CASE WORK: Evaluating GLP-1 Receptor Agonists in Patient-Centered Care for Type 2 Diabetes. Ft Lauderdale, FLorida.

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1 CASE WORK: Evluting GLP-1 Receptor Agonists in Ptient-Centered Cre for Type 2 Dibetes Ft Luderdle, FLorid Eduction Prtner Februry 7, 213

2 Session 1: Cse Work: Evluting GLP-1 Receptor Agonists in Ptient-Centered Cre for Type 2 Dibetes Lerning Objectives 1. Evlute nd pply current evidence regrding GLP-1 RA (glucgon-like peptide-1 receptor gonist) efficcy reltive to other gents nd cross dibetes progression. 2. Evlute nd pply current evidence regrding sfety of GLP-1 RAs, including recent dt on specific lbel precutions (eg, thyroid cncer, pncretitis, renl filure) nd crdiovsculr disese. 3. Evlute nd pply current evidence regrding tolerbility nd tretment stisfction with GLP-1 RAs. 4. Evlute nd pply current evidence regrding nonglycemic effects of GLP-1 RAs (eg, effects on weight, blood pressure, lipid levels). Fculty Derek LeRoith, MD, PhD, FACP Professor of Medicine Director of Reserch Division of Endocrinology, Dibetes, nd Bone Disese Mount Sini School of Medicine New York, New York Dr Derek LeRoith is currently professor of medicine nd director of reserch in the Division of Endocrinology, Dibetes, nd Bone Disese t Mount Sini School of Medicine in New York City. He received his medicl nd reserch trining t the University of Cpe Town in South Afric, with postgrdute trining in London. Subsequently, Dr LeRoith joined the medicl fculty t the Ben-Gurion University Medicl School in Isrel. From 1979 until 25, Dr LeRoith worked in the field of endocrinology nd dibetes t the Ntionl Institutes of Helth (NIH), where he eventully becme dibetes brnch chief. His reserch interests include the role of insulin nd insulin-like growth fctors in norml physiology nd disese sttes, including obesity, type 2 dibetes mellitus (T2DM), nd cncer. His clinicl focus primrily involves the pthophysiology nd mngement of T2DM. Dr LeRoith hs published over 5 reserch nd review rticles on these topics. Jvier Morles, MD Vice President Principl Trils Investigtor Advnced Internl Medicine Group, PC New Hyde Prk, New York Dr Jvier Morles is in privte prctice with the Advnced Internl Medicine Group in New Hyde Prk, New York. After grduting from the University of Medicine nd Dentistry of New Jersey, he underwent medicl trining tht included residencies t Memoril Slon-Kettering Cncer Center nd North Shore University Hospitl t Forest Hills, where he served s chief medicl resident. Dr Morles serves on multiple committees t St. Frncis Hospitl in Roslyn, New York. In ddition to uthoring severl publictions, he hs served s principl investigtor for severl different studies nd clinicl trils. He is ctive in the eductionl sector nd hs presented t mny Pri-Med symposi. Dr Morles lso serves s clinicl instructor for severl nurse prctitioner, physicin ssistnt, nd internl medicine residency progrms t both North Shore University nd Winthrop University Hospitls. He is n vid musicin nd percussionist nd is fluent in Spnish, Itlin, nd Portuguese. Session 1

3 Jy Shubrook, DO, FACOFP, FAAFP Associte Professor of Fmily Medicine Director of Clinicl Reserch Deprtment of Fmily Medicine Director of Dibetes Fellowship The Dibetes Institute Ohio University Heritge College of Osteopthic Medicine Athens, Ohio Dr Jy Shubrook is fmily physicin nd dibetes specilist. He serves s director of the Dibetes Institute t Ohio University Heritge College of Osteopthic Medicine nd director of the dibetes fellowship for primry cre physicins. His reserch focuses on childhood obesity, dibetes prevention, nd erly intervention. His fvorite roles re s husbnd to his wife nd fther to 2 dughters. Fculty Finncil Disclosure Sttements The presenting fculty reports the following: Dr LeRoith is n dvisor for nd receives grnt/reserch support from AstrZenec Phrmceuticls LP, Jnssen Phrmceuticls, nd Merck & Co., Inc. Dr Morles is n dvisor for Novo Nordisk Inc. nd Boehringer Ingelheim; receives honorri from Novo Nordisk Inc., Boehringer Ingelheim, nd Wrner Chilcott; nd is speker for Novo Nordisk Inc. nd Wrner Chilcott. Dr Shubrook receives grnt/reserch support from Snofi U.S. LLC. Eduction Prtner Finncil Disclosure Sttement The content collbortors t the Institute for Medicl nd Nursing Eduction, Inc, report the following: Kimberly McFrlnd, PhD, Senior Medicl Writer, holds stock in Pfizer Inc. nd Procter & Gmble. Amy Crbonr, Director of Progrm Development; Angel McIntosh, PhD, Scientific Director; nd Steve Weinmn, RN, Executive Director, hve no finncil reltionships to disclose. Acronym List Acronym A1C ACS AGI ALBI ALT AST BID BMI CHD CHF CI CKD CV CVD DET DPP-4 DPP-4i DULA EGFR ELIXA ER Definition glycted hemoglobin cute coronry syndrome ɑ-glucosidse inhibitor lbiglutide lnine minotrnsferse sprtte minotrnsferse twice dily body mss index coronry hert disese coronry hert filure confidence intervl chronic kidney disese crdiovsculr crdiovsculr disese insulin detemir dipeptidyl peptidse-4 dipeptidyl peptidse-4 dipeptidyl peptidse-4 inhibitor estimted glomerulr filtrtion rte Tril to evlute crdiovsculr outcomes in ptients with type 2 dibetes fter cute coronry syndrome during tretment with lixisentide extended relese Acronym ESRD EXN EXSCEL FBG FFA FPG GIP GLAR GLIM GLP-1 HCC HDL-C HF HR IDET IGT KATP LDL-C Definition end-stge renl disese exentide Exentide Study of Crdiovsculr Event Lowering Tril: A Tril to Evlute Crdiovsculr Outcomes After Tretment With Exentide Once Weekly in Ptients With Type 2 Dibetes Mellitus fsting blood glucose free ftty cid fsting plsm glucose glucose-dependent insulinotropic polypeptide insulin glrgine glimepiride glucgon-like peptide-1 heptocellulr crcinom high-density lipoprotein cholesterol hert filure hzrd rtio insulin detemir impired glucose tolernce ATP-sensitive potssium chnnels low-density lipoprotein cholesterol Session 1

4 Acronym Definition LEAD Lirglutide Effect nd Action in Dibetes LEADER Lirglutide Effect nd Action in Dibetes: Evlution of Crdiovsculr Outcome Results A Long-Term Evlution LIRA lirglutide LIXI lixisentide MEN2 multiple endocrine neoplsi type 2 MET metformin MRS mgnetic resonnce spectroscopy MTC medullry thyroid crcinom NAFLD nonlcoholic ftty liver disese NASH nonlcoholic stetoheptitis NDEP Ntionl Dibetes Eduction Progrm OAD orl ntidibetic gent OR odds rtio Acronym ORL PIO PP PPAR PPG PTC P-Y QD RCT RI SBP SITA SU TG TZD Definition orlistt pioglitzone postprndil peroxisome prolifertor-ctivted receptor postprndil plsm glucose ppillry thyroid crcinom ptient-yer dily rndomized controlled tril renl insufficiency systolic blood pressure sitgliptin sulfonylure triglyceride thizolidinedione Suggested Reding List Americn Dibetes Asscition. Stndrds of medicl cre in dibetes 213. Dibetes Cre. 213;36(Suppl 1):S11-S66. Arod V, Henry RR, Hn J, et l. Efficcy of GLP-1 receptor gonists nd DPP-4 inhibitors: met-nlysis nd systemtic review. Clin Ther. 212;34(36): Blevins T, Pullmn J, Mlloy J, et l. DURATION-5: exentide once weekly resulted in greter improvements in glycemic control compred with exentide twice dily in ptients with type 2 dibetes. J Clin Endocrinol Metb. 211;96(5): Buse JB, Nuck M, Forst T, et l. Exentide once weekly versus lirglutide once dily in ptients with type 2 dibetes (DURATION-6): rndomised, open-lbel study. Lncet. 213;381(9861): Buse JB, Rosenstock J, Sesti G, et l. Lirglutide once dy versus exentide twice dy for type 2 dibetes: 26-week rndomised, prllel-group, multintionl, open-lbel tril (LEAD-6). Lncet. 29;374(9683): Drucker DJ, Buse JB, Tylor K, et l.; DURATION-1 Study Group. Exentide once weekly versus twice dily for the tretment of type 2 dibetes: rndomised, open-lbel, non-inferiority study. Lncet. 28;372(9645): Inzucchi SE, Bergenstl RM, Buse JB, et l. Mngement of hyperglycemi in type 2 dibetes: ptient-centered pproch: position sttement of the Americn Dibetes Assocition (ADA) nd the Europen Assocition for the Study of Dibetes (EASD). Dibetes Cre. 212;35(6): Kirkmn M, Briscoe VJ, Clrk N, et l. Dibetes in older dults. Dibetes Cre. 212;35(12): Kruger DF, Bode B, Spollett GR. Understnding GLP-1 nlogs nd enhncing ptients success. Dibetes Educ. 21;36(Suppl 3):44S-72S. Vilsbøll T, Christensen M, Junker AE, et l. Effects of glucgon-like peptide-1 receptor gonists on weight loss: systemtic review nd met-nlyses of rndomised controlled trils. BMJ. 212;344:d7771. Session 1

5 SESSION 1 8: AM 9:3 AM Cse Work: Evluting GLP-1 Receptor Agonists in Ptient-Centered Cre for Type 2 Dibetes SPEAKERS Derek LeRoith, MD, PhD, FACP Jvier Morles, MD Jy Shubrook, DO, FACOFP, FAAFP Presenter Disclosure Informtion The following reltionships exist relted to this presenttion: Dr LeRoith is n dvisor for nd receives grnt/reserch support from AstrZenec Phrmceuticls LP, Jnssen Phrmceuticls, nd Merck & Co., Inc. Dr Morles is n dvisor for Novo Nordisk Inc. nd Boehringer Ingelheim; receives honorri from Novo Nordisk Inc., Boehringer Ingelheim, nd Wrner Chilcott; nd is speker for Novo Nordisk Inc. nd Wrner Chilcott. Dr Shubrook receives grnt/reserch support from Snofi U.S. LLC. Off-Lbel/Investigtionl Discussion In ccordnce with pmicme policy, fculty hve been sked to disclose discussion of unlbeled or unpproved use(s) of drugs or devices during the course of their presenttions. Generic nd Associted Brnd Nmes Progrm Abbrevition Generic Brnd or Trde Nme ALBI lbiglutide Syncri not FDA-pproved DULA dulglutide [No brnd or trde nme] not FDA-pproved EXN BID exentide BID Byett EXN ER exentide ER Bydureon Cse Work: Evluting GLP-1 RAs in Ptient-Centered Cre for Type 2 Dibetes GLIM glimepiride Amryl IDET insulin detemir Levemir GLAR insulin glrgine Lntus LIRA lirglutide Victoz [No bbrevition used] lisinopril Prinivil, Zestril LIXI lixisentide not FDA-pproved MET metformin Fortmet, Glucophge, Glumetz, Riomet ORL orlistt Xenicl, Alli PIO pioglitzone Actos Derek LeRoith, MD, PhD Professor of Medicine Director of Reserch Division of Endocrinology, Dibetes nd Bone Disese Mount Sini School of Medicine New York, New York SITA sitgliptin Jnuvi Lerning Objectives Demogrphic Question Evlute nd pply current evidence regrding: GLP-1 RA efficcy reltive to other gents nd cross dibetes progression Sfety of GLP-1 RAs, including recent dt on specific lbel precutions (eg, thyroid cncer, pncretitis, renl filure) nd crdiovsculr disese Nonglycemic effects of GLP-1 RAs (eg, effects on weight, blood pressure, lipid levels) How mny ptients with dibetes do you see ech week? 1. None Over 3 Tolerbility nd tretment stisfction with GLP-1 RAs 1

6 Pretest Question 1 Identify the TRUE sttement. 1. GLP-1 RAs significntly reduce A1C but lso significntly increse risk of hypoglycemi. 2. Long-cting GLP-1 RAs provide better FBG control compred to short-cting GLP-1 RAs. 3. DPP-4 inhibitors re ssocited with greter weight loss compred to GLP-1 RAs nd 2 only Pretest Question 2 Identify the TRUE sttement. 1. All GLP-1 RAs should be voided in ptients with moderte to severe renl impirment 2. GLP-1 RAs hve been shown to hve direct toxic effect on renl tubules 3. Renl dysfunction tht cn occur with GLP-1 RA therpy is often reversible 4. None of the bove re true Pretest Question 3 Which pproch would you tke when prescribing GLP-1 RA for ptient currently tking sulfonylure but hs history of repeted hypoglycemic events? 1. Would not prescribe GLP-1 RA for this ptient 2. Mintin the current dose of sulfonylure nd dd GLP-1 RA 3. Discontinue the sulfonylure before strting GLP-1 RA 4. Lower the dose of the sulfonylure before strting GLP-1 RA Outline Introduction: Overview of GLP-1 RAs Mechnism/physiologicl ction of GLP-1 RAs vs other ntihyperglycemic gents Distinction between incretin-bsed therpies GLP-1 RAs vs DPP-4 inhibitors Hed-to-hed comprisons of GLP-1 RAs Descriptions of GLP-1 RAs Avilble for clinicl use In lte-stge clinicl development Actions of GLP-1 RAs Complement Those of Commonly Used Antihyperglycemic Agents Clss Insulins Effectiveness Highest Cellulr Mechnism Activte insulin receptors GLP-1 RAs High Activte GLP-1 receptors Primry Physiologicl Actions Glucose disposl Heptic glucose production Insulin secretion (glucose-dependent) Glucgon secretion (glucose-dependent) Slow gstric emptying Stiety Bigunides High Activte AMPkinse Heptic glucose production SUs High Close β-cell K ATP chnnels Insulin secretion TZDs High Activte PPAR-γ Insulin sensitivity DPP-4 inhibitors Intermedite b Inhibit DPP-4 GLP-1 nd GIP Insulin secretion (glucose-dependent) Glucgon secretion (glucose-dependent) GIP, glucose-dependent insulinotropic peptide; GLP-1, glucgon-like peptide-1; RA, receptor gonist; SU, sulfonylure; TZD, thizolidinedione. Anticipted A1C reduction 1.%-1.5%. b Anticipted A1C reduction.5%-1.%. Inzucchi S, et l. Dibetes Cre. 212;35: Hour Postprndil Plsm Level (pm) Compring Actions of DPP-4 Inhibitors nd GLP-1 RAs Cross-over study, 2-week segments (N = 61) 1 Bseline SITA EXN BID EXN BID, exentide twice dily; SITA, sitgliptin. Endogenous GLP-1 Level 7 GLP-1 RA Level DPP-4 inhibitors 1 Orl dministrtion Block DPP-4 degrdtion of GLP-1 Increse endogenous GLP-1 levels 2-fold GLP-1 RAs 1,2 Subcutneous dministrtion Add exogenous GLP-1 ctivity Increse GLP-1 ctivity 9-fold Greter A1C nd weight effects thn DPP-4 inhibitors 1. DeFronzo RA, et l. Curr Med Res Opin. 28;24: Inzucchi S, et l. Dibetes Cre. 212;35:

7 Mechnisms of Protrction for Mrketed nd Investigtionl GLP-1 RAs Durtion of Action 1 Agent Protrction Mechnism 1 Bse Peptide 1 Approvl Sttus Short EXN BID Modified DPP-4 clevge site Exendin-4 Mrketed 2 Short LIXI Modified DPP-4 clevge site Exendin-4 Regultory filing 3, Long Long EXN ER LIRA EXN in biodegrdble microspheres Amino cid modifictions, noncovlent lbumin binding vi FFA chin Exendin-4 Mrketed 2 GLP-1 Mrketed 2 Long ALBI Covlent lbumin ttchment GLP-1 Regultory filing 4 Long DULA IgG fusion GLP-1 Phse 3 5,b ALBI, lbiglutide; DULA, dulglutide; EXN BID, exentide twice dily; EXN ER, exentide extended-relese; LIRA, lirglutide; LIXI, lixisentide. Regultory filing in Europe. b Clinicl dt presented s vilble. 1. Meier J. Nt Rev Endocrinol. 212;8: US FDA. Drugs@FDA Europen Medicines Agency Fiercebiotech Ntionl Institutes of Helth. Short- vs Long-Acting GLP-1 RAs: Overview Prmeters Short-Acting 1,,c Long-Acting 1,b,c Hlf-life 2-5 h 12 h-severl dys FBG levels Modest reduction Strong reduction Fsting insulin secretion Modest stimultion Strong stimultion PP hyperglycemi Strong reduction Modest reduction PP insulin secretion Reduction Modest stimultion Gstric emptying rte Decelertion No substntil long-term effects Glucgon secretion Reduction Reduction Blood pressure Reduction Reduction Hert rte increse None/smll ( -2 bpm) Moderte ( 2-5 bpm) Body weight reduction 1-5 kg 2-5 kg Nuse induction/ttenution 2%-5%/weeks-months 2%-4%/ 4-8 weeks Exentide BID, lixisentide. b Lirglutide, exentide ER, lbiglutide, dulglutide. c Albiglutide, dulglutide, nd lixisentide re not FDA pproved Meier J. Nt Rev Endocrinol. 212;8: US FDA. Drugs@FDA. Glycemic Control With Avilble GLP-1 RAs: Hed-to-Hed Tril Results A1C (%) FPG (mg/dl) EXN BID, exentide twice dily; EXN ER, exentide extended-relese; LIRA, lirglutide. P <.5 vs EXN BID. EXN BID (1 mcg) LIRA (1.8 mg) EXN ER (2. mg) LEAD-6 1 (N = 464) DURATION-1 2 (N = 295) DURATION-5 3 (N = 252) DURATION-6 4 (N = 911) Buse J, et l. Lncet. 29;374: Drucker D, et l. Lncet. 28;372: Blevins T, et l. J Clin Endocrinol Metb. 211;96: Buse J, et l. Lncet. 213;381: Glycemic Control With Investigtionl GLP-1 RAs: Hed-to-Hed Tril Results Tril: Size (N): Study length (weeks): A1C (%) FPG (mg/dl) GetGol-X ALBI, lbiglutide; EXN BID, exentide twice dily; LIRA, lirglutide; LIXI, lixisentide. ALBI nd LIXI re not FDA pproved. Hrmony LIXI met noninferiority vs EXN BID 26.1 ALBI did not meet noninferiority vs LIRA EXN BID LIXI LIRA ALBI 1. Rosenstock J, et l. EASD 47th Annul Meeting. 212; Prtley R, et l. ADA 72nd Scientific Sessions. 212;945-P. Summry Actions of GLP-1 RAs complement those of other ntihyperglycemic gents commonly used in ptients with T2DM GLP-1 RA Efficcy: Cse Study 1 DPP-4 inhibitors re not orl versions of GLP-1 RAs Short- nd long-cting GLP-1 RAs differ in their effects on glycemic control Greter PPG reduction with short-cting GLP-1 RAs Greter FPG reduction with long-cting GLP-1 RAs Greter A1C reduction with long-cting GLP-1 RAs Jvier Morles, MD St. Frncis Hospitl Advnced Internl Medicine Group New Hyde Prk, New York Unique clinicl chrcteristics of individul GLP-1 RAs my be leverged for ptient-centered cre 3

8 Cse 1: Sndy Overweight femle (BMI 27 kg/m 2 ) Age: 59 yers T2DM for 9 yers Medictions Metformin 2 mg/d Glimepiride 4 mg/d Insulin glrgine 46 U/d A1C 7.9% ARS Question Sndy is not good cndidte for GLP-1 RA therpy becuse she is too lte in T2DM progression. 1. True 2. Flse Outline GLP-1 RA Efficcy Across T2DM Progression Tretment recommendtions Prescribing informtion ADA/EASD consensus sttement Evidence for use cross T2DM progression Predibetes Erly (monotherpy) Erly (dded to metformin s second-line gent) Lte T2DM (dded to multiple orl ntihyperglycemic gents) Lte T2DM (with insulin) Lbel Recommendtions Indicte GLP-1 RA Use Across T2DM Progression Indictions nd Usge EXN BID LIRA EXN ER Adjunct to diet nd exercise X X X Not recommended s first line X X Approved with bsl insulin (not prndil) X X EXN BID, exentide twice dily; LIRA, lirglutide; EXN ER, exentide extended-relese. GLP-1 RAs re not substitutes for insulin nd re not currently FDA pproved for use in ptients with T1DM. US FDA. Drugs@FDA. GLP-1 RAs in ADA/EASD Recommendtions for Antihyperglycemic Therpy in T2DM Second line, in ddition to metformin In 3-drug combintions With bsl insulin Among preferred gents in specific situtions When gol is to void weight gin DPP-4 inhibitors GLP-1 RAs When gol is to void hypoglycemi Thizolidinediones DPP-4 inhibitors GLP-1 RAs Conversion From Predibetes to Norml Glucose Tolernce With GLP-1 RAs GLP-1 RAs re not FDA pproved for tretment of predibetes. 1 Rosenstock et l 2 Astrup et l 3 EXN BID (1 mcg) PBO LIRA 2./3. mg ORL 1 (N = 38) 1 (N = 176) b Normlized Glucose Tolernce (% of pts with BL predibetes) Results t 24 weeks Normlized Glucose Tolernce (% of pts with BL predibetes) Results t 14 weeks My be used s first-line gent if metformin cnnot be used nd weight loss is desirble. Inzucchi S, et l. Dibetes Cre. 212;35: ; Mngement of hyperglycemi in type 2 dibetes: ptient-centered pproch slide set. BL, bseline; EXN BID, exentide twice dily; LIRA, lirglutide; ORL, orlistt; PBO, plcebo. Predibetes: impired glucose tolernce or impired fsting glucose. b 52% to 62%, depending on strting group. 1. US FDA. Drugs@FDA Rosenstock J, et l. Dibetes Cre. 21;33: Astrup A, et l. Int J Obes (Lond). 212;36:

9 Efficcy of Mrketed GLP-1 RAs s Monotherpy Efficcy of Mrketed GLP-1 RAs Added to Metformin s Second-Line Agents Study Length (Number) GLP-1 RA Bseline A1C EXN BID 1,2 24 wk (N = 232) 7.8%-7.9% LIRA 1,3 52 wk (N = 746) 8.3%-8.4% EXN ER 1,4 26 wk (N = 82) 8.4%-8.6% GLP-1 RA A1C (%) 1 mcg:.9 PBO: mg: mg: mg: 1.5 Comprtor(s) A1C (%) GLIM:.5 MET: 1.5 PIO: 1.6 SITA: 1.2 Study Length (Number) GLP-1 RA Bseline A1C EXN BID 1,2 3 wk (N = 336) 8.2% LIRA 1,3 26 wk (N = 187) 8.3%-8.4% EXN ER 1,4 26 wk (N = 491) 8.5%-8.6% GLP-1 RA A1C (%) Comprtor(s) A1C(%) 1 mcg:.8 PBO: mg: mg: 1. 2 mg: 1.5 PBO: +.1 GLIM: 1. PIO: 1.2 SITA:.9 EXN BID, exentide twice dily; EXN ER, exentide extendedrelese; GLIM, glimepiride; LIRA, lirglutide; MET, metformin; PBO, plcebo; PIO, pioglitzone; SITA, sitgliptin. P <.5 vs GLP-1 RA. 1. US FDA. Drugs@FDA Moretto TJ, et l. Clin Ther. 28;3: Grber A, et l. Lncet. 29;373: Russell-Jones D, et l. Dibetes Cre. 212;35: EXN BID, exentide twice dily; EXN ER, exentide extended-relese; GLIM, glimepiride; LIRA, lirglutide; PBO, plcebo; PIO, pioglitzone. P <.5 vs GLP-1 RA. 1. US FDA. Drugs@FDA DeFronzo RA, et l. Dibetes Cre. 25;28: Nuck MA, et l. Dibetes Cre. 29;32: Bergenstl RM, et l. Lncet. 21;376: GLP-1 RAs Added to Multiple Orl Agents: Comprisons With Bsl Insulin A1C (%) MET + SU OADs 3 MET + GLIM (N = 535) (N = 235) (N = 576) Noninferior vs insulin P = NS vs insulin P =.15 vs insulin EXN ER dded to 1-2 OADs A1C: 1.5% with EXN ER vs 1.3% with GLAR (P <.5, N = 456) 4, A1C: 1.3% with EXN ER vs.9% with IDET (P <.1, N = 216) 5 EXN BID, exentide twice dily; EXN ER, exentide extended-relese; GLAR, insulin glrgine; GLIM, glimepiride; IDET, insulin detemir; LIRA, lirglutide; MET, metformin; OAD, orl ntidibetic gent; SU, sulfonylure. > 5% of prticipnts on MET monotherpy bckground. GLAR EXN BID LIRA 1. Heine R, et l. Ann Intern Med. 25;143: Dvies M, et. Dibetes Obes Metb. 29;11: Russell-Jones D, et l. Dibetologi. 29;52: Dimnt M, et l. Lncet. 21;375: Dvies M, et l. Dibetes Cre. 212 Dec 28. [Epub hed of print]. GLP-1 RAs Added to Bsl Insulin (N = 259). FDA Approved 1 Investigtionl P <.5 Hypoglycemi generlly similr vs PBO in bsence of SU ( 2%-35%) 1-4 but lower with ALBI (32.6%) vs LIS (49.8%) 5 A1C (%) PBO EXN BID ALBI, lbiglutide; EXN BID, exentide twice dily; LIS, insulin lispro; LIXI, lixisentide; PBO, plcebo; SU, sulfonylure. Use with bsl insulin is FDA pproved for EXN BID. b LIXI nd ALBI re not FDA pproved. A1C (%).5 PBO LIXI b LIS ALBI b 1. Buse JB, et l. Ann Intern Med. 211;154: Rosenstock J, et l. ADA 72nd Scientific Sessions. 212;62-OR. 3. Riddle M, et l. ADA 72nd Scientific Sessions. 212;983-P. 4. Seino Y, et l. Dibetes Obes Metb. 212;14: Rosenstock J, et l. ADA 72nd Scientific Sessions. 212;55-OR. Bsl Insulin Added to GLP-1 RAs Ptient-Centered Considertions: Sndy A1C (%) LIRA 1.8 mg + IDET vs Control (26-wk clinicl tril) P <.1.51 MET + LIRA 1.8 mg control (n = 157) MET + LIRA 1.8 mg + IDET (n = 162) Hypoglycemi LIRA + IDET Minor: 9.2% of LIRA + IDET group vs 1.3% of control group No mjor hypoglycemi Ptient is overweight Current ADA/EASD lgorithm highlights GLP-1 RAs for use when voidnce of hypoglycemi or weight gin is therpeutic gol Ptient is not chieving glycemic control on MET + SU + insulin Prescribing informtion nd ADA/EASD lgorithm indicte GLP-1 RAs my be used cross T2DM progression GLP-1 RAs effectively improve glycemic control in combintion with insulin Ptient needs to improve A1C bout.9% to rech pproprite glycemic control GLP-1 RAs in combintion with bsl insulin my provide dequte glycemic control for the ptient to rech her gol IDET, insulin detemir; LIRA, lirglutide; MET, metformin. Use with bsl insulin is FDA pproved for LIRA. DeVries J, et l. Dibetes Cre. 212;35:

10 ARS Question Wht else would you like to know bout Sndy before inititing GLP-1 RA? 1. Renl function sttus 2. History of endocrine tumors 3. History of hypoglycemi 4. History of crdiovsculr events 5. History of pncretitis/gll bldder disese Cse 1: Fculty Discussion Drs LeRoith, Morles, Shubrook Cse 2: Mike GLP-1 RA Sfety: Cse Study 2 Jy Shubrook, DO, FACOFP, FAAFP Associte Professor of Fmily Medicine Director of Clinicl Reserch Director of Dibetes Fellowship The Dibetes Institute t Ohio University Heritge College of Osteopthic Medicine Athens, Ohio Mle Age: 72 yers BMI 28 kg/m 2 T2DM for 8 yers Active, self-sufficient Medictions Metformin 2 mg/d Glimepiride 4 mg/d A1C: 8.9% Comorbidities/sfety concerns Congestive hert filure Mild to moderte renl insufficiency (egfr 5 ml/min/1.73 m 2 ) Repeted hypoglycemic events ARS Question Mike is not good cndidte for GLP-1 RA therpy becuse he hs renl insufficiency. 1. True 2. Flse Outline GLP-1 RA Sfety Use in ptients with comorbid conditions (eg, some elderly ptients) Specific precutions Acute renl filure/renl insufficiency Pncretitis Thyroid cncer Crdiovsculr sfety nd risk of hypoglycemi 6

11 GLP-1 RAs in Ptients With Comorbidities: Older Ptients Frmework for Considering Glycemic Gols in Older Adults With Dibetes Clssic Dibetes Comorbidities 1-4 Renl disese: 41% of ptients 65 y hve CKD 2 CVD: 43% of ptients y nd 55% of ptients > 75 y hve CVD 3 41% of ptients 65 y hve CHF 2 Heptic disese Nerly 75% of ptients 6 y hve NAFLD 4 Geritric Syndromes 1 Cognitive dysfunction Functionl impirment Flls nd frctures Polyphrmcy Depression Vision nd hering impirment Pin from neuropthy or other cuses Urinry incontinence Ptient Chrcteristics/ Helth Sttus Helthy few coexisting chronic illnesses, intct cognitive nd functionl sttus Complex/intermedite multiple coexisting illnesses or 2+ instrumentl ADL impirments or mild to moderte cognitive impirment Very complex/poor helth long-term cre or end-stge chronic illnesses or moderte to severe cognitive impirment or 2+ ADL dependencies Rtionle Longer remining life expectncy Intermedite remining life expectncy, high tretment burden, hypoglycemi vulnerbility, fll risk Limited remining life expectncy mkes benefit uncertin Resonble A1C Gol < 7.5% < 8.% < 8.5% b 1. Kirkmn M, et l. Dibetes Cre. 212;35: Slon FA, et l. Arch Intern Med. 28;168: CDC. Dibetes Dt & Trends Trgher G, et l. Dibetes Cre. 27;3: ADL, ctivities of dily living. Lower gol my be set if chievble without recurrent or severe hypoglycemi or undue tretment burden. b Looser trgets my expose ptients to risks from glycosuri, dehydrtion, hyperglycemic hyperosmolr syndrome, nd poor wound heling. Kirkmn M, et l. Dibetes Cre. 212;35: GLP-1 RA Effects in Older nd Younger Ptients: Pooled Anlyses of Phse 3 Trils Clinicl Outcome Hypoglycemi, mjor nd minor, % EXN BID 1 (1 mcg) 16 trils Comprble, significnt A1C from bseline for ptients < 65 y nd 65 y Effects lso comprble for ptients < 75 y nd 75 y receiving LIXI EXN BID, exentide twice dily; EXN ER, exentide extended-relese; LIRA, lirglutide; LIXI, lixisentide. Lixisentide is not FDA pproved; b 27.7% nd 3.2% treted with SU, 4.% nd 1.2% without SU; c 12.7% nd 12.% treted with SU, 2.% nd 4.2% without SU; d Includes.5% mjor hypoglycemi, ll treted with SU; e %-5% monotherpy or metformin only, 14%-22% SU but no insulin, 27%-42% bsl insulin but no SU, 45%-53% bsl insulin nd SU. EXN ER 2 (2. mg) 7 trils LIRA 3 (1.8 mg) 6trils LIXI 4, (2 mcg) 6 trils < 65 y 65 y < 65 y 65 y < 65 y 65 y < 65 y 65 y 16 b 19 b 6 c 8 c 14 d e -53 e Nuse, % Vomiting, % Dirrhe, % Pencek R, et l. Postgrd Med. 212;124: Pencek R, et l. Int J Clin Prct. 212;66; Bode B, et l. Am J Geritr Phrmcother. 211;9: Rcch D, et l. 72nd ADA Scientific Sessions. 212;972-P. Evidence Regrding Renl Impirment With GLP-1 RAs Evidence does not indicte direct renl toxicity with GLP-1 RAs 1-3 Renl impirment (RI) impcts clernce of EXN but not LIRA 1,4,5 Hypovolemi due to nuse/vomiting my worsen renl function 1 Renl impirment hs been reported in ptients tking GLP-1 RAs 1 Reversed in mny cses with supportive tretment nd discontinution of potentilly custive gents Sometimes required hemodilysis or trnsplnttion Some cses occurred in ptients who 1,6-9 Experienced nuse, vomiting, dirrhe, dehydrtion Took medictions known to ffect renl function or hydrtion sttus Hd no known underlying renl disese 1. US Food nd Drug Administrtion. Drugs@FDA Pendergrss M, Chen W. ADA 7th Scientific Sessions. 21:11-LB; 3. Tuttle K, et l. ADA 71st Scientific Sessions. 211:971-P; 4. Linnebjerg H, et l. Br J Clin Phrmcol. 27;64: ; 5. Jcobsen L, et l. Br J Clin Phrmcol. 29;68:898-95; 6. Johnsen O, Whitfield R. Br J Clin Phrmcol. 28;66: ; 7. Weise WJ, et l. Dibetes Cre. 29;32:e22-e23; 8. Ferrer-Grci JC, et l. Dibet Med. 21;27: ; 9. López-Ruiz A, et l. Phrm World Sci. 21;32: Recommendtions for GLP-1 RA Use: Possible Renl Impirment Risk Evidence Regrding Acute Pncretitis Risk With GLP-1 RAs Cses hve been reported in ptients tking GLP-1 RAs 1 Prescribing Informtion Precutions EXN BID LIRA EXN ER Renl impirment Recommendtions Not in severe RI or ESRD Use with cution Not in severe RI or ESRD Use with cution in ptients with RI or renl trnsplnttion, especilly when inititing or esclting doses Hypovolemi due to nuse/vomiting my worsen renl function Do not use EXN BID or EXN ER in ptients with severe RI or ESRD ESRD, end-stge renl disese; EXN BID, exentide twice dily; EXN ER, exentide extended-relese; LIRA, lirglutide; RI, renl impirment. US FDA. Drugs@FDA. Pncretitis risk is 1.5- to 3-fold higher in individuls with dibetes 2-6 Controversil nlyses of FDA sfety dtbse yielded mixed results 7,8 Clinicl tril nd insurnce clims dt hve demonstrted no incresed risk with exentide or lirglutide US FDA. Drugs@FDA Noel RA, et l. Dibetes Cre. 29;32: ; 3. Girmn CJ, et l. Dibetes Obes Metb. 21;12: ; 4. Grg R, et l. Dibetes Cre. 21;33: ; 5. Xue Y, et l. Eur J Gstroenterol Heptol. 212;24: ; 6. Yng L, et l. Eur J Gstroenterol Heptol. 213;25: ; 7. Elshoff M, et l. Gstroenterology. 211;141:15-156; 8. Rschi E, et l. Act Dibetol. 211 Oct 19. [Epub hed of print]; 9. Dore DD, et l. Curr Med Res Opin. 29;25: ; 1. Dore DD, et l. Dibetes Obes Metb. 211;13: ; 11. McConell L, et l. Dibetes Metb Syndr Obes. 212;5:29-41; 12. Wenten M, et l. Dibet Med. 212;29: ; 13. McConell L, et l. 72nd ADA Scientific Sessions. 212;2372-PO; 14. Alves C, et l. Dibetes Res Clin Prct. 212;98: ; 15. Romley J, et l. Dibetes Technol Ther. 212;14:

12 Recommendtions for GLP-1 RA Use: Possible Pncretitis Risk Prescribing Informtion Precutions EXN BID LIRA EXN ER History of pncretitis Recommendtions Consider other gents Use with cution Educte ptients nd monitor for signs nd symptoms Ask bout medicl history of pncretitis Discontinue promptly if pncretitis symptoms occur (eg, persistent severe bdominl pin tht my or my not be ccompnied by vomiting) If cute pncretitis is confirmed, do not restrt GLP-1 RA Report cses of pncretitis to EXN BID, exentide twice dily; EXN ER, exentide extended-relese; LIRA, lirglutide. Consider other gents US FDA. Evidence Regrding Thyroid Cncer Risk With GLP-1 RAs Rodents, but not nonhumn primtes, developed thyroid C-cell tumors when treted with GLP-1 RAs 1,2 Unknown whether GLP-1 RAs cuse C-cell tumors in humns; relevnce of niml studies cnnot be determined through trils becuse MTC is rre 1,3 Clinicl trils 1,4 LIRA: 1.5 PTC cses per 1 P-Ys vs.5 in controls, no confirmed MTC EXN BID:.3 thyroid neoplsms per 1 P-Ys vs in controls Met-nlysis of published studies 5 No reported thyroid mlignncies with EXN No incresed thyroid cncer risk with LIRA (OR 1.54 [95% CI.4-6.2]) 1. US Food nd Drug Administrtion. Drugs@FDA Bjerre Knudsen L, et l. Endocrinology. 21;151: Prks M, Rosebrugh C. N Engl J Med. 21;362: EXN, exentide; LIRA, lirglutide; MTC, medullry 4. McConell L, et l. Dibetes Metb Syndr Obes. 212;5: thyroid crcinom; PTC, ppillry thyroid crcinom. 5. Alves C, et l. Dibetes Res Clin Prct. 212 Sep 22. [Epub hed of print]. PTC usully tretble; 6. Ntionl Cncer Institute. Generl informtion bout thyroid cncer. MTC rre, poorer prognosis. 6 Recommendtions for GLP-1 RA Use: Possible Thyroid Tumor Risk Prescribing Informtion Contrindictions EXN BID LIRA EXN ER Possible thyroid tumor risk do not use if history of MTC or MEN2 Recommendtions LIRA nd EXN ER re contrindicted in ptients with MEN2 or personl or fmily history of MTC 1 Counsel ptients regrding MTC risk nd symptoms of thyroid tumors 1 Vlue of routine clcitonin nd/or ultrsound monitoring is uncertin; such monitoring my led to unnecessry procedures 1 Ptients with thyroid nodules or elevted serum clcitonin levels identified for other resons should be sent to n endocrinologist 1 To monitor potentil ssocitions, report MTC to stte cncer registry, regrdless of tretment 1,2 EXN BID, exentide twice dily; EXN ER, exentide extended-relese; LIRA, lirglutide; MTC, medullry thyroid 1. US FDA. Drugs@FDA. crcinom; MEN2, multiple endocrine neoplsi syndrome type Prks M, Rosebrugh C. N Engl J Med. 21;362: X X GLP-RA Crdiovsculr Sfety: Post Hoc Anlyses of Pooled Clinicl Tril Dt Study Comprtors Outcome Risk Assessment Rtner et l 1 EXN BID (n = 2316) Non-EXN BID (n = 1629) Mrso et l 2 LIRA (n = 4257) Non-LIRA (n = 2381) b Long-term trils to further evlute the impct of GLP-1 RAs on the occurrence of CV events re in progress 3 LIRA (LEADER NCT117948): results nticipted in 216 EXN ER (EXSCEL NCT ): results nticipted in 217 LIXI d (ELIXA NCT114725) c : results nticipted in 214 ACS, cute coronry syndrome; CV, crdiovsculr; EXN BID, exentide twice dily; EXN ER, exentide extended-relese; IR, incidence rtio; LIRA, lirglutide; LIXI, lixisentide; MI, myocrdil infrction; RR, risk rtio. Insulin or plcebo; b Active comprtor or plcebo; c In ptients who hve experienced cute coronry syndrome; d LIXI not FDA pproved. CV deth, stroke, MI, ACS, revsculriztion CV deth, stroke, MI RR (95% CI).7 ( ) IR (95% CI).73 ( ) 1. Rtner R, et l. Crdiovsc Dibetol. 211;1: Mrso S, et l. Dibetes Vsc Dis Res. 211;8: Ntionl Institutes of Helth. Hypoglycemic Risk of Antihyperglycemic Agents Added to Metformin: A Network Met-Anlysis Odds Rtio vs Plcebo Incresed Risk vs Plcebo No Incresed Risk vs Plcebo Hypoglycemi With GLP-1 RAs: With nd Without Sulfonylures in Hed-to-Hed Trils LIRA (1.8 mg QD) EXN (1 mcg BID) EXN (2. mg ER) Without Sulfonylure With Sulfonylure 5 5 n = 34 n = 19 n = n = 127 n = 186 n = Minor Hypoglycemi (% of ptients) Minor Hypoglycemi (% of ptients) Only 2 cses of mjor hypoglycemi (EXN BID + SU in LEAD-6) 1-3 Less minor hypoglycemi with LIRA vs EXN BID (1.93 vs 2.6 events per P-Y; P =.131) 1 AGI, ɑ-glucosidse inhibitor; SU, sulfonylure; TZD, thizolidinedione. 39 rndomized controlled trils. Liu S, et l. Dibetes Obes Metb. 212;14: EXN, exentide; LIRA, lirglutide; P-Y, ptient-yer. Minor hypoglycemi = self-tretble, with plsm glucose < 55 mg/dl; mjor hypoglycemi = requiring third-prty ssistnce. 1. Buse J, et l. Lncet. 29;374: Drucker DJ, et l. Lncet. 28;372: Buse J, et l. Lncet. 213;381:

13 Recommendtions for GLP-1 RA Use: Possible Hypoglycemi Risk Prescribing Informtion Precutions EXN BID LIRA EXN ER Incresed risk of hypoglycemi with secretgogues/insulin X X X Recommendtion: Consider lowering the dose of insulin secretgogue (eg, sulfonylure) or insulin to reduce the risk of hypoglycemi Ptient-Centered Considertions: Mike Ptient is > 65 yers old GLP-1 RA efficcy, sfety profiles re similr in older nd younger ptients Be wre of geritric syndromes tht my ffect bility to use GLP-1 RAs (eg, cognitive dysfunction, functionl impirment, vision impirment, pin) Ptient hs renl impirment GLP-1 RAs re not directly nephrotoxic, but should be used cutiously in ptients with RI EXN BID nd EXN ER should not be used in ptients with severe RI or ESRD Hypovolemi my worsen renl function Ptient hs congestive hert filure Anlyses hve demonstrted no incresed risk of CV events with GLP-1 RAs Long-term studies to better ssess CV risk re in progress Ptient hs experienced multiple hypoglycemic episodes GLP-1 RAs re ssocited with low risk of hypoglycemi Risk of hypoglycemi is incresed in combintion with insulin/insulin secretgogues consider decresing sulfonylure dose EXN BID, exentide twice dily; EXN ER, exentide extended-relese; LIRA, lirglutide. US FDA. Drugs@FDA. ARS Question Wht else would you like to know bout Mike before inititing GLP-1 RA? Cse 2: Fculty Discussion 1. Functionl limittions (ie, bility to dminister injection) 2. Vision impirments 3. Gstrointestinl disese (eg, gstropresis) 4. Sttus of nonglycemic gols (ie, BP, lipids, weight) 5. Nutritionl considertions Drs LeRoith, Morles, Shubrook Cse 3: Mrv GLP-1 RA Nonglycemic Effects: Cse Study 3 Jvier Morles, MD St. Frncis Hospitl Advnced Internl Medicine Group New Hyde Prk, New York Obese mle (BMI 31 kg/m 2 ) Age: 45 yers T2DM for 3 yers Medictions Metformin 2 mg/d Lisinopril 2 mg/d A1C: 8.1% Hypertension BP 133/82 mm Hg Truck driver Bck pin nd voction re brriers to regulr exercise Also mentions discomfort in upper right bdomen 9

14 ARS Question Mrv is not good cndidte for GLP-1 RA therpy becuse it my increse his blood pressure. 1. True 2. Flse Outline GLP-1 RA Nonglycemic Effects Overview of nonglycemic effects Weight Lipid levels Blood pressure Implictions for cre beyond glycemic control T2DM tretment gols other thn hyperglycemi NAFLD Monotherpies Weight (24-month medin, kg) T2DM Tretment Selection Cn Impct Body Weight MET DPP-4 inhibitor SU TZD Insulin MET Combintion Therpies Weight (24-month medin, kg) All P <.1 vs bseline EXCEPT P =.6 vs bseline for DPP-4 inhibitor monotherpy MET, metformin; SU, sulfonylure; TZD, thizolidinedione. Anlysis of UK Generl Prctice Reserch Dtbse w/ DPP-4 inhibitor w/ SU w/ TZD w/ INS w/ SU + TZD Morgn C, et l. Dibetes Obes Metb. 212;14: Weight (kg) GLP-1 RA Weight Effects in Ptients With T2DM Met-Anlysis (8 Published RCTs) EXN BID LIRA EXN ER ALBI, lbiglutide; EXN BID, exentide twice dily; EXN ER, exentide extended-relese; LIRA, lirglutide; LIXI, lixisentide; RCT, rndomized controlled tril. Weight chnges in ptients treted for 12 weeks. b ALBI nd LIXI re not yet FDA pproved. Generlly similr weight chnges reported for individul GLP-1 RAs in hed-to-hed trils EXN BID vs LIRA 2 EXN BID vs EXN ER 3,4 EXN BID vs LIXI 5,b Exceptions LIRA ( 3.6) vs EXN ER ( 2.7; P =.5) 6 LIRA ( 2.2 kg) vs ALBI b (.6 kg) 7 1. Arod V, et l. Clin Ther. 212;34: e Buse J, et l. Lncet. 29;374: Drucker DJ, et l. Lncet. 28;372: Blevins T, et l. J Clin Endocrinol Metb. 211;96: Rosenstock J, et l. EASD 47th Annul Meeting. 212; Buse J, et l. Lncet. 212 Nov 16. [Epub hed of print]. 7. Prtley R, et l. ADA 72nd Scientific Sessions. 212;945-P. Proportion of Prticipnts With Weight Loss: Hed-to-Hed GLP-1 RA Trils DURATION-1 (N = 295) 1 Weight Loss (% of prticipnts) EXN BID 79 EXN ER 76 LEAD-6 (N = 464) 2 Weight Loss (% of prticipnts) EXN BID LIRA Weight Loss With GLP-1 RAs Is Not Driven by Gstrointestinl Adverse Events LIRA (Met-Anlysis/6 26-Week Trils) 1 EXN (3-Week DURATION-1 Tril) 2 Weight Chnge (kg) PBO 1.2 mg LIRA 1.8 mg LIRA EXN ER EXN BID No NVD Some NVD No Nuse Nuse 1 2 3,b,b P <.5 P <.5,b In 82-week EXN completer cohort, weight loss ws (1) similr cross degrees of nuse, (2) progressive despite stble nuse incidence, nd (3) unlikely to be driven by nuse 3 Weight Chnge (kg) EXN BID, exentide twice dily; EXN ER, exentide extended-relese; LIRA, lirglutide; 1. Drucker D, et l. Lncet. 28;372: Buse J, et l. Lncet. 29;374: EXN, exentide, LIRA, lirglutide; NVD, nuse/vomiting/dirrhe. P <.5 vs bseline; b P <.5 vs plcebo. 1. Russell-Jones D, et l. 7th ADA Scientific Sessions. 21;1886-P. 2. Drucker D, et l. Lncet. 28;372: Blonde L, et l. Dibetes Obes Metb. 26;8:

15 Blood Pressure nd Lipid Chnges With GLP-1 RAs: Met-Anlysis of RCTs 1, Prmeter Chnge 95% Confidence Intervl Systolic blood pressure 3.57 mm Hg 5.49 to 1.66 Distolic blood pressure 1.38 mm Hg 2.2 to.73 Totl cholesterol 3.9 mg/dl 6.19 to 1.55 (.1 mmol/l) (.16 to.4) In hed-to-hed trils BP chnges were similr for individul GLP-1 RAs 2-4 Totl cholesterol chnges rnged from 3 to 12 mg/dl 2-4 LDL-cholesterol chnges rnged from 17 mg/dl to 1 mg/dl 2,3 Triglyceride chnges rnged from 8 mg/dl to 36 mg/dl 2-4 How Much Cn GLP-1 RAs Help? Benefits of Incrementl Chnges in CV Risk Fctors Risk Fctor Incrementl Chnge Potentil Benefits Overweight/obesity 1 6% weight loss over 4 yers A1C (.4%) SBP (5 mm Hg) HDL-C (4 mg/dl) TRIG (26 mg/dl) Hypertension 2 1 mm Hg decrese in SBP Risks: Dibetes-relted deth (17%) All-cuse mortlity (12%) MI (12%) Stroke (19%) HF (15%) Dyslipidemi mg/dl increse in HDL-C 2% to 3% in CHD risk 4 mg/dl decrese in LDL-C 1% in ll-cuse mortlity 1 mg/dl decrese in TRIGs 5% in CVD events Includes overweight nd obese individuls without T2DM; tretments include exentide nd lirglutide. 1.Vilsbøll T, et l. BMJ. 212;344:d Drucker D, et l. DURATION-1 Study Group. Lncet. 28;372: Buse J, et l. LEAD-6 Study Group. Lncet. 29;374: Buse J, et l. Lncet. 212 Nov 6. [Epub hed of print]. 1. Look AHEAD Reserch Group. Arch Intern Med. 21;17: Adler AI, et l; UKPDS Group. BMJ. 2;321: CTT Collbortion. Lncet. 21;376: Shrm RK, et l. Vsc Helth Risk Mng. 29;5: Wtts G, Krpe F. Hert. 211;97: Wht is Nonlcoholic Ftty Liver Disese (NAFLD)? Most prevlent liver disese in T2DM ( 2 vs no T2DM) 1,2 Chronic disese Heptic ft ccumultion (stetosis) in the bsence of other cuses 1 Associted with insulin resistnce, impired glucose tolernce (IGT), nd T2DM 3,4 Nturl history poorly understood 1 Simple stetosis or progression to nonlcoholic stetoheptitis (NASH) liver dmge with inflmmtion, necrosis, nd fibrosis 1 Fibrosis progression in 3% to 4% of cses 4 My progress to cirrhosis, heptocellulr crcinom (HCC) 1 1. Tolmn K, et l. Dibetes Cre. 27;3: Cusi K. Curr Opin Endocrinol Dibetes Obes. 29;16: Ali R, Cusi K. Ann Med. 29;41: Angulo P. Alimentry Phrmcol Ther. 27;25: Clinicl Considertions for NAFLD/NASH Few clinicl symptoms 1 My or my not be ssocited with elevted ALT/AST My be detected using ultrsound (sensitivity not good) Liver biopsy to distinguish NAFLD vs NASH Currently no specific therpies for NAFLD/NASH Recommend weight reduction, helthy diet, incresed physicl ctivity, voidnce of lcohol nd unnecessry medictions 2 Intensive lifestyle benefit supported by Look AHEAD tril 3 Antioxidnts (ie, vitmin E) nd insulin sensitizers (ie, pioglitzone) my be effective 4-6 NAFLD, nonlcoholic ftty liver disese; NASH, nonlcoholic heptic stetosis. Pioglitzone is not FDA pproved for treting NAFLD/NASH Ali R, Cusi K. Ann Med. 29;41: Ntionl Digestive Diseses Informtion Clering House. Nonlcoholic stetoheptitis Lzo M, et l. Dibetes Cre. 21;33: Snyl A, et l. N Engl J Med. 21;362: Belfort R, et l. N Engl J Med. 26;355: Aithl G, et l. Gstroenterology. 28;135: US FDA. Drugs@FDA. GLP-1 RA Effects on NAFLD/NASH Indictors Liver Enzymes Chnge From BL (IU/L) EXN BID 1, LIRA 2,b 1 c 4 c 8 d ALT AST Improvements correlted with weight loss 1,2 nd A1C 2 EXN BID, exentide twice dily; LIRA, lirglutide; MRS, mgnetic resonnce spectroscopy; PIO, pioglitzone. Completers, 3-y open-lbel tril extension; b Met-nlysis of 26- week led trils; c P <.1 vs bseline; d P =.3 vs comprtors. Stetosis Technique Effect heptic ft with EXN MRS 3 BID + PIO (12% to 5%; P <.5 vs PIO lone) Reltive intrheptic MRS 4 lipid (42%) with GLP-1 RA (ie, EXN BID, LIRA) Improvements correlted with A1C 2,4 ; AST 3 ; ALT 4 ; triglyceride nd diponectin chnges 3 1. Klonoff D, et l. Curr Med Res Opin. 28;24: Armstrong M, et l. Aliment Phrmcol Ther. 213;37: Sthynryn P, et l. Obesity. 211;19: Cuthbertson D, et l. PLoS One. 212;7(12):e5117. Ptient-Centered Considertions: Mrv Ptient is obese GLP-1 RAs do not promote weight gin nd my encourge weight loss Ptient needs to void hypoglycemi due to his profession GLP-1 RAs re ssocited with low risk of hypoglycemi Ptient needs to improve hypertension control GLP-1 RAs my hve beneficil effects on blood pressure nd lipid levels Ptient hs nonspecific symptoms consistent with NAFLD GLP-1 RA effects on weight re consistent with recommended mngement of NAFLD Preliminry results suggest GLP-1 RAs my hve beneficil effects in the mngement of NAFLD 11

16 ARS Question Wht else would you like to know bout Mrv before inititing GLP-1 RA? Cse 3: Fculty Discussion 1. Willingness to dminister injection 2. Postprndil glucose level to determine pproprite GLP-1 RA 3. Preference for twice-dily, once-dily, or onceweekly dministrtion 4. History of pncretitis nd endocrine tumors Drs LeRoith, Morles, Shubrook Cse 4: Srh GLP-1 RA Sfety: Cse Study 2 Jy Shubrook, DO, FACOFP, FAAFP Associte Professor of Fmily Medicine Director of Clinicl Reserch Director of Dibetes Fellowship The Dibetes Institute t Ohio University Heritge College of Osteopthic Medicine Athens, Ohio Overweight femle (BMI 28 kg/m 2 ) Age: 52 yers T2DM for 5 yers A1C (before dding EXN BID): 7.6% Metformin 2 mg/d Follow-up EXN BID initition Still reports nuse fter 8 weeks, usully tolerble Hppy bout weight loss Doesn t like injecting 2 dily occsionlly misses evening dose ARS Question Switching GLP-1 RAs my be resonble considertion for Srh. 1. True 2. Flse Outline GLP-1 RA Tolerbility nd Tretment Stisfction Brriers, common dverse effects, nd ptient eduction Injections Nuse Concerns regrding hypoglycemi Tretment stisfction Ptient-reported outcomes (eg, tretment stisfction, qulity of life) from clinicl trils Resources (ptient communiction, ptient ssistnce) 12

17 Ptient Priorities: Willingness to Py for Tretment Chrcteristics Internet survey (N = 461) Avoid nuse A1C (1%) Avoid injection Avoid 1 kg wt Avoid hypoglycemi Weight (1 kg) Willingness to Py (USD/month) Ptient vlues Weight loss/voiding weight gin Avoiding hypoglycemi Avoiding injection Efficcy Avoiding nuse Jendle J, et l. Curr Med Res Opin. 21;26: Self-Reported Hypoglycemi Negtively Affects Ptient Helth-Relted Qulity of Life Study Respondents (N) Reported Hypoglycemi (%) Alvrez Guissol 1 Mrrett Even mild hypoglycemi cn significntly ffect helth-relted qulity of life The mgnitude of the impct of hypoglycemi increses with reported severity Hypoglycemi lso ssocited with lower tretment stisfction, poorer dherence, nd greter resource utliztion 3 Decrement on EuroQol visul nlogue scle (EQ-5D VAS) 1 nd EQ-5D US weighted summry score. 2 Severity (%) HRQoL Decrement vs No Hypoglycemi P Vlue Mild Moderte 6.42 <.1 Severe 16.9 <.1 Mild.1 NR Moderte.6 <.1 Severe.13 <.1 Very severe.21 <.1 1. Alvrez-Guissol F, et l. Helth Qul Life Outcomes. 21;8: Mrrett E, et l. BMC Res Notes. 211;4: Willims S, et l. Dibetes Res Clin Prct. 211;91: Wht Should the Ptient Do to Reduce the Risk of Hypoglycemi? The risk of hypoglycemi is low with GLP-1 RAs, but you, your fmily, nd your friends should be wre of hypoglycemi signs nd symptoms 1,2 Hve pln to mnge hypoglycemi be redy to tke 15-2 grms of sugrs or crbohydrtes if needed (eg, ½ cup juice, 4-5 sltines) 2 Be sure your helthcre provider knows ll the medicines you re tking Signs nd Symptoms of Hypoglycemi 1,2 Hedche Irritbility Drowsiness Hunger Wekness Fst hert bet Dizziness Sweting Confusion Feeling jittery 1. US FDA. Drugs@FDA ADA. Hypoglycemi (low blood glucose). GLP-1 RAs Are Administered by Subcutneous Injection Exentide BID 5 mcg ornge, 1 mcg yellow Strt with 5 mcg, increse to 1 mcg fter 1 month Inject within 6 min of 2 min mels Lirglutide Adjust to deliver dose (.6 mg, 1.2 mg, or 1.8 mg) Strt with.6 mg, increse fter 1 week to 1.2 mg My increse to 1.8 mg, if needed Inject once dily, ny time Exentide ER Inject immeditely fter suspension Prior exentide BID tretment not required Inject missed dose only if next dose is 3 dys wy Inject single 2-mg dose once weekly, ny time US FDA. Drugs@FDA. Smller Pen Needle Size Is Effective nd Preferred Smoothing the Trnsition to Injections 4 mm 32 G vs 5 mm 31 G or 8 mm 31 G study prticipnts 1 Men BMI: 31. kg/m 2 BMI rnge: 2 to 49 kg/m 2 52% with BMI > 3 kg/m 2 No difference in glycemic control or sfety mong needle sizes 1 Significntly lower pin scores for 4 mm vs 5 mm nd 8 mm needles 1 Equivlent glycemic control for obese vs nonobese prticipnts 2 4 mm Preferred Over 5 mm or 8 mm Preference (% of prticipnts) mm vs 8 mm 4 mm vs 5 mm Other little more Other lot more No preference 4 mm little more 4 mm lot more 1. Hirsch L, et l. Curr Med Res Opin. 21;26: Hirsch L, et l. Curr Med Res Opin. 212;28: Identify regimen with flexibility the ptient needs/desires EXN BID dminister before 2 (lrgest) mels of dy 1,2 LIRA, EXN ER less frequent dosing 1 Injection is reltively pinless 3 Smll, fine needle Ftty tissue vs muscle See one, do one, tech one. 3 Hve ptient see/use pen nd needle before leving office Refer ptient to productspecific resources for strting tretment Rpid Response Kit 1. US FDA. Drugs@FDA Forti A, et l. Curr Med Res Opin. 28;24: Kruger D, et l. Dibetes Educ. 21;36(suppl 3):44S-72S. Photo courtesy of Scott V Joy. 13