CASE WORK: Evaluating GLP-1 Receptor Agonists in Patient-Centered Care for Type 2 Diabetes. Rosemont, Illinois October 16, 2013.

Transcription

1 CASE WORK: Evluting GLP-1 Receptor Agonists in Ptient-Centered Cre for Type 2 Dibetes Rosemont, Illinois October 16, 213 Eduction Prtner

2 Session 3: Cse Work: Evluting GLP-1 RAs 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 Professor of Medicine Director of Reserch Division of Endocrinology, Dibetes, nd Bone Disese Mount Sini School of Medicine New York Dr LeRoith is currently professor of medicine nd director of reserch of the division of endocrinology, dibetes, nd bone disese 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, nd completed his postgrdute trining in London, United Kingdom. Subsequently, he ws member of 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 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. Jmes LSlle, DO, FAAFP Medicl Director Excelsior Springs Clinic Excelsior Springs, Missouri Dr LSlle is fellow of the Americn Acdemy of Fmily Physicins. He received his medicl degree from Knss City University of Medicine nd Biosciences (formerly the University of Helth Sciences) in Knss City, Missouri. Dr LSlle holds membership in vrious stte nd ntionl professionl orgniztions. He is member of the Excelsior Springs Clinic nd is prcticing fmily physicin. Dr LSlle is lso n uthor nd/or principl investigtor of more thn 15 clinicl trils, plcing him t the forefront of new clinicl informtion nd securing his role s key opinion leder in his field. His reserch ctivities include extensive work in type 2 dibetes, hypertension, dyslipidemi, nd the metbolic bnormlities commonly encountered with these disese sttes. Dr LSlle s interests hve focused on primry preventive crdiovsculr medicine for much of his 3-yer medicl creer. Session 3

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 clinicl reserch 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 report the following: Derek LeRoith, MD, PhD, FACP, prticiptes in dvisory bords for AstrZenec, Jnssen Phrmceuticls, nd Merck & Co., Inc. He receives grnt/reserch support from AstrZenec, Jnssen Phrmceuticls, nd Merck & Co., Inc. Jmes LSlle, DO, FAAFP, is consultnt for Novo Nordisk Inc. He receives honorri from Boehringer Ingelheim, Eli Lilly nd Compny, nd Novo Nordisk Inc. Dr LSlle is lso on the spekers bureus for Boehringer Ingelheim nd Eli Lilly nd Compny. 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 nothing to disclose. Kimberly McFrlnd, PhD, Senior Medicl Writer, holds stock in Pfizer Inc nd Procter & Gmble. Angel McIntosh, PhD, Scientific Director, hs nothing to disclose. Steve Weinmn, RN, Executive Director, hs nothing to disclose. Acronym List Acronym A1C AACE ACS ADA ACE ADL AERS AGI ALBI ALT AMP ASP AST BL Definition glycted hemoglobin Americn Assocition of Clinicl Endocrinologists cute coronry syndrome Americn Dibetes Assocition Americn College of Endocrinology ctivities of dily living dverse events reporting system ɑ-glucosidse inhibitor lbiglutide lnine minotrnsferse denosine monophosphte insulin sprt sprtte minotrnsferse bseline Acronym BP BPM BID BMI CHD CHF CI CKD CrCl CV CVD d DM DPP-4 DPP-4i Definition blood pressure bets per minute twice dily body mss index coronry hert disese congestive hert filure confidence intervl chronic kidney disese cretinine clernce crdiovsculr crdiovsculr disese dy dibetes mellitus dipeptidyl peptidse-4 dipeptidyl peptidse-4 inhibitor Session 3

4 DULA DURATION EASD egfr EPY ESRD EXN EXSCEL FDA FFA FPG GIP GLAR GLIM GLP-1 GLP-1 RA h HCC HDL-C HF HRQoL IDET IGT INS IR KATP LDL-C LEAD LEADER 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 events per ptient yer 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 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 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 Effect nd Action in Dibetes: Evlution of Crdiovsculr Outcome Results A Long Term Evlution LIRA lirglutide LIS insulin lispro LIXI lixisentide MEN2 multiple endocrine neoplsi type 2 MET metformin MI myocrdil infrction MTC medullry thyroid crcinom NAFLD nonlcoholic ftty liver disese NASH nonlcoholic stetoheptitis NDEP Ntionl Dibetes Eduction Progrm Noct nocturnl NR not reported NVD nuse, vomiting, dirrhe OAD orl ntidibetic gent OR odds rtio ORL orlistt PBO plcebo PG plsm glucose PIO pioglitzone PP postprndil PPAR peroxisome prolifertor-ctivted receptor PPG postprndil plsm glucose PTC ppillry thyroid crcinom P-Y ptient-yer PYE ptient yers of exposure QD dily QW once-weekly RCT rndomized controlled tril RI renl insufficiency RR risk rtio SBP systolic blood pressure SEMA semglutide SITA sitgliptin SU sulfonylure T2DM type 2 dibetes mellitus TRIG triglyceride TZD thizolidinedione U unit USD United Sttes dollr Wt weight Suggested Reding List Americn Dibetes Assocition. 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: Session 3

5 Buse J, 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: Buse J, 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: 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: Inzucchi SE, Bergenstl RM, Buse JB, et l; for the Americn Dibetes Assocition (ADA) nd Europen Assocition for the Study of Dibetes (EASD). 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 3

6 SESSION 3 1:3m 12pm Cse Work: Evluting GLP-1 Receptor Agonists in Ptient- Centered Cre for Type 2 Dibetes SPEAKERS Derek LeRoith, MD, PhD Jmes LSlle, DO, FAAFP Jy Shubrook, DO, FACOFP, FAAFP Presenter Disclosure Informtion The following reltionships exist relted to this presenttion: Derek LeRoith, MD, PhD, FACP, prticiptes in dvisory bords for AstrZenec, Jnssen Phrmceuticls, nd Merck & Co., Inc. He receives grnt/reserch support from AstrZenec, Jnssen Phrmceuticls, nd Merck & Co., Inc. Jmes LSlle, DO, FAAFP, is consultnt for Novo Nordisk Inc. He receives honorri from Boehringer Ingelheim, Eli Lilly nd Compny, nd Novo Nordisk Inc. Dr LSlle is lso on the spekers bureus for Boehringer Ingelheim nd Eli Lilly nd Compny. Jy Shubrook, DO, FACOFP, FAAFP, receives grnt/reserch support from Snofi US. Presenter Disclosure Informtion 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. 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 Introduction: Overview of GLP-1 RAs 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) Outline 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 Tolerbility nd tretment stisfction with GLP-1 RAs 1

7 Actions of GLP-1 RAs Complement Those of Commonly Used Antihyperglycemic Agents Compring Actions of DPP- 4 Inhibitors nd GLP-1 RAs 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) 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: Mrketed nd Investigtionl GLP-1 RAs Short- vs Long-Acting GLP-1 RAs: Overview Durtion of Action 1 Agent Dosing or Anticipted Dosing Bse Peptide US Approvl Sttus Short EXN BID Twice dily 2 Exendin-4 2 Mrketed 2 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 once weekly; 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. Prmeters Short-Acting 1,,c Long-Acting 1,b,c Hlf-life 2-5 h 12 h-severl dys Fsting blood glucose levels Modest reduction Strong reduction Gstric emptying rte Decelertion No substntil longterm 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%/weeksmonths 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 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) Exentide BID Reduces PPG More Thn Exentide QW nd Lirglutide DURATION-1: Mel Tolernce Testing 1 27 EXN BID Bseline EXN BID Week EXN QW Bseline EXN QW Week 14 A1C (%) FPG (mg/dl) EXN BID, exentide twice dily; EXN QW, exentide once weekly; LIRA, lirglutide. P <.5 vs EXN BID 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: PPG (mg/dl) mg/dl,b Time (min) LEAD-6: SMBG 2 Significntly greter PPG decreses with EXN BID vs LIRA Brekfst estimted tretment difference: 24 mg/dl b Dinner estimted tretment difference: 18 mg/dl b PPG (mg/dl) 18 EXN BID, exentide twice dily; EXN QW, exentide once weekly; LIRA, lirglutide; PPG, posprndil plsm glucose; SMBG, self-monitoring of blood glucose. Significnt chnge vs bseline; b P <.5 vs EXN QW or LIRA mg/dl Time (min) 1. Drucker DJ, et l. Lncet. 28;372: Buse J, et l. Lncet. 29;374:

8 Summry Actions of GLP-1 RAs complement those of other ntihyperglycemic gents commonly used in ptients with T2DM 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 A1C nd FPG reduction with long-cting GLP-1 RAs Unique clinicl chrcteristics of individul GLP-1 RAs my be leverged for ptient-centered cre GLP-1 RA Efficcy: Cse 1 Jmes R LSlle, DO, FAAFP Medicl Director Excelsior Springs Clinic Excelsior Springs, Missouri Cse 1: Sndy Obese femle (BMI 32 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 nd AACE/ACE) 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. Lbel Recommendtions Indicte GLP-1 RA Use Across T2DM Progression Indictions nd Usge EXN BID LIRA EXN QW Adjunct to diet nd exercise (includes monotherpy) X X X Not recommended s first-line therpy for ptients indequtely controlled on diet nd exercise X X With bsl insulin (not prndil) X X Recent Tretment Algorithm Recommendtions for GLP-1 RAs in T2DM ADA/EASD 1 Combintion Second-line with metformin In 3-drug combintions tht do not include DPP-4 inhibitors With bsl insulin Among preferred gents for specific gols Avoiding weight gin (GLP-1 RAs, DPP-4 inhibitors) Avoiding hypoglycemi (GLP-1 RAs, DPP-4 inhibitors, TZDs) AACE/ACE 2 Monotherpy - first option in suggested usge hierrchy if metformin is not pproprite,b Combintion therpy First option in suggested usge hierrchy for second-line combintion with metformin b With bsl insulin Cutiously consider in pre-dm c,d if Glycemi not normlized with low risk gents (metformin, crbose) Multiple pre-dm criteri EXN BID, exentide twice dily; LIRA, lirglutide; EXN QW, exentide once weekly. GLP-1 RAs re not substitutes for insulin nd re not currently FDA pproved for use in ptients with T1DM. US FDA. Drugs@FDA. Lirglutide nd exentide QW re not recommended s first-line gents for monotherpy, bsed on prescribing informtion Inzucchi S, et l. Dibetes Cre. 212;35: b Recommendtion bsed on few dverse events or possible benefits. 2. Grber A, et l. Endocr Prct. 213;19: c FPG > 1 mg/dl nd/or 2 hour PG > 14 mg/dl. 3. US FDA. Drugs@FDA. d Not n FDA-pproved indiction. 3

9 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 EXN BID (1 mcg) PBO (N = 38) Results t 24 weeks Normlized Glucose Tolernce (% of pts with BL predibetes) BL, bseline; EXN BID, exentide twice dily; LIRA, lirglutide; ORL, orlistt; PBO, plcebo. Predibetes: impired glucose tolernce or impired fsting glucose. b Metformin or crbose c 52% to 62%, depending on strting group. Astrup et l 3 LIRA 2.4/3. mg Normlized Glucose Tolernce (% of pts with BL predibetes) c ORL (N = 176) 26 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 once weekly; 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 once weekly; 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 once weekly; 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]. A1C (%) GLP-1 RAs Added to Bsl Insulin PBO + GLAR vs EXN BID + GLAR 1 (3-wk clinicl tril) GLAR + PBO (n = 122) 1. P < GLAR, insulin glrgine; EXN BID, exentide twice dily; PBO, plcebo. Use with bsl insulin is FDA pproved for EXN BID. GLAR + EXN BID (n = 137) Hypoglycemi Minor: 25% of EXN group vs 29%of PBO group 1 mjor hypoglycemic event in PBO group Weight loss kg EXN BID.96 kg PBO (P <.1) Similrly, LIRA improves glycemic control when dded to bsl insulin 2 1. Buse JB, et l. Ann Intern Med. 211;154: Li CJ, et l. Crdiovsc Dibetol. 212;11:142. A1C (%) Bsl Insulin Added to GLP-1 RAs LIRA 1.8 mg + IDET vs Control 1 (26-wk clinicl tril) MET + LIRA 1.8 mg (n = 157).1 MET + LIRA 1.8 mg + IDET (n = 162).2. Hypoglycemi.1 Minor: 9.2% of LIRA + IDET group vs 1.3% of control group.2 No mjor hypoglycemi.3.4 Weight loss -.16 kg LIRA + IDET kg control (P =.3).6 P <.1 Dt from retrospective dtbse nlysis with exentide BID hs demonstrted comprble benefit 2 IDET, insulin detemir; LIRA, lirglutide; MET, metformin. Use with bsl insulin is FDA pproved for LIRA. 1. DeVries J, et l. Dibetes Cre. 212;35: Pwskr M, et l. Endocr Prct. 212;18:

10 A1C (%) EXN BID GLP-1 RAs vs Prndil Insulin Added to Bsl Insulin Added to GLAR (3 wk, N = 637) 1 Added to IDEG (26 wk, N = 177) 2, LIS TID Noninferior Outcome EXN BID LIS TID Weight, kg b Minor hypo, E/Y Noct hypo, E/Y Nuse, % 32 2 IDEG, insulin degludec; EPY, events/ptient-yer; EXN BID, exentide twice dily; E/Y, events/yer; GLAR, insulin glrgine; LIS, insulin lispro; LIRA, lirglutide; QD, once dily; TID, three times dily. Insulin degludec is not pproved by the US FDA; b P <.5. A1C (%) LIRA QD ASP QD P = Outcome LIRA QD ASP QD Weight, kg b Minor hypo, EPY b Noct hypo, EPY b Nuse LIRA>ASP, first 2 wk 1. Dimnt M, et l. ADA 73 rd Scientific Sessions. 213 ;7-OR. 2. Mthieu C, et l. ADA 73 rd Scientific Sessions. 213;911-P. 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 QW) Without Sulfonylure With Sulfonylure 5 5 n = n = 19 n = n = 127 n = 186 n = 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 EXN, exentide; LIRA, lirglutide; P-Y, ptient-yer. Minor hypoglycemi = self-tretble, with plsm glucose < 55 mg/dl; mjor hypoglycemi = requiring third-prty ssistnce. Minor Hypoglycemi (% of ptients) 1. Buse J, et l. Lncet. 29;374: Drucker DJ, et l. Lncet. 28;372: Buse J, et l. Lncet. 213;381: Hypoglycemic Risk of Antihyperglycemic Agents Added to Metformin: A Network Met-Anlysis Recommendtions for GLP-1 RA Use: Possible Hypoglycemi Risk 25 Incresed Risk vs Plcebo Odds Rtio vs Plcebo No Incresed Risk vs Plcebo 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 AGI, ɑ-glucosidse inhibitor; SU, sulfonylure; TZD, thizolidinedione. 39 rndomized controlled trils. Liu S, et l. Dibetes Obes Metb. 212;14: EXN BID, exentide twice dily; EXN QW, exentide once weekly; LIRA, lirglutide. US FDA. Drugs@FDA. Ptient-Centered Considertions: Sndy Ptient is obese 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 current tretment lgorithms 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 nd insulin Cse 1: Fculty Discussion Drs LeRoith, LSlle, Shubrook 5

11 Cse 2: Mike GLP-1 RA Sfety: Cse 2 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 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 GLP-1 RA Sfety Specific precutions Acute renl filure/renl insufficiency Pncretitis Medullry thyroid cncer Use in ptients with comorbid conditions (eg, some elderly ptients) Post Hoc Anlyses of GLP-1 RA Clinicl Tril Dt Revel No Incresed Risk of CV Events 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 CV deth, stroke, MI, ACS, revsculriztion CV deth, stroke, MI RR (95% CI).7 ( ) IR (95% CI).73 ( ) 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 ACS, cute coronry syndrome; CV, crdiovsculr; EXN BID, exentide twice dily; EXN QW, exentide once weekly; IR, incidence rtio; LIRA, lirglutide; MI, myocrdil infrction; RR, risk rtio. 1. Rtner R, et l. Crdiovsc Dibetol. 211;1:22. Insulin or plcebo; b Active comprtor or plcebo; c In ptients who 2. Mrso S, et l. Dibetes Vsc Dis Res. 211;8: hve experienced cute coronry syndrome; d LIXI not FDA pproved. 3. Ntionl Institutes of Helth. Evidence Regrding Renl Impirment With GLP-1 RAs Evidence does not indicte direct renl toxicity with GLP-1 RAs 1-3 Renl impirment impcts clernce of EXN but not LIRA 1,4,5 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 hve 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. Am J Kidney Dis. 213 My 16. Epub hed of print]; 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: Prescribing Informtion Precutions Renl impirment Recommendtions for GLP-1 RA Use: Possible Renl Impirment Risk EXN BID LIRA EXN QW Not in severe RI (CrCl < 3 ml/min) or ESRD Use with cution in moderte RI (CrCl 3-5 ml/min) Use with cution in ptients with RI Not in severe RI (CrCl < 3 ml/min) or ESRD Use with cution in moderte RI (CrCl 3-5 ml/min Recommendtions 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 once weekly; LIRA, lirglutide; RI, renl impirment. US FDA. Drugs@FDA. 6

12 Risk of Acute Pncretitis With GLP-1 RAs Cses hve been reported in ptients tking GLP-1 RAs 1 Risk is 1.5- to 2.5-fold higher in individuls with dibetes 2 Mixed results regrding GLP-1 RA risk in dtbse nlyses 3-1 Recent sttements US Food nd Drug Administrtion (3/14/13) 11 Ongoing investigtion prompted by postmortem tissue study 1 Current recommendtions Ptients continue s directed until discussed with HCP HCPs follow drug lbel prescribing recommendtions Europen Medicines Agency (7/25/13) 12 Review of postmortem tissue study nd other vilble dt 1 Conclusions No new dt to indicte higher risk thn previously identified Current lbel informtion, monitoring efforts, nd ongoing sfety studies re sufficient 1. US FDA. Drugs@FDA Yng L, et l. Eur J Gstroenterol Heptol. 213;25: ; 3. Elshoff M, et l. Gstroenterology. 211;141:15-156; 4. Rschi E, et l. Act Dibetol. 211 Oct 19. [Epub hed of print]; 5. McConell L, et l. Dibetes Metb Syndr Obes. 212;5:29-41; 6. Wenten M, et l. Dibet Med. 212;29: ; 7. Alves C, et l. Dibetes Res Clin Prct. 212;98: ; 8. Romley J, et l. Dibetes Technol Ther. 212;14:94-911; 9. Singh S, et l. JAMA Intern Med. 213;173: ; 1. Butler A, et l. Dibetes. 213;62: ; 11. US Food nd Drug Administrtion EMA. Assessment report for GLP-1 bsed therpies. Recommendtions for GLP-1 RA Use: Possible Pncretitis Risk Prescribing Informtion Precutions EXN BID LIRA EXN QW Consider other gents if history of pncretitis X X X Recommendtions 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 once weekly; LIRA, lirglutide. 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 ;98: 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 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 once weekly; 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 GLP-1 RAs in Ptients With Comorbidities: Older Ptients Frmework for Considering Glycemic Gols in Older Adults With Dibetes 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: 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:

13 GLP-1 RA Effects in Older nd Younger Ptients: Pooled Anlyses of Phse 3 Trils Clinicl Outcome EXN BID 1 (1 mcg) 16 trils Comprble, significnt A1C from bseline for ptients < 65 y nd 65 y EXN BID, exentide twice dily; EXN QW, exentide once weekly; LIRA, lirglutide. 27.7% nd 3.2% treted with SU, 4.% nd 1.2% without SU; b 12.7% nd 12.% treted with SU, 2.% nd 4.2% without SU; c Includes.5% mjor hypoglycemi, ll treted with SU EXN QW 2 (2. mg) 7 trils LIRA 3 (1.8 mg) 6trils < 65 y 65 y < 65 y 65 y < 65 y 65 y Hypoglycemi, mjor nd minor, % b 8 b 14 c 15 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: 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 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 Cse 2: Fculty Discussion GLP-1 RA Nonglycemic Effects: Cse 3 Drs LeRoith, LSlle, Shubrook Jmes R LSlle, DO, FAAFP Medicl Director Excelsior Springs Clinic Excelsior Springs, Missouri Cse 3: Mrv GLP-1 RA Nonglycemic Effects 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 Outline Overview of nonglycemic effects Weight Lipid levels Blood pressure Implictions for cre beyond glycemic control T2DM tretment gols other thn hyperglycemi NAFLD 8

14 Monotherpies Weight (24-mo medin, kg) T2DM Tretment Selection Cn Impct Body Weight MET DPP-4 inhibitor SU TZD Insulin MET Combintion Therpies Weight (24-mo medin, kg) w/glp-1 RA w/ DPP-4 inhibitor w/ SU w/ TZD w/ INS Weight (kg) GLP-1 RA Weight Effects in Ptients With T2DM Met-Anlysis (8 Published RCTs) 1, Generlly similr between in hed-to-hed GLP-1 RA trils EXN BID vs LIRA 2 EXN BID vs EXN QW 3,4 Exception: LIRA (-3.6 kg) vs EXN QW (-2.7 kg, P =.5) 5 Weight loss in > 75% of hed-tohed tril prticipnts 3,5 Weight loss significnt in the bsence of GI AEs, but greter with GI AEs 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: EXN BID LIRA EXN QW EXN BID, exentide twice dily; EXN QW, exentide once weekly; LIRA, lirglutide; RCT, rndomized controlled tril. Weight chnges in ptients treted for 12 weeks. 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: Buse J, et l. Lncet. 213;381: Russell-Jones D, et l. 7th ADA Scientific Sessions. 21;1886-P. 7. 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 Lirglutide Effects on Systolic Blood Pressure With or Without Antihypertensive (AH) Agents Prmeter Systolic blood pressure Distolic blood pressure Totl cholesterol Chnge 95% Confidence Intervl 3.57 mm Hg 5.49 to mm Hg 2.2 to mg/dl (.1 mmol/l) 6.19 to 1.55 (.16 to.4) SBP (mm Hg) Met-nlysis of 6 26-week clinicl trils (N = 3967) PBO LIRA (1.8 mg) Overll With AH gent No AH gent Includes overweight nd obese individuls without T2DM; tretments include exentide nd lirglutide. Vilsbøll T, et l. BMJ. 212;344:d7771. P <.5 vs PBO. Fonsec V, et l. 7th ADA Scientific Sessions. 21:296-OR. 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: Clinicl Considertions for NAFLD/NASH Heptic ft ccumultion in the bsence of other cuses 1 Most prevlent liver disese in T2DM ( 2 vs no T2DM) 1,2 My progress to NASH (liver dmge with inflmmtion, necrosis, nd fibrosis), cirrhosis, or heptocellulr crcinom (HCC) 1 Few clinicl symptoms 3 My or my not be ssocited with elevted ALT/AST My be detected using ultrsound (sensitivity not good) Currently no specific therpies Recommend weight reduction, helthy diet, incresed physicl ctivity, voidnce of lcohol nd unnecessry medictions 4 Antioxidnts (ie, vitmin E) nd insulin sensitizers (ie, pioglitzone) my be effective 5-7 NAFLD, nonlcoholic ftty liver disese; NASH, nonlcoholic heptic stetosis. Pioglitzone is not FDA pproved for treting NAFLD/NASH Tolmn K, et l. Dibetes Cre. 27;3: ; 2. Cusi K. Curr Opin Endocrinol Dibetes Obes. 29;16: ; 3. Ali R, Cusi K. Ann Med. 29;41: ; 4. Ntionl Digestive Diseses Informtion Clering House. Nonlcoholic stetoheptitis Snyl A, et l. N Engl J Med. 21;362: ; 6. Belfort R, et l. N Engl J Med. 26;355: ; 7. Aithl G, et l. Gstroenterology. 28;135: ; 8. US FDA. Drugs@FDA. 9

15 Effects of GLP-1 RAs on Heptic Stetosis GLP-1 RAs re not FDA-pproved for NAFLD/NASH 1 Improved heptic stetosis with GLP-1 RA tretment Exentide BID + pioglitzone 2 Significnt heptic ft reduction from 12.1% to 4.7% fter 12 months (P <.5 vs pioglitzone lone) Lirglutide 3 Heptic ft reduced 15.9% fter 6 months (P <.5 vs bseline) GLP-1 RA (ie, exentide BID, lirglutide) 4 42% reltive decrese in intrheptic lipid (P <.5 vs bseline) Improvements correlted with AST nd ALT decreses 2,4, triglyceride nd diponectin chnges 2, A1C decrese 4 1. US FDA. Drugs@FDA Web site. 2. Sthynryn P, et l. Obesity (Silver Spring). 211;19: Ogino J, ADA 73 rd Scientific Sessions. 213;1-P. Assessed by mgnetic resonnce spectroscopy. 4. Cuthbertson DJ, 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 GLP-1 RA Tretment Stisfction nd Tolerbility: Cse 4 Drs LeRoith, LSlle, Shubrook 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 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 EXN BID t 1 mcg twice dily Still reports nuse fter 8 weeks, usully tolerble Hppy bout weight loss (4 lbs) Doesn t like injecting 2 dily occsionlly misses evening dose 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) 1

16 Ptient Concerns Regrding Antihyperglycemic Tretments for T2DM Ptients will py extr to Decrese weight by 1 kg ($11/month) Avoid hypoglycemi ($13/month) Avoid 1-kg weight gin ($17/month) Avoid injection ($24/month) Improve A1C 1% ($26/month) Avoid nuse ($35/month) Self-Reported Hypoglycemi Negtively Affects Ptient Helth-Relted Qulity of Life 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 qulity of life The mgnitude of hypoglycemi impct increses with severity Hypoglycemi lso ssocited with lower tretment stisfction, poorer dherence, nd greter resource utliztion 3 Jendle J, et l. Curr Med Res Opin. 21;26: 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: 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 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 1. US FDA. Drugs@FDA. 2. 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 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. Smller Pen Needle Size Is Effective nd Preferred 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 Equivlent glycemic control for obese vs nonobese prticipnts 2 Significntly lower pin scores for 4 mm vs 5 mm nd 8 mm needles 1 6% preferred 4mm over 5 mm or 8 mm 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 t lest 6 hours prt 1,2 LIRA, EXN QW less frequent dosing 1 Injection is reltively pinless 3 Smll, fine needle Subcutneous vs muscle Hve ptient see/use pen nd needle before leving office 3 Refer ptient to product 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. 11

17 Nuse (%) 4 2 P <.5 vs EXN BID. Reports of Nuse Vry by Agent Nuse my resolve more quickly with some gents 1 Prticipnts (%) Time (weeks) The proportion of ptients reporting nuse is lower with some gents EXN BID LIRA LIRA 1.8 mg QD EXN 1 mcg BID 1 LEAD-6 DURATION-1 DURATION-5 DURATION P <.1 EXN QW 1.Buse JB, 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: 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 wit until GI effects to ese before incresing dose 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 1. US FDA. Drugs@FDA. EXN BID, exentide twice dily; EXN QW, 2. Kruger D, et l. Dibetes Educ. 21;36(suppl 3):44S-72S. exentide once weekly; LIRA, lirglutide. 3. Finemn M, et l. Dibetes Metb Res Rev. 24;2: 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: Tretment Stisfction With GLP-1 RAs Agent Comprtor Significnt Outcomes EXN BID LIRA EXN QW GLAR 1 COMPARABLE HRQoL nd tretment stisfction improvement GLIM 2 BETTER HRQoL, weight ssessment nd concern, mentl nd emotionl helth, generl perceived helth (P <.5 for ll) SITA 3 BETTER tretment stisfction (P =.3); comprble convenience of tretment (orl vs injection) EXN BID 4 BETTER overll tretment stisfction (P <.5) PIO 5 BETTER improvement in weight-relted qulity of life (P.5) SITA 5 COMPARABLE improvement in weight-relted qulity of life, HRQoL, nd tretment stisfction EXN BID 6 IMPROVED tretment stisfction on switch from EXN BID EXN BID, exentide twice dily; EXN QW, exentide once weekly; GLAR, insulin glrgine; GLIM, glimepiride; HRQoL, helth-relted qulity of life; LIRA, lirglutide; PIO, pioglitzone; SITA, sitgliptin. Comprtive terms indicte effect of gent vs comprtor. 1. Secnik Boye KS, et l. Helth Qul Life Outcomes. 26;4:8. 2. Bode BW, et l. Dibetes Obes Metb. 21;12: Prtley RE, et l. Lncet. 21;375: Schmidt WE, et l. Dibet Med. 211;28: Best JH, et l. Dibetes Cre. 211;34: Best J, et l. Dibet Med. 29;26: Ptient-Centered Considertions: Srh Ptient is hppy bout weight loss Avilble GLP-1 RAs generlly promote similr weight loss Ptient hs persistent nuse Nuse is tolerble Provide eduction regrding mel sizes nd ft content Consider decresing GLP-1 RA dose Ptient hs expressed disstisfction with dosing frequency GLP-1 RAs with different dosing frequencies re vilble (twice dily, once dily, once weekly) Other Resources Generl resources Ptient ssistnce progrms Provide mediction ccess for eligible ptients nd my improve dherence nd outcomes 1 3 Specific informtion often vilble t product website Assessment tools for elderly ptients 4 Unidentified cognitive deficits, functionl sttus, nutritionl needs: Mini-Nutritionl Assessment: 1. Strum MW, et l. Am J Helth Syst Phrm. 25;62: Chisholm MA, et l. Am J Helth Syst Phrm. 27;64: Schoen MD, et l. Phrmcotherpy. 21;21: Kirkmn M, et l. Dibetes Cre. 212;35: