemia 2. Significantly better glycemic control 3. Significantly less weight gain 4. Better patient adherence 5. 1 and 3 6. All of the above PRE-TEST QUESTION 4 7 PRE-TEST QUESTION 5 The following Tricks help with intensifying insulin management except for: 1. Using the rule of 1800 to calculate correction factors for glucose 2. Using the rule of 500 to calculate carbohydrate ratios 3. Using sliding scale short acting insulin based on blood sugar 4. Using 3/0/3 titration models to adjust basal insulin 8 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-4

5 PRE-TEST QUESTION 6 Which of the following strategies have NOT been shown to help enhance injectable adherence? 1. Use of pens vs syringes 2. Avoidance of hypoglycemia when possible 3. Keeping total daily dose as low as possible for glycemic control 4. Making injectable regimen flexible 5. Having the physician directly teach injectable administration 9 WHAT PATIENTS THINK OF WHEN WE SAY INJECTION 10 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-5

6 WHAT ELSE PATIENTS THINK WHEN THEY HEAR INSULIN 11 NEGATIVE REACTIONS TO DIAGNOSIS ARE COMMON G u i l t y T y p e 1 T y p e 2 A n g r y D e p r e s s e d A n x i o u s % Agreeing Base: all patients Peyrot M, et al. Diabetes Care. 2005;28(11): NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-6

7 VIDEO ONE: WHAT PATIENTS THINK AND FEEL AT DIAGNOSIS OF DIABETES 13 PERCEIVED BARRIERS TO DIABETES CARE DIFFER BETWEEN PATIENTS AND HEALTHCARE PROFESSIONALS Professionals N = 436 Healthcare professionals ² Motivation ² Systems barriers ² Diabetes knowledge Patients N = 3890 Patients with diabetes ² Strictness of regimen ² Influence of other health problems ² Systems barriers ² Influence of other health problems (10 th or less important) ² Knowledge (least important) Joy SV. Diabetes Educ. 2008;34 Suppl 3:54S-59S. Simmons, Lillis, et al. Diabetes Care. 2007;30(3), NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-7

8 BARRIERS TO INJECTABLES: THE PATIENT/PARTNER/CAREGIVER SIDE OF THE EQUATION ² ² ² ² ² ² ² ² Pain/fear of injections Disease is bad/ much worse Mis-attribution: bad outcomes in others who used insulin Weight gain Loss of control of daily activities (eg, driving, occupation) Hypoglycemia Medication regimen complexity (multi-pill + injection) Loss of privacy (people observe insulin equipment ) 15 BARRIERS TO INJECTABLES: THE CLINICIAN SIDE OF THE EQUATION ² Misperceptions It s always something: the need to advance Rx is never-ending (therapeutic fatigue) Insulin: most appropriate for endstage Rx GLP1 AE profile unacceptable to most patients Patients don t want to use injectables Nothing I m doing seems to work ² Reality-based Concerns Time demands of instructing patients about injections Unfamiliarity with the variety of devices (e.g., various pens) ² Misplaced Blame If only the patient would exercise and lose weight,they wouldn t need insulin ² Knowledge gaps Impact of Glucotoxicity on therapeutic response Effects of medications on theromegenics Insulin/Incretins?OHA Typical weight changes (loss): GLP1 Changing and non-directive ADA/EASD and AACE Guidelines 16 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-8

9 PATIENT EMPOWERMENT ² Patients choose what to do/not do based on: Culture, environment, life demands, lifestyle Emotional resources, motivation, beliefs Information /understanding of information ² Empowerment: helping patients discover/develop inherent capacity to be responsible for life ² An effective self-care plan: Combines clinician knowledge of disease with patients knowledge about themselves, their values, priorities, goals as well as diabetes Is a working partnership led by the patient. Insulin initiation is too often parent/child structure 17 Funnell M, Anderson RM. Clin Diabetes. 2004;22: RELATIONSHIP WITH PROVIDER PREDICTS DIABETES OUTCOMES (US) Good diabetes control Poor relationship Good relationship Good adherence High diabetes distress % Patients Peyrot M, et al. Diabetes Care. 2005;28(11): NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-9

10 NURSES ADDRESS CRITICAL PSYCHOSOCIAL NEEDS Provide a feeling of security and hope Act as intermediary between doctor and patient Overall Data US Data Brief doctors about possible complications/ psychological problems % Patients Receiving Support Base: all nurses Peyrot M, et al. Diabetes Care. 2005;28(11): PATIENT-PROVIDER CONCORDANCE IN PRIORITIZATION OF HEALTH CONCERNS ² Survey of patients (N = 1004) with diabetes and hypertension and their primary care providers ² 60% of patient-provider pairs agreed on the patient s most important health concerns ² Patients and physicians were more likely to rate glycemic control and hypertension as most important (Numerical targets) ² Patients were more likely to list symptomatic conditions a and weight loss/increased activity among top concerns (How I feel) ² Office based diabetes encounters often are a mismatch between target driven providers and symptom/ function motivated patients ( I don t feel any better on insulin My sugar is down but I m heavier ) a. Pain, depression, breathing problems. Zulman DM, et al. J Gen Intern Med Feb 2. [Epub ahead of print]. 20 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-10

11 INSULIN INITIATION DELAYED ² Kaiser Permanente Northwest (KPNW) patients, observational study ² n = 3,891 newly initiated sulfonylurea/metformin ² Mean follow-up 54.6 ± 28.6 months; 41.9% added insulin, and 11.8% were on maximum oral agents ² Half of the sulfonylurea/metformin group had an A1C of ~9% for 3 years after some initial success; another 18% never achieved the first goal and continued oral agents for 30 months with an A1C of ~10% Nichols GA, Koo YH, Shah SN. J Gen Intern Med. 2007;22: TRANSLATING RESEARCH INTO ACTION FOR DIABETES (TRIAD) INSULIN PROJECT (PHYSICIAN PERSPECTIVE) ² Most primary care providers (64%) reported that patients were resistant to new oral or insulin therapies because of fears about the therapy and what it meant about their disease progression. ² 64% cited patient resistance as a barrier to insulin initiation, and 43% cited problems with patient selfmanagement, including cognitive or mental health issues, dexterity, or ability to adhere. ² 80% felt that patient nonadherence would dissuade them from initiating insulin at least some of the time. Ratanawongsa N, Crosson JC, Schillinger D, Karter AJ, Saha CK, Marrero DG. Diabetes Educ. 2012;38: NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-11

12 THE TRIAD STUDY (CONT.) Attitudes % Perceived reasons why patients refuse to initiate insulin* Fear of injections 97 Beliefs that insulin will mean they will get worse, go blind, die sooner, etc. 38 Inconvenience due to injections and self-monitoring of blood glucose (SMBG) 22 Perceived reasons why patients refuse to continue or adhere poorly to insulin* Inconvenience due to injections and SMBG 34 Fear of hypoglycemia 30 Discomfort from injections 28 Inability to self-manage with insulin 15 * Respondents were asked to select >1 response, so proportions do not add up to 100%. Ratanawongsa N, Crosson JC, Schillinger D, Karter AJ, Saha CK, Marrero DG. Diabetes Educ. 2012;38: THE TRIAD STUDY (CONT.) Attitudes % Reasons for deciding not to initiate insulin therapy* Patient refusal or resistance 64 Concerns about patient s self-management skills 43 Discomfort from injections 28 * Respondents were asked to select >1 response, so proportions do not add up to 100%. Ratanawongsa N, Crosson JC, Schillinger D, Karter AJ, Saha CK, Marrero DG. Diabetes Educ. 2012;38: NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-12

13 DELAY IN INITIATING INSULIN THERAPY IS COMMON I prefer to delay initiation of oral therapy until absolutely essential GP Specialist MD Nurse I prefer to delay initiation of insulin until absolutely essential USA Overall % Agreeing Base: All Respondents DAWN=Diabetes Attitudes Wishes & Needs 25 SO WHAT CAN WE DO TO ENHANCE INJECTABLE ACCEPTANCE? ² Overall approach: create a situation in which both providers and patients have a POSITIVE experience. Ensure adequate educational resources/time for training. And explaining Provide staff for outreach to patients (via phone, text, e- mail) to answer questions and up-titrate insulin. ² Provider approach: project positive opinion of injectables Never threaten with injectables, especially insulin. Offer flexible tools and approaches. Its no longer always insulin for injectable therapy. Listen to patient concerns; address them as possible. Explain the physiology of their disease and why injectables will make a favorable health difference 26 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-13

14 SYNCHRONIZING TREATMENT AND PATIENT NEEDS ASK THESE QUESTIONS WHEN CONSIDERING GLP-1 VS INSULIN ² What does the patient need/want? Appropriate health beliefs Disease severity and consequences Treatment efficacy Ability to succeed with regimen Sensible, effective, cost-effective, simple treatment regimens with minimal lifestyle impact (Pens vs syringe) Supportive environment Regular, frequent contact with healthcare providers (HCPs) Satisfactory relationship with HCPs Organizational factors promoting adherence (reminder cards, calls) Encouragement for self-care Delamater AM. Clin Diabetes. 2006;24: VIDEO TWO: PATIENT 2 (94 YO) 28 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-14

15 STARTING WITH INJECTABLES: THE GLP-1 STORY 29 PROGRESSIVE β-cell DYSFUNCTION IS A KEY DRIVER OF PROGRESSIVE DYSGLYCEMIA IN T2D By the time of diabetes onset, up to 80% of β-cell function may be lost 1,2 Deteriorating β-cell function is partially driven by the incretin defect PPG FPG Normal Glucose Tolerance β-cell Function Impaired Glucose Tolerance Insulin Resistance Insulin Secretion Diagnosis Severity of Glucose Intolerance Time in Years 30 PPG indicates postprandial plasma glucose; FPG, fasting plasma glucose; T2D, type 2 diabetes; 1. Defronzo RA. Diabetes 2009;58: ; 2. Fehse F, et al. J Clin Endocrinol Metab 2005;90: ; Figure adapted from Kendall DM, et al. Am J Med 2009;122(6 Supp):S37-S50 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-15

16 OMINOUS OCTET DeFronzo RA. Diabetes. 2009;58: THE INCRETIN EFFECT IN SUBJECTS WITHOUT AND WITH TYPE 2 DIABETES IR Insulin, mu/l Control Subjects (n=8) Incretin Effect nmol / L IR Insulin, mu/l Patients With Type 2 Diabetes (n=14) The incretin effect is diminished in type 2 diabetes nmol/l Time, min Time, min Oral glucose load Intravenous (IV) glucose infusion Adapted from Nauck M et al. Diabetologia. 1986;29: Copyright 1986 Springer-Verlag NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-16

17 INCRETIN MIMETICS: GLP-1 ANALOGUES ² Mechanism of Action Synthetic analog of human glucagon-like peptide-1, resistant to DPP-4, results in supraphysiologic (pharmacologic) incretin levels, causing a glucose-dependent increase in insulin secretion a glucose-dependent inhibition of glucagon secretion reduced gastric emptying increased satiety MEANING: A means of enhancing endogenous insulin delivery in response to glycemic demand in real time unlike estimated glycemic demand with injected insulin 33 GLP-1 EFFECTS IN HUMANS: GLUCOREGULATORY ROLE OF INCRETINS GLP 1 secreted upon the ingestion of food Promotes satiety and reduces appetite Alpha cells: Postprandial glucagon secretion Beta cells: Enhances glucose-dependent insulin secretion Liver: Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Adapted from Flint A, et al. J Clin Invest. 1998;101: ; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: ; Adapted from Nauck MA, et al. Diabetologia. 1996;39: ; Adapted from Drucker DJ. Diabetes. 1998;47: NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-17

18 CASE 1: DARA ² Dara is a 38 year old female with a 5 year history of type 2 diabetes on maximum SFU and metformin ² She could not tolerate TZDs and refused to start insulin ² Her A1c for the past 2 years has been between 7.8% and 8.5%. Most recent: 8.7% ² PMH sig. for dyslipidemia, hypertension and central obesity (BMI 41) ² Strong family history of type 2 diabetes } } FBS mg/dl PPG mg/dl 35 WHAT WOULD YOU RECOMMEND NOW FOR DARA? 1 Try to convince her to try bedtime basal insulin in addition to her oral agents 2 Start a SGLT-2 inhibitor 3 Start an injectable glp-1 analogue (exenatide or liraglutide 4 Gastric bypass surgery 36 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-18

19 CURRENTLY AVAILABLE GLP-1 ANALOGUES ² Incretin Mimetic Exenatide injection - Mimic (or possess) many of the glucoregulatory effects of GLP-1 - Resist degradation by DPP-IV (long lasting) - Can be dosed twice daily or once weekly - One weekly injection about to be in pen form ( a prior barrier) ² Incretin Mimetic Liraglutide injection - Binds to Albumin to allow for one day dosing - Can be safely used in patients with renal impairment Adapted from Drucker DJ. Diabetes Care. 2003;26: See accompanying Prescribing Information and safety information included in this presentation 37 ONCE-DAILY INJECTION OF LIRAGLUTIDE COVERS 24-H BG PROFILE IN TYPE 2 DIABETES 14 Placebo Liraglutide (6 µg/kg OD) Plasma glucose (mmol/l) n=13 24-h glucose AUC (mmol/l/h, mean ± SE) ± ± 14.0 (p = 0.01) Time after injection (hours) Injection (08.00) 38 Adapted from: Degn et al. Diabetes 2004;53: NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-19

20 DURATION-2: EXENATIDE QW DEMONSTRATED SUPERIOR A1C REDUCTION VS. SITAGLIPTIN AND PIOGLITAZONE p Exenatide QW; BL=8.6% Exenatide QW, N=160 Sitagliptin; Sitagliptin, BL=8.5% N=166 p Pioglitazone; Pioglitazone, BL=8.5% N=165 Δ A1C (%) p p * p * p * * * p p p * -0.9% -1.2% -1.6% Time (Weeks) ITT Population, N=491. *p<0.05 vs. sitagliptin. p<0.05 vs. pioglitazone. Bergenstal RB, et al. The Lancet Published online June 26, DOI: /S (10) A1C REDUCTION IN PATIENTS SWITCHED FROM SITAGLIPTIN TO EXENATIDE QW Δ HbA 1c (%) Blinded Period Open-Label Period 0.0 Sitagliptin exenatide QW Pioglitazone -0.5 exenatide QW Exenatide QW-only Week (% [95% CI]) [-0.50, -0.13]* [-0.29, 0.09] [-0.13, 0.25] Time (weeks) A1C improvements were maintained in patients who continued exenatide QW and patients who switched from pioglitazone week Evaluable Population (N=319). LS mean change + SE; * P<0.05 vs Week 26 Wysham et al. Diabetic Medicine DOI: /j NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-20

21 LIRAGLUTIDE OR EXENATIDE QW VS SITAGLIPTIN ADDED TO METFORMIN LIRA 1.8 mg 26- week trial (N = 658) 1 BL A1C (%): % LIRA 1.2 mg SITA EXN QW 26- week trial (N = 491) 3 BL A1C (%): % A1C Change (%)!0.5%!1.0%!1.5%!2.0% a P <.05 vs SITA. b P <.0013 vs LIRA 1.2 mg.!1.5% a,b!1.2% a!0.9% LIRA results sustained over 1 year 2 A1C Change (%)!0.5%!1.0%!1.5%!2.0%!1.5% a!0.9% 1. Pratley R, et al. Lancet. 2010;375: Pratley R, et al. In J Clin Pract. 2011;65: Bergenstal R, et al. Lancet. 2010;376: EXENATIDE TO LIRAGLUTIDE COMPARISON/SWITCH STUDY Pratley RE et al. Diabetes Care. 2010;33: NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-21

22 EXENATIDE: SUSTAINED A1C REDUCTION AND WEIGHT LOSS OVER 3 YEARS 10 Change in A1c (%) Baseline A1c: 8.2% + 0.1% 0 Change in Body Weight Baseline Weight: 219 lbs % + 0.1% % ± 0.4 lb ± 0.9 lb Treatment (wk) Treatment (wk) N=217; Mean±SE. Reference: Klonoff DC, et al. Curr Med Res Opin. 2008;24: % OF 3-YEAR COMPLETERS REDUCED A1C AND LOST WEIGHT Δ Weight (lbs) From Baseline % 6% % 16% Δ A1C (%) from Baseline N=217. Reference: Klonoff DC, et al. Curr Med Res Opin. 2008;24: See information about hypoglycemia, nausea, or pancreatitis and the Important Safety Information included in this presentation, and the accompanying full Prescribing Information. 44 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-22

23 GLP-1 SAFETY AND TOLERABILITY ² Most common AEs for Exenatide/Liraglutide are GI-related Nausea 33 to 43 percent of subjects Mostly mild-to-moderate episodes ² Low dropout rates due to GI effects Exenatide 5 7 percent vs. comparator 0 3 percent ² Concurrent use of SFUs can lead to hypoglycemia ² Pancreatitis has been observed with incretin based therapies. Although recent trials have shown rates are no different compared to other diabetes meds, these drugs should not be used in patients with a history of pancreatitis and abdominal pain on glp-1 therapy must be promptly evaluated. Noel R, Increased Risk of Acute Pancreatitis and Biliary Disease Observed in Patients With Type 2 Diabetes" by R. Noel, D. Braun, R. Patterson and G. Bloomgren. Diabetes Care, 2008;32: Dore D, Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide.cmro Vol25(4),2009; CASE 1: LET S GET BACK TO DARA ² Dara is a 38 year old female with a five year history of type 2 diabetes on maximum SFU and metformin with an A1c of 8.7% and a BMI of 41 ² She agreed to start exenatide (Exenatide, 5 ug BID for the first month and then 10 ug BID). She had mild nausea for the first 3 days ² Over the next two months she lost 13 pounds and her A1c came down to 7.3% Pre- ExenaQde FBS: mg/dl PPG: mg/dl Post- ExenaQde FBS: mg/dl PPG: mg/dl ² She experienced no hypoglycemia and now has joined a gym and is going HGM not a requirement regularly 46 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-23

24 VIDEO THREE: PATIENT ON ONCE WEEKLY EXENATIDE 47 CASE TWO: THE REFRACTORY DIABETIC ON MAXIMAL THERAPY ² Bruce is a 55 y.o. single construction foreman who has had diabetes for eight years. He was initially started on oral agents but has never achieved glycemic control with A1c readings that range from 8-10%. He was started on insulin 2 years ago after failing triple metformin/tzd/dpp-4 therapy and his most recent A1c was 9.1% ² Despite good compliance with medication he is now on glargine 90 units bid, metformin 1000 mg bid and glipizide 10mg bid. His job requires him to visit multiple construction sites and he works at his computer up to 10 hrs a day when not on site. Despite multiple visits to a diabetes educator, he has not been able to institute a successful weight loss program and most meals are consumed outside the home or in the car. 48 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-24

25 CASE TWO (CONT): THE REFRACTORY DIABETIC ON MAXIMAL THERAPY ² Current medications include atorvastatin 40mg/day and lisinopril 20mg/day. PMH of spinal stenosis causes daily chronic mild back pain. He has mild DJD of both knees and occasional flares of plantar fasciitis for which he takes ibuprofen. All labs with the exception of his A-1c and glucose are at target or normal. 49 PHYSICAL EXAMINATION ² Height 70 inches weight 255 lbs, BMI 36.6 ² Physical exam is unremarkable except for limited ROM of back, hips and knees. There is mild decrease in sensation to midfoot and 1+ edema bilaterally 50 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-25

26 QUESTIONS FOR DISCUSSION: ² What are your remaining therapeutic options for this patient? ² What is the role of oral therapy at this point? ² Will intensive insulin management be effective? Would Glp-1 analogues be more effective? ² What is the role of gastric bypass in patients like this? 51 LIRAGLUTIDE COMPARED WITH INSULIN GLARGINE LEAD 5 (N = 581) LIRA MET + GLIM GLAR + MET + GLIM A1c Change % -1.3a,b Weight Change (kg) -1.81a,b % Reporting Minor Hypo Events & Reporting Nausea PBO + MET + GLIM a P <.05 vs MET + GLIM; b P <.05 vs GLAR + MET + GLIM. Russell-Jones D, et al. Diabetes. 2008;57(suppl 1):536-P. 52 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-26

27 ACHIEVED HBA 1C TARGETS: PATIENTS TAKING EXENATIDE OR PLACEBO WITH INSULIN GLARGINE P<0.001 P<0.001 Percentage of patients achieving target HbA 1c 7.0% and HbA 1c 6.5% with exenatide vs. placebo. Buse et al. Ann Intern Med. 2011;154: Change in A1C (%) Change in Weight (lb) ADA 7 GOAL EXENATIDE VS INSULIN STUDIES: A1C AND WEIGHT Exenatide vs Insulin Aspart 70/ lb +6.4 lb Exenatide vs Insulin Glargine 9 lb lb lb +5.1 lb -5.1 lb -4.9 lb Exenatide vs Insulin Glargine + MET or SFU Nauck et al 1 Heine et al 2 Barnett et al 3 n=253 n=248 n=228 n=242 N=138 Crossover -1.0% 12 lb -0.9% -1.1% -1.1% -1.4% -1.4% exenatide Insulin aspart 70/30 Insulin glargine Exenatide vs Insulin Glargine +MET+/-TZD +/- SFU Davies et al 4 n=118 n= lb 13 lb +6.6 lb Exenatide vs Insulin Glargine +/- MET Bunck et al 5 n=36 n=33-1.3% -1.3% -0.8% -0.7% -7.8 lb 10 lb +2.2 lb References: 1. Nauck MA, et al. Diabetologia. 2007;50: , Heine RJ, et al. Ann Int Med. 2005;143: ; 3. Barnett AH, et al. Clin Ther. 2007;29: ; 4. Davies M. Presented at EASD Bunck MC. Diabetologia. 2007;50:(Suppl 1):S111. Abstract NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-27

28 CASE TWO (CONT): ² Bruce was started on exenatide once weekly because of his variable work schedule. His insulin dose was reduced to 75 units bid and glipizide was discontinued, replaced with an sglt-2 inhibitor ² At six week follow up morning sugars had declined to 150 and an interval A1c was 8.1% He had lost 8 pounds and feels differently about himself and his disease 55 INTENSIFYING DIABETES THERAPY: UTILIZING INJECTABLES ² The need for insulin providing therapies is paramount in a disease that progresses from relative to absolute insulin deficiency over time ² Earlier use of basal insulin at bedtime is an effective means of lowering fasting and diurnal glycemia ² The need for basal insulin implies deficiency post prandially as well. Glp-1 analogues and short acting insulin both meet that of unmonitored need ² Glp-1 analogues are a very effective means of providing endogenous insulin with less hypoglycemia and weight gain than exogenous insulin and may be a very effective entry into injectable therapy 56 NACE Emerging Challenges in Primary Care: 2014 Diabetes Part 1-28