TYPE 2 DIABETES Integrating GLP-1 Receptor Agonists Into Multimodal Treatment Regimens

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1 Eductionl prtner IMPROVING OUTCOMES IN TYPE 2 DIABETES Integrting GLP Receptor Agonists Into Multimodl Tretment Regimens OCTOBER 15, 214 Donld E. Stephens Convention Center Rosemont, IL

2 IMPROVING OUTCOMES IN TYPE 2 DIABETES Integrting GLP Receptor Agonists Into Multimodl Tretment Regimens FACULTY Vivin A. Fonsec, MD, FRCP Interctive Professor (Prerecorded) Professor of Medicine nd Phrmcology Tullis Tulne Alumni Chir in Dietes Chief, Section of Endocrinology Tulne University Helth Sciences Center New Orlens, Louisin Lwrence Blonde, MD, FACP, FACE Director, Ochsner Dietes Clinicl Reserch Unit Deprtment of Endocrinology, Dietes nd Metolism Associte Internl Medicine Residency Progrm Director Ochsner Medicl Center New Orlens, Louisin Jeffrey R. Unger, MD Director, Metolic Studies Ctlin Reserch Institute Chino, Cliforni Director, Unger Primry Cre Privte Medicine Group Rncho Cucmong, Cliforni LEARNING OBJECTIVES Upon completion of these eductionl ctivities, prticipnts will e etter prepred to: 1. Discuss the pthologic mechnisms of T2DM tht support the need for prompt dignosis nd ggressive tretment 2. Identify ptient-centered tretment gols for ptients with T2DM tht encompss good overll glycemic control nd improvements in other clinicl prmeters 3. Evlute the clinicl profiles of GLP receptor gonists for the tretment of T2DM 4. Individulize therpeutic regimens for T2DM to mximize efficcy nd minimize hypoglycemi, weight gin, nd other potentil tretment-relted risks 5. Communicte with ptients with T2DM out lifestyle modifictions, ntihyperglycemic options, nd the need for tretment dherence FACULTY FINANCIAL DISCLOSURE STATEMENTS The presenting fculty reported the following: Vivin Fonsec, MD, receives grnt reserch support vi Tulne University from Aott Lortories; Eli Lilly nd Compny; GI Dynmics, Inc.; Novo Nordisk A/S; Pn Americn Lortories; Ret Phrmceuticls Inc.; nd snofi-ventis US LLC. He receives honorri for consulting nd lectures from Aott Lortories; AstrZenec; Boehringer Ingelheim GmH; Bristol-Myers Squi Compny; Diichi Snkyo Compny, Limited; Eli Lilly nd Compny; GlxoSmithKline; Jnssen Phrmceuticls, Inc.; Novo Nordisk A/S; PmL, Inc.; snofi-ventis US LLC.; nd Tked Phrmceuticls USA, Inc. his role s consultnt to AstrZenec, GlxoSmithKline, Jnssen Phrmceuticls, Inc., Merck & Co., Inc., Novo Nordisk A/S, Quest Dignostics, nd snofi-ventis US LLC. Jeffrey Unger, MD, receives honorri from Aott Lortories; Jnssen Phrmceuticls, Inc.; Novo Nordisk A/S; nd Vlerits, Inc. EDUCATION PARTNER FINANCIAL DISCLOSURE STATEMENTS The content collortors t Integrits Communictions hve reported the following: Jim Kppler, PhD, hs nothing to disclose. Lwrence Blonde, MD, receives grnt reserch support from Eli Lilly nd Compny, Novo Nordisk A/S nd snofi-ventis US LLC. He receives honorri for his role s speker from AstrZenec, Jnssen Phrmceuticls, Inc., Merck & Co., Novo Nordisk A/S, nd snofi-ventis US LLC. He receives honorri for Eduction Prtner CLINICAL RESOURCE CENTER Access the progrm syllus nd dditionl resources y scnning the imge on the left. If you do not hve QR Code Reder on your moile device, visit getscnlife.com for free downlod. EXCHANGECME.com/T2DM214

3 SESSION 4 12:45pm 2:pm Improving Outcomes in Type 2 Dietes: Integrting GLP Receptor Agonists Into Multimodl Tretment Regimens SPEAKERS Vivin Fonsec, MD Lwrence Blonde, MD, FACP, FACE Jeff Unger, MD Presenter Disclosure Informtion The following reltionships exist relted to this presenttion: Vivin Fonsec, MD, receives grnt reserch support vi Tulne University from Aott Lortories; Eli Lilly nd Compny; GI Dynmics, Inc.; Novo Nordisk A/S; Pn Americn Lortories; Ret Phrmceuticls Inc.; nd snofi-ventis US LLC. He receives honorri for consulting nd lectures from Aott Lortories; AstrZenec; Boehringer Ingelheim GmH; Bristol- Myers Squi Compny; Diichi Snkyo Compny, Limited; Eli Lilly nd Compny; GlxoSmithKline; Jnssen Phrmceuticls, Inc.; Novo Nordisk A/S; PmL, Inc.; snofi-ventis US LLC.; nd Tked Phrmceuticls USA, Inc. Presenter Disclosure Informtion Lwrence Blonde, MD, receives grnt reserch support from Eli Lilly nd Compny, Novo Nordisk A/S nd snofi-ventis US LLC. He receives honorri for his role s speker from AstrZenec, Jnssen Phrmceuticls, Inc., Merck & Co., Novo Nordisk A/S, nd snofi-ventis US LLC. He receives honorri for his role s consultnt to AstrZenec, GlxoSmithKline, Jnssen Phrmceuticls, Inc., Merck & Co., Inc., Novo Nordisk A/S, Quest Dignostics, nd snofi-ventis US LLC. Jeffrey Unger, MD, receives honorri from Aott Lortories; Jnssen Phrmceuticls, Inc.; Novo Nordisk A/S; nd Vlerits, Inc. Off-Lel/Investigtionl Discussion In ccordnce with pmicme policy, fculty hve een sked to disclose discussion of unleled or unpproved use(s) of drugs or devices during the course of their presenttions. Mediction clsses GLP receptor gonists DPP-4 inhiitors Sttins ACE inhiitors Insulins Amylin mimetics Thizolidinediones Meglitinides SGLT-2 inhiitors α-glucosidse inhiitors Sulfonylures Medictions Discussed in Progrm Specific medictions Lisinopril Atenolol Atorvsttin Metformin Insulin glrgine Insulin detemir Colesevelm Bromocriptine Sitgliptin Sxgliptin Lingliptin Exentide BID Exentide QW Lirglutide Aliglutide Dulglutide Semglutide Lixisentide IMPROVING OUTCOMES IN TYPE 2 DIABETES Integrting GLP Receptor Agonists Into Multimodl Tretment Regimens Lwrence Blonde, MD, FACP, FACE Director, Ochsner Dietes Clinicl Reserch Unit Deprtment of Endocrinology, Dietes, nd Metolism Ochsner Medicl Center New Orlens, Louisin Vivin Fonsec, MD, FRCP Professor of Medicine nd Phrmcology Tullis-Tulne Alumni Chir in Dietes Chief, Section of Endocrinology Tulne University Helth Sciences Center New Orlens, Louisin Jeff Unger, MD Director Unger Primry Cre Concierge Medicl Center Rncho Cucmong, Cliforni Eductionl Ojectives Discuss the pthologic mechnisms of T2DM tht support the need for prompt dignosis nd ggressive tretment Identify ptient-centered tretment gols for ptients with T2DM tht encompss good overll glycemic control nd improvements in other clinicl prmeters Evlute the clinicl profiles of GLP receptor gonists for the tretment of T2DM Individulize therpeutic regimens for T2DM to mximize efficcy nd minimize hypoglycemi, weight gin, nd other potentil tretment-relted risks Communicte with ptients with T2DM out lifestyle modifictions, ntihyperglycemic options, nd the need for tretment dherence GLP, glucgon-like peptide; T2DM, type 2 dietes mellitus.

4 Scientific Insights Into INCRETIN SIGNALING nd TYPE 2 DIABETES Vivin Fonsec, MD, FRCP Professor of Medicine nd Phrmcology Tullis-Tulne Alumni Chir in Dietes Chief, Section of Endocrinology Tulne University Helth Sciences Center New Orlens, Louisin Scientific Insights Into Incretin Signling nd T2DM Key Points Incretin effect: more insulin is secreted in response to orlly delivered glucose compred with intrvenously dministered glucose 1 The gstrointestinl hormones GLP nd GIP stimulte insulin relese in response to food intke 2 GLP lso reduces glucgon relese following food intke, slows gstric emptying, nd increses stiety 2 Reduced incretin effect is n erly sign of T2DM development 3 GLP nd GIP re rpidly degrded y DPP-4 2 Clinicl reserch hs focused on degrdtion-resistnt GLP RAs nd inhiitors of DPP-4 DPP-4, dipeptidyl peptidse-4; GIP, glucose-dependent insulinotropic polypeptide; GLP RA, glucgon-like peptide receptor gonist; T2DM, type 2 dietes mellitus. 1. Elrick H, et l. J Clin Endocrinol Met. 1964;24:17682; 2. Grunerger G. J Dietes. 213;5(3): ; 3. Holst JJ, et l. Dietes Cre. 211;34 (suppl 2):S251-S257. Reducing T2DM Complictions Multidimensionl Tretment Gols BP <14/8 mm Hg (<13/8 mm Hg for some people) A1c <7.% Comprehensive Dietes Mngement Lipids LDL-C: <1 mg/dl (<7 mg/dl with CVD) HDL-C: >4 mg/dl in men >5 mg/dl in women TG: <15 mg/dl Lifestyle Modifictions Helthy Diet; Exercise; Smoking Cesstion BMI <25 mg/kg ACC/AHA guidelines on tretment of lood cholesterol: Bsed on 1-yer ASCVD risk, use high-intensity (lower LDL-C y 5%) or moderte-intensity (lower LDL-C y 3% to <5%) sttin therpy for ptients ged 4-75 yers with T2DM nd initil LDL-C 7 mg/dl. A1c, glycted hemogloin; ASCVD, therosclerotic CVD; BMI, ody mss index; BP, lood pressure; CVD, crdiovsculr disese; HDL-C, low-density lipoprotein cholesterol; LDL-C, high-density lipoprotein cholesterol; TG, triglycerides. ADA. Dietes Cre. 214;37(suppl 1):S14-S8; Stone NJ, et l. Circultion. 214;129(25 suppl 2):S1-S45. Ptients Achieving Gol, % Achieving Tretment Gols Room for Improvement in T2DM A1c <7.% BP <13/8 mm Hg LDL <1 mg/dl A1c <7.%, BP <13/8 mm Hg, nd LDL <1 mg/dl P<.1. N=1497 ( ) nd 1447 (27-21) dults ged 2 yers with self-reported dignosis of dietes. Retrospective nlysis of dt otined from the Ntionl Helth nd Nutrition Exmintion Surveys. Strk Csgrnde S, et l. Dietes Cre. 213;36(8): yer-old Africn Americn mn Retired wrehouse mnger Divorced Lives lone BMI, 3.1 kg/m 2 (oese) BP, 135/78 mm Hg Unhelthy lifestyle Little physicl ctivity Regulrly consumes fried food, red met, nd sugry sod Rrely ets fruits or vegetles Wlter PCP Visit Fmily history Mother hd T2DM Medicl history Hypertension dignosis 5 yers go Lisinopril 4 mg dily Atenolol 5 mg dily Episode of unstle ngin 2 yers go Dily low-dose spirin Forgets medictions 1-2 times weekly Despite no overt symptoms of hyperglycemi, should Wlter e screened for T2DM? PCP, primry cre provider. ADA 1 AACE 2 Wlter s risk fctors Screening Asymptomtic Persons for Dietes Screen 45 yers of ge, t lest every 3 yers Screen t ny ge nd more frequently if BMI 25 kg/m 2 nd n dditionl risk fctor is present Screening should e considered in the presence of ny risk fctors for T2DM Oese First-degree reltive with dietes -risk rce or ethnic group (eg, Blck, Hispnic) Hypertension (BP 14/9 mm Hg, or therpy) History of crdiovsculr disese Previously undignosed dietes is common in ptients presenting with myocrdil infrction 3 AACE, Americn Assocition of Clinicl Endocrinologists; ADA, Americn Dietes Assocition. 1. ADA. Dietes Cre. 214;37(suppl 1):S14-S8; 2. Grer AJ, et l. Endocr Prct. 213;19(suppl 1):1-48; 3. Lnkisch M, et l. Clin Res Crdiol. 28;97(1):

5 Wlter Workup nd Dignosis A1c, 8.8% FPG, 199 mg/dl Second test 197 mg/dl egfr, 8 ml/min/1.73 m 2 ACR, 2.4 mg/mmol Norml sensory exm Lipids LDL-C, 13 mg/dl HDL-C, 4 mg/dl TG, 155 mg/dl TC, 25 mg/dl Wlter receives dignosis of T2DM Age, 62 yers Newly Dignosed Hypertension Wlter Setting Glycemic Trgets BMI, 3.1 kg/m 2 A1C, 8.8% Mother treted for T2DM History of unstle ngin Norml renl function Not dherent to other drug therpies Wht would you set s n A1c trget for Wlter? ACR, lumin/cretinine rtio; egfr, estimted glomerulr filtrtion rte; FPG, fsting plsm glucose; TC, totl cholesterol. Inzucchi SE, et l. Dietes Cre. 212;35(6): Wlter Initil Tretment Trget A1c <7.% Wlter nd PCP discuss lifestyle modifictions PCP suggests certified dietes eductor Ptient eduction Detiled dietry nd exercise recommendtions Dietes Eduction nd Lifestyle Modifictions Skills-sed dietes eduction to support informed self-mngement Disese process nd tretment options Nutritionl mngement nd physicl ctivity Blood glucose monitoring Sfe use of medictions (eg, risks of hypoglycemi) Strtegies to ddress psychosocil issues nd promote ehvior chnge Physicl ctivity At lest 15 min/week of moderte ctivity Aeroic, resistnce, flexiility Individulize dietry recommendtions Discuss mcronutrient content nd eting ptterns Monitor crohydrte intke Reduce clories to chieve weight loss Moderte clorie restriction (5 kcl/dy) recommended initilly Wht re the potentil enefits of these pproches? ADA. Dietes Cre. 214;37(suppl 1):S14-S8; Evert AB, et l. Dietes Cre. 214;37(suppl 1):S12-S143; Jensen MD, et l. Circultion. 213 Nov 12. [Epu hed of print]; Hs L, et l. Dietes Cre. 214;37(suppl 1):S144-S153. LOOK AHEAD Study Intensive Lifestyle Intervention nd Risk Reduction Diet modifiction, exercise, ehviorl trining Group support with in-person nd telephone follow-ups Prmeter P<.1; P=.1 vs support nd eduction lone. N=257 for lifestyle intervention nd 2575 for support nd eduction. MET, metolic equivlent. Look AHEAD Reserch Group. Arch Intern Med. 21;17(17): Intensive Lifestyle Intervention Support nd Eduction Weight loss, % Tredmill fitness, % METs A1c, % Systolic pressure, mm Hg Distolic pressure, mm Hg HDL-C, mg/dl Triglycerides, mg/dl Prevlence, % Look AHEAD Intensive Lifestyle Interventions nd Dietes Remission Remission Prevlence Intensive lifestyle intervention Dietes support nd eduction Yer N=453 dults with T2DM nd BMI 25 kg/m 2. Gregg EW, et l. JAMA. 212;38(23): Estimte, % Remission Durtion Intensive lifestyle intervention Dietes support nd eduction Yers of Continuous Remission (Prtil or Complete)

6 Annulized rte of severe hypoglycemi, % Rtes of Severe Hypoglycemi Intensive vs Stndrd Therpy UKPDS 1 ADVANCE 2 ACCORD 3 VADT 4 P<.1 vs CON HR 1.86 ( ) P<.1 P<.1 P= CON GLY INS STD INT STD INT STD INT A1c= 7.9% 7.1% 7.2% 7.3% 6.5% 7.5% 6.4% 8.4% 6.9% ADVANCE Severe Hypoglycemi vs Adverse End Points HR (95% CI): 3.53 ( ) HR (95% CI): 2.19 ( ) HR (95% CI): 3.27 ( ) HR (95% CI): HR (95% CI): 3.79 ( ) 2.8 ( ) Hypoglycemi requiring ny ssistnce; Intensive glycemic control ws defined differently in these trils. ACCORD, Action to Control Crdiovsculr Risk in Dietes; ADVANCE, Action in Dietes nd Vsculr Disese: PreterAx nd DimicroN MR Controlled Evlution; CON, conventionl therpy; GLY, glienclmide; HR, hzrd rtio; INS, insulin; INT, intensive therpy; STD, stndrd therpy; UKPDS, UK Prospective Dietes Study; VADT, Veterns Affirs Dietes Tril. 1. UKPDS Group. Lncet. 1998;352(9131): ; 2. Ptel A, et l; [ADVANCE]. N Engl J Med. 28;358(24): ; 3. Gerstein HC, et l; [ACCORD]. N Engl J Med. 28;358(24): ; 4. Duckworth W, et l. N Engl J Med. 29;36(2): Adjusted for multiple seline covrites; Primry end points. Mjor mcrovsculr event=cv deth, nonftl myocrdil infrction, or nonftl stroke. Mjor microvsculr event=new or worsening nephropthy or retinopthy. Zoungs S, et l. N Engl J Med. 21;363(15): Wlter Overview 62-yer-old Africn-Americn with n unhelthy lifestyle BMI, 3.1 kg/m 2 (oese) BP, 135/78 mm Hg A1c, 8.8% Trget A1c, <7.% FPG, 199 mg/dl egfr, 8 ml/min/1.73 m 2 ACR, 2.4 mg/mmol Norml sensory exm Lipids TC, 25 mg/dl LDL-C, 13 mg/dl HDL-C, 4 mg/dl TG, 155 mg/dl Mother hd T2DM Medicl history Hypertension Lisinopril nd tenolol Previous unstle ngin Dily low-dose spirin Often forgets medictions Should Wlter e treted initilly with monotherpy or multidrug regimen? ADA/EASD Recommendtions Mnging Hyperglycemi in T2DM Initil Drug Monotherpy Efficcy ( A1c) Hypoglycemi Weight Side Effects Costs Two-Drug Comintion, Efficcy ( A1c) Hypoglycemi Weight Mjor Side Effect(s) Costs Helthy Eting, Weight Control, Incresed Physicl Activity Metformin Low risk Neutrl/Loss GI/Lctic cidosis Low If needed to rech individulized A1c trget fter ~3 months, proceed to 2-drug comintion + SU Moderte risk Gin Hypoglycemi Low + TZD Low risk Gin Edem, HF, Fx s Metformin + DPP-4 inhiitor Intermedite Low risk Neutrl Rre + GLP RA Low risk Loss GI + Insulin est risk Gin Hypoglycemi Vrile Consider eginning t this stge in ptients with high A1c (eg, 9%); At puliction, SGLT-2 inhiitors hd not een FDA-pproved. EASD, Europen Assocition for the Study of Dietes; FDA, US Food nd Drug Administrtion; Fx s, one frctures; GI, gstrointestinl; HF, hert filure; SGLT-2, sodium glucose cotrnsporter-2; SU, sulfonylure; TZD, thizolidinedione. Inzucchi SE, et l. Dietes Cre. 212;35(6): AACE/ACE Algorithm for Glycemic Control Lifestyle Modifiction Entry A1c <7.5% Entry A1c 7.5% Entry A1c > 9.% Monotherpy Dul Therpy No Metformin GLP RA Symptoms Symptoms GLP RA DPP-4 inhiitor AG inhiitor SGLT-2 inhiitor DPP-4 inhiitor TZD SGLT-2 inhiitor Bsl Insulin Dul Therpy OR Insulin ±Other TZD SU/GLN If A1c >6.5% in 3 months, Colesevelm Bromocriptine QR AG inhiitor SU/GLN Add or Intensify Insulin Triple Agents Therpy dd second drug If not t gol in 3 months, Possile enefits or few dverse events (Dul Therpy) proceed to triple therpy Use with cution Order of medictions listed re suggested hierrchy of usge; Bsed on phse 3 clinicl trils. ACE, Americn College of Endocrinology; AG, α-glucosidse; GLN, glinide; QR, quick relese. Grer AJ, et l. Endocr Prct. 213;19(3): METFORMIN or other first-line gent Wlter Tretment Initition nd Follow-up Prescried metformin 5 mg twice dily Titrted up to 1 mg twice dily over next month 3-month follow-up ppointment A1c, 8.% Previous vlue, 8.8% Trget vlue, <7.% FPG, 14 mg/dl Previous vlue, 199 mg/dl PPG, 21 mg/dl (2-h postmel) No significnt chnges in ny other clinicl prmeters PCP suggests dding n incretin-sed gent to Wlter's regimen PPG, postprndil glucose.

7 GLP Receptor Agonists Effects on Humn Physiology Pncres 1 Insulin secretion (glucose-dependent) nd β-cell sensitivity 2,3 Insulin synthesis 4 Glucgon secretion 3 (glucose-dependent) Stomch 1,4 Gstric emptying Brin 1,5-7 Body weight Stiety Energy intke Crdiovsculr System 1,8 Systolic BP Liver 1,4 Heptic glucose output 1. Holst JJ, et l. Trends Mol Med. 28;14(4):16168; 2. Flint A, et l. Adv Ther. 211;28(3): ; 3. Degn K, et l. Dietes. 24;53(5): ; 4. Bggio LL, Drucker DJ. Gstroenterology. 27;132(6): ; 5. Horowitz M, et l. Dietes Res Clin Prct. 212;97(2): ; 6. Vilsøll T, et l. BMJ. 212;344:d7771; 7. Niswender K, et l. Dietes Oes Met. 213(1);15:42-54; 8. Fonsec V, et l. Dietes. 21;59(suppl 1):A79(296-OR). Mediction Exentide BID 1 Lirglutide 2 FDA-Approved GLP RAs Dily Formultions Dosge forms Adverse events Dosing 5 μg/dose in 1.2-mL Nuse, vomiting, 1.Strt t 5 μg twice dily prefilled pen 1 μg/dose in 2.4-mL prefilled pen dyspepsi (1 hour efore morning nd evening mels) 2.Increse to 1 μg twice dily fter 1 month Prefilled, multidose pen tht delivers doses of.6 mg, 1.2 mg, or 1.8 mg Nuse, dirrhe, vomiting, constiption, hedche 1.Initite t.6 mg once dily, regrdless of mels 2.After 1 week, increse dose to 1.2 mg 3.If glycemic control is not cceptle, dose cn e incresed to 1.8 mg Tretment-emergent dverse rections with 5% incidence in clinicl trils with drug s monotherpy (excluding hypoglycemi). 1. See Drugs@FDA ( 2. See Drugs@FDA ( Mediction Exentide QW 1 Aliglutide 2 FDA-Approved GLP RAs Weekly Formultions Dosge forms Single-dose try with 2 mg vil Single-dose 2 mg prefilled pen 3-mg or 5-mg lyophilized powder in single-dose pen for reconstitution Dulglutide 3 Single-dose pen in.75 mg or 1.5 mg doses Prefilled, single-dose syringe in.75 mg or 1.5 mg doses Adverse events Nuse, dirrhe, injection-site nodule, constiption, hedche, dyspepsi URTI, dirrhe, nuse, injection-site rection, cough, ck pin, rthrlgi, sinusitis, influenz Dosing 1. Administer t 2. mg once every 7 dys (weekly), independent of mels 1. Administer t 3 mg once every 7 dys (weekly), regrdless of mels 2. If glycemic control not cceptle, dose cn increse to 5 mg Nuse, dirrhe, 1. Initite t.75 mg weekly, vomiting, dominl regrdless of mels or time of dy; pin, nd decresed dose cn e incresed to 1.5mg ppetite 2. If dose is missed, missed dose must e tken within 3 dys URTI, upper respirtory trct infection. Tretment-emergent dverse rections with 5% incidence in clinicl trils with drug s monotherpy (excluding hypoglycemi). 1. See Drugs@FDA ( 2. Trynor K. Am J Helth Syst Phrm. 214;71(11):888; 3. Dulglutide prescriing informtion. Accessed Septemer 23rd, Exentide BID Glucose Control nd Weight Loss A1c,% Weight, kg Bckground TZD ± SU + TZD ± SU + 1 Therpy c None MET SU 4 MET MET None MET 3 SU 4 MET MET Exentide BID 1 μg Plceo Exentide BID 1 μg P<.1 vs plceo; P<.1 vs plceo; c 16 to 3 weeks, seline A1c: 7.8%-8.7. MET, metformin. 1. Moretto TJ, et l. Clin Ther. 28;3(8):144846; 2. DeFronzo RA, et l. Dietes Cre. 25;28(8):1921; 3. Buse JB, et l. Dietes Cre. 24;27: ; 4. Zinmn B, et l. Ann Intern Med. 27;146(7): ; 5. Kendll DM, et l. Dietes Cre. 25;28(5): Plceo Lirglutide Glucose Control nd Weight Loss A1c,% Weight, kg Bckground Therpy d None1 MET SU TZD ± MET 4 SU + MET None MET 3 SU TZD ± 4 MET SU + MET c c Lirglutide 1.8 mg Plceo Sulfonylure P<.1 vs comprtor; P<.1 vs comprtor; c P<.1 vs comprtor; d 26 weeks (except 52 weeks for monotherpy), men seline A1c: 8.2%-8.6%. 1. Grer A, et l. Lncet. 29;373(9662): ; 2. Nuck M, et l. Dietes Cre. 29;32(1):84-9; 3. Mrre M, et l. Diet Med. 29;26(3): ; 4. Zinmn B, et l. Dietes Cre. 29;32(7):122423; 5. Russell-Jones D, et l. Dietologi. 29;52(1): Exentide QW Glucose Control nd Weight Loss A1c,% Weight, kg Bckground ± MET, SU, nd/or ± MET, SU, nd/or 2, 2, Therpy 1, None TZD MET MET ± SU None1, TZD MET MET ± SU Exentide QW Exentide BID Sitgliptin Pioglitzone Insulin Glrgine P<.5 for ll comprtors vs exentide QW 2 mg. Only SITA comprtor shown (study lso included MET nd PIO s comprtors); Comintion therpy llowed. 1. Russell-Jones D, et l. Dietes Cre. 212;35(2): ; 2. Blevins T, et l. J Clin Endocrinol Met. 211;96:13131; 3. Bergenstl RM, et l. Lncet. 21;376: ; 4. Dimnt M, et l. Lncet. 21;375:

8 Aliglutide Glucose Control nd Weight Loss A1c,% Weight, kg Bckground TZD ± SU + TZD ± SU Therpy None MET SU MET MET None MET 3 SU MET MET c Aliglutide 3 mg or 5 mg Plceo Insulin Glrgine P<.1 vs comprtor; P<.1 vs comprtor; c P =.86 vs insulin glrgine nd met noninferiority mrgin. 1. Nuck M, et l. HARMONY 2 Wk 52 Results: Aliglutide Monotherpy in Drug Nïve Ptients with Type 2 Dietes Mellitus. ADA 73 rd Scientific Sessions; June 21-25, 213; Chicgo, IL; 2. Ahren B, et l. Dietes Cre. 214;37(8): ; 3. Stewrt M, et l. 52-Week Efficcy of Aliglutide vs Plceo nd vs Pioglitzone in Triple Therpy (Bckground Metformin nd Glimepiride) in Ptients With Type 2 Dietes: HARMONY 5 study. 49 th Annul Meeting for the EASD; Septemer 23-27, 213; Brcelon, Spin; 4. Reusch J, et l. HARMONY 1 Week 52 Results: Aliglutide vs. Plceo in Ptients with Type 2 Dietes Mellitus not Controlled On Pioglitzone ± Metformin. ADA 73 rd Scientific Sessions; June 21-25, 213; Chicgo, IL; 5. Prtley R, et l. HARMONY 4: 52-Wk Efficcy of Aliglutide vs. Insulin Glrgine in Ptients with T2DM. ADA 73 rd Scientific Sessions; June 21-25, 213; Chicgo, IL. Dulglutide Glucose Control nd Weight Loss A1c,% Bckground MET + MET + Therpy d 1 None MET 3 PIO GLIM INS 2 4 5,e c c c Dulglutide 1.5 mg Exentide BID Insulin glrgine Metformin Sitgliptin P<.5 vs comprtor; P<.1 vs comprtor; c Met superiority mrgin vs comprtor; d Dt reflect week 26 or 52; e Comprtors were dded to insulin lispro nd conventionl ckground insulin. 1. Umpierrez G, et l. Dietes Cre. 214;37(8): ; 2. Nuck M, et l. Dietes Cre. 214;37(8): ; 3. Wyshm C, et l. Dietes Cre. 214;37(8): ; 4. Giorgino F, et l. Efficcy nd Sfety of Once-Weekly Dulglutide vs. Insulin Glrgine in Comin-tion with Metformin nd Glimepiride in Type 2 Dietes Ptients (AWARD-2). Astrct 33-OR. Presented t 74th ADA Scientific Sessions; June 137, 214; Sn Frncisco, CA.; 5. Jendle J, et l. Better Glycemic Control nd Less Weight Gin with Once-Weekly Dulglutide vs. Once-Dily Insulin Glrgine, Both Comined with Premel Insulin Lispro, in Type 2 Dietes Ptients (AWARD-4). Astrct 962-P. Presented t 74th ADA Scientific Sessions; June 137, 214; Sn Frncisco, CA Weight, kg MET + MET + 1 None MET 3 PIO GLIM INS 2 4 5,e Weight Effects of GLP RAs in T2DM Met-nlysis of pulished studies Exentide QW Lirglutide Exentide BID Weight (kg) With Exentide BID or QW 1% lost >1 kg 2% lost 5 kg 48% lost -5 kg 2%-23% gined -5 kg 1%-2% gined 5 kg Weight chnges in ptients treted for 12 weeks. Arod VR, et l. Clin Ther. 212;34(6): ; Blevins T, et l. J Clin Endocrinol Met. 211;96(5):13131; Buse JB, et l. Lncet. 29;374(9683):39-47; Buse J, et l. Lncet. 213;381(9861):11724; Drucker DJ, et l. Lncet. 28;372(9645):12425; Rosenstock J, et l. 47th EASD Annul Meeting Weight Loss With GLP RAs Not Driven y Gstrointestinl Adverse Events Lirglutide (Met-Anlysis/6 26-Week Trils) 1 No NVD Some NVD Weight Chnge (kg) , 6,.62 P<.5 PBO 1.2 mg LIRA -2.45, 1.8 mg LIRA P<.5 Exentide (3-Week DURATION Tril) 2 No Nuse Nuse In 82-week exentide completer cohort, weight loss ws 1) similr cross degrees of nuse, 2) progressive despite stle nuse incidence, nd 3) unlikely to e driven y nuse. 3 NVD, nuse, vomiting, dirrhe. P<.5 vs seline; P<.5 vs plceo. 1. Russell-Jones D, et l. 7th ADA Scientific Sessions. 21;1886-P; 2. Drucker DJ, et l. Lncet. 28;372(9645):12425; 3. Blonde L, et l. Dietes Oes Met. 26;8(4): EXN QW EXN BID Select Antidietic Therpies nd Hypoglycemi GLP RAs in T2DM Improved Lipid Profiles Drug A1c Reduction, % Hypoglycemi Incidence, % Exentide twice dily Exentide weekly Lirglutide Aliglutide.7-.9 e Dulglutide e DPP-4 inhiitors f SGLT-2 inhiitors e Sulfonylures Pioglitzone Bsl Insulin c d Chnge in Lipid Level, mg/dl LEAD-6, 26 Weeks 1 TC LDL-C HDL-C TG Lirglutide -25 Exentide BID -3 DURATION, 3 Weeks 2 TC LDL-C HDL-C TG Exentide QW Exentide BID Similr to plceo; Includes cngliflozin, dpgliflozin, nd empgliflozin; c Includes NPH, insulin glrgine, nd insulin detemir; d No dose or A1c-lowering limit; e Hypoglycemi risk is higher when used with insulin; f Includes sxgliptin, lingliptin, stigliptin nd logliptin. Amlee A. Drugs Tody (Brc). 214;5(4): ; Bolnd CL, et l. Ann Phrmcother. 213;47:49-55; Woodwrd HN, Anderson SL. Ptient Prefer Adherence. 214;8:789-83; Zhng Q, et l. Dietes Res Clin Prct. 214 Jun 22. [Epu hed of print]. P<.5 vs exentide BID; Signifcnt difference vs exentide BID sed on confidence intervls. 1. Buse J, et l. Lncet. 29;374(9683): N=464 ptients with indequtely controlled T2DM on mximlly tolerted doses of metformin, sulfonylure, or oth. 2. Drucker DJ, et l. Lncet. 28;372(9645): N=295 ptients with T2DM who were nive to drug therpy, or on 1 or more orl ntidietic gents.

9 GLP RAs nd Blood Pressure Met-Anlysis of Dt From Oese nd Overweight Individuls Prmeter Chnge vs Control 95% CI Systolic lood pressure 3.57 mm Hg 5.49 to 1.66 Distolic lood pressure 1.38 mm Hg 2.2 to.73 Tril REWIND (NCT ) EXSCEL (NCT ) LEADER (NCT117948) ELIXA (NCT114725) SUSTAIN 6 (NCT172446) GLP RAs nd Crdiovsculr Outcomes Ongoing Trils Agent Ptients (N) Durtion (y) Ptient- Yers Estimted Completion Dulglutide , Exentide QW , Lirglutide , Lixisentide ,4 214 Semglutide Includes 11 or 12 trils exmining overweight nd oese individuls with or without T2DM; tretments included exentide BID, exentide QW, or lirglutide. Vilsøll T, et l. BMJ. 212;344:d7771. Ntionl Institutes of Helth wesite. Accessed My 2, 214; Petrie JR. Crdiovsc Dietol. 213;12:13. Sfe Prescriing With GLP RAs Acute Pncretitis Precutions 1-5 Cses hve een reported Consider tretments other thn GLP RAs in ptients with history of pncretitis Recommendtions 1-5 Ask out pncretitis history Educte ptients, monitor for signs nd symptoms Discontinue promptly if pncretitis symptoms occur If cute pncretitis is confirmed, do not restrt GLP RA Report cses of pncretitis to Pncretitis risk is 1.5- to 3-fold higher in individuls with dietes Trynor K. Am J Helth Syst Phrm. 214;71(11):888; 2. See Drugs@FDA ( 3. See Drugs@FDA ( 4. See Drugs@FDA ( 5. Dulglutide prescriing informtion. Accessed Septemer 23rd, 214; 6. Noel RA, et l. Dietes Cre. 29;32(5): ; 7. Girmn CJ, et l. Dietes Oes Met. 21;12(9): ; 8. Grg R, et l. Dietes Cre. 21;33(11): ; 9. Yng L, et l. Eur J Gstroenterol Heptol. 213;25(2): Sfe Prescriing With GLP RAs Possile Thyroid nd Endocrine Risk Contrindictions 1-5 Aliglutide Dulglutide Exentide BID Exentide QW Lirglutide Do not use if personl/fmily history of MTC or X X X X presence of MEN2 Recommendtions Counsel ptients regrding MTC risk nd symptoms of thyroid tumors 1-4 Vlue of routine clcitonin nd/or ultrsound monitoring is uncertin; such monitoring my led to unnecessry procedures 1-4 Ptients with thyroid nodules or elevted serum clcitonin levels identified for other resons should e sent to n endocrinologist 1-4 Report MTC to stte cncer registry, regrdless of tretment MEN2, multiple endocrine neoplsi syndrome type 2; MTC, medullry thyroid crcinom. 1. Trynor K. Am J Helth Syst Phrm. 214;71(11):888; 2. See Drugs@FDA ( 3. See Drugs@FDA ( 4. See Drugs@FDA ( 5. Dulglutide prescriing informtion. Accessed Septemer 23rd, 214; 6. Prks M, et l. N Engl J Med. 21;362: Recommendtions for GLP RA Use Possile Renl Impirment Risk Precutions 1-5 Aliglutide Dulglutide Exentide BID Lirglutide Exentide QW Renl impirment Use with cution Use with cution Use with cution Should not e used with severe renl impirment (CrCl <3 ml/min) or ESRD Use with cution Recommendtions Use with cution in ptients with renl impirment or renl trnsplnttion, especilly when inititing or esclting doses Hypovolemi due to nuse/vomiting my worsen renl function CrCl, cretinine clernce; ESRD, end-stge renl disese. 1. Trynor K. Am J Helth Syst Phrm. 214;71(11):888; 2. See Drugs@FDA ( 3. See Drugs@FDA ( 4. See Drugs@FDA ( 5. Dulglutide prescriing informtion. Accessed Septemer 23rd, 214. Use with cution Should not e used with severe renl impirment (CrCl <3 ml/min) or ESRD Wlter Tretment Tiloring Metformin 5 mg twice dily Titrted up to 1 mg twice dily over next month 3-month follow-up ppointment A1c, 8.% Previous vlue, 8.8% Trget vlue, <7.% FPG, 155 mg/dl Previous vlue, 199 mg/dl PPG, 21 mg/dl (2-h postmel) No significnt chnges in ny other clinicl prmeters If you re going to prescrie Wlter GLP RA, wht fctors would you consider when choosing mediction? Would you comine GLP RA with sl insulin nlog?

10 Compring GLP RAs Shorter- vs Longer-Acting Formultions Shorter Acting Longer Acting Aliglutide, dulglutide, Exentide BID, Compounds lixisentide exentide QW, lirglutide, semglutide Hlf-life 2-5 hours 12 hours to severl dys Effects FPG reduction Postprndil hyperglycemi reduction Fsting insulin secretion stimultion Glucgon secretion Weight reduction, kg Potentil for nuse Modest Strong Modest Reduction Yes Yes Not pproved y the FDA for use in the United Sttes. Brunton S. Int J Clin Prct. 214;68(5): ; Fonsec VA. Clin Ther. 214;36(4): ; Klr S. Dietes Ther. 214 Fe 19. [Epu hed of print]. Strong Modest Strong Reduction Yes Yes Nuse my e limited y using n incrementl dosing pproch Recommend eting smller mels nd not overeting Ptients with irregulr mel hits my enefit from longer-cting formultions Comining GLP RA nd Bsl Insulin Anlogs Bsl Insulin Anlogs Simple to initite Control nocturnl hyperglycemi nd FPG Lower hypoglycemi risk thn NPH Modest weight increse (1 to 3 kg) Achieve A1c trgets in ~5%-6% Complementry Actions Additive Effects Grunerger G. J Dietes. 213;5: ; Holst JJ, Vilsøll T. Dietes Oes Met. 213;15(1):34; Vor J, et l. Dietes Met. 213;39:65. GLP RAs Simple to initite Cn control FPG nd PPG Do not impir α-cell response to hypoglycemi (reduce severe hypoglycemi) Weight-lowering Achieve A1c trgets in ~4%-6% Potentil for etter overll A1c control Wlter Key Points Individulize gols nd tretment intensity for T2DM Consider comoridities Address psychosocil fctors Tke steps to reduce risk of hypoglycemi Ensure lifestyle modifictions re the foundtion of ny tretment regimen for T2DM Monitor multiple metolic trgets for comprehensive mngement nd reduction of crdiovsculr risk A1c, lipids, BP Consider pproprite roles of GLP RAs Cliniclly relevnt reductions in A1c Reltively low risks of hypoglycemi Potentil for weight loss nd other crdiovsculr enefits Build--Cse Vivin Fonsec, MD, FRCP Professor of Medicine nd Phrmcology Tullis-Tulne Alumni Chir in Dietes Chief, Section of Endocrinology Tulne University Helth Sciences Center New Orlens, Louisin Build--Cse Oliver: Bckground Build--Cse Oliver: Bckground 53-yer-old fifth-grde techer Lives with wife of 25 yers nd 2 dughters Visits PCP for check-up fter missing lst 2 ppointments Reports feeling rundown over lst 4 months Gets up 2 times nightly to urinte 1-2 glsses of wine with dinner ech night Does not smoke Trying to et helthily ut hs found it difficult Drinks cffeinted sod ech dy No exercise other thn wlking to nd from school Medicl history Dyslipidemi dignosis 9 yers go Atorvsttin 2 mg once dily Fmily history Mother ws oese Died of MI t ge 63 Fther treted for dyslipidemi BMI, 32.1 kg/m 2 BP, 125/79 mm Hg MI, myocrdil infrction. Drk discolored skin round neck nd underrms A1c, 8.9% FPG, 185 mg/dl TC, 19 mg/dl TG, 145 mg/dl HDL-C, 5 mg/dl LDL-C, 9 mg/dl

11 Additionl Considertions in T2DM Erectile Dysfunction How does Oliver s erectile dysfunction ffect your pproch to ptient ssessment? Erectile dysfunction nd T2DM commonly co-occur 1 In ptients with dietes, erectile dysfunction is s predictive for future crdiovsculr events s trditionl risk fctors 2,3 eg, smoking, hyperlipidemi Erectile dysfunction my lso reflect low testosterone More common in men with dietes independent of ge or BMI 4 Testing testosterone levels in ll mle ptients with dietes? 5 Testosterone replcement therpy hs not consistently improved erectile dysfunction or crdiometolic helth in clinicl trils 6,7 1. Rosen RC, et l. J Sex Med. 29;6(5): ; 2. Btty GD, et l. J Am Coll Crdiol. 21;56(23):198913; 3. Miner M, et l. Am Hert J. 212;164(1):21-28; 4. Coron G, et l. Int J Impot Res. 26;18(2):1997; 5. Bhsin S, et l. J Clin Endocrinol Met. 21;95(6): ; 6. ADA. Dietes Cre. 214;37(suppl 1):S14-S8; 7. Jones TH, et l. Dietes Cre. 211;34(4): How do Oliver s reports of flling sleep t work nd excessive snoring t night ffect your pproch to ptient ssessment? Additionl Considertions in T2DM Excessive Sleepiness nd Snoring Excessive sleepiness during dy nd snoring suggest OSA 1 OSA is common in ptients with T2DM, especilly oese individuls 1 Risk fctors for OSA 2 Lrge neck circumference Excessive use of lcohol or sedtives efore edtime Mllmpti score, clss III or IV Polysomnogrphy testing required to confirm the dignosis CPAP my improve glycemic control in ptients with dietes, lthough pulished dt re not consistent 3,4 CPAP, continuous positive irwy pressure; OSA, ostructive sleep pne. 1. Foster GD, et l. Dietes Cre. 29;32(6):11719; 2. Nuckton TJ, et l. Sleep. 26;29(7):93-98; 3. Hur NW, et l. Eur J Crdiovsc Prev Rehil. 27;14(2): ; 2. Nooyens AC, et l. Dietes Cre. 21;33(9): Additionl Considertions in T2DM Depression How do Oliver s feelings of depression ffect your pproch to ptient ssessment? Emotionl well-eing should e ssessed routinely nd not only when deteriortion in psychologicl sttus is evident Key opportunities for depression screening include Time of dignosis During follow-up or emergency visits Any time the ptient s overll medicl sttus chnges Consider simple questions to identify individuls who should undergo more extended evlutions eg, How re you sleeping? or How re your energy levels? Ongoing reltionships with ptients provide n importnt opportunity for uncovering depression My increse likelihood tht mentl helth referrls will e ccepted 1. Foster GD, et l. Dietes Cre. 29;32(6):11719; 2. Nuckton TJ, et l. Sleep. 26;29(7):93-98; 3. Hur NW, et l. Eur J Crdiovsc Prev Rehil. 27;14(2): ; 2. Nooyens AC, et l. Dietes Cre. 21;33(9):

12 Build--Cse Oliver: Dignosis Oliver receives dignosis of T2DM Advised to lose weight vi exercise nd reduced cloric intke Referred to dieticin who specilizes in dietes counseling Fmily committed to helping Oliver with his dietes Build--Cse Oliver: Initil Tretment nd Follow-up Prescried metformin 5 mg twice dily Sxgliptin 5 mg once dily dded 2 months lter 4-month follow-up ppointment Prticipting in wter eroics twice weekly Complying with recommendtions from the dieticin Lost 5 ls (BMI, 31.4 kg/m 2 ) A1c, 8.1% FPG, 152 mg/dl No retinopthy Adherence prolems ddressed with pill ox, eduction for his wife, nd switch to sxgliptin/metformin ER 5 mg/1 mg comintion tken once dily Begin converstion out other options if Oliver is unle to rech his glycemic gol Additionl Considertions in T2DM Chronic Kidney Disese How does the presence of chronic kidney disese ffect your tretment recommendtions for Oliver? Updted system for clssifying kidney disese severity 1 Mintined the thresholds for estimted GFR nd luminuri Added 3 luminuri stges to consider with previous GFR stges Emphsizes the need for n overll clinicl dignosis Use of mny ntihyperglycemic gents my e limited y impired renl function (eg, specil precutions or dose djustments) 2 Metformin GLP RAs DPP-4 inhiitors SGLT-2 inhiitors Sulfonylures Insulin For exmple, impired insulin excretion requires slow titrtion of doses to reduce risks of hypoglycemi 3 1. Levey AS, et l. Kidney Int. 211;8(1):17-28; 2. Grer AJ, et l. Endocr Prct. 213;19(2): ; 3. Inzucchi SE, et l. Dietes Cre. 212;35(6): How does Oliver s history of lcohol use ffect your tretment recommendtions? Additionl Considertions in T2DM Alcoholism Ptients with T2DM nd lcoholism history should e educted on incresed hypoglycemi risks with continued hevy lcohol use 1 Especilly with insulin or insulin secretgogues Sulfonylures nd other secretgogues should e voided in ptients with dvnced liver disese 2 Doses of DPP-4 inhiitors ville in the United Sttes do not need to e djusted for mild or moderte heptic impirment 2 GLP RAs sfe ptients with moderte liver dysfunction 3-5 My even improve liver enzyme profiles, lthough overll results mixed Appropritely dosed insulin preferred over other dietes gents in ptients with dvnced liver disese 2 1. ADA. Dietes Cre. 214;37(suppl 1):S14-S8; 2. Inzucchi SE, et l. Dietes Cre. 212;35(6): ; 3. Armstrong MJ, et l. Aliment Phrmcol Ther. 213;37(2): ;4. Vilsoll T, et l. BMJ. 212;344:d7771; 5. Klonoff DC, et l. Curr Med Res Opin. 28;24(1):

13 Additionl Considertions in T2DM Coronry Artery Disese How does Oliver s history of coronry rtery disese ffect tretment recommendtions? Oliver is t very high crdiovsculr risk 1 Exercise should strt with short periods t low intensity, with slow increses in intensity nd durtion Should exercise recommendtions e mde in consulttion with Oliver s crdiologist? Should Oliver s sttin therpy e djusted? 2 TC, 19 mg/dl TG, 145 mg/dl HDL-C, 5 mg/dl LDL-C, 9 mg/dl Significnt efforts needed to help Oliver lose weight 2 Tiloring of his ntihyperglycemic regimen should minimize the chnces of weight gin How much weight loss is required to see enefits? 1. ADA. Dietes Cre. 214;37(suppl 1):S14-S8; 2. Jellinger PS, et l. Endocr Prct. 212;18(suppl 1):1-78. Build--Cse Oliver: Tretment Tiloring At follow-up ppointment 6 weeks lter, Oliver reports etter dherence A1c, 7.8% FPG, 14 mg/dl 2-hour PPG, 185 mg/dl All other clinicl prmeters re unchnged You discuss further djustments to his tretment regimen Conclusions Comprehensive T2DM mngement requires diligent monitoring of lood sugrs, lipid profile, lood pressure, nd ody weight Tretment is founded on lifestyle nd ehviorl modifictions Significnt hypoglycemic episodes re ssocited with serious dverse outcomes GLP RAs ugment signling in the pleiotropic incretin hormone system Efficcy in reducing hyperglycemi, with reltively low risks of hypoglycemi nd potentil for weight loss Potentil crdiovsculr enefits remin n re of ctive reserch