CASE WORK: Evaluating GLP-1 Receptor Agonists in Patient-Centered Care for Type 2 Diabetes. anaheim, California may 1, 2013.

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1 CASE WORK: Evluting GLP-1 Receptor Agonists in Ptient-Centered Cre for Type 2 Dibetes nheim, Cliforni my 1, 213 Eduction Prtner

2 Session 4: 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 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 LeRoith is currently professor of medicine nd director of reserch of the division of endocrinology, dibetes, nd bone diseses t Mount Sini School of Medicine in New York, New York. Dr LeRoith received his medicl nd reserch trining t University of Cpe Town in Cpe Town, South Afric, with postgrdute trining in London, United Kingdom. Subsequently, he worked on the medicl fculty t the Ben Gurion University Medicl School in Isrel. Dr LeRoith worked t the Ntionl Institutes of Helth (NIH) from 1979 until 25 in the field of endocrinology nd dibetes nd dvnced to dibetes brnch chief t the NIH in Bethesd, Mrylnd. His reserch interests include the role of insulin nd the 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, P.C. New Hyde Prk, New York Dr 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 completed residencies t Memoril Slon-Kettering Cncer Center nd North Shore University Hospitl, 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 Hospitl nd Winthrop-University Hospitl. He is n vid musicin nd percussionist nd is fluent in Spnish, Itlin, nd Portuguese. Session 4

3 Jy Shubrook, DO, FACOFP, FAAFP Associte Professor of Fmily Medicine Director of Clinicl Reserch Director of Dibetes Fellowship Deprtment of Fmily Medicine The Dibetes Institute Ohio University Heritge College of Osteopthic Medicine Athens, Ohio Dr Shubrook is fmily physicin nd dibetes specilist. He serves s the director of The Dibetes Institute t Ohio University Heritge College of Osteopthic Medicine nd director of 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: Derek LeRoith, MD, PhD, FACP, prticiptes on n dvisory bord for AstrZenec, Jnssen Phrmceuticls, nd Merck & Co., Inc. He receives grnt/reserch support from AstrZenec, Jnssen Phrmceuticls, nd Merck & Co. Jvier Morles, MD, prticiptes on n dvisory bord for Novo Nordisk Inc. nd Boehringer Ingelheim. He receives honorri from Novo Nordisk Inc., Boehringer Ingelheim, nd Wrner Chilcott. Dr Morles is lso on the spekers bureu for Novo Nordisk Inc. nd Wrner Chilcott. Jy Shubrook, DO, FACOFP, FAAFP, receives grnt/reserch support from Snofi US. Eduction Prtner Finncil Disclosure Sttement The content collbortors t the Institute for Medicl nd Nursing Eduction, Inc, hve reported the following: Amy Crbonr, Director of Progrm Development, hs no finncil reltionships to disclose. Kimberly McFrlnd, PhD, Senior Medicl Writer, holds stock in Pfizer Inc nd Procter & Gmble. Angel McIntosh, PhD, Scientific Director, hs no finncil reltionships to disclose. Steve Weinmn, RN, Executive Director, hs no finncil reltionships to disclose. Acronym List Acronym A1C ACS ADA ADL AGI ALBI ALT AST BL BP BPM BID BMI CHD CHF CI CKD CV CVD d Definition glycted hemoglobin cute coronry syndrome Americn Dibetes Assocition ctivities of dily living ɑ-glucosidse inhibitor lbiglutide lnine minotrnsferse sprtte minotrnsferse bseline blood pressure bets per minute twice dily body mss index coronry hert disese congestive hert filure confidence intervl chronic kidney disese crdiovsculr crdiovsculr disese dy Acronym DET DPP-4 DPP-4i DULA DURATION EASD egfr ELIXA ER ESRD EXN Definition insulin detemir dipeptidyl peptidse-4 dipeptidyl peptidse-4 inhibitor dulglutide Dibetes Therpy Utiliztion: Reserching Chnges in A1C, Weight nd Other Fctors Through Intervention With Exentide Once Weekly Europen Assocition for the Study of Dibetes 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 end-stge renl disese exentide Session 4

4 Acronym EXSCEL FBG FDA FFA FPG GIP GLAR GLIM GLP-1 GLP-1 RA h HCC HDL-C HF HR HRQoL IDET IGT INS IR KATP LDL-C LEAD LIRA LEADER Definition 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 US Food nd Drug Administrtion free ftty cid fsting plsm glucose glucose-dependent insulinotropic polypeptide insulin glrgine glimepiride glucgon-like peptide-1 glucgon-like peptide-1 receptor gonist hour heptocellulr crcinom high-density lipoprotein cholesterol hert filure hzrd rtio helth-relted qulity of life insulin detemir impired glucose tolernce insulin incidence rtio ATP-sensitive potssium chnnels low-density lipoprotein cholesterol Lirglutide Effect nd Action in Dibetes lirglutide Lirglutide Effect nd Action in Dibetes: Evlution of Crdiovsculr Outcome Results A Long Term Evlution Acronym Definition LIXI lixisentide MEN2 multiple endocrine neoplsi type 2 MET metformin MI myocrdil infrction MTC medullry thyroid crcinom MRS mgnetic resonnce spectroscopy NAFLD nonlcoholic ftty liver disese NASH nonlcoholic stetoheptitis NDEP Ntionl Dibetes Eduction Progrm NVD nuse, vomiting, dirrhe OAD orl ntidibetic gent OR odds rtio ORL orlistt PBO plcebo PIO pioglitzone PP postprndil PPAR peroxisome prolifertor-ctivted receptor PPG postprndil plsm glucose PIO pioglitzone PTC ppillry thyroid crcinom P-Y ptient-yer QD dily RCT rndomized controlled tril RI renl insufficiency SBP systolic blood pressure SITA sitgliptin SU sulfonylure T2DM type 2 dibetes mellitus TRIG triglyceride TZD thizolidinedione U unit USD United Sttes dollr Suggested Reding List Americn Dibetes Asscoition. 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: 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: Buse JB, Rosenstock J, Sesti G, et l; for the LEAD-6 Study Group. 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: 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: Drucker DJ, Buse JB, Tylor K, et l; for the 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: Session 4

5 Inzucchi SE, Bergenstl RM, Buse JB, et l; for the Americn Dibetes Assocition nd Europen Assocition for the Study of Dibetes. 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: Kirkmn M, Briscoe VJ, Clrk N, et l. Dibetes in older dults. Dibetes Cre. 212;35: 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 4

6 SESSION 4 1: PM 2:3 PM 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: Derek LeRoith, MD, PhD, FACP, prticiptes on n dvisory bord for AstrZenec, Jnssen Phrmceuticls, nd Merck & Co., Inc. He receives grnt/reserch support from AstrZenec, Jnssen Phrmceuticls, nd Merck & Co. Jvier Morles, MD, prticiptes on n dvisory bord for Novo Nordisk Inc. nd Boehringer Ingelheim. He receives honorri from Novo Nordisk Inc., Boehringer Ingelheim, nd Wrner Chilcott. Dr Morles is lso on the spekers bureu for Novo Nordisk Inc. nd Wrner Chilcott. Jy Shubrook, DO, FACOFP, FAAFP, receives grnt/reserch support from Snofi US. Presenter Disclosure Informtion 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 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. EXN BID exentide BID Byett EXN ER exentide ER Bydureon 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 SITA sitgliptin Jnuvi Cse Work: Evluting GLP-1 RAs in Ptient-Centered Cre for Type 2 Dibetes 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 Lerning Objectives 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) Tolerbility nd tretment stisfction with GLP-1 RAs 1

7 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: Compring Actions of DPP- 4 Inhibitors nd GLP-1 RAs Mrketed nd Investigtionl GLP-1 RAs 2-Hour Postprndil Plsm Level (pm) Endogenous GLP GLP-1 Bseline = 7 pm 15 EXN BID, exentide twice dily; SITA, sitgliptin. Cross-over study, 2-week segments (N = 61). 1 8 EXN 64 SITA EXN BID Tretment 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: Durtion of Action 1 Agent Dosing or Anticipted Dosing Bse Peptide Short EXN BID Twice dily 2 Exendin-4 2 Mrketed 2 US Approvl Sttus Short LIXI Once dily 1 Exendin-4 1 Regultory filing Long LIRA Once dily 2 GLP-1 2 Mrketed 2 Long EXN QW Once weekly 2 Exendin-4 2 Mrketed 2 Long ALBI Once weekly 1 GLP-1 1 Regultory filing Long DULA Once weekly 1 GLP-1 1 Phse 3 3 Long SEMA Once weekly 4 GLP-1 4 Phse 3 3 ALBI, lbiglutide; DULA, dulglutide; EXN BID, exentide twice dily; EXN QW, exentide extended-relese; LIRA, lirglutide; LIXI, lixisentide; SEMA, semglutide. 1. Meier J. Nt Rev Endocrinol. 212;8: US FDA. Drugs@FDA. 3. Ntionl Institutes of Helth Nuck M, et l. EASD 48th Annul Meeting. 212;2. 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 Gstric emptying rte Decelertion No substntil long-term effects PP hyperglycemi Strong reduction Modest reduction 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 QW, 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 QW, exentide extended-relese; LIRA, lirglutide. P <.5 vs EXN BID. EXN BID (1 mcg) LIRA (1.8 mg) EXN QW (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:

8 2-Hour PPG (mg/dl) Exentide BID Reduces PPG More Thn Exentide QW nd Lirglutide DURATION-1 1, EXN BID 124 b,c EXN QW 95 b LEAD-6 2 Self-mesured plsm glucose profiles Significntly greter PPG decreses with EXN BID vs LIRA fter brekfst nd dinner Estimted tretment differences Brekfst: 24 mg/dl c Dinner: 18 mg/dl c Glycemic Control With Investigtionl GLP-1 RAs: Hed-to-Hed Tril Results Outcome GetGol-X 1 N = weeks Hrmony 7 2 N = weeks EXN BID LIXI LIRA ALBI A1C (%) FPG (mg/dl) Noninferiority LIXI met noninferiority ALBI did not meet vs EXN BID noninferiority vs LIRA EXN BID, exentide twice dily; EXN QW, exentide once weekly; LIRA, lirglutide; PPG, posprndil plsm glucose. Dt is bsed on mel tolernce testing (n=51); b significnt chnge vs bseline; c P <.5 vs EXN QW or LIRA. 1. Drucker DJ, et l. Lncet. 28;372: Buse J, et l. Lncet. 29;374: ALBI, lbiglutide; EXN BID, exentide twice dily; LIRA, lirglutide; LIXI, lixisentide. ALBI nd LIXI re not FDA pproved. 1. Rosenstock J, et l. EASD 47th Annul Meeting. 211; 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 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 Unique clinicl chrcteristics of individul GLP-1 RAs my be leverged for ptient-centered cre Jvier Morles, MD St. Frncis Hospitl Advnced Internl Medicine Group New Hyde Prk, New York 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% Outline GLP-1 RA Efficcy Across T2DM Progression Tretment recommendtions Prescribing informtion Recent consensus sttement (ADA/EASD) 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) GLP-1 RAs re not FDA pproved for tretment of predibetes. 3

9 Lbel Recommendtions Indicte GLP-1 RA Use Across T2DM Progression GLP-1 RAs in ADA/EASD Recommendtions for Antihyperglycemic Therpy in T2DM Indictions nd Usge EXN BID LIRA EXN QW Adjunct to diet nd exercise X X X Includes indiction for first line therpy X Approved with bsl insulin (not prndil) X X 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 EXN BID, exentide twice dily; LIRA, lirglutide; EXN QW, 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. 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. Conversion From Predibetes to Norml Glucose Tolernce With GLP-1 RAs Efficcy of Mrketed GLP-1 RAs s Monotherpy 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 2.4/3. mg ORL 1 (N = 38) 1 (N = 176) b Normlized Glucose Tolernce (% of pts with BL predibetes) Results t 24 weeks 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. Normlized Glucose Tolernce (% of pts with BL predibetes) Results t 14 weeks 1. US FDA. Drugs@FDA. 2. Rosenstock J, et l. Dibetes Cre. 21;33: Astrup A, et l. Int J Obes (Lond). 212;36: 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 QW 1,4, 26 wk (N = 82) 8.4%-8.6% EXN BID, exentide twice dily; EXN QW, exentide extendedrelese; GLIM, glimepiride; LIRA, lirglutide; MET, metformin; PBO, plcebo; PIO, pioglitzone; SITA, sitgliptin. EXN BID is indicted for monotherpy, with no restrictions on use s initil monotherpy; LIRA nd EXN QW re indicted for use s monotherpy, but re not recommended s initil monotherpy. b P <.5 vs GLP-1 RA. GLP-1 RA A1C (%) Comprtor(s) A1C (%) 1 mcg:.9 PBO:.2 b 1.2 mg: mg: mg: 1.5 GLIM:.5 b MET: 1.5 PIO: 1.6 SITA: 1.2 b 1. US FDA. Drugs@FDA. 2. Moretto TJ, et l. Clin Ther. 28;3: Grber A, et l. Lncet. 29;373: Russell-Jones D, et l. Dibetes Cre. 212;35: Efficcy of Mrketed GLP-1 RAs Added to Metformin s Second-Line Agents GLP-1 RAs Added to Multiple Orl Agents: Comprisons With Bsl Insulin 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% LIRA 1,4 26 wk (N = 658) 8.5% EXN QW 1,5 26 wk (N = 491) 8.5%-8.6% GLP-1 RA A1C (%) Comprtor(s) A1C(%) 1 mcg:.8 PBO: mg: mg: mg: mg: mg: 1.5 PBO: +.1 GLIM: 1. SITA: -.9 PIO: 1.2 SITA:.9 A1C (%) -1-2 GLAR EXN BID LIRA MET + SU (N = 535) Noninferior vs insulin OADs MET + GLIM (N = 235) (N = 576) EXN QW MET ± SU (N = 456) P = NS P =.15 vs insulin vs insulin P <.5 vs insulin 4, 5,b MET ± SU (N = 216) -.9 IDET -1.3 P <.1 vs insulin EXN BID, exentide twice dily; EXN QW, exentide extended-relese; GLIM, glimepiride; LIRA, lirglutide; PBO, plcebo; PIO, pioglitzone. P <.5 vs GLP-1 RA. 1. US FDA. Drugs@FDA. 2. DeFronzo RA, et l. Dibetes Cre. 25;28: Nuck MA, et l. Dibetes Cre. 29;32: Bergenstl RM, et l. Lncet. 21;376: EXN BID, exentide twice dily; EXN QW, exentide extended-relese; GLAR, insulin glrgine; GLIM, glimepiride; IDET, insulin detemir; LIRA, lirglutide; MET, metformin; OAD, orl ntidibetic gent; SU, sulfonylure. 7% on MET monotherpy bckground. b 7% on MET + SU bckground. 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]. 4

10 GLP-1 RAs Added to Bsl Insulin Bsl Insulin Added to GLP-1 RAs A1C (%) (N = 259). FDA Approved 1 Investigtionl 2-5 PBO EXN BID 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 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. A1C (%) LIRA 1.8 mg + IDET vs Control (26-wk clinicl tril) P <.1.51 IDET, insulin detemir; LIRA, lirglutide; MET, metformin. Use with bsl insulin is FDA pproved for LIRA. MET + LIRA 1.8 mg control (n = 157) MET + LIRA 1.8 mg + IDET (n = 162) Hypoglycemi Minor: 9.2% of LIRA + IDET group vs 1.3% of control group No mjor hypoglycemi Weight loss -.16 kg LIRA + IDET -.95 kg control (P =.3) DeVries J, et l. Dibetes Cre. 212;35: Hypoglycemi With GLP-1 RAs: With nd Without Sulfonylures in Hed-to-Hed Trils Hypoglycemic Risk of Antihyperglycemic Agents Added to Metformin: A Network Met-Anlysis LIRA (1.8 mg QD) EXN (1 mcg BID) EXN (2. mg QW) Without Sulfonylure With Sulfonylure 5 5 n = 34 n = 19 n = n = 127 n = 186 n = Minor Hypoglycemi (% of ptients) Minor Hypoglycemi (% of ptients) Odds Rtio vs Plcebo Incresed Risk vs Plcebo No Incresed Risk vs Plcebo 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 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: AGI, ɑ-glucosidse inhibitor; SU, sulfonylure; TZD, thizolidinedione. 39 rndomized controlled trils. Liu S, et l. Dibetes Obes Metb. 212;14: Recommendtions for GLP-1 RA Use: Possible Hypoglycemi Risk Prescribing Informtion Precutions EXN BID LIRA EXN QW 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 EXN BID, exentide twice dily; EXN QW, exentide extended-relese; LIRA, lirglutide. US FDA. Drugs@FDA. Ptient-Centered Considertions: Sndy 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 Ptient my be t incresed risk of hypoglycemi if gents re dded to current regimen GLP-1 RAs re ssocited with low risk of hypoglycemi Consider reducing dose of SU 5

11 Cse 1: Fculty Discussion GLP-1 RA Sfety: Cse 2 Drs LeRoith, Morles, Shubrook 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 Cse 2: Mike GLP-1 RA Sfety 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 ) Outline Crdiovsculr sfety Specific precutions Acute renl filure/renl insufficiency Pncretitis Medullry thyroid cncer Use in ptients with comorbid conditions (eg, some elderly ptients) GLP-RA Crdiovsculr Sfety: Post Hoc Anlyses of Pooled Clinicl Tril Dt Evidence Regrding Renl Impirment With GLP-1 RAs 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 QW (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 QW, 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. 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:

12 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 QW Renl impirment Recommendtions Not in severe RI (CrCl < 3 ml/min) or ESRD Use with cution Not in severe RI (CrCl < 3 ml/min) 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 QW in ptients with severe RI or ESRD ESRD, end-stge renl disese; EXN BID, exentide twice dily; EXN QW, 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 Severl nlyses of clinicl tril nd insurnce clims dt demonstrted no incresed risk with exentide or lirglutide 9-14 Recent independent nlyses of lrge insurnce dtbses yielded mixed results 15,16 1. 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;14:94-911; 16. Singh S, et l. JAMA Intern Med. 213 Feb 25. [Epub hed of print]. Recommendtions for GLP-1 RA Use: Possible Pncretitis Risk Prescribing Informtion Precutions EXN BID LIRA EXN QW 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 QW, exentide extended-relese; LIRA, lirglutide. Consider other gents US FDA. Drugs@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. 2. 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 GLP-1 RAs in Ptients With Comorbidities: Older Ptients Prescribing Informtion Contrindictions EXN BID LIRA EXN QW Possible thyroid tumor risk do not use if history of MTC or MEN2 Recommendtions LIRA nd EXN QW 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 QW, exentide onceweekly; LIRA, lirglutide; MTC, medullry thyroid crcinom; MEN2, multiple endocrine neoplsi syndrome type US FDA. Drugs@FDA. 2. Prks M, Rosebrugh C. N Engl J Med. 21;362: X X Clssic Dibetes Comorbidities 1-3 Renl disese: 3X higher ESRD prevlence in ptients > 65 y with dibetes vs those without 1 CVD: 43% of ptients y nd 55% of ptients > 75 y hve CVD 2 2X higher CHF prevlence in ptients > 65 y with dibetes vs those without 1 Heptic disese Nerly 75% of ptients 6 y hve NAFLD 3 Geritric Syndromes 4 Cognitive dysfunction Functionl impirment Flls nd frctures Polyphrmcy Depression Vision nd hering impirment Pin from neuropthy or other cuses Urinry incontinence 1. Slon FA, et l. Arch Intern Med. 28;168: CDC. Dibetes Dt & Trends Trgher G, et l. Dibetes Cre. 27;3: Kirkmn M, et l. Dibetes Cre. 212;35:

13 Frmework for Considering Glycemic Gols in Older Adults With Dibetes 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% or < 7.% c < 8.% < 8.5% b 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. c If chievble without risk. 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 QW, exentide onceweekly; 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 QW 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. 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 QW should not be used in ptients with severe RI or ESRD Hypovolemi my worsen renl function Cse 2: Fculty Discussion Drs LeRoith, Morles, Shubrook 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 GLP-1 RA Nonglycemic Effects: Cse 3 Jvier Morles, MD St. Frncis Hospitl Advnced Internl Medicine Group New Hyde Prk, New York Cse 3: Mrv 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 8

14 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) w/ DPP-4 inhibitor w/ SU w/ TZD w/ INS w/ SU + TZD 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. 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 QW ALBI, lbiglutide; EXN BID, exentide twice dily; EXN QW, exentide once-weekly; 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 QW 3,4 EXN BID vs LIXI 5,b Exceptions LIRA ( 3.6) vs EXN QW ( 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) 1 EXN BID EXN BID, exentide twice dily; EXN QW, exentide once-weekly; LIRA, lirglutide; EXN QW 76 LEAD-6 (N = 464) 2 Weight Loss (% of prticipnts) EXN BID LIRA Drucker D, et l. Lncet. 28;372: Buse J, et l. Lncet. 29;374: Weight Chnge (kg) Weight Loss With GLP-1 RAs Is Not Driven by Gstrointestinl Adverse Events LIRA (Met-Anlysis/6 26-Week Trils) ,b,b EXN, exentide, LIRA, lirglutide; NVD, nuse/vomiting/dirrhe. P <.5 vs bseline; b P <.5 vs plcebo. P <.5 P <.5,b Weight Chnge (kg) EXN (3-Week DURATION-1 Tril) 2 PBO 1.2 mg LIRA 1.8 mg LIRA EXN QW EXN BID No NVD Some NVD No Nuse Nuse 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 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: 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 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]. 9

15 Potentil 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 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) GLP-1 RAs re not FDA pproved for NAFLD/NASH 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 Cse 3: Fculty Discussion Drs LeRoith, Morles, Shubrook 1

16 GLP-1 RA Tretment Stisfction nd Tolerbility: Cse 4 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 Cse 4: Srh 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 GLP-1 RA Tolerbility nd Tretment Stisfction Ptient Priorities: Willingness to Py for Tretment Chrcteristics Outline 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) 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 Wht Should the Ptient Do to Reduce the Risk of Hypoglycemi? Study Respondents (N) Reported Hypoglycemi (%) Alvrez Guissol 1 Mrrett 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 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 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 professionl 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 Decrement on EuroQol visul nlogue scle (EQ-5D VAS) 1 nd EQ-5D US weighted summry score 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: US FDA. Drugs@FDA. 2. ADA. Hypoglycemi (low blood glucose). 11

17 GLP-1 RAs Are Administered by Subcutneous Injection Smller Pen Needle Size Is Effective nd Preferred 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 QW 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. 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: Smoothing the Trnsition to Injections Identify regimen with flexibility the ptient needs/desires EXN BID dminister before 2 (lrgest) mels of dy 1,2 LIRA, EXN QW 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 product-specific resources for strting tretment 1. US FDA. Drugs@FDA. 2. 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. A1C From Switch to Study End (%) A1C From Switch to Study End (%) Glycemic Control Following Switch in Incretin-Bsed Therpies Switch From SITA Switch From EXN BID SITA to LIRA 1.8 mg1 (n = 135).5 EXN BID to LIRA 1.8 mg (n = 187).3 c EXN BID, exentide twice dily; EXN QW, exentide onceweekly; LIRA, lirglutide; SITA, sitgliptin. P =.1 week 78 vs week 52; b P =.1 week 5 vs week 26; c P <.1 week 4 vs week 26. SITA to EXN QW2 (n = 116).3 b 3 4 EXN BID to EXN QW (n = 13).2 1. Prtley R, et l. Dibetes Cre. 212;35: Wyshm C, et l. Dibet Med. 211;28: Buse J, et l. Dibetes Cre. 21;33: Buse J, et l. Dibetes Cre. 21;33: Reports of Nuse Vry by Agent Nuse my resolve more quickly with some gents 1 2 LIRA 1.8 mg QD 16 EXN 1 mcg BID 12 8 P < Time (weeks) The proportion of ptients reporting nuse is lower with some gents EXN BID LIRA EXN QW LIXI ALBI LEAD DURATION-1 DURATION-5 DURATION-6 GetGol-X Hrmony 7 ALBI nd LIXI not FDA pproved. 1. Buse JB, et l. Lncet. 29;374:39-47; 2. Drucker D, et l. Lncet. 28;372: ; 3. Blevins T, et l. J Clin b P <.5 vs Endocrinol Metb. 211;96: ; 4. Buse J, et l. Lncet. 212 Nov 6. [Epub hed of print]; 5. Rosenstock J, EXN BID. et l. EASD 47th Annul Meeting. 212;786; 6. Prtley R, et l. ADA 72nd Scientific Sessions. 212;945-P Nuse (%) Prticipnts (%) Mnging Nuse Associted With GLP-1 RAs Drw on experience with other gents 7% to 26% of ptients experience nuse/vomiting with metformin 1 Discuss expecttions 2 Nuse is likely to be mild nd resolve in few weeks Nuse my ctully be fullness Suggest behviorl chnges 2 Mels decrese portion sizes nd reduce ft content Keep log to identify foods tht cuse nuse Titrte more slowly keep dose lower for longer period 2,3 Be wre of severe persistent bdominl pin, possibility of pncretitis 1 Prescribing Informtion Precutions EXN BID LIRA EXN QW Severe gstrointestinl disese (eg, gstropresis) X X EXN BID, exentide twice dily; EXN QW, exentide once-weekly; LIRA, lirglutide. 1. US FDA. Drugs@FDA. 2. Kruger D, et l. Dibetes Educ. 21;36(suppl 3):44S-72S. 3. Finemn M, et l. Dibetes Metb Res Rev. 24;2: