DECEMBER 2, 2016 Los Angeles, California NOV PriMed IntroPages LA R1.indd 1

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1 DECEMBER, 16 Los Angeles, Cliforni FOR ADDITIONAL CME ACTIVITIES LOG ON TO 16 NOV PriMed IntroPges LA R1.indd 1 11/7/16 11:34 AM

2 Improving Comprehensive Ptient Cre FACULTY EILEEN Egn, DNP, FNP-C, CDE Chief Nurse Prctitioner, Winthrop Center for Comprehensive Dibetes Cre Winthrop Endocrine, Dibetes & Metbolism Fculty Prctice Mineol, New York Adjunct Fculty Deprtment of Grdute Studies & Advnced Prctice Nursing Stony Brook University Stony Brook, New York SCOTT V. Joy, MD, MBA, FACP Professor of Clinicl Prctice University of Colordo School of Medicine Medicl Director Uptown Primry Cre The Colordo Helth Foundtion & Presbyterin/St. Luke s Medicl Center Denver, Colordo ETIE Moghissi, MD, FACP, FACE Associte Clinicl Professor of Medicine UCLA Dvid Geffen School of Medicine Los Angeles, Cliforni Consultnt in Dibetes, Endocrinology nd Metbolism Mrin Dibetes nd Endocrinology Center Mrin del Rey, Cliforni LEARNING OBJECTIVES Describe the underlying mechnisms of TDM, focusing on the pthophysiologic nd potentilly therpeutic roles of incretin hormone signling Identify comprehensive tretment gols for TDM tht reflect the degree of hyperglycemi, relevnt comorbidities, nd other ptient-specific fctors Discuss the comprehensive clinicl profiles of incretin-bsed therpies, including the potentil benefits nd risks of combining these gents with insulin Intensify ntihyperglycemic regimens with incretin-bsed therpies to chieve individulized glycemic trgets Educte ptients with TDM to motivte lifestyle modifictions, reduce hypoglycemi risks, nd enhnce tretment dherence FACULTY FINANCIAL DISCLOSURE STATEMENTS The presenting fculty reported the following: Eileen Egn, DNP, FNP-C, CDE, hs nothing to disclose. Scott. V. Joy, MD, MBA, FACP, is member of the Advisory Bord for Eli Lilly nd Compny, Boehringer Ingelheim GmbH, nd Exct Sciences Corportion. Etie Moghissi, MD, FACP, FACE, is member of the Spekers Bureu for AstrZenec plc, Boehringer Ingelheim GmbH, Eli Lilly nd Compny, Jnssen Phrmceuticls, Inc., nd Novo Nordisk A/S. She is member of the Advisory Bord for AstrZenec plc, Boehringer Ingelheim GmbH, Eli Lilly nd Compny, Jnssen Phrmceuticls, Inc., nd Novo Nordisk A/S. She hs Ownership Interest in Novo Nordisk A/S nd Jnssen Phrmceuticls, Inc. EDUCATION PARTNER FINANCIAL DISCLOSURE STATEMENT The content collbortors t Integrits Communictions hve reported the following: Jim Kppler, PhD, hs nothing to disclose. PMICME CLINICAL STAFF AND TUFTS HEALTH CARE ITITUTE EXPERT REVIEWER FINANCIAL DISCLOSURE As continuing medicl eduction provider ccredited by the ACCME, it is the policy of pmicme to require ny individul in position to influence eductionl content to disclose the existence of ny finncil interest or other personl reltionship with the mnufcturer(s) of ny commercil product(s). pmicme clinicl stff nd Tufts Helth Cre Institute expert content reviewers hve provided finncil disclosure nd hve no conflicts of interest to resolve for ech of the sessions relted to this ctivity. CONFLICT OF INTEREST RESOLUTION STATEMENT pmicme requires ll individuls in position to influence eductionl content for pmicme-certified CME ctivities to disclose relevnt personl finncil reltionship(s) with commercil interests prior to contributing to the ctivity. pmicme ssesses disclosed reltionships nd follows defined process to resolve rel or implied conflicts to ensure, to the best of our bility, tht ll eductionl content is free of commercil bis. Finncil disclosures re listed in this progrm nd will lso be nnounced prior to the strt of ech presenttion nd posted on OFF-LABEL/ INVESTIGATIONAL DISCLOSURES During the course of their presenttions, the fculty my mention uses of products tht hve not been pproved in the United Sttes for the indiction(s) being discussed. All presenters re instructed to notify prticipnts when they re discussing unpproved uses or investigtionl gents. In ddition, specific slides will include nottion of the off-lbel use or investigtionl gent being discussed. Views presented during this progrm relted to unpproved uses of products re solely those of the presenter(s) nd re not endorsed by pmicme, DBC Pri-Med, LLC, or ACP. ACCREDITATION STATEMENT pmicme is ccredited by the Accredittion Council for Continuing Medicl Eduction to provide continuing medicl eduction for physicins. ACKNOWLEDGMENT OF COMMERCIAL SUPPORT This ctivity is supported by n eductionl grnt from Novo Nordisk. CLINICAL RESOURCE CENTER Access the progrm syllbus nd dditionl resources by scnning the imge on the left. If you do not hve QR Code Reder on your mobile device, visit getscnlife.com for free downlod NOV PriMed IntroPges LA R1.indd 11/7/16 11:34 AM

3 Scientific Insights Into Incretin Signling nd TDM Key Points Incretin effect: more insulin is secreted in response to orlly delivered glucose compred with intrvenously dministered glucose 1 The gstrointestinl hormones GLP-1 nd GIP stimulte insulin relese in response to food intke GLP-1 lso reduces glucgon relese following food intke, slows gstric emptying, nd increses stiety Reduced incretin effect is n erly sign of TDM development 3 GLP-1 nd GIP re rpidly degrded by DPP-4 Clinicl reserch hs focused on degrdtion-resistnt GLP-1 RAs nd inhibitors of DPP-4 DPP-4, dipeptidyl peptidse-4; GIP, glucose-dependent insulinotropic polypeptide; GLP-1 RA, glucgon-like peptide-1 receptor gonist; TDM, type dibetes mellitus. 1. Elrick H, et l. J Clin Endocrinol Metb. 1964;4:176-18;. Grunberger G. J Dibetes. 13;(3):41-3; 3. Holst JJ, et l. Dibetes Cre. 11;34 (suppl ):S1-S7. Reducing TDM Complictions BP <14/9 mm Hg (<13/8 mm Hg for some people) Multidimensionl Tretment Gols Comprehensive Dibetes Mngement A1c ADA <7.% AACE 6.% Lipids LDL-C: <1 mg/dl (<7 mg/dl with CVD) HDL-C: >4 mg/dl in men > mg/dl in women TG: <1 mg/dl Lifestyle Modifictions Helthy Diet; Exercise; Smoking Cesstion BMI < kg/m 1 ADA/AHA guidelines: Tret ptients 4-7 yers old with TDM nd LDL-C levels between 7 nd 189 mg/dl with moderte-intensity sttin therpy (lower LDL-C by 3%-%); use high-intensity therpy (lower LDL-C by %) if 1-yer ASCVD risk is 7.%). A1c, glycted hemoglobin; AACE, Americn Assocition of Clinicl Endocrinologists; ADA, Americn Dibetes Assocition; AHA, Americn Hert Assocition; ASCVD, therosclerotic crdiovsculr disese; BMI, body mss index; BP, blood pressure; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; TG, triglycerides. ADA. Dibetes Cre. 16;39(suppl 1):S1-S11; Grber AJ, et l. Endocr Prct. 16;(1):84-113; Fox CS, et l. Dibetes Cre. 1;38(9): ADA/EASD Position Sttement Setting Glycemic Gols in TDM More Stringent Fctors Less Stringent ly motivted, dherent, excellent selfcre cpcities Low Ptient ttitude nd expected tretment efforts Risks potentilly ssocited with hypoglycemi, other dverse events EASD, Europen Assocition for the Study of Dibetes. Inzucchi SE, et l. Dibetes Cre. 1;3: ; Inzucchi SE, et l. Dibetes Cre. 1;38(1):14-149; Ismil-Beigi F, et l. Ann Intern Med. 11(6);14:4-9. Less motivted, nondherent, poor self-cre cpcities Newly dignosed Disese durtion Long-stnding Long Life expectncy Short Absent Importnt comorbidities Severe Absent Estblished vsculr complictions Severe Redily vilble Resources, support system Limited Monotherpy Efficcy ( A1c) Hypoglycemi Weight Side Effects Costs Dul Therpy Efficcy ( A1c) Hypoglycemi Weight Mjor Side Effect(s) Costs ADA Recommendtions Mnging Hyperglycemi in TDM + SU Moderte risk Gin Hypoglycemi Low Helthy Eting, Weight Control, Incresed Physicl Activity Metformin Low risk Neutrl/Loss GI/Lctic cidosis Low If individulized A1c trget not reched fter ~3 months, proceed to -drug combintion + TZD Low risk Gin Edem, HF, Fx + DPP-4 Inhibitor Intermedite Low risk Neutrl Rre Metformin + SGLT- Inhibitor Intermedite Low risk Loss GU, Dehydrtion + GLP-1 RA Low risk Loss GI Consider strting t this stge when A1c 9%. Fx, bone frcture; GI, gstrointestinl; GU, genitourinry; HF, hert filure; SGLT-, sodium glucose cotrnsporter-; SU, sulfonylure; TZD, thizolidinedione. ADA. Dibetes Cre. 1;38(suppl 1):S1-S94. + Insulin (Bsl) est risk Gin Hypoglycemi Vrible AACE/ACE Algorithm Glycemic Control nd Erly Dul Therpy Lifestyle Modifiction Entry A1c <7.% Entry A1c 7.% Entry A1c >9.% Monotherpy Metformin GLP-1 RA SGLT- inhibitor DPP-4 inhibitor TZD AG inhibitor SU/GLN If not t gol in 3 months, proceed to dul therpy METFORMIN or other first-line gent Dul Therpy GLP-1 RA SGLT- inhibitor DPP-4 inhibitor TZD Bsl Insulin Colesevelm Bromocriptine QR AG inhibitor SU/GLN If not t gol in 3 months, proceed to triple therpy Order of medictions listed re suggested hierrchy of usge. ACE, Americn College of Endocrinology; AG, α-glucosidse; GLN, glinide; QR, quick relese. Grber AJ, et l. Endocr Prct. 16;(1): NO Dul Therpy OR Triple Therpy Symptoms YES Insulin ± Other Agents Add or Intensify Insulin Possible benefits or few dverse events Use with cution Annulized Rte of Severe Hypoglycemi, % Hurdles to Intensive Therpy Rtes of Severe Hypoglycemi UKPDS 1 ADVANCE ACCORD 3 VADT 4 P<.1 vs CON HR 1.86 (1.4,.4) P<.1 P<.1 P= CON GLY I STD INT b STD INT b STD INT b A1c= 7.9% 7.1% 7.% 7.3% 6.% 7.% 6.4% 8.4% 6.9% Hypoglycemi requiring ny ssistnce; b Intensive glycemic control ws defined differently in these trils. ACCORD, Action to Control Crdiovsculr Risk in Dibetes; ADVANCE, Action in Dibetes nd Vsculr Disese: PreterAx nd DimicroN MR Controlled Evlution; CON, conventionl therpy; GLY, glibenclmide; HR, hzrd rtio; I, insulin; INT, intensive therpy; STD, stndrd therpy; UKPDS, UK Prospective Dibetes Study; VADT, Veterns Affirs Dibetes Tril. 1. UKPDS Group. Lncet. 1998;3(9131):837-83;. Ptel A, et l; [ADVANCE]. N Engl J Med. 8;38(4):6-7; 3. Gerstein HC, et l; [ACCORD]. N Engl J Med. 8;38(4):4-9; 4. Duckworth W, et l. N Engl J Med. 9;36():

4 ADVANCE Severe Hypoglycemi vs Adverse Endpoints Pthophysiologic CV Consequences of Hypoglycemi Ptients With 1 Hypoglycemic Event(s), % HR (9% CI): 3.3 (.41,.17) HR (9% CI):.19 (1.4, 3.4) b HR (9% CI): 3.7 (.9, 4.6) Adjusted for multiple bseline covrites; b Primry endpoints. Mjor mcrovsculr event=cv deth, nonftl myocrdil infrction, or nonftl stroke. Mjor microvsculr event=new or worsening nephropthy or retinopthy. CI, confidence intervl. Zoungs S, et l. N Engl J Med. 1;363(1): b HR (9% CI): HR (9% CI): 3.79 (.36, 6.8).8 (1.64, 4.79) Mcrophge/ neutrophil ctivtion Pltelet ctivtion Fctor VIII CRP Blood cogultion bnormlities Rhythm bnormlities Hert rte vribility VEGF Inflmmtion Hypoglycemi IL-6 Sympthodrenl response Nordrenline CRP, C-rective protein; IL-6, interleukin-6; VEGF, vsculr endothelil growth fctor. Desouz CV, et l. Dibetes Cre. 1;33(6): Endothelil dysfunction Hemodynmic chnges Hert worklod Contrctility Output Vsodiltion GLP-1 Signling Effects Relted to Glucose Control Pncres 1 Insulin secretion (glucose-dependent) nd β-cell sensitivity,3 Insulin synthesis 4 Glucgon secretion 3 (glucose-dependent) Liver 4 Brin -7 Stiety Energy intke Body weight Crdiovsculr System 8 Systolic BP Heptic glucose output Stomch 1,4 Gstric emptying 1. Holst JJ, et l. Trends Mol Med. 8;14(4): ;. Flint A, et l. Adv Ther. 11;8(3):13-6; 3. Degn K, et l. Dibetes. 4;3(): ; 4. Bggio LL, Drucker DJ. Gstroenterology. 7;13(6):131-17;. Horowitz M, et l. Dibetes Res Clin Prct. 1;97():8-66; 6. Vilsbøll T, et l. BMJ. 1;344:d7771; 7. Niswender K, et l. Dibetes Obes Metb. 13(1);1:4-4; 8. Fonsec V, et l. Dibetes. 1;9(suppl 1):A79(96-OR). Glucose Control nd DPP-4 Inhibitors Monotherpy nd Metformin Combintions Therpy vs Comprtor Monotherpy vs Plcebo ΔA1c for Sxgliptin vs Comprtor, % 1-3 ΔA1c for Sitgliptin vs Comprtor, % 4-6 ΔA1c for Lingliptin vs Comprtor, % 7-9 ΔA1c for Alogliptin vs Comprtor, % vs vs.1 b -.44 vs. -.9 vs -. b Initil Combintion With Metformin vs Metformin -. vs vs b -1.7 vs vs -1.6 c Add on to Metformin vs Metformin vs vs -. b -.49 vs vs -.1 b P<.1 vs comprtor; b P<.1 vs comprtor; c P<. vs comprtor. 1. Rosenstock J, et l. Curr Med Res Opin. 9;:41-411;. Jdzinsky M, et l. Dibetes Obes Metb. 9;11:611-6; 3. DeFronzo RA, et l. Dibetes Cre. 9;3: ; 4. Rz I, et l. Dibetologi. 6;49:64-71;. Goldstein BJ, et l. Dibetes Cre. 7;3: ; 6. Scott R, et l. Dibetes Obes Metb. 8;1:99-969; 7. Del Prto S, et l. Dibetes Obes Metb. 11;13:8-67; 8. Hk T, et l. Dibetes Obes Metb. 1;14:6-74; 9. Tskinen MR, et l. Dibetes Obes Metb. 11;13:6-74; 1. DeFronzo RA, et l. Dibetes Cre. 8;31:31-317; 11. Drugs@FDA ( 1. Nuck MA, et l. Int J Clin Prct. 9;63:46-. Cumultive Incidence of Primry Endpoint Events, % EXAMINE Alogliptin After ACS in TDM HR,.96 (upper boundry of 1-sided repeted CI, 1.16) P<.1 for noninferiority P=.3 for superiority Plcebo Alogliptin Months No significnt between-group differences in deth from ny cuse, CV deth, or the secondry endpoint b Composite: deth from CV cuse, nonftl myocrdil infrction, or nonftl stroke. b Composite: deth from CV cuse, nonftl myocrdil infrction, nonftl stroke, or revsculriztion due to UA in 4 h fter hospitliztion. N=38 ptients with TDM nd either n cute myocrdil infrction, or UA requiring hospitliztion within the previous 1 to 9 dys. ACS, cute coronry syndrome; EXAMINE, Exmintion of Crdiovsculr Outcomes with Alogliptin versus Stndrd of Cre. White WB, et l. N Engl J Med. 13;369(14): Ptients With Events, % 1 1 TECOS Sitgliptin in Ptients With TDM nd CVD Primry Endpoint Sitgliptin Plcebo Secondry Endpoint b HR,.98 (9% CI:.89, 1.8) HR,.99 (9% CI:.89,1.1) P=.6 P= Months Months Composite of CV deth, nonftl myocrdil infrction, nonftl stroke, nd hospitliztion for UA. b Composite of first confirmed event of CV deth, nonftl myocrdil infrction, or nonftl stroke. N=14,671 ptients t lest yers of ge with TDM nd estblished CV disese. TECOS, Tril to Evlute Crdiovsculr Outcomes fter Tretment with Sitgliptin. Green JB, et l. N Engl J Med. 1;373(3): Sitgliptin Plcebo

5 DPP-4 Inhibitors Additionl Sfety Considertions Generlly well tolerted Most common dverse effects Nsophryngitis Hedche Nuse Hypersensitivity Skin rections Dose reductions re required for logliptin, sxgliptin, nd sitgliptin in ptients with moderte or severe renl impirment, or ESRD (CrCl ml/min) CrCl, cretinine clernce; ESRD, end-stge renl disese. Grunberger G. J Dibetes. 13;(3):41-3. DPP-4 Inhibitors Recent FDA Wrnings Joint pin DPP-4 inhibitor clss crries wrning bout joint pin tht cn be severe nd disbling In rre identified cses, symptoms bte <1 month fter drug is stopped My relte to cytokines, chemokines, nd mtrix metlloproteinses Hert filure For sxgliptin nd logliptin, consider benefits vs risks in ptients t risk for hert filure, nd consider discontinuing if hert filure develops SAVOR: more ptients hospitlized for hert filure in the sxgliptin group thn in the plcebo group (HR, 1.7; 9% CI: 1.7, 1.1) Post hoc nlysis showed tht ptients t highest risk of hert filure relted hospitliztion hd previous hert filure or chronic kidney disese 4 EXAMINE: more ptients hospitlized for hert filure in the logliptin group (3.9%) thn in the plcebo group (3.3%) Mscolo A, et l. Drug Sf. 16;39():41-47; Sciric BM, et l. Circultion. 14;13(18): ; White WB, et l. N Engl J Med. 13;369(14): ; See Drugs@FDA: FDA Approved Drug Products; Accessed September, 16. Short Acting Long Acting Mediction Exentide BID 1 Lixisentide Lirglutide 3 FDA-Approved GLP-1 RAs Dily Formultions Dosge Forms μg/dose in 1.-mL prefilled pen 1 μg/dose in.4-ml prefilled pen 1 μg/dose in 3-mL green prefilled pen μg/dose in 3-mL burgundy prefilled pen Prefilled, multidose pen tht delivers doses of.6 mg, 1. mg, or 1.8 mg Adverse Events Nuse, vomiting, dyspepsi Nuse, vomiting, hedche, dirrhe, dizziness Nuse, dirrhe, vomiting, constiption, hedche Dosing 1. Strt t μg BID (1 h before morning nd evening mels). Increse to 1 μg BID t 1 month 1. Strt t 1 μg once dily for 14 dys (1 h before morning mel). Increse to μg once dily on dy 1 1. Initite t.6 mg once dily, regrdless of mels. After 1 week, increse to 1. mg once dily 3. If control is not t glycemic gol, dose cn be incresed to 1.8 mg Tretment-emergent dverse rections with % incidence in clinicl trils with drug s monotherpy (excluding hypoglycemi). BID, twice dily. 1. See Drugs@FDA ( See Drugs@FDA ( 3. See Drugs@FDA ( Long Acting FDA-Approved GLP-1 RAs Weekly Formultions Mediction Dosge Forms Adverse Events Dosing Exentide QW 1 Albiglutide Dulglutide 3 Single-dose try with -mg vil Single-dose -mg prefilled pen 3-mg or -mg lyophilized powder in single-dose pen for reconstitution.7-mg or 1.-mg single-dose pen Prefilled, single-dose syringe in.7-mg or 1.-mg doses Nuse, dirrhe, injection-site nodule, 1. Administer t. mg once constiption, weekly, regrdless of mels hedche, dyspepsi URTI, dirrhe, 1. Administer t 3 mg once nuse, injection-site weekly, regrdless of mels rection, cough, bck pin, rthrlgi,. If glycemic control not t gol, sinusitis, influenz dose cn be incresed to mg Nuse, dirrhe, vomiting, bdominl pin, nd decresed ppetite 1. Initite t.7 mg weekly, regrdless of mels; dose cn be incresed to 1. mg. If dose is missed, missed dose must be tken within 3 dys QW, once weekly; URTI, upper respirtory trct infection. Tretment-emergent dverse rections with % incidence (excluding hypoglycemi) in clinicl trils with drug s monotherpy. 1. See Drugs@FDA ( See Drugs@FDA ( 3. Dulglutide prescribing informtion. Accessed September, 16. Δ From Bseline, % or kg EXEN BID 1 (1 μg) GLP-1 RAs Plus Metformin Glucose Control nd Weight Loss.8.1 A1c, % LIRA (1.8 mg) LIXI 3 ( μg) EXEN QW 4 ( mg) ALBI (3 or mg) Body Weight, kg DULA 6 (1. mg) All dt re significnt vs plcebo (P<.1 to P<.1), except for nonsignificnt Δ body weight for lbiglutide vs plcebo. 1. DeFronzo RA, et l. Dibetes Cre. ;8(8):19-11;. Nuck M, et l. Dibetes Cre. 9;3(1):84-9; 3. Bolli GB, et l. Dibet Med. 14;31(): ; 4. Bergenstl RM, et l. Lncet. 1;376(9739): ;. Ahren B, et l. Dibetes Cre. 14;37(8): ; 6. Nuck M, et l. Dibetes Cre. 14;37(8): SITA Plcebo ΔA1c From Bseline, % GLP-1 RAs vs DPP-4 Inhibitors P<.1 P<.1 P<.1 P< EXEN QW ( mg),f DULA (1. mg) 3,g Added to Metformin LIRA (1.8 mg) 1,e ALBI (3 or mg) 4,h SITA Agent Δ Weight, kg Hypoglycemi, % of ptients GLP-1 GLP-1 DPP-4i RA RA DPP-4i LIRA 3,e d EXEN QW,f -.3 b d 3 DULA 4,g -3. b d ALBI,h -.8 c -. 4 d,i 16 i P<.1 vs DPP-4 inhibitor; b P<.1 vs DPP-4 inhibitor; c P<. vs DPP-4 inhibitor; d No sttisticl nlysis performed; e LIRA: 6-week tril with lirglutide; bseline A1c, 8.%; f EXEN QW: 6-week tril of exentide once weekly; bseline A1c, 8.4%; g DULA: -week tril; bseline A1c, 8.1%; h ALBI: 6-week tril of lbiglutide; bseline A1c, 8.%; i Almost ll ptients experiencing hypoglycemi were lso tking sulfonylure. 1. Prtley RE, et l. Lncet. 1;37(974): ;. Bergenstl RM, et l. Lncet. 1;376(376): ; 3. Nuck M, et l. Dibetes Cre. 14;37(8):149-18; 4. Leiter LA, et l. Dibetes Cre. 14;37(1):73-73.

6 Chnge in A1c From Bseline, % -3-4 Bseline A1c, % End of Tril A1c, % GLP-1 RAs vs Bsl Insulin Ptient Qurtiles Bsed on Bseline A1c 1st nd 3rd 4th Exentide QW Glrgine n st nd 3rd 4th Lirglutide -4 Glrgine Post hoc nlysis of DURATION-3 (exentide QW) nd LEAD- (lirglutide). DURATION, Dibetes therpy Utiliztion: Reserching chnges in A1c, weight nd other fctors Through Intervention with exentide ONce weekly; LEAD-, Lirglutide Effect nd Action in Dibetes. Buse JB, et l. Dibetes Obes Metb. 1;17():14-11; Dimnt M, et l. Lncet Dibetes Endocrinol. 14;(6): ; Russell-Jones D, et l. Dibetologi. 9;(1): Chnge in A1c, % -. GLP-1 RAs nd ΔA1c Hed-to-Hed Trils -1. Noninferiority P<.1 P= P<.1 P<.1 P=. P<.1 -. P<. P<.1 Exentide BID Lirglutide Dulglutide 1. mg Lixisentide Exentide QW Albiglutide Dulglutide.7 mg Did not meet predefined noninferiority mrgin. AWARD, Assessment of Weekly AdministRtion of LY1896 in Dibetes;, not significnt. Nuck M, et l. Dibetes Cre. 16;39(9):11-19; Trujillo JM, et l. Ther Adv Endocrinol Metb. 1;6(1):19-8. Chnge in Weight, kg GLP-1 RAs nd ΔBody Weight Hed-to-Hed Trils Exentide BID Exentide QW P=. Lirglutide Albiglutide Not Reported P<.1 Dulglutide 1. mg Dulglutide.7 mg Nuck M, et l. Dibetes Cre. 16;39(9):11-19; Trujillo JM, et l. Ther Adv Endocrinol Metb. 1;6(1):19-8. P<.1 P<.1 P<. Lixisentide GLP-1 RAs nd Blood Pressure Prmeter Met-Anlysis of Dt From Obese nd Overweight Individuls Chnge vs Control 9% CI Systolic blood pressure 3.7 mm Hg.49 to 1.66 Distolic blood pressure 1.38 mm Hg. to.73 Includes 11 or 1 trils exmining overweight nd obese individuls with or without TDM; tretments included exentide BID, exentide QW, or lirglutide. Vilsbøll T, et l. BMJ. 1;344:d7771. Ptients Experiencing Primry Outcome, % ELIXA Lixisentide in Ptients With TDM After ACS 1 1 Lixisentide Months Primry outcome: CV deth, nonftl myocrdil infrction, nonftl stroke, or hospitliztion for UA. N=668 ptients with TDM who hd myocrdil infrction or hd been hospitlized for UA within the previous 18 dys. Pfeffer MA, et l. N Engl J Med. 1;373(3):47-7. Plcebo HR, 1. (9% CI,.89, 1.17) P<.1 for noninferiority P=.81 for superiority No significnt between-group differences in the rtes of hospitliztion or deth Ptients With Event, % 1 1 LEADER Lirglutide in TDM With CV Risk Primry Outcome HR,.87 (9% CI:.78,.97) P<.1 for noninferiority P=.1 for superiority Plcebo CV-Relted Deth Lirglutide Lirglutide Lirglutide Months Since Rndomiztion Composite of deth from CV cuses, nonftl myocrdil infrction, or nonftl stroke. N=934 ptients with TDM nd high CV risk. Mrso SP, et l. N Engl J Med. 16;37(4): HR,.78 (9% CI:.66,.93) 1 P=.7 Plcebo Deth From Any Cuse HR,.8 (9% CI:.74,.97) P=. Plcebo

7 Ptients With Event, % SUSTAIN-6 Semglutide in TDM With CV Risk Primry Outcome Nonftl Stroke Deth From CV Cuses Hzrd rtio,.74 (9% CI,.8.9) P<.1 for noninferiority P=. for superiority Plcebo Semglutide Hzrd rtio,.61 (9% CI,.38.99) P=.4 Plcebo Semglutide Weeks Since Rndomiztion Composite of deth from CV cuses, nonftl myocrdil infrction, or nonftl stroke. N=397 ptients with TDM (A1c 7.%) who were yers old with estblished CV disese or chronic kidney disese (Stge 3 or worse) OR were 6 yers old with 1 CV risk fctor were rndomized to plcebo or semglutide. mg or 1. mg once weekly. Mrso SP, et l. N Engl J Med. 16 Sep 1. [Epub hed of print] Hzrd rtio,.98 (9% CI, ) P=.9 16 Plcebo Semglutide Incretin Therpy nd Acute Pncretitis Pncretitis risk is 1.-fold to 3-fold higher in ll individuls with dibetes Study OR (9% CI) Dore 9 (Exentide) 1. (.9, 1.7) Dore 9 (Sitgliptin) 1. (., 1.99) Grg 1 (Exentide).9 (.7, 1.41) Grg 1 (Sitgliptin).9 (.4, 1.6) Dore 11 (Exentide). (.4, 1.) Romley 1 (Exentide).9 (.6, 1.37) Seong 13 (Sitgliptin) 1.3 (.77, 1.38) Funch 14 (Lirglutide) 1.17 (.86, 1.61) Fillie (.9, 1.7) Singh 13 (Exentide nd Sitgliptin). (1.38, 3.67) Giord 13 b.98 (.69, 1.39) Overll (I-squred=3.6%, P=.114) 1.3 (.87, 1.) Decresed Risk With Incretin Therpy -. 1 Fillie et l included exentide, lirglutide, sitgliptin, sxgliptin, vildgliptin, nd lingliptin; b Giord et l. included exentide, lirglutide, sitgliptin, sxgliptin, nd vildgliptin. OR, odds rtio. Wng T, et l. Dibetes Obes Metb. 1;17(1):3-41; Yng L, et l. Eur J Gstroenterol Heptol. 13;():-31. Incresed Risk With Incretin Therpy Sfety of Incretin Therpy 14 FDA nd EMA Anlysis FDA nd EMA conducted prllel, independent sfety ssessments of incretin-bsed drugs following postmrketing reports of pncretitis or pncretic cncer in treted individuls Assertions of cusl ssocition re not consistent with current dt Product informtion nd lbeling reflect current understnding of risk Both gencies continue to investigte sfety signls nd dt from ongoing trils EMA, Europen Medicines Assocition. Egn AG, et l. N Engl J Med. 14;37(9): Gstrointestinl Adverse Rections With GLP-1 RAs Results From Pooled Plcebo-Controlled Trils Mediction 1, Nuse, % of Ptients Vomiting, % of Ptients Dirrhe, % of Ptients Albiglutide 11% 4% 13% Dulglutide 1%, 1% 6%, 13% 9%, 13% Exentide BID b 44% 13% 13% Exentide QW c 4% 11% % Lirglutide d 18%, % 6%, 9% 1%, 1% Lixisentide % 1% 8% Potentil pproches to reduce risks for nuse nd vomiting 1,3 Educte on mel size, eting pce, nd dose timing reltive to mels Use incrementl dose titrtion, prticulrly with shorter-cting gents Two numbers in ech column reflect.7 mg nd 1. mg doses, respectively; b Dt from dd on to metformin +/- sulfonylure tril; c Dt from dd on to metformin tril; d Two numbers in ech column reflect 1. mg nd 1.8 mg doses, respectively. 1. See Drugs@FDA: FDA Approved Drug Products; Accessed September, 16;. Dulglutide prescribing informtion. Accessed September, 16; 3. Ellero C, et l. Dibet Med. 1;7(1): Sfety With Incretin-Bsed Agents Precutions Cses hve been reported Consider tretments other thn GLP-1 RAs in ptients with history of pncretitis Unknown if pncretitis history increses risk with DPP-4 inhibitors Acute Pncretitis Recommendtions Ask bout pncretitis history Educte ptients bout signs nd symptoms of pncretitis Discontinue if pncretitis symptoms occur Report cses of pncretitis to See Drugs@FDA: FDA Approved Drug Products; Accessed September, 16. Weight Chnge (kg) Weight Loss With GLP-1 RAs Not Driven by Gstrointestinl Adverse Events Lirglutide (Met-Anlysis/6 6-Week Trils) 1 No NVD Some NVD ,b -1.6,b -1.6 P<. PBO 1. mg LIRA -.4,b 1.8 mg LIRA P<. Exentide (3-Week DURATION-1 Tril) No Nuse Nuse In 8-week exentide completer cohort, weight loss ws 1) similr cross degrees of nuse, ) progressive despite stble nuse incidence, nd 3) unlikely to be driven by nuse. 3 NVD, nuse, vomiting, dirrhe; PBO, plcebo. P<. vs bseline; b P<. vs plcebo. 1. Russell-Jones D, et l. 7th ADA Scientific Sessions. 1;1886-P;. Drucker DJ, et l. Lncet. 8;37(964):14-1; 3. Blonde L, et l. Dibetes Obes Metb. 6;8(4): EXEN QW EXEN BID

8 GLP-1 RAs Additionl Sfety Considertions Use with cution in ptients with renl impirment or renl trnsplnttion, especilly when inititing or esclting doses 1-3 Hypovolemi due to nuse/vomiting my worsen renl function Do not use exentide formultions in ptients with severe renl impirment (CrCl <3 ml/min) or ESRD All long-cting GLP-1 RAs should not be used in ptients with MEN or personl/fmily history of MTC 1, Counsel regrding MTC risk nd symptoms of thyroid tumors Report MTC to stte cncer registry, regrdless of tretment MEN, multiple endocrine neoplsi syndrome type ; MTC, medullry thyroid crcinom. 1. See Drugs@FDA: FDA Approved Drug Products; Accessed September, 16;. Dulglutide prescribing informtion. Accessed September, 16; 3. Idorn T, et l. Dibetes Cre. 16;39():6-13. Combining GLP-1 RAs nd Bsl Insulin Anlogs Bsl Insulin Anlogs Simple to initite Control nocturnl hyperglycemi nd FPG Less hypoglycemi risk vs NPH Cn cuse weight gin Achieve A1c trget in ~% Complementry Actions Additive Effects GLP-1 RAs Simple to initite Cn control FPG nd PPG Do not impir α-cell response to hypoglycemi (reduce severe hypoglycemi) Reduce weight Achieve A1c trget in ~6% Insulin degludec/lirglutide nd insulin glrgine/lixisentide fixed combintions hve received recommendtions for pprovl from n FDA dvisory pnel Percentge chieving <7% cross bseline A1c qurtiles for lirglutide nd exentide QW vs insulin glrgine. FPG, fsting plsm glucose; NPH, neutrl protmine Hgedorn; PPG, postprndil glucose. Buse JB, et l. Dibetes Obes Metb. 1;17():14-11; Holst JJ, Vilsbøll T. Dibetes Obes Metb. 13;1(1):3-14; Vor J, et l. Dibetes Metb. 13;39(1):6-1. GLP-1 RAs Plus Bsl Insulin Met-nlysis for ΔA1c ΔA1c, % Weighted Men Difference (9% CI) Buse et l (11) -.7 (-.7 to -.68) DeVries et l (1) -.43 (-.68 to -.18) Li et l (1) -.13 (-.3 to.6) Seino et l (L-Asi; 1) -.88 (-.93 to -.83) Riddle et l (Duo-1; 13) -.3 (-.8 to -.) Riddle et l (L; 13) -.3 (-.8 to -.) Dimnt et l (14) -.3 (-.17 to.11) Lne et l (14) -.6 (-. to.) Mthieu et l (14) -.3 (-.48 to -.) Rosenstock et l (14) -.16 (-.33 to.1) Sho et l (14) -.11 (-.3 to.1) Wit et l (14) -.78 (-1.1 to -.46) Ahmnn et l (14) (-1.36 to -1.) Rosenstock et l (LixiLn; 14) -. (-.4 to -.) Seino et l (LIRA-ADDIULIN; 14) -.8 (-.96 to -.64) Overll (I =96.6%, P<.1) -.44 (-.6 to -.9) Fvors GLP-1 RA + Bsl Insulin Fvors Comprtor 1 studies were eligible nd included in the nlysis (N=4348 prticipnts). Eng C, et l. Lncet. 14;384(9961):8-34. GLP-1 RAs Plus Bsl Insulin Met-nlysis for ΔBody Weight ΔBody Weight, kg Weighted Men Difference (9% CI) Buse et l (11) -.74 (-.83 to -.6) DeVries et l (1) -.79 (-1.43 to -.1) Li et l (1) -7.6 (-7.79 to -7.4) Riddle et l (Duo-1; 13) -.9 (-1.7 to -.8) Riddle et l (L; 13) -1.3 (-1.86 to -.74) Dimnt et l (14) -4.6 (-.38 to -3.8) Mthieu et l (14) -3.7 (-4.6 to -.7) Rosenstock et l (14) -1. (-. to -.9) Sho et l (14) (-1.7 to -9.39) Ahmnn et l (14) -3.1 (-3.8 to -.66) Rosenstock et l (LixiLn; 14) -1.4 (-.7 to -.63) Seino et l (LIRA-ADDIULIN; 14) -.3 (-.91 to.1) Overll (I =99.6%, P<.1) -3. (-4.9 to -1.4) Fvors GLP-1 RA + Bsl Insulin Fvors Comprtor 1 studies were eligible, were included in the nlysis, nd ssessed posttretment chnge in body weight. Eng C, et l. Lncet. 14;384(9961):8-34. GLP-1 RAs Plus Bsl Insulin Met-nlysis for Hypoglycemi Hypoglycemi Risk Reltive Risk (9% CI) Buse et l (11).87 (.8 1.3) Li et l (1).38 (.1.98) Seino et l (L-Asi; 1) 1.8 (1.3.4) Riddle et l (L; 13) 1.3 ( ) Dimnt et l (14).7 (..9) Rosenstock et l (14).6 (..83) Sho et l (14).14 (.1.6) Wit et l (14) 1.73 ( ) Ahmnn et l (14) 1.46 (.94.8) Rosenstock et l (LixiLn; 14) 1. ( ) Seino et l (LIRA-ADDIULIN; 14).99 ( ) Overll (I =77.1%, P<.1).99 ( ) Fvors GLP-1 RA + Bsl Insulin studies were eligible, were included in the nlysis, nd ssessed reltive risk of hypoglycemi. Eng C, et l. Lncet. 14;384(9961):8-34. Fvors Comprtor A1c, % GLP-1 RA/Bsl Insulin Fixed-Rtio Combintion Glycemic Control in DUAL I IDegLir IDeg Lir 1.8 mg Initil A1c Finl A1c >7. 8. >8. 9. >9. Bseline A1c Ctegory, % n= Totl Tril Popultion P<.1. N=166 insulin-nïve dults with TDM (men A1c, 8.3%; men BMI, 31. kg/m ) uncontrolled on orl gents ssigned to IDegLir, insulin degludec, or lirglutide 1.8 mg dily (DUAL I Extension). Gough SC, et l. Lncet Dibetes Endocrinol. 14;(11):88-893; Rodbrd HW, et l. Dibetes Obes Metb. 16;18(1):4-48.

9 Confirmed Hypoglycemi Events Per 1 Ptient-Yers GLP-1 RA/Bsl Insulin Fixed-Rtio Combintion c Sfety in DUAL I IDegLir IDeg Lir 7. >7. 8. >8. 9. >9. Totl Tril Bseline A1c Ctegory, % Popultion n= Finl A1c, % b Fewer ptients in the IDegLir group thn in the lirglutide group reported GI dverse events (nuse, 8.8% vs 19.7%) Study Nme (Drug) DUAL II 1 (IDegLir) DUAL III (IDegLir) DUAL IV 3 (IDegLir) DUAL V 4 (IDegLir) Additionl Published IDegLir Studies Study Popultion Indequte control with MET + bsl insulin ± SU Indequte control with GLP-1 RAs + OADs Indequte control with SU ± MET Indequte control with MET + insulin glrgine - U Bckground Therpy MET Pretril OADs SU ± MET MET Comprtor Degludec (mx dose, U) Continued GLP-1 RA Plcebo Up-titrtion of glrgine ΔA1c IDegLir, -1.9% Degludec, -.9% P<.1 IDegLir, -1.3% Plcebo, -.3% P<.1 IDegLir, -1.% Plcebo, -.% P<.1 IDegLir, -1.81% Glrgine, -1.13% P<.1 P<.1; b P=.1; c P<.. N=166 insulin-nïve dults with TDM (A1c, 8.3%; BMI, 31. kg/m ) uncontrolled on orl gents ssigned to IDegLir, insulin degludec, or lirglutide 1.8 mg dily (DUAL I Extension). Gough SC, et l. Lncet Dibetes Endocrinol. 14;(11):88-893; Rodbrd HW, et l. Dibetes Obes Metb. 16;18(1):4-48. OADs, orl ntidibetes drugs (MET±PIO±SU); PIO, pioglitzone. 1. Buse JB, et l. Dibetes Cre. 14;37(11):96-933;. Linjwi S, et l. Dibetes. 1;64(suppl 1):A.bstrct 1-P; 3. Rodbrd HW, et l. Dibetes. 1;64(suppl 1):A-A6. bstrct 13-P; 4. Lingvy I, et l. JAMA. 16;31(9): Men Chnge in A1c ± SE, % Fixed-Rtio IGlrLixi vs Glrgine Add-on to Metformin in TDM IGlrLixi (n=161) c Glrgine (n=16) LS men difference, -.17% 9% CI, -.31, Sc LOCF Weeks Men Chnge in Body Weight ±SE, kg IGlrLixi (n=161) c Glrgine (n=16) b LOCF Visit Symptomtic hypoglycemi ( 7 mg/dl): % with IGlrLixi vs 3% with glrgine Incidence of nuse/vomiting ws 7.%/.% with IGlrLixi P=.13; b P<.1 vs glrgine; c IGlrLixi formultion: insulin glrgine U/lixisentide 1 µg. LOCF, lst observtion crried forwrd; LS, lest squres. Rosenstock J, et l. Benefits of Fixed-rtio Formultion of Once-Dily Insulin Glrgine/Lixisentide (LixiLn) vs. Glrgine in Type Dibetes (TDM) Indequtely Controlled on Metformin. Presented t the 74 th Scientific Sessions of the ADA; June 13-17, 14: Sn Frncisco, CA. Abstrct 33-OR. # Injections 3+ ADA/EASD Position Sttement When Bsl Insulin ± Orl Agents Do Not Achieve Trget Glycemi If not controlled fter FPG trget is reched (or if dose >. U/kg/dy), tret PPG excursions with meltime insulin. (Consider initil GLP-1 RA tril) Add 1 rpid insulin injection before lrgest mel Initite, Adjust, nd Monitor for Hypoglycemi If not controlled, consider bsl-bolus Flexibility More Flexible Less Flexible Inzucchi SE, et l. Dibetes Cre. 1;38(1): Add rpid insulin injections before mels ( bsl-bolus ) Initite, Adjust, nd Monitor for Hypoglycemi Chnge to premixed insulin twice dily Initite, Adjust, nd Monitor for Hypoglycemi If not controlled, consider bsl-bolus Complexity Moderte ΔA1c, % Blood Glucose, mmol/l c GLP-1 RA or Bolus Insulin With Optimized Bsl Insulin for TDM Insulin Lispro TID Exentide BID Weeks Since Rndomiztion Pre Post Pre Post Pre Post 3AM Brekfst Lunch Dinner ΔFPG, mmol/l ΔBody Weight, kg Weeks Since Rndomiztion 3 1 b -1 b b b b b - b b Weeks Since Rndomiztion Compred with lispro, exentide cused more GI issues (47% vs 13%), but fewer nonnocturnl hypoglycemic episodes (1% vs 34%) P<.1 for exentide BID vs insulin lispro TID; b P<.1 for exentide BID vs insulin lispro TID; c Open symbols nd dshed lines re t rndomiztion, wheres closed symbols nd solids lines re t 3 weeks. N=67 ptients with insufficient A1c control fter 1 weeks of bsl insulin optimiztion (men bckground dosing ws insulin glrgine 61 units/dy nd metformin mg/dy). Dimnt M, et l. Dibetes Cre. 14;37(1): Lirglutide vs Bolus Insulin Once Dily ΔA1c, % Confirmed Hypoglycemi, Cumultive Events Per Ptient In Ptients Treted With Insulin Degludec IDeg+Lir (n=88) IDeg+IAsp (n=89) Time, weeks IDeg+Lir (n=87) IDeg+IAsp (n=86) Tretment difference, -.3% (9% CI: -.3, -.1) 87% lower rte with IDeg+Lir P< Time, weeks ΔWeight From Bseline, kg P<.; b P<.1. IAsp, insulin sprt. N=177 ptients with TDM nd A1c 7.% despite completing 14-week tril on insulin degludec + MET. Mthieu C, et l. Dibetes Obes Metb. 14;16(7): Tretment difference, -3.7 kg b (9% CI: -4.7, -.79) IDeg+Lir (n=88) IDeg+IAsp (n=89)

10 Men A1c, % Albiglutide Once Weekly vs Thrice-Dily Insulin Lispro Week With Bsl Insulin for TDM Men FPG, mmol/l Week Compred with lispro, lbiglutide cused more nuse (11.% vs 1.4%) nd vomiting (6.7% vs 1.4%), but less hypoglycemi (1.8% vs 9.9%) N=63 ptients with TDM treted with insulin glrgine with metformin nd/or pioglitzone. Rosenstock J, et l. Dibetes Cre. 14;37(1): ΔWeight From Bseline, kg Lispro (n=81) Albiglutide (n=8) -1. (9% CI: -.1, -1.) Week 66-yer-old owner of locl bkery Lives with husbnd of 3 yers Visits you for the first time in 3 yers Hs felt rundown over lst 6 months Recently wkes often to urinte t night SARAH Bckground Hs trouble eting helthy Sttes tht she needs to smple her offerings t the bkery ech dy -3 glsses of wine with dinner ech night Smokes ½ pck/dy Does not exercise other thn wlking b/w commuter trin nd work 6 dys/week Medicl history SARAH Ptient History Hyperlipidemi dignosis 6 yers go Atorvsttin mg once dily Stge 3 CKD, first dignosed yers go egfr, 4 ml/min/1.73 m UACR, 8 mg/g Fmily history Fther died of mjor stroke t 74 yers old Mother ws obese Died following MI t 6 yers old SARAH Physicl Exm nd Lb Testing Height, 4 Weight, 17 lb BMI, 3. kg/m Abdominl obesity Afebrile BP, 131/78 mm Hg FPG, 181 mg/dl nd test, 179 mg/dl A1c, 8.8% Norml sensory nd fundoscopic exms Lipids TC, 186 mg/dl LDL-C, 1 mg/dl HDL-C, 4 mg/dl TG, 1 mg/dl Receives dignosis of TDM SARAH Initil Tretment JOSEPH Bckground Trget A1c, <7.% (provided hypoglycemi is not problem) PCP begins initil discussions bout lifestyle modifictions Suggests certified dibetes eductor Ptient eduction Detiled dietry nd exercise recommendtions 6-yr-old Cucsin mn Advertising executive Lives with wife of yers nd dughters Fmily history Prents hd long history of HTN nd died from CVD Socil history Does not smoke or use illicit drugs Rrely drinks lcohol Does not follow dietry recommendtions Medicl history TDM dignosis 7 yers go Metformin 1 mg twice dily Insulin glrgine, 48 U ech morning Hypertension dignosis 1 yers go Lisinopril 4 mg dily Atenolol mg dily

11 JOSEPH Recent Lb Testing JOSEPH Current Presenttion Height, 7 Weight, 6 lb BMI, 4.7 kg/m BP, 14/78 mm Hg (on therpy) Recent FPG, 87 mg/dl A1c, 7.8% A1c Gol, <7.% Lipids TC, 187 mg/dl LDL-C, 1 mg/dl HDL-C, mg/dl TG, 16 mg/dl egfr, 9 ml/min/1.73 m UACR,. mg/g Numerous episodes of shkiness nd sweting over the lst few months Often occur when he is lte nd skips brekfst Occsionlly wkes feeling unwell nd offkilter Spordic BGM shows morning hypoglycemi episodes Blood glucose redings 4-6 mg/dl JOSEPH Follow-Up Visit JOHNNY Bckground At follow-up ppointment 1 week lter, Joseph presents more detiled blood glucose testing Dy AM Fsting -h PPG Bedtime / / / / / / yer-old Blck mn Retired construction worker Lives lone Divorced wife of 3 yers yers go Presents for check-up Lst visit 6 months go Nonsmoker Reltively unhelthy lifestyle Some physicl ctivity Regulrly consumes fst food Rrely ets fruits or vegetbles Drinks 4- beers ech night JOHNNY Ptient History Medicl history Hypertension dignosis yers go Lisinopril 4 mg dily nd tenolol mg dily TE myocrdil infrction yers go PCI, 1 months of ticgrelor, dily low-dose spirin TDM dignosis t dmission for the MI Metformin 1 mg twice dily Glyburide 1 mg once dily Hyperlipidemi dignosis 1 yer go Atorvsttin 4 mg dily Fmily history Mother died of MI t 6 yers old Fther is live t 8 yers old but hs TDM Cse Question Bsed on Johnny s current glycemic control, crdiovsculr profile, nd other medicl issues, which of the following mediction clsses would you consider dding to his ntihyperglycemic regimen? 1. TZD. DPP-4 inhibitor 3. SGLT- inhibitor 4. GLP-1 RA. Bsl insulin TE, non ST-segment elevtion; PCI, percutneous coronry intervention.

12 JOHNNY Clinicl interview Forgets to tke vrious pills -3 times/week Hs been tking wlks but is hving difficult time sticking to dietry recommendtions Wife used to do the cooking Now tht he lives lone he often ets fst food even though he know tht he shouldn t Hs been skipping brekfst occsionlly in n effort to lose weight Ends up sncking more lter in the dy Describes 3 occsions over the lst 6 months where he felt shky nd swety Conclusions Monitor multiple prmeters for good TDM mngement nd reduced CV risk A1c, lipids, BP Hypoglycemic episodes re ssocited with serious dverse outcomes Consider pproprite roles for DPP-4 inhibitors Modest reductions in A1c Weight neutrl nd low risks of hypoglycemi Well tolerted with few mjor side effects Consider pproprite roles for GLP-1 RAs Robust reductions in A1c Reltively low risks of hypoglycemi Most common side effects re gstrointestinl Potentil for weight loss nd CV benefits