Faculty Mark W. Stolar, MD

Transcription

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2 Disclaimer This slide deck in its iginal and unaltered fmat is f educational purposes and is current as of November The content and views presented in this educational activity are those of the auths/presenters and do not necessarily reflect those of Creative Educational Concepts the suppter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and offlabel uses of approved products. A qualified healthcare professional should be consulted befe using any therapeutic product discussed. Readers should verify all infmation and data befe treating patients employing any therapies strategies described in this educational activity.

3 Usage Rights This slide deck is provided f educational purposes and slides may be used f personal, non-commercial presentations only as long as content and references remain the same. No part of this slide deck may be published distributed in print electronic fmat without pri written permission from Creative Educational Concepts.

4 Faculty Mark W. Stolar, MD Associate Profess of Clinical Medicine Nthwestern University School of Medicine Chicago, IL

5 Disclosures to Participants (also located in participant handout materials) This Activity is Presented by Creative Educational Concepts, Inc. (CEC) an Accredited Continuing Medical Education Company. Conflicts of Interest and Financial Relationships Disclosures: Planners: Adrienne Matson, PharmD, BCPS nothing to disclose Auths/Presenters: Kate Mann, PharmD nothing to disclose Mark W. Stolar, MD is a member of the speakers bureaus f AstraZeneca, Sanofi, and Takeda. Peer Reviewer: Jeff Unger, MD, ABFM, FACE receives royalties from Lippincott; stockholder in Novo Ndisk; member of the speakers bureas f Janssen and Novo Ndisk; consultant f Abbott Diabetes, Halozyme, Itarcia, Janssen, and Novo Ndisk; and recieves research grants from GlaxoSmithKline, Lilly, and Merck. Commercial Suppt: This activity is suppted by an educational grant from Lilly. F further infmation concerning Lilly grant funding please visit

6 Prevalence, per 100 Persons per Year Prevalence Trends f Diagnosed Diabetes Adults Aged 20 to 79 years, United States, Observed Modeled Change in diagnostic criteria Year Geiss LS, et al. JAMA

7 Ambulaty Treatment of T2DM in U.S., Ambulaty visits f Diabetes, Millions Treatment of diabetes has grown in complexity while older treatments continue to be replaced supplemented by newer therapies. Turner LW, et al. Diabetes Care

8 Events per 10,000 Adult Population with Diagnosed Diabetes Changes in Diabetes-Related Complications (United States, ) Acute MI Stroke Amputation Much of the improvement in outcomes likely reflects me regular contact with health professionals and better management of care ESRD Death from Hyperglycemic Crisis MI=myocardial infarction; ESRD=end stage renal disease 1 Gregg EW, et al. N Engl J Med. 2014; 2 Yashkin AP, et al. Med Care

9 What s New in 2015

10 Modulation of the intensiveness of glucose lowering therapy in T2DM Patient/Disease Features Risks potentially associated with hypoglycemia and other drug adverse effects Approach to the Management of Hyperglycemia Me stringent Low A1C 7% Less stringent High Disease duration Newly diagnosed Long-standing Life expectancy Long Sht Usually not modifiable Imptant combidities Absent Few/Mild Severe Established vascular complications Absent Few/Mild Severe Patient attitude & expected treatment effts Resources & suppt system Highly motivated, adherent, excellent selfcare capacities Readily available Less motivated, non-adherent, po self-care capacities Potentially modifiable Limited Inzucchi SE, et al. Diabetes Care

11 AACE/ACE and ADA Goals f Glycemic Control: 2015 Treatment Target AACE/ACE ADA A1C 6.5%* <7.0% Fasting glucose Postprandial glucose Fasting and premeal plasma glucose: <110 mg/dl 2-hour postprandial glucose: <140 mg/dl Preprandial capillary plasma glucose: mg/dl Peak postprandial capillary plasma glucose : <180 mg/dl * Individualize on the basis of age, combidities, duration of disease, in general 6.5% f most; nmal f healthy; less stringent f less healthy Me less stringent glycemic goals may be appropriate f individual patients. Goals should be individualized based on duration of diabetes, age/life expectancy, combid conditions, known CVD advanced microvascular complications, hypoglycemia unawareness, and individual patient considerations. Postprandial glucose maybe targeted if A1C goals are not met despite reaching preprandial glucose goals. Postprandial glucose measurements should be made 1 2 h after the beginning of the meal, generally peak levels in patients with diabetes. AACE=American Association of Clinical Endocrinologists; ACE=American College of Endocrinology; 1 ADA=American Diabetes Association Handelsman Y, et al. Endocr Pract. 2015; American Diabetes Association. 2 American Diabetes Association. Diabetes Care

12 Pharmacological Therapy Selection Considerations Efficacy (effects on A1C, FBG, PPG) Hypoglycemia risk Effect on weight Mechanism of action Likely adherence Route of administration Ease of use Patient preference Cost Adverse effects/tolerability Effect on nonglycemic facts (eg, serum lipids, blood pressure) Contraindications from combidities (eg, hepatic renal impairment, cardiovascular disease) FBG=fasting blood glucose; PPG=postprandial plasma glucose American Diabetes Association. Diabetes Care

13 Monotherapy Dual therapy Efficacy * Hypo risk Weight Side effects Costs Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin high low risk neutral/loss GI/lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea high moderate risk gain hypoglycemia low Metfmin Thiazolidinedione high low risk gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate low risk neutral rare high Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration high Metfmin GLP-1 recept agonist high low risk loss GI high Metfmin Insulin (basal) highest high risk gain hypoglycemia variable If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Triple therapy Metfmin Sulfonylurea TZD Metfmin Thiazolidinedione SU Metfmin DPP-4 Inhibit SU Metfmin SGLT-2 Inhibit SU Metfmin GLP-1 recept agonist SU Metfmin Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i Insulin SGLT2-i GLP-1-RA GLP-1-RA Insulin Insulin GLP-1-RA Insulin Insulin Combination injectable therapy If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGLT2-i: Metfmin Basal Insulin Mealtime Insulin GLP-1-RA Inzucchi SE, et al. Diabetes Care

14 ADA/EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Patient-Centered Approach...providing care that is respectful of and responsive to individual patient preferences, needs, and values - ensuring that patient values guide all clinical decisions. Gauge patient s preferred level of involvement Exple, where possible, therapeutic choices Consider using decision aids Shared Decision Making a collabative process between patient and clinician, using best available evidence and taking into account the patient s preferences and values Final decisions regarding lifestyle choices ultimately lie with the patient Inzucchi SE, et al. Diabetes Care

15 Promote Self-Management Self-Management Education (SME) should be discussed at every diabetes-focused visit and individualized accding to type of diabetes, patient ability, and motivation f learning and change Set S.M.A.R.T. Goals Specific Measurable Achievable Realistic Timely Self-Management Areas of Focus Diabetes Education Nutrition Physical Activity Weight loss (5-10% of initial weight) Medication Hypoglycemia Self-Moniting Blood Glucose (SMBG) Foot Care Mental Health & Mood Disders Smoking Cessation Collabate with your patient to create an action plan on their identified area of focus Enable timely, culturally and literacy appropriate diabetes education and resources Encourage comprehensive visit with RD CDE within 1 year of diagnosis per ADA guidelines Minimum 150 minutes aerobic activity per week and resistance exercise 2-3 times per week Can substantially improve glycemic control and cardiovascular disease risk facts in overweight patients Counsel about adherence (dose, timing, frequency), anticipated effects, and mechanism of action Counsel about the prevention, recognition, and treatment of drug-induced hypoglycemia Not on insulin: Individualized to type of antihyperglycemic agents, level of control, and risk of hypoglycemia On insulin only once a day: SMBG once a day at variable times On insulin >once a day: SMBG 3 times per day including pre- and post-prandial values Educate on proper foot care including daily foot inspection Screen f depressive and anxious symptoms by interview a standardized questionnaire (eg, PHQ-9) Include fmal smoking prevention and cessation counseling Inzucchi SE, et al. Diabetes Care

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17 Case Study: Consuela 47-year-old Latin American female with 3 year histy of T2DM presents f follow-up. Hypertension and dyslipidemia both controlled on medications. No histy of CVD. Recent histy of genital yeast infection treated with fluconazole. Currently on metfmin 1,000 mg BID and attempting to follow lifestyle interventions, weight=210 lbs, height 5 10 (BMI=30.1 kg/m 2 ). A1C initially decreased from 8% to 7% after starting metfmin therapy two years ago. However, today in clinic her A1C is up to 7.8%. CVD=cardiovascular disease; BMI=body mass index

18 Case Study: Consuela She also tells you she doesn t want to take any medication that may make her gain weight What agent would you select f her now?

19 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Efficacy * Hypo risk Weight Side effects Costs Metfmin Sulfonylurea high moderate risk gain hypoglycemia low Healthy eating, weight control, increased physical activity & diabetes education Metfmin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin high low risk gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate low risk neutral rare high Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration high Metfmin GLP-1 recept agonist high low risk loss GI high Metfmin Insulin (basal) highest high risk gain hypoglycemia variable Triple therapy Metfmin Sulfonylurea TZD If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Thiazolidinedione Thiazolidinedione SU Metfmin DPP-4 Inhibit SU Metfmin SGLT-2 Inhibit SU Metfmin GLP-1 recept agonist SU Metfmin Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i Insulin SGLT2-i GLP-1-RA GLP-1-RA Insulin Insulin GLP-1-RA Insulin Insulin Combination injectable therapy If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGLT2-i: Metfmin Figure 2B. Anti-hyperglycemic therapy in T2DM: Avoidance of weight gain Mealtime Insulin Basal Insulin GLP-1-RA Inzucchi SE, et al. Diabetes Care

20 Multifactial Nature of Hyperglycemia in T2DM Dictates Need f Multiple Mechanisms of Action Impaired insulin secretion SUs Glinides TZDs Increased glucagon secretion DPP-4 inhibits GLP-1 RAs DPP-4 inhibits GLP-1 RAs Islet α-cell Islet β-cell Hyperglycemia Decreased incretin effect DPP-4 inhibits GLP-1 RAs Increased lipolysis Insulin TZDs Increased glucose reabsption via kidney Insulin SGLT2 inhibits Increased hepatic glucose production Insulin MET TZDs DPP-4=dipeptidyl peptidase-4; GLP-1 RA=glucagon-like peptide-1 recept agonist; MET=metfmin; SU=sulfonylurea; TZD=thiazolidinedione Neurotransmitter dysfunction Bromocriptine Decreased glucose uptake Insulin MET TZDs DeFronzo RA. Diabetes

21 Role of Incretins in Glucose Homeostasis Ingestion of food GI tract Inactive GLP-1 Release of gut hmones Incretins Active GLP-1 & GIP DPP-4 enzyme Inactive GIP DPP-4=dipeptidyl peptidase-4 GIP=glucose-dependent insulinotropic peptide GLP-1=glucagon-like peptide-1 Beta cells Alpha cells Pancreas Glucosedependent insulin from beta cells (GLP-1, GIP) Glucose dependent glucagon from alpha cells (GLP-1) Glucose uptake by muscles Glucose production by liver Blood Glucose Kieffer TJ, et al. Endocrinology. 1995; Ahrén B. Curr Diab Rep. 2003; Drucker DJ. Diabetes Care. 2003; Holst JJ. Metab Res Rev

22 Baggio LL, Drucker DJ. Gastroenterology

23 2-Hour Postprandial Plasma Level (pm) GLP-1 Activity Is Higher With GLP-1 RAs Than With DPP-4 Inhibits 75 Baseline Sitagliptin Exenatide twice daily Added GLP-1 Activity Endogenous GLP-1 Activity N=61 metfmin-treated, evaluable patients. DeFronzo RA, et al. Curr Med Res Opin

24 Once Weekly Exenatide vs. Twice Daily Exenatide DURATION-1 Trial 0 A1C Reductions (%) P= Fasting Plasma Glucose Reductions (mg/dl) P< Exenatide 2 mg once weekly -1.5 Exenatide 10 mcg twice daily Exenatide 10 mcg twice daily Exenatide 2 mg once weekly Nausea: Exenatide once weekly, 26.4% of patients vs, 34.5% of patients f twice daily Drucker D, et al. Lancet 2008.

25 Weight (kg) A1C (%) A1C and Weight Change With Sitagliptin vs. Liraglutide Exenatide QW Added to Metfmin * SITA LIRA 1.2 mg LIRA 1.8 mg EXN QW week trial (N=658) 1, BL A1C (%): ,** week trial (N=491) 2 BL A1C (%): * All as add-on to MET; Results sustained over 52 weeks 3 ; P<.05 vs. SITA; ** P<.0013 vs. LIRA 1.2 mg 1 Pratley RE, et al. Lancet. 2010;375: ; 2 Bergenstal RM, et al. Lancet. 2010;376: ; 3 Pratley R, et al. Int J Clin Pract. 2011;65:

26 LS Change in A1C (%) A1C and Weight Change with Sitagliptin vs. Dulaglutide Once Weekly added to Metfmin after 52 weeks (AWARD-5) LS Change in Weight A1C Reductions (%) Weight Loss (kg) P<.001 P< Dulaglutide mg Dulaglutide 1.5 mg Sitagliptin 100 mg Dulaglutide 1.5 mg -2.6 Dulaglutide 0.75 mg Sitagliptin 100 mg Nauck M, et al. Diabetes Care

27 A GLP-1 RA is selected f Consuela

28 Clinical Inertia to Initiation and Intensification of Injectable Therapies Self-blame Less with histy of better adherence, less DM stress Avoidance of injections Concerns of risk Hypoglycemic effects Complexity of regimens Misconceptions about complications Weight gain Skepticism of efficacy Negative impact on social life Karter A, et al. Diabetes Care. 2010;33: ; Peyrot M, et al. Diabetes Care. 2005;28:

29 Clinician Barriers/Resistance Complexity of training/availability of resources Time facts Resources (educats) Weight gain Perception of patient failure Age facts Fear of hypoglycemia Peyrot M, et al. Diabetes Care. 2005;28:

30 Suggestions f Overcoming Fear of Injections Dry run injection (Insert needle without injecting drug) Reinfce that injection is relatively painless Injection is into fatty tissue versus muscle Reinfce that injection is easy Injection devices are quick and easy-to-use Have pen available f demonstration

31 GLP-1 Recept Agonists Exenatide 5-10 mcg twice daily (Byetta 2005) 2 mg once weekly (Bydureon 2012) Liraglutide mg daily (Victoza 2010) 3 mg daily (weight loss indication, Saxenda 2014) Albiglutide mg once weekly (Tanzeum 2014) Dulaglutide mg once weekly (Trulicity 2014) Lixisenatide (submitted to the FDA September 2015)

32 GLP-1 Recept Agonists Exenatide, Exenatide LAR, Liraglutide, Albiglutide, Dulaglutide Mechanism Primary physiological action(s) Advantages Limitations Cost Activates GLP-1 recepts glucose-dependent insulin secretion glucose-dependent glucagon secretion Satiety Slows gastric emptying Postprandial glucose excursions Weight Patient training requirements (injectable therapy) Gastrointestinal side effects (nausea, vomiting [less with longer-acting agents]) Hypoglycemia possible when used with insulin, if insulin doses are not reduced High (relative to other generic agents, ie metfmin) Inzucchi SE, et al. Diabetes Care 2015.

33 Once Weekly Exenatide vs. Twice Daily Exenatide DURATION-1 Trial 0 A1C Reductions (%) P= Fasting Plasma Glucose Reductions (mg/dl) P< Exenatide 2 mg once weekly -1.5 Exenatide 10 mcg twice daily Exenatide 10 mcg twice daily Exenatide 2 mg once weekly Nausea: Exenatide once weekly, 26.4% of patients vs, 34.5% of patients f twice daily Drucker D, et al. Lancet 2008.

34 Once-Weekly Albiglutide vs. Once-Daily Liraglutide in Patients with T2DM: HARMONY-7 Trial Change in A1C (%) P= Albiglutide 30 mg once weekly Liraglutide titrated to 1.8 mg daily Injection site reactions were me common in albiglutide-treated patients, 12 9% vs 5 4%, P=.0002 Gastrointestinal Adverse Effects (% of patients experiencing) Albiglutide P= Liraglutide Pratley RE, et al. Lancet Diabetes Endocrinol

35 Dulaglutide Once-Weekly vs. Liraglutide Once-Daily: AWARD-6 in Metfmin-Treated Patients Open label noninferiity trial N=599 P noninferiity <.0001 Once-weekly dulaglutide 1.5 mg Once-daily liraglutide 1.8 mg A1C % reduction 0.34 Hypoglycemia events/year Maximum dose once-weekly dulaglutide is non-inferi to maximum dose once-daily liraglutide with low hypoglycemia events in both treatment groups Dungan K, et al. Lancet

36 Case Study 2: Two years later, she is admitted to the hospital f pneumonia She is currently taking a GLP-1 RA and metfmin Her A1C at this time is 7.6%; Her admission blood glucose is 190 mg/dl Her GLP-1 RA is stopped on admission and she is placed on basal insulin with crection fact prandial insulin She is discharged home on 18 units of basal insulin detemir (~0.2 units/kg) and metfmin

37 What would you tell her if she calls your office the next mning after discharge and asks if she can just restart her GLP-1 RA instead of taking the insulin?

38 Basal Insulin vs. GLP-1 RA

39 A1C (%) GLP-1 RAs Added to Multiple Oral Agents: Comparisons With Basal Insulin 0 MET SU (N=535) OADs (N=235) MET GLIM (N=576) MET ± SU (N=456) 4,* 5, MET ± SU (N = 216) Noninferi vs. insulin -1.3 P=NS vs. insulin P=.0015 vs. insulin P<.05 vs. insulin P<.0001 vs. insulin GLAR EXN BID LIRA EXN QW IDET * 70% on MET monotherapy background 70% on MET SU background 1 Heine R, et al. Ann Intern Med. 2005;143: ; 2 Davies M, et a. Diabetes Obes Metab. 2009;11: ; 3 Russell-Jones D, et al. Diabetologia. 2009;52: ; 4 Diamant M, et al. Lancet. 2010;375: ; 5 Davies M, et al. Diabetes Care. 2013;36:

40 Comparisons of Dulaglutide vs. Basal Insulin, Both in Combination with Prandial Insulin, in Patients with T2DM A1C % Reductions (%) Dulaglutide 0.75 mg onceweekly Dulaglutide 1.5 mg onceweekly Blonde L, et al. Lancet Insulin glargine, given at bedtime 20% 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% Percent of Patients with Serious Adverse Events 9% 15% Dulaglutide Dulaglutide 1.5 mg onceweekly once-weekly 0.75 mg (N=27) (N=44) 18% Insulin glargine, given at bedtime (N=54)

41 Case Study: Consuela After discussing her options she actually decides to continue the insulin detemir since she already got the prescription filled. She agrees to follow-up with the diabetes nurse educat f instructions on selftitration.

42 Case Study: Consuela 3 months later she presents to her PCP office f follow-up Her A1C=7.8% on metfmin 1000 mg BID and insulin detemir 30 units QHS (~0.4 units/kg) She is compliant with her insulin therapy and has been successful with self-titration She has been checking her blood sugar every mning and her FBG range from mg/dl

43 Inzucchi S, et al. Diabetes Care # Injections 1 Approach to Starting and Adjusting Insulin in T2DM Basal Insulin (usually with metfmin /- other noninsulin agent) Start: 10 U/day U/kg/day Adjust: 1-15% 2-4 U once-twice weekly to reach FBG target F hypo: Determine and address cause: dose by 4 U 10-20% Complexity Low 2 3 Add 1 rapid insulin injection befe largest meal Start: 4 U, 0.1 U/kg, 10% basal dose. If A1C<8%, consider basal by same amount Adjust: dose by 1-2 U 10-15% once-twice weekly until SMBG target reached F hypo: Determine and address cause: cresponding dose by 2-4 U 10-20% If not controlled, consider basal-bolus If not controlled after FBG target is reached ( if dose >0.5 U/kg/day), treat PPG excursions with mealtime insulin (Consider initial GLP-1 RA trial) Add 2 rapid insulin injections befe meals ( basal-bolus ) Start: 4 U, 0.1 U/kg, 10% basal dose/meal. If A1C<8%, consider basal by same amount Adjust: dose by 1-2 U 10-15% once-twice weekly until SMBG target reached F hypo: Determine and address cause; cresponding dose by 2-4 U 10-20% Change to premixed insulin twice daily Start: Divide current basal dose into 2/3 AM, 1/3 PM 1/2 AM, 1/2 PM Adjust: dose by 1-2 U 10-15% oncetwice weekly until SMBG target reached F hypo: Determine and address cause: cresponding dose by 2-4 U 10-20% If not controlled, consider basal-bolus Mod. High Flexibility Me flexible Less flexible

44 Garber AJ, et al. Endocr Pract. 2013;19(2):

45 After Basal Insulin, Once-Weekly GLP-1 RA vs. Three Times Daily Prandial Insulin A1C Control Rosenstock J, et al. Diabetes Care

46 After Basal Insulin, Once-Weekly GLP-1 RA vs. Three Times Daily Prandial Insulin Weight Rosenstock J, et al. Diabetes Care

47 Rationale f GLP-1 Recept Agonists and Insulin The combination of a GLP-1RA and insulin may be highly effective f optimal glucose control, ameliating the adverse effects often associated with insulin Data from clinical studies suppt the therapeutic potential of GLP-1RA-insulin combination therapy, typically showing beneficial effects on: glycemic control body weight with a low incidence of hypoglycemia and, in established insulin therapy, facilitating reductions in insulin dose

48 One-year Sustained Glycemic Control and Weight Loss After Adding Basal Insulin to GLP-1 RA Rosenstock J, et al. Diabetes Complications

49 GI Adverse Events Pancreatitis Pancreatic Cancer Medullary Thyroid Cancer Renal Impairment Safety Considerations with GLP-1 Recept Agonist Common Usually dose dependent, transient with GLP-1 RAs Usually reduced with dose titration Patients should be counseled that pancreatitis has been repted with postmarketing use of some of these agents Labeling f all agents states that these agents should be immediately discontinued if pancreatitis suspected Labeling f liraglutide states that caution and appropriate moniting be used in patients with a histy of pancreatitis Albiglutide, dulaglutide, exenatide, and exenatide LAR labeling note that alternate antidiabetic therapy be used in patients with a histy of pancreatitis Further assessments required from long duration-controlled studies epidemiological databases Black Box Warning with albiglutide, dulaglutide, liraglutide, exenatide LAR; Patients should be counseled regarding the risk of medullary thyroid carcinoma and the symptoms of thyroid tums Contraindicated in patients with personal/family histy, patients with multiple endocrine neoplasia syndrome type 2 Renal impairment has been repted postmarketing, usually in association with nausea, vomiting, diarrhea, dehydration. Use caution when initiating escalating doses in patients with renal impairment. Exenatide should not be used in patients with severe renal insufficiency end stage renal disease Despite rarity of some of these safety issues, they are also serious in nature. Helpful to discuss these issues early on in therapy up front without minimizing patients concerns but putting them into perspective. Fineman MS, et al. Diabetes Obes Metab. 2012; FDA Prescribing Infmation.

50 GLP-1 Dosing Devices Drug Dosing Frequency How Supplied Comments Albiglutide Dulaglutide Exenatide Exenatide LAR (once weekly) Liraglutide Once a week on the same day each week, any time of the day, without regard to meals Once weekly at any time of day, with without food 60 minutes pri to mning and evening meals, befe the 2 main meals of the day, about 6 hours me apart Once every 7 days (weekly) at any time of day, with without meals One time each day, at any time during the day, without regard to food Single-dose pen f SQ injection Solution in a singledose pen f SQ injection Solution in a singledose prefilled syringe f SQ injection Multi-dose pen f SQ injection Single-dose pen f SQ injection Single-dose tray containing vial/syringe f SQ injection Pre-filled, multi-dose pen f SQ injection Must be reconstituted, use within 8 hours after reconstitution, may ste in refrigerat until expiration date at room temperature f 4 weeks Refrigerate, may be kept at room temperature f a total of 14 days Refrigerate, may ste at room temperature after first use, discard 30 days after first use Must be reconstituted, administer immediately after reconstitution, ste in refrigerat until preparing f use Refrigerate, may ste at room temperature after first use, discard 30 days after first use SQ=subcutaneous FDA Prescribing Infmation.

51 Medication Exenatide (twice daily) Renal Dosing Adjustment Required Not recommended in endstage renal disease in severe renal impairment (CrCl <30 ml/min). In moderate renal impairment (CrCl ml/min) caution should be exercised when initiating increasing the dose of exenatide from 5 mcg to 10 mcg. Hepatic Dosing Adjustment Liraglutide No No Exenatide LAR (once weekly) Not recommended in endstage renal disease in severe renal impairment (CrCl <30 ml/min). In moderate renal impairment (CrCl ml/min) renal transplantation use caution. Albiglutide No No Dulaglutide If a patient with severe renal impairment end-stage renal disease experiences adverse gastrointestinal side effects, monit renal function closely. No No No Drug Interactions Orally administered medications with a narrow therapeutic index require rapid GI absption may be affected by exenatide-induced delayed gastric emptying, use with caution Oral hmonal contraceptives and antibiotics should be used be taken 1 hour befe exenatide injection Warfarin, monit INR closely Orally administered medications may be affected by liraglutide-induced delayed gastric emptying, use with caution Orally administered medications may be affected by exenatide-induced delayed gastric emptying, use with caution Orally administered medications may be effected by albiglutide-induced delayed gastric emptying, use with caution Orally administered medications with a narrow therapeutic index may be affected by dulaglutide-induced delayed gastric emptying, use with caution Pregnancy Categy C C C C C FDA Prescribing Infmation.

52 Questions?