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-1 Receptor Agonists Into Multimodl Tretment Regimens DECEMBER 3, 214 Tmp Convention Center Tmp, FL

2 IMPROVING OUTCOMES IN TYPE 2 DIABETES Integrting GLP-1 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 Dibetes Chief, Section of Endocrinology Tulne University Helth Sciences Center New Orlens, Louisin Lwrence Blonde, MD, FACP, FACE Director, Ochsner Dibetes Clinicl Reserch Unit Deprtment of Endocrinology, Dibetes nd Metbolism Associte Internl Medicine Residency Progrm Director Ochsner Medicl Center New Orlens, Louisin Jvier Morles, MD Vice President Principl Trils Investigtor Advnced Internl Medicine Group, PC New Hyde Prk, New York LEARNING OBJECTIVES Upon completion of these eductionl ctivities, prticipnts will be better 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-1 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 bout 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 Abbott Lbortories; Eli Lilly nd Compny; GI Dynmics, Inc.; Novo Nordisk A/S; Pn Americn Lbortories; Ret Phrmceuticls Inc.; nd snofi-ventis US LLC. He receives honorri for consulting nd lectures from Abbott Lbortories; AstrZenec; Boehringer Ingelheim GmbH; Bristol-Myers Squibb Compny; Diichi Snkyo Compny, Limited; Eli Lilly nd Compny; GlxoSmithKline; Jnssen Phrmceuticls, Inc.; Novo Nordisk A/S; PmLb, Inc.; snofi-ventis US LLC.; nd Tked Phrmceuticls USA, Inc. 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. Eduction Prtner Jvier Morles, MD, receives honorri from Boehringer Ingelheim GmbH; Bristol-Myers Squibb Compny; Eli Lilly nd Compny; Novo Nordisk A/S; nd snofi-ventis U.S. LLC. EDUCATION PARTNER FINANCIAL DISCLOSURE STATEMENTS The content collbortors t Integrits Communictions hve reported the following: Jim Kppler, PhD, hs nothing to disclose. 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. EXCHANGECME.com/T2DM214

3 SESSION 2 8:45m 1:m Improving Outcomes in Type 2 Dibetes: Integrting GLP-1 Receptor Agonists Into Multimodl Tretment Regimens SPEAKERS Vivin Fonsec, MD Lwrence Blonde, MD Jvier Morles, MD Presenter Disclosure Informtion The following reltionships exist relted to this presenttion: Vivin Fonsec, MD, receives grnt reserch support vi Tulne University from Abbott Lbortories; Eli Lilly nd Compny; GI Dynmics, Inc.; Novo Nordisk A/S; Pn Americn Lbortories; Ret Phrmceuticls Inc.; nd snofi-ventis US LLC. He receives honorri for consulting nd lectures from Abbott Lbortories; AstrZenec; Boehringer Ingelheim GmbH; Bristol-Myers Squibb Compny; Diichi Snkyo Compny, Limited; Eli Lilly nd Compny; GlxoSmithKline; Jnssen Phrmceuticls, Inc.; Novo Nordisk A/S; PmLb, Inc.; snofi-ventis US LLC.; nd Tked Phrmceuticls USA, Inc. 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. Presenter Disclosure Informtion The following reltionships exist relted to this presenttion: Jvier Morles, MD, receives honorri from Boehringer Ingelheim GmbH; Bristol-Myers Squibb Compny; Eli Lilly nd Compny; Novo Nordisk A/S; nd snofi-ventis U.S. LLC. Off-Lbel/Investigtionl Discussion In ccordnce with pmicme policy, fculty hve been sked to disclose discussion of unlbeled or unpproved use(s) of drugs or devices during the course of their presenttions Mediction clsses GLP-1 receptor gonists DPP-4 inhibitors Sttins ACE inhibitors Insulins Amylin mimetics Thizolidinediones Meglitinides SGLT-2 inhibitors α-glucosidse inhibitors 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 Albiglutide Dulglutide Semglutide Lixisentide IMPROVING OUTCOMES IN TYPE 2 DIABETES Integrting GLP-1 Receptor Agonists Into Multimodl Tretment Regimens Lwrence Blonde, MD, FACP, FACE Director, Ochsner Dibetes Clinicl Reserch Unit Deprtment of Endocrinology, Dibetes, nd Metbolism Ochsner Medicl Center New Orlens, Louisin Vivin Fonsec, MD, FRCP Professor of Medicine nd Phrmcology Tullis-Tulne Alumni Chir in Dibetes Chief, Section of Endocrinology Tulne University Helth Sciences Center New Orlens, Louisin Jvier Morles, MD Vice President Principl Trils Investigtor Advnced Internl Medicine Group, PC New Hyde Prk, New York Eductionl Objectives 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-1 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 bout lifestyle modifictions, ntihyperglycemic options, nd the need for tretment dherence GLP-1, glucgon-like peptide-1; T2DM, type 2 dibetes 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 Dibetes 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-1 nd GIP stimulte insulin relese in response to food intke 2 GLP-1 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-1 nd GIP re rpidly degrded by DPP-4 2 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; T2DM, type 2 dibetes mellitus. 1. Elrick H, et l. J Clin Endocrinol Metb. 1964;24: ; 2. Grunberger G. J Dibetes. 213;5(3): ; 3. Holst JJ, et l. Dibetes 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 Dibetes 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 blood cholesterol: Bsed on 1-yer ASCVD risk, use high-intensity (lower LDL-C by 5%) or moderte-intensity (lower LDL-C by 3% to <5%) sttin therpy for ptients ged 4-75 yers with T2DM nd initil LDL-C 7 mg/dl. A1c, glycted hemoglobin; ASCVD, therosclerotic CVD; BMI, body mss index; BP, blood pressure; CVD, crdiovsculr disese; HDL-C, low-density lipoprotein cholesterol; LDL-C, high-density lipoprotein cholesterol; TG, triglycerides. ADA. Dibetes 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 dibetes. Retrospective nlysis of dt obtined from the Ntionl Helth nd Nutrition Exmintion Surveys. Strk Csgrnde S, et l. Dibetes Cre. 213;36(8): yer-old Africn Americn mn Retired wrehouse mnger Divorced Lives lone BMI, 3.1 kg/m 2 (obese) BP, 135/78 mm Hg Unhelthy lifestyle Little physicl ctivity Regulrly consumes fried food, red met, nd sugry sod Rrely ets fruits or vegetbles PCP Visit Fmily history Mother hd T2DM Medicl history Hypertension dignosis 5 yers go Lisinopril 4 mg dily Atenolol 5 mg dily Episode of unstble ngin 2 yers go Dily low-dose spirin Forgets medictions 1-2 times weekly Despite no overt symptoms of hyperglycemi, should be screened for T2DM? PCP, primry cre provider. ADA 1 AACE 2 s risk fctors Screening Asymptomtic Persons for Dibetes 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 be considered in the presence of ny risk fctors for T2DM Obese First-degree reltive with dibetes -risk rce or ethnic group (eg, Blck, Hispnic) Hypertension (BP 14/9 mm Hg, or therpy) History of crdiovsculr disese Previously undignosed dibetes is common in ptients presenting with myocrdil infrction 3 AACE, Americn Assocition of Clinicl Endocrinologists; ADA, Americn Dibetes Assocition. 1. ADA. Dibetes Cre. 214;37(suppl 1):S14-S8; 2. Grber AJ, et l. Endocr Prct. 213;19(suppl 1):1-48; 3. Lnkisch M, et l. Clin Res Crdiol. 28;97(1):

5 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 Age, 62 yers Newly Dignosed Hypertension Setting Glycemic Trgets BMI, 3.1 kg/m 2 A1C, 8.8% Mother treted for T2DM History of unstble ngin Norml renl function Not dherent to other drug therpies receives dignosis of T2DM Wht would you set s n A1c trget for? ACR, lbumin/cretinine rtio; egfr, estimted glomerulr filtrtion rte; FPG, fsting plsm glucose; TC, totl cholesterol. Inzucchi SE, et l. Dibetes Cre. 212;35(6): Initil Tretment Trget A1c <7.% nd PCP discuss lifestyle modifictions PCP suggests certified dibetes eductor Ptient eduction Detiled dietry nd exercise recommendtions Dibetes Eduction nd Lifestyle Modifictions Skills-bsed dibetes 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 behvior chnge Physicl ctivity At lest 15 min/week of moderte ctivity Aerobic, resistnce, flexibility Individulize dietry recommendtions Discuss mcronutrient content nd eting ptterns Monitor crbohydrte intke Reduce clories to chieve weight loss Moderte clorie restriction (5-1 kcl/dy) recommended initilly Wht re the potentil benefits of these pproches? ADA. Dibetes Cre. 214;37(suppl 1):S14-S8; Evert AB, et l. Dibetes Cre. 214;37(suppl 1):S12-S143; Jensen MD, et l. Circultion. 213 Nov 12. [Epub hed of print]; Hs L, et l. Dibetes Cre. 214;37(suppl 1):S144-S153. LOOK AHEAD Study Intensive Lifestyle Intervention nd Risk Reduction Diet modifiction, exercise, behviorl trining Group support with in-person nd telephone follow-ups Prmeter P<.1; b P=.1 vs support nd eduction lone. N=257 for lifestyle intervention nd 2575 for support nd eduction. MET, metbolic 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 b HDL-C, mg/dl Triglycerides, mg/dl b Prevlence, % Look AHEAD Intensive Lifestyle Interventions nd Dibetes Remission Remission Prevlence Intensive lifestyle intervention Dibetes 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 Dibetes 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 b STD INT b STD INT b 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; 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; INS, insulin; INT, intensive therpy; STD, stndrd therpy; UKPDS, UK Prospective Dibetes Study; VADT, Veterns Affirs Dibetes 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): b b Adjusted for multiple bseline covrites; b 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): Overview 62-yer-old Africn-Americn with n unhelthy lifestyle BMI, 3.1 kg/m 2 (obese) 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 unstble ngin Dily low-dose spirin Often forgets medictions Should be 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 Combintion,b 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 combintion + SU Moderte risk Gin Hypoglycemi Low + TZD Low risk Gin Edem, HF, Fx s Metformin + DPP-4 inhibitor Intermedite Low risk Neutrl Rre + GLP-1 RA Low risk Loss GI + Insulin est risk Gin Hypoglycemi Vrible Consider beginning t this stge in ptients with high A1c (eg, 9%); b At publiction, SGLT-2 inhibitors hd not been FDA-pproved. EASD, Europen Assocition for the Study of Dibetes; FDA, US Food nd Drug Administrtion; Fx s, bone frctures; GI, gstrointestinl; HF, hert filure; SGLT-2, sodium glucose cotrnsporter-2; SU, sulfonylure; TZD, thizolidinedione. Inzucchi SE, et l. Dibetes 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-1 RA Symptoms Symptoms GLP-1 RA DPP-4 inhibitor AG inhibitor SGLT-2 inhibitor b DPP-4 inhibitor TZD SGLT-2 inhibitor b Bsl Insulin Dul Therpy OR Insulin ±Other TZD SU/GLN If A1c >6.5% in 3 months, Colesevelm Bromocriptine QR AG inhibitor SU/GLN Add or Intensify Insulin Triple Agents Therpy dd second drug If not t gol in 3 months, Possible benefits or few dverse events (Dul Therpy) proceed to triple therpy Use with cution Order of medictions listed re suggested hierrchy of usge; b Bsed on phse 3 clinicl trils. ACE, Americn College of Endocrinology; AG, α-glucosidse; GLN, glinide; QR, quick relese. Grber AJ, et l. Endocr Prct. 213;19(3): METFORMIN or other first-line gent Tretment Initition nd Follow-up Prescribed 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-bsed gent to 's regimen PPG, postprndil glucose.

7 GLP-1 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): ; 2. Flint A, et l. Adv Ther. 211;28(3): ; 3. Degn K, et l. Dibetes. 24;53(5): ; 4. Bggio LL, Drucker DJ. Gstroenterology. 27;132(6): ; 5. Horowitz M, et l. Dibetes Res Clin Prct. 212;97(2): ; 6. Vilsbøll T, et l. BMJ. 212;344:d7771; 7. Niswender K, et l. Dibetes Obes Metb. 213(1);15:42-54; 8. Fonsec V, et l. Dibetes. 21;59(suppl 1):A79(296-OR). Mediction Exentide BID 1 Lirglutide 2 FDA-Approved GLP-1 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 before 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 cceptble, dose cn be 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 Albiglutide 2 Dulglutide 3 FDA-Approved GLP-1 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 Adverse events Nuse, dirrhe, injection-site nodule, constiption, hedche, dyspepsi Dosing 1. Administer t 2. mg once every 7 dys (weekly), independent of mels URTI, dirrhe, 1. Administer t 3 mg once nuse, injection-site every 7 dys (weekly), regrdless rection, cough, of mels bck pin, rthrlgi, 2. If glycemic control not cceptble, sinusitis, influenz dose cn increse to 5 mg Single-dose syringe in.75 mg or 1.5 mg doses Prefilled, single-dose syringe in.75 mg or 1.5 mg doses Nuse, dirrhe, vomiting, bdominl pin, nd decresed ppetite 1. Initite t.75 mg weekly, regrdless of mels or time of dy; dose cn be incresed to 1.5mg 2. If dose is missed, missed dose must be 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 prescribing informtion. Accessed September 23rd, 214. Weight Effects of GLP-1 RAs in T2DM Met-nlysis of published studies Exentide QW Lirglutide Exentide BID Weight (kg) With Exentide BID or QW 1% lost >1 kg 2% lost 5-1 kg 48% lost -5 kg 2%-23% gined -5 kg 1%-2% gined 5-1 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 Metb. 211;96(5): ; Buse JB, et l. Lncet. 29;374(9683):39-47; Buse J, et l. Lncet. 213;381(9861): ; Drucker DJ, et l. Lncet. 28;372(9645): ; Rosenstock J, et l. 47th EASD Annul Meeting Weight Loss With GLP-1 RAs Not Driven by Gstrointestinl Adverse Events Lirglutide (Met-Anlysis/6 26-Week Trils) 1 No NVD Some NVD Weight Chnge (kg) ,b -1.56,b P<.5 PBO 1.2 mg LIRA -2.45,b 1.8 mg LIRA P<.5 Exentide (3-Week DURATION-1 Tril) 2 No Nuse Nuse In 82-week exentide completer cohort, weight loss ws 1) similr cross degrees of nuse, 2) progressive despite stble nuse incidence, nd 3) unlikely to be driven by nuse. 3 NVD, nuse, vomiting, dirrhe. P<.5 vs bseline; b P<.5 vs plcebo. 1. Russell-Jones D, et l. 7th ADA Scientific Sessions. 21;1886-P; 2. Drucker DJ, et l. Lncet. 28;372(9645): ; 3. Blonde L, et l. Dibetes Obes Metb. 26;8(4): EXN QW EXN BID Select Antidibetic Therpies nd Hypoglycemi Drug A1c Reduction, % Hypoglycemi Incidence, % Exentide twice dily Exentide weekly Lirglutide Albiglutide e Dulglutide e DPP-4 inhibitors f SGLT-2 inhibitors b e Sulfonylures Pioglitzone Bsl Insulin c d Similr to plcebo; b 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. Amblee 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. Dibetes Res Clin Prct. 214 Jun 22. [Epub hed of print].

8 GLP-1 RAs in T2DM Improved Lipid Profiles GLP-1 RAs nd Blood Pressure Met-Anlysis of Dt From Obese nd Overweight Individuls Chnge in Lipid Level, mg/dl LEAD-6, 26 Weeks 1 TC LDL-C HDL-C TG Lirglutide -25 Exentide BID -3 DURATION-1, 3 Weeks 2 TC LDL-C HDL-C TG b b Exentide QW Exentide BID Prmeter Chnge vs Control 95% CI Systolic blood pressure 3.57 mm Hg 5.49 to 1.66 Distolic blood pressure 1.38 mm Hg 2.2 to.73 P<.5 vs exentide BID; b Signifcnt difference vs exentide BID bsed 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 both. 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 ntidibetic gents. Includes 11 or 12 trils exmining overweight nd obese individuls with or without T2DM; tretments included exentide BID, exentide QW, or lirglutide. Vilsbøll T, et l. BMJ. 212;344:d7771. Tril REWIND (NCT ) EXSCEL (NCT ) LEADER (NCT117948) ELIXA (NCT114725) SUSTAIN 6 (NCT172446) GLP-1 RAs nd Crdiovsculr Outcomes Ongoing Trils Agent Ptients (N) Durtion (y) Ptient- Yers Estimted Completion Dulglutide , Exentide QW , Lirglutide , Lixisentide ,4 214 Semglutide Ntionl Institutes of Helth website. Accessed My 2, 214; Petrie JR. Crdiovsc Dibetol. 213;12:13. Sfe Prescribing With GLP-1 RAs Acute Pncretitis Precutions 1-5 Cses hve been reported Consider tretments other thn GLP-1 RAs in ptients with history of pncretitis Recommendtions 1-5 Ask bout pncretitis history Educte ptients, monitor for signs nd symptoms Discontinue promptly if pncretitis symptoms occur If cute pncretitis is confirmed, do not restrt GLP-1 RA Report cses of pncretitis to Pncretitis risk is 1.5- to 3-fold higher in individuls with dibetes 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 prescribing informtion. Accessed September 23rd, 214; 6. Noel RA, et l. Dibetes Cre. 29;32(5): ; 7. Girmn CJ, et l. Dibetes Obes Metb. 21;12(9): ; 8. Grg R, et l. Dibetes Cre. 21;33(11): ; 9. Yng L, et l. Eur J Gstroenterol Heptol. 213;25(2): Sfe Prescribing With GLP-1 RAs Possible Thyroid nd Endocrine Risk Contrindictions 1-5 Albiglutide 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 be 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 prescribing informtion. Accessed September 23rd, 214; 6. Prks M, et l. N Engl J Med. 21;362: Recommendtions for GLP-1 RA Use Possible Renl Impirment Risk Precutions 1-5 Albiglutide Dulglutide Exentide BID Lirglutide Exentide QW Renl impirment Use with cution Use with cution Use with cution Should not be 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 prescribing informtion. Accessed September 23rd, 214. Use with cution Should not be used with severe renl impirment (CrCl <3 ml/min) or ESRD

9 Compring GLP-1 RAs Shorter- vs Longer-Acting Formultions Shorter Acting Longer Acting Albiglutide, 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 by 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. Dibetes Ther. 214 Feb 19. [Epub hed of print]. Strong Modest Strong Reduction Yes Yes Nuse my be limited by using n incrementl dosing pproch Recommend eting smller mels nd not overeting Ptients with irregulr mel hbits my benefit from longer-cting formultions 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 prescribe GLP-1 RA, wht fctors would you consider when choosing mediction? Would you combine GLP-1 RA with bsl insulin nlog? Combining GLP-1 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 GLP-1 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 better overll A1c control Key Points Individulize gols nd tretment intensity for T2DM Consider comorbidities Address psychosocil fctors Tke steps to reduce risk of hypoglycemi Ensure lifestyle modifictions re the foundtion of ny tretment regimen for T2DM Monitor multiple metbolic trgets for comprehensive mngement nd reduction of crdiovsculr risk A1c, lipids, BP Consider pproprite roles of GLP-1 RAs Cliniclly relevnt reductions in A1c Reltively low risks of hypoglycemi Potentil for weight loss nd other crdiovsculr benefits Grunberger G. J Dibetes. 213;5: ; Holst JJ, Vilsbøll T. Dibetes Obes Metb. 213;15(1):3-14; Vor J, et l. Dibetes Metb. 213;39:6-15. Build--Cse Vivin Fonsec, MD, FRCP Professor of Medicine nd Phrmcology Tullis-Tulne Alumni Chir in Dibetes Chief, Section of Endocrinology Tulne University Helth Sciences Center New Orlens, Louisin 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 but hs found it difficult Drinks cffeinted sod ech dy No exercise other thn wlking to nd from school

10 Build--Cse Oliver: Bckground Medicl history Dyslipidemi dignosis 9 yers go Atorvsttin 2 mg once dily Fmily history Mother ws obese Died of MI t ge 63 Fther treted for dyslipidemi BMI, 32.1 kg/m 2 BP, 125/79 mm Hg 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 How does Oliver s erectile dysfunction ffect your pproch to ptient ssessment? MI, myocrdil infrction. Additionl Considertions in T2DM Erectile Dysfunction Erectile dysfunction nd T2DM commonly co-occur 1 In ptients with dibetes, 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 dibetes independent of ge or BMI 4 Testing testosterone levels in ll mle ptients with dibetes? 5 Testosterone replcement therpy hs not consistently improved erectile dysfunction or crdiometbolic helth in clinicl trils 6,7 How do Oliver s reports of flling sleep t work nd excessive snoring t night ffect your pproch to ptient ssessment? 1. Rosen RC, et l. J Sex Med. 29;6(5): ; 2. Btty GD, et l. J Am Coll Crdiol. 21;56(23): ; 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):19-197; 5. Bhsin S, et l. J Clin Endocrinol Metb. 21;95(6): ; 6. ADA. Dibetes Cre. 214;37(suppl 1):S14-S8; 7. Jones TH, et l. Dibetes Cre. 211;34(4): 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 obese individuls 1 Risk fctors for OSA 2 Lrge neck circumference Excessive use of lcohol or sedtives before bedtime Mllmpti score, clss III or IV Polysomnogrphy testing required to confirm the dignosis CPAP my improve glycemic control in ptients with dibetes, lthough published dt re not consistent 3,4 How do Oliver s feelings of depression ffect your pproch to ptient ssessment? CPAP, continuous positive irwy pressure; OSA, obstructive sleep pne. 1. Foster GD, et l. Dibetes Cre. 29;32(6): ; 2. Nuckton TJ, et l. Sleep. 26;29(7):93-98; 3. Hur NW, et l. Eur J Crdiovsc Prev Rehbil. 27;14(2): ; 2. Nooyens AC, et l. Dibetes Cre. 21;33(9):

11 Additionl Considertions in T2DM Depression Emotionl well-being should be 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 be ccepted 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 dibetes counseling Fmily committed to helping Oliver with his dibetes 1. Foster GD, et l. Dibetes Cre. 29;32(6): ; 2. Nuckton TJ, et l. Sleep. 26;29(7):93-98; 3. Hur NW, et l. Eur J Crdiovsc Prev Rehbil. 27;14(2): ; 2. Nooyens AC, et l. Dibetes Cre. 21;33(9): Build--Cse Oliver: Initil Tretment nd Follow-up Prescribed metformin 5 mg twice dily Sxgliptin 5 mg once dily dded 2 months lter 4-month follow-up ppointment Prticipting in wter erobics twice weekly Complying with recommendtions from the dieticin Lost 5 lbs (BMI, 31.4 kg/m 2 ) A1c, 8.1% FPG, 152 mg/dl No retinopthy Adherence problems ddressed with pill box, eduction for his wife, nd switch to sxgliptin/metformin ER 5 mg/1 mg combintion tken once dily Begin converstion bout other options if Oliver is unble to rech his glycemic gol How does the presence of chronic kidney disese ffect your tretment recommendtions for Oliver? Additionl Considertions in T2DM Chronic Kidney Disese Updted system for clssifying kidney disese severity 1 Mintined the thresholds for estimted GFR nd lbuminuri Added 3 lbuminuri stges to consider with previous GFR stges Emphsizes the need for n overll clinicl dignosis Use of mny ntihyperglycemic gents my be limited by impired renl function (eg, specil precutions or dose djustments) 2 Metformin GLP-1 RAs DPP-4 inhibitors SGLT-2 inhibitors Sulfonylures Insulin For exmple, impired insulin excretion requires slow titrtion of doses to reduce risks of hypoglycemi 3 How does Oliver s history of lcohol buse ffect your tretment recommendtions? 1. Levey AS, et l. Kidney Int. 211;8(1):17-28; 2. Grber AJ, et l. Endocr Prct. 213;19(2): ; 3. Inzucchi SE, et l. Dibetes Cre. 212;35(6):

12 Additionl Considertions in T2DM Alcoholism Ptients with T2DM nd lcoholism history should be educted on incresed hypoglycemi risks with continued hevy lcohol use 1 Especilly with insulin or insulin secretgogues Sulfonylures nd other secretgogues should be voided in ptients with dvnced liver disese 2 Doses of DPP-4 inhibitors vilble in the United Sttes do not need to be djusted for mild or moderte heptic impirment 2 GLP-1 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 dibetes gents in ptients with dvnced liver disese 2 How does Oliver s history of coronry rtery disese ffect tretment recommendtions? 1. ADA. Dibetes Cre. 214;37(suppl 1):S14-S8; 2. Inzucchi SE, et l. Dibetes Cre. 212;35(6): ; 3. Armstrong MJ, et l. Aliment Phrmcol Ther. 213;37(2): ;4. Vilsboll T, et l. BMJ. 212;344:d7771; 5. Klonoff DC, et l. Curr Med Res Opin. 28;24(1): Additionl Considertions in T2DM Coronry Artery Disese 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 be mde in consulttion with Oliver s crdiologist? Should Oliver s sttin therpy be 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 benefits? 1. ADA. Dibetes 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 better 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 blood sugrs, lipid profile, blood pressure, nd body weight Tretment is founded on lifestyle nd behviorl modifictions Significnt hypoglycemic episodes re ssocited with serious dverse outcomes GLP-1 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 benefits remin n re of ctive reserch