Achieving Treatment Goals Room for Improvement in T2DM

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1 9: 1:3 m Noninsulin Approches to Mnging Type 2 Dietes: Best Prctices in Comintion Therpy SPEAKERS Jvier Morles, MD Richrd E. Prtley, MD Presenter Disclosure Informtion The following reltionships exist relted to this presenttion: Jvier Morles, MD: Medicl Advisory Bord for Boehringer Ingelheim Phrmceuticls, Inc.; Eli Lilly nd Compny; Novo Nordisk Inc.; nd snofiventis U.S. Consultnt for Eli Lilly nd Compny; Novo Nordisk Inc.; nd snofi-ventis U.S. Spekers Bureu for Eli Lilly nd Compny; Jnssen Phrmceuticls, Inc.; nd Novo Nordisk Inc. Richrd E. Prtley, MD: Consultnt for AstrZenec; Boehringer Ingelheim Phrmceuticls, Inc.; Eli Lilly nd Compny; GlxoSmithKline; Hnmi Phrmceuticl Co., Ltd; Jnssen Phrmceuticls, Inc.; Lignd Phrmceuticls, Inc.; Merck & Co., Inc.; Novo Nordisk Inc.; nd Tked Phrmceuticl Compny. Spekers Bureu for AstrZenec nd Novo Nordisk Inc. Reserch Support for Eli Lilly nd Compny; Merck & Co., Inc.; Novo Nordisk Inc.; snofi-ventis U.S.; nd Tked Phrmceuticl Compny. 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. Eductionl Ojectives Individulize therpeutic gols for ptients with T2DM sed on disese severity, comoridities, tretmentrelted risks, nd psychosocil sttus Discuss the clinicl profiles of current nd emerging fixed-dose comintions of ntihyperglycemic medictions Intensify multidrug noninsulin regimens for vrious ptient types to ddress poor glycemic control nd other relevnt clinicl prmeters Engge ptients in their ntidietes mngement plns to motivte lifestyle chnges nd improve tretment dherence T2DM, type 2 dietes mellitus. 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): Events per 1, Adults With Dignosed Dietes Dietes-Relted Complictions Rtes in the United Sttes Stroke Amputtion ESRD Acute MI Deth from Hyperglycemic Crisis Dt otined from the Ntionl Helth Interview Survey, the Ntionl Hospitl Dischrge Survey, the US Renl Dt System, nd the US Ntionl Vitl Sttistics System. ESRD, end stge renl disese; MI, myocrdil infrction. Gregg EW, et l. N Engl J Med. 214;37(16): ADA/EASD Position Sttement Setting Glycemic Gols in T2DM More Stringent Fctors Less Stringent ly motivted, dherent, excellent self-cre cpcities Low Ptient ttitude nd expected tretment efforts Risks potentilly ssocited with hypoglycemi, other dverse events ADA, Americn Dietes Assocition; EASD, Europen Assocition for the Study of Dietes. Inzucchi SE, et l. Dietes Cre. 212;35: ; Ismil-Beigi F, et l. Ann Intern Med. 211;4: Less motivted, nondherent, poor self-cre cpcities Newly dignosed Disese durtion Long-stnding Long Life expectncy Short Asent Importnt comoridities Severe Asent Estlished vsculr complictions Severe Redily ville Resources, support system Limited

2 Reducing T2DM Complictions BP <14/9 mm Hg (<13/8 mm Hg for some people) Multidimensionl Tretment Gols A1c ADA <7.% AACE 6.5% 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: < mg/dl Lifestyle Modifictions Helthy Diet, Exercise, Smoking Cesstion BMI <25 kg/m 2 2 ADA/AHA guidelines: Tret ptients 4-75 yers old with T2DM nd LDL-C levels etween 7 nd 189 mg/dl with moderteintensity sttin therpy (lower LDL-C y 3%-5%); use high-intensity therpy (lower LDL-C y 5%) if 1-yer ASCVD risk is 7.5%). ACC, Americn College of Crdiology; AHA, Americn Hert Assocition; ASCVD, therosclerotic crdiovsculr disese. ADA. Dietes Cre. 2;38(suppl 1):S1-S94; Grer AJ, et l. Endocr Prct. 2;21(4): ; Fox CS, et l. Dietes Cre. 2;38(9): Dietes Eduction nd Lifestyle Modifictions Skills-Bsed Dietes Eduction Disese process nd tretment options Blood glucose monitoring Mediction sfety (eg, hypoglycemi) Strtegies to promote ehvior chnge Physicl Activity At lest min/wk of moderte ctivity Aeroic, resistnce, flexiility Individulized Dietry Recommendtions Dehydrtion nd nutritionl deficits Discuss mcronutrient content nd eting ptterns Monitor crohydrte intke Reduce clories to chieve weight loss Initil moderte clorie restriction (5-1 kcl/d) ADA. Dietes Cre. 2;38(suppl 1):S1-S91; Evert AB, et l. Dietes Cre. 214;37(suppl 1):S12-S143; Jensen MD, et l. Circultion. 214;129(25 suppl 2):S12-S138; Hs L, et l. Dietes Cre. 214;37(suppl 1):S144-S3. Monotherpy Efficcy ( A1c) Weight Side Effects Costs Dul Therpy Efficcy ( A1c) Weight Mjor Side Effect(s) Costs ADA Recommendtions Mnging Hyperglycemi in T2DM + SU Moderte risk Gin Low Helthy Eting, Weight Control, Incresed Physicl Activity Metformin Neutrl/Loss GI/Lctic cidosis Low If individulized A1c trget not reched fter ~3 months, proceed to 2-drug comintion Dul Therpy + Gin Edem, HF, Fx + Intermedite Neutrl Rre Metformin + Intermedite Loss GU, Dehydrtion + GLP-1 RA Loss GI Consider strting strting t this stge t this when stge A1c 9%. when A1c 9%., dipeptidyl peptidse-4; Fx, one frcture; GI, gstrointestinl; GLP-1 RA, glucgon-like peptide-1 receptor gonist; GU, genitourinry; HF, hert filure;, sodium glucose cotrnsporter-2; SU, sulfonylure;, thizolidinedione. ADA. Dietes Cre. 2;38(suppl 1):S1-S94. + Insulin (Bsl) est risk Gin Vrile AACE/ACE Algorithm Glycemic Control nd Erly Dul Therpy Lifestyle Modifiction Entry A1c <7.5% Entry A1c 7.5% Entry A1c >9.% Monotherpy Metformin GLP-1 RA inhiitor inhiitor AG inhiitor If not t gol in 3 months, proceed to dul therpy FORMIN or other first-line gent Dul Therpy GLP-1 RA inhiitor inhiitor Bsl Insulin Colesevelm Bromocriptine QR AG inhiitor If not t gol in 3 months, proceed to triple therpy Order of of medictions listed re listed suggested re hierrchy suggested of usge. hierrchy of usge. ACE, Americn College of Endocrinology; AG, α-glucosidse; GLN, glinide; QR, quick relese. Grer AJ, et l. Endocr Prct. 216;22(1): NO Dul Therpy OR Triple Therpy Symptoms YES Insulin ± Other Agents Add or Intensify Insulin Possile enefits or few dverse events Use with cution Comintion Regimens for T2DM Trgeting Multiple Disese Mechnisms Incresed Glucgon Secretion Impired Insulin Secretion Incresed Heptic Glucose Production Defronzo RA. Dietes. 29;58(4): Decresed Incretin Effect Hyperglycemi Neurotrnsmitter Dysfunction Incresed Lipolysis Decresed Glucose Uptke Incresed Glucose Resorption Annulized Rte of Severe, % Hurdles to Intensive Therpy Rtes of Severe UKPDS 1 ADVANCE 2 ACCORD 3 VADT 4 vs CON HR 1.86 ( ) 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% 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):

3 Ptients With 1 Hypoglycemic Event(s), % ADVANCE Severe vs Adverse Endpoints HR (95% CI): 3.53 ( ) HR (95% CI): 2.19 ( ) HR (95% CI): 3.27 ( ) Adjusted for multiple seline covrites; Primry endpoints. Mjor mcrovsculr event=crdiovsculr 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. 21;363(): HR (95% CI): HR (95% CI): 3.79 ( ) 2.8 ( ) Effects of on Thromosis in T2DM Euglycemi Bseline End of Dy 1 Dy 7 Bseline End of Dy 1 Dy 7 4 Clmp 2 Clmp Bseline End of Dy 1 Dy 7 Bseline End of Dy 1 Dy 7 Clmp Clmp Timepoint Timepoint P<.5 vs euglycemi; P<.1 vs euglycemi prt (dt re men ± stndrd error of the men). N=1 ptients with T2DM underwent pired hyperinsulinemic clmp stuides t lest 4 weeks prt. hscrp, high-sensitivity CRP. Chow EYK, et l. Dietologi. 213;56(suppl 1):S243. Mximum Asornce, AU ΔClot Lysis Time, s ΔFirinogen, mg/ml ΔhsCRP, mg/l Risks of Crdic Arrhythmis Risks of Events During vs Euglycemi in Insulin-Treted Ptients Dy Night IRR 95% CI P IRR 95% CI P Brdycrdi NA NA NA Atril ectopic VPB < <.1 Complex VPB IRR, incident rte rtios; VPB, ventriculr premture ets. N=25 insulin-treted ptients with T2DM nd history of CVD or 2 crdiovsculr risk fctors underwent simultneous continuous interstitil glucose nd multory electrocrdiogrm monitoring. Chow E, et l. Dietes. 214;63(5): Drug Clss With Antidietes Therpies Estimted A1c Reduction, % Incidence, % Short-cting GLP-1 RA 1, * Long-cting GLP-1 RA 1, * inhiitors 2,c * inhiitors 3,.7-6 * Sulfonylures Pioglitzone Bsl insulin 6,d * risks re higher when gents re comined with sulfonylure or insulin. Exentide twice dily; Includes lirglutide, exentide once weekly, liglutide, nd dulglutide; c Includes sxgliptin, lingliptin, nd sitgliptin; d Includes cngliflozin, dpgliflozin, nd empgliflozin; d Includes neutrl protmine Hgedorn insulin, insulin glrgine, nd insulin detemir. 1. Drugs@FDA Bolnd CL, et l. Ann Phrmcother. 213;47(4):49-55; 3. Nuck MA. Drug Des Devel Ther. 214;8: Noninsulin Antihyperglycemic Therpy Potentil 2-Drug Comintions in the US c d GLP-1 Receptor Agonist e Metformin f 9 Possile Noninsulin Comintions in 2-Drug Regimens 2 Not recommended in comintion Potentil Comintions Not Recommended Possile SUs nd GLNs include glimepiride, glipizide, glyuride, nteglinide, nd repglinide; Possile s include pioglitzone nd rosiglitzone; c Possile inhiitors include logliptin, sitgliptin, lingliptin, nd sxgliptin; d Possile inhiitors include cngliflozin, dpgliflozin, nd empgliflozin; e Possile GLP-1 RAs include exentide twice dily, exentide once weekly, lirglutide, dulglutide, nd liglutide; f Possile metformin drugs include stndrd nd extended relese formultions. ADA. Dietes Cre. 2;38(suppl 1):S1-S94; Nuck M, et l. Dietes. 2;64(suppl 1):A3 [strct 1-OR]. Noninsulin Dul Therpy Avoiding Agents With Risks c d GLP-1 Receptor Agonist e Potentil Comintions Not Recommended Metformin f Comintions With Agents Associted With Risks 79 Remining Possile Noninsulin 2-Drug Regimens 2 Not recommended in comintion Possile SUs nd GLNs include glimepiride, glipizide, glyuride, nteglinide, nd repglinide; Possile s include pioglitzone nd rosiglitzone; c Possile inhiitors include logliptin, sitgliptin, lingliptin, nd sxgliptin; d Possile inhiitors include cngliflozin, dpgliflozin, nd empgliflozin; e Possile GLP-1 RAs include exentide twice dily, exentide once weekly, lirglutide, dulglutide, nd liglutide; f Possile metformin drugs include stndrd nd extended-relese formultions. ADA. Dietes Cre. 2;38(suppl 1):S1-S94; Nuck M, et l. Dietes. 2;64(suppl 1):A3 [strct 1-OR].

4 c d GLP-1 Receptor Agonist e Potentil Comintions Not Recommended Noninsulin Dul Therpy Avoiding Agents With Risks of Weight Gin or Metformin f 51 Remining Possile Noninsulin 2-Drug Regimens 2 Not recommended in comintion Comintions With Agents Associted With or Weight Gin Risks Possile SUs nd GLNs include glimepiride, glipizide, glyuride, nteglinide, nd repglinide; Possile s include pioglitzone nd rosiglitzone; c Possile inhiitors include logliptin, sitgliptin, lingliptin, nd sxgliptin; d Possile inhiitors include cngliflozin, dpgliflozin, nd empgliflozin; e Possile GLP-1 RAs include exentide twice dily, exentide once weekly, lirglutide, dulglutide, nd liglutide; f Possile metformin drugs include stndrd nd extended-relese formultions. ADA. Dietes Cre. 2;38(suppl 1):S1-S94; Nuck M, et l. Dietes. 2;64(suppl 1):A3 [strct 1-OR]. GLP-1 Signling Effects Relted to Glucose Control 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 5-7 Stiety Energy intke Body weight Crdiovsculr System 8 Systolic BP Liver 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. 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);:42-54; 8. Fonsec V, et l. Dietes. 21;59(suppl 1):A79(296-OR). ΔA1c From Bseline, % s vs Sulfonylures P=.1 (2 yers) Noninferior vs SU (2 yers).16 Added to Metformin Noninferiority vs SU demonstrted t 52 weeks ALO (25 mg) 1, GLIP LINA (5 mg) 2,c GLIM SAXA (5 mg) 3,d SITA (1 mg) 4,e Agent Δ Weight, kg inhiitor SU % of ptients inhiitor SU ALO 1, LINA 2, SAXA 3,c SITA 4,d vs SU; ALO: 14-week tril of logliptin; seline A1c, 7.6%; c LINA: 14-week tril of lingliptin; seline A1c, 7.7%; d SAXA: 14-week tril of sxgliptin; seline A1c, 7.7%; e SITA: 14-week tril of sitglptin; seline A1c, 7.3%. 1. Del Prto S, et l. Dietes Oes Met. 214;16: ; 2. Gllwitz B, et l. Lncet. 212;38: ; 3. Göke B, et l. Int J Clin Prct. 213;67:37-316; 4. Seck T, et l. Int J Clin Prct. 21;64: ; 5. Nuck MA, et l. Dietes Oes Met. 27;9: ΔA1c From Bseline, % GLP-1 RAs vs s P<.1 P<.1.8 Added to Metformin Agent Δ Weight, kg GLP-1 i RA, % of ptients GLP-1 RA i EXEN 2.8 NA 5 NA BID 1,d EXEN QW 2,e d 3 LIRA 3,f d DULA 4,g d ALBI 5,h.8 c d,j 16 j EXEN BID (1 μg) 1,e DULA (1.5 mg) 4,h EXEN QW (2 mg) 2,f ALBI (3 or 5 mg) 5,i SITA LIRA (1.8 mg) 3,g Plceo P<.1 vs inhiitor; vs inhiitor; c P<.5 vs inhiitor; d No sttisticl nlysis performed; e EXEN BID: 3-week study of exentide twice dily; seline A1C, 8.2%; f EXEN QW: 26-week tril of exentide once weekly; seline A1c, 8.4%; g LIRA: 26-week tril with lirglutide; seline A1c, 8.5%; h DULA: 52-week tril; seline A1c, 8.1%; i ALBI: 26-week tril of liglutide; seline A1c, 8.2%; j Almost ll ptients experiencing hypoglycemi were lso tking sulfonylure. 1. DeFronzo RA, et l. Dietes Cre. 25;28:192-11; 2. Bergenstl RM, et l. Lncet. 21;376: ; 3. Prtley RE, et l. Lncet. 21;375(9724): ; 4. Nuck M, et l. Dietes Cre. 214;37(8): ; 5. Leiter LA, et l. Dietes Cre. 214;37(1): Sfety With Incretin-Bsed Agents Precutions 1-5 Cses hve een reported Consider tretments other thn GLP-1 RAs in ptients with history of pncretitis Unknown if pncretitis history increses risk with inhiitors Acute Pncretitis Recommendtions 1-5 Ask out pncretitis history Educte ptients out signs nd symptoms of pncretitis Discontinue if pncretitis symptoms occur Report cses of pncretitis to Pncretitis risk is 1.5- to 3-fold higher in individuls with dietes See Drugs@FDA ( 2. See Drugs@FDA ( 3. See Drugs@FDA ( 4. Aliglutide prescriing informtion. IFU-COMBINED.PDF; 5. Dulglutide prescriing informtion Girmn CJ, et l. Dietes Oes Met. 21;12(9): ; 7. Grg R, et l. Dietes Cre. 21;33(11): ; 8. Yng L, et l. Eur J Gstroenterol Heptol. 213;25(2): Sfety of Incretin Therpy 214 FDA nd EMA Anlysis FDA nd EMA conducted prllel, independent sfety ssessments of incretin-sed 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 leling 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. 214;37(9):

5 s Sfety: Additionl Considertions Generlly well-tolerted 1 Most common dverse effects 1 Nsophryngitis Hedche Nuse Hypersensitivity Skin rections Recent sttement from the FDA wrned out the risks of joint pin tht cn e severe nd disling 2 Dose reductions re required for logliptin, sxgliptin, nd sitgliptin in ptients with moderte or severe renl impirment, or ESRD (CrCl 5 ml/min) 1 CrCl, cretinine clernce. 1. Grunerger G. J Dietes. 213;5: ; 2. US FDA: Aville t Accessed Septemer 4, 2. Nuse/Vomiting With GLP-1 RAs Pooled Results From Plceo-Controlled Trils Mediction Nuse Incidence, % Vomiting Incidence, % Aliglutide 1 11% 4% Dulglutide 2 12%-21% 6%-13% Exentide BID 3 8%-44% 4%-18% Exentide QW 4 11%-27% 11% Lirglutide 5 8%-35% 6%-17% Potentil pproches to reduce risks for nuse nd vomiting 3,6 Educte on mel size, eting pce, nd dose timing reltive to mels Use incrementl dose titrtion, prticulrly with shorter-cting gents Prescrie short-term ntiemetic therpy for select ptients 1. Aliglutide prescriing informtion. Prescriing_Informtion/Tnzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF; 2. Dulglutide prescriing informtion Drugs@FDA ( 4. Drugs@FDA ( 5. Drugs@FDA ( 6. Ellero C, et l. Diet Med. 21;27(1): GLP-1 RAs Sfety: Additionl Considertions Use with cution in ptients with renl impirment or renl trnsplnttion, especilly when inititing or esclting doses 1-6 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 e used in ptients with MEN2 or personl/fmily history of MTC 2-5 Counsel regrding MTC risk nd symptoms of thyroid tumors Report MTC to stte cncer registry, regrdless of tretment MEN2, multiple endocrine neoplsi syndrome type 2; MTC, medullry thyroid crcinom. 1. See Drugs@FDA ( 2. See Drugs@FDA ( 3. See Drugs@FDA ( 4. Aliglutide prescriing informtion. GlxoSmithKline/US/en/Prescriing_Informtion/Tnzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF; 5. Dulglutide prescriing informtion Idorn T, et l. Dietes Cre. 216;39(2): ΔA1c From Bseline, % s vs Sulfonylures Added to Metformin Noninferior vs SU CANA (3 mg) 1, GLIP DAPA (1 mg) 2,c GLIM EMPA (25 mg) 3,d Agent Δ Weight, kg SU, % of ptients SU CANA 1, DAPA 2, EMPA 3,c P<.1 vs SU. CANA: 52-week tril of cngliflozin; seline A1c, 7.8%; c DAPA: 52-week tril of dpgliflozin; seline A1c, 7.7%; d EMPA:14-week tril of empgliflozin; seline A1c, 7.9%. 1. Ceflu WT, et l. Lncet. 213;382(9896):941-95; 2. Nuck MA, et l. Dietes Cre. 211;34(9):2-222; 3. Ridderstråle M, et l. Lncet Dietes Endocrinol. 214;2(9): Ptients With Event, % Ptients With Event, % Ptients With Event, % EMPA-REG Tril Cumultive Incidence of the Primry Outcome P=.4 for superiority Hzrd rtio,.86 (95.2% CI,.74.99) Cumultive incidence of deth from crdiovsculr cuses, nonftl myocrdil infrction, or nonftl stroke. N=72 ptients with T2DM t high risk of crdiovsculr events. Zinmn B, et l. N Engl J Med. 2;373(22): Plceo Empgliflozin Cumultive Incidence of Deth From CV Cuses Plceo 6 Hzrd rtio,.62 (95% CI,.49.77) 3 Empgliflozin P=.2 Hzrd rtio,.65 (95% CI,.5.85) Hospitliztion for Hert Filure Plceo Empgliflozin Month s Sfety Considertions Generlly well-tolerted with good sfety profile 1,2 Most common AEs include genitl mycotic infections nd UTIs Dose-relted increses in serum cretinine nd decresed egfr 3-5 Evlute renl function efore inititing tretment nd during therpy Do not use dpgliflozin if egfr is <6 ml/min/1.73 m 2 Do not use cngliflozin or empgliflozin if egfr is <45 ml/min/1.73 m 2 Cuse intrvsculr volume depletion, which my led to symptomtic hypotension 3-5 At risk popultions include ptients on loop diuretics, elderly individuls, ptients with low systolic BP, nd those with egfr <6 ml/min/1.73 m 2 Assess nd correct volume sttus efore inititing therpy Chnges in plsm lipids were oserved in clinicl trils 3-5 Monitor LDL-C nd tret per stndrd of cre Recent FDA wrning clls out risks of euglycemic dietic ketocidosis s well s cngliflozin for one frcture UTI, urinry trct infection. 1. Adul-Ghni MA, Defronzo RA. J Intern Med. 214 Apr 1; 2. List JF, et l. Dietes Cre. 29;32(4):65-657; 3. See Drugs@FDA ( 4. See Drugs@FDA ( 5. See Drugs@FDA (

6 s nd Dietic Ketocidosis Concerns 2 cses of DKA in ptients with T2DM reported to the FDA Adverse Events Reporting System (3/213 to 6/214) 13 pulished cses of euglycemic DKA in ptients with T1DM (9 cses) or T2DM (4 cses) Most ptients were women Most cses linked to reduced insulin doses Possile links to incresed ctivity, recent illness, lcohol use, nd decresed food intke Some ptients hd no identifying cuse All ptients responded to IV rehydrtion nd insulin Ptients with T1DM should e counseled when s re used off-lel Potentil Mechnisms Inhiition Increses glucose renl clernce Decreses renl clernce of ketone odies Endogenous nd/or exogenous insulin levels reduced + Dehydrtion or incresed ctivity level + Incresed α-cell secretion of glucgon (medited y ) Incresed lipolysis Eudietic Ketocidosis DKA, dietic ketocidosis; IV, intrvenous. Tylor SI, et l. J Clini Enocrinol Met. 2;1(8): ; Peters AL, et l. Dietes Cre. 2;38(9): Plus Trgeting Multiple Disese Mechnisms Impired Insulin Secretion Incresed Glucgon Secretion Incresed Heptic Glucose Production Defronzo RA. Dietes. 29;58(4): Decresed Incretin Effect Hyperglycemi Neurotrnsmitter Dysfunction Incresed Lipolysis Decresed Glucose Uptke Incresed Glucose Resorption Chnge From Bseline in A1c, % Empgliflozin/Lingliptin Comintion 24-Week Dt for Initil T2DM Therpy Men Bseline, 64 mmol/mol 7.99 % 8.4% 7.99% 8.5% 8.5% (n=134) (n=135) (n=133) (n=132) (n=133) (-.33,.6) P= (-.61, -.21) -.57 (-.76, -.21) -.41 (-.61, -.21) Empgliflozin 25 mg/lingliptin 5 mg Empgliflozin 1 mg/lingliptin 5 mg Chnge From Bseline in Body Weight, kg N=674 individuls with T2DM who hd not received dietes therpy for 12 weeks (week 24 dt). Lewin A, et l. Dietes Cre. 2;38(3): Empgliflozin 25 mg Empgliflozin 1 mg Men Bseline (n=134) (n=135) (n=133) (n=132) (n=133).1 (-.9, 1.1) P= (-1.5,.5) P= (-3., -1.) -1.2 (-2.2, -.2) P=.18 Lingliptin 5 mg Adjusted Men (95% CI) Chnge From Bseline in HA1c, % Sxgliptin nd/or Dpgliflozin Add-on to Metformin 24-Week Dt for Initil T2DM Therpy SAXA+ DAPA+ (n=8) SAXA+ (n=143) -.59% (-.81%, -.37%) P< % (-.48%, -.5%) P=.166 DAPA+ (n=1) Ptients Achieving A1c Vlue <7.%, % N=534 ptients with T2DM, A1c vlues etween 8.% nd 12.% (men A1c, 8.9%), nd n indequte response to metformin. Rosenstock J, et l. Dietes Cre. 2;38(3): SAXA+ DAPA+ (n=179) SAXA+ (n=176) DAPA+ (n=179) LS Men Chnge (±se) in HA1c From Bseline, % LS Men % Chnge (±se) in Body Weight From Bseline GLP-1 RA + Improved Glycemic Control nd Weight Loss Plceo CANA 1 mg CANA 3 mg Plceo -4. CANA 1 mg CANA 3 mg Time Point, week.17% -.83% -.89% N=95 sujects with T2DM in CANVAS study who were tking GLP-1 receptor gonists. Fulcher G, et l. Dietes Oes Met. 216;18(1): % (-.6 kg) -3.% (-3.3 kg) -3.7% (-3.9 kg) -1.% (95% CI: -1.35, -.65) -1.6% (95% CI: -1.43, -.69) -2.5% (95% CI: -3.7, -1.4) (-2.7 kg [95% CI: -3.9, -1.4]) -3.2% (95% CI: -4.5, -2.) (-3.3 kg [95% CI: -4.6, -1.9]) Adherence, % Dily Dosing Frequency nd Adherence x 2x 3x 4x Dily Dosing Frequency Clxton AJ, et l. Clin Ther. 21;23: ; Lufs U, et l. Eur Hert J. 211;32:

7 Core Principles Adjust timing, frequency, mount, nd dosge Mtch regimen to ptient s ctivities of dily living Recommend ll medictions re tken together Avoid medictions with specil requirements Avoid unnecessry side effects Simplify the Regimen Action Prescrie once-dily medictions Dose to regulr ctivities (eg, mels) Consider comintion formultions Assess for drug-drug interctions nd food sorption issues Avoid medictions tht should not e tken with mels Evlute ll potentil side effects My need to choose mong side effects Chnge the sitution rther thn chnge the ptient! Americn College of Preventtive Medicine. Aville t: dherencecliniclreference.pdf. Accessed Septemer 3, 2. Orl Comintion Formultions With s nd s Fixed Dose Comintions + Metformin Clinicl Sttus Sitgliptin + Metformin Sitgliptin + Metformin ER Sxgliptin + Metformin ER Lingliptin + Metformin Alogliptin + Metformin + Metformin Dpgliflozin + Metformin Cngliflozin + Metformin Empgliflozin + Metformin + Empgliflozin + Lingliptin Dpgliflozin + Sxgliptin A recent FDA response letter sks for more dt efore the comintion cn e pproved Ertugliflozin + Sitgliptin Phse 3 + Alogliptin + Pioglitzone There re lso comintions formultions ville in the US of metformin plus sulfonylures (glyuride or glipizide), metformin plus pioglitzone, nd pioglitzone plus glimepiride. Efficcy of Dpgliflozin/Sxgliptin Comintion Added to Metformin Chnge from Bseline in A1c Ptients Achieving A1c <7% t Week 24 SAXA+DAPA 45 + SAXA+ DAPA+ 41 Bseline, % N A1c, % % (-.81%, -.37%) P< % (-.48%, -.5%) P=.166 Ptients, % SAXA+DAPA + 18 SAXA+ 22 DAPA+ No mjor hypoglycemi episodes (incidence of ny hypoglycemic episode, 1.1 % in SAXA+DAPA nd DAPA groups,.6% in SAXA group). N=534 ptients with T2DM (A1c, 8.% nd 12.%) treted with metformin XR mg dily. Rosenstock J, et l. Dietes Cre. 2;38(3): Decision Aids for T2DM Exmples from the Myo Clinic Decision id crds provide informtion on T2DM medictions Crd orgnized into 7 issues tht my e of interest to the ptient A1c reduction Dily routine Lower lood sugr Costs Dily sugr testing Other considertions Weight chnge Aville t decision-ids-for-chronic-disese/dietes-mediction-mngement/. Motivtionl interviewing is collortive converstion style for strengthening person's own motivtion nd commitment to chnge y eliciting nd exploring the persons own resons for chnge Miller & Rollnick, 213 Motivtionl Interviewing Stges of Chnge 6. Recurrence Definition: Experienced recurrence of the prolems 5. Mintennce Definition: Hs chieved the gols nd is working to mintin chnge 1. Precontempltion Definition: Not yet considered or is unwilling or unle to chnge 4. Action Definition: Tking steps towrd chnge ut hsn t stilized in the chnge process 2. Contempltion Definition: Sees the possiility of chnge ut is mivlent nd uncertin 3. Determintion Definition: Committed to chnging ut still considering wht to do

8 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 Hypoglycemic episodes re ssocited with serious dverse outcomes Certin comintions of noninsulin gents cn effectively reduce hyperglycemi with reltively low risks of hypoglycemi nd potentil for weight loss