Noninsulin Approaches to Managing Type 2 Diabetes: Best Practices in Combination Therapy

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2 Achieving Tretment Gols Room for Improvement in T2DM Noninsulin Approches to Mnging Type 2 Dietes: Best Prctices in Comintion Therpy Ptients Achieving Gol, % 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): yer-old ccountnt Mrried with 1 son t college Wife ttends ppointment Dietry hits Primrily pst nd red met Few fruits or vegetles 1-3 lcoholic drinks/dy Smokes 1-2 pcks/week Medicl history Hypertension dignosis 5 yers go Lisinopril 4 mg dily Atenolol 5 mg dily Forgets medictions 1-2 times weekly Cse Bckground Fmily history Fther treted for T2DM nd died of MI t 55 yers of ge T2DM dignosis lst week Complints of incresed thirst nd urintion Drk ptches of skin ehind his neck nd under his rms (cnthosis nigricns) BMI, 31. kg/m 2 (oese) BP, 129/75 mm Hg FPG, 22 mg/dl Second test, 198 mg/dl A1c, 8.7% egfr, 84 ml/min/ 1.73 m 2 ACR, 2.4 mg/mmol Recent L Results Lipids TC, 165 mg/dl TG, mg/dl LDL-C, 95 mg/dl HDL-C, 4 mg/dl ApoB, 82 mg/dl Sensory nd eye exms unremrkle 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 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 ACR, lumin/cretinine rtio; ApoB, polipoprotein B; BMI, ody mss index; egfr, estimted glomerulr filtrtion rte; FPG, fsting plsm glucose; HDL-C, high-density lipoprotein cholesterol; TC, totl cholesterol; TG, triglycerides. 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:

3 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) Hypoglycemi Weight Side Effects Costs Dul Therpy Efficcy ( A1c) Hypoglycemi Weight Mjor Side Effect(s) Costs ADA Recommendtions Mnging Hyperglycemi in T2DM + SU Moderte risk Gin Hypoglycemi 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 Hypoglycemi 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 Hurdles to Intensive Therpy Rtes of Severe Hypoglycemi ADVANCE Severe Hypoglycemi vs Adverse Endpoints Annulized Rte of Severe Hypoglycemi, % 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% Ptients With 1 Hypoglycemic Event(s), % 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 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():

4 Mximum Asornce, AU ΔClot Lysis Time, s Effects of Hypoglycemi on Thromosis in T2DM Bseline Bseline End of Clmp Dy 1 Dy 7 End of Clmp Dy 1 Dy 7 Timepoint ΔFirinogen, mg/ml ΔhsCRP, mg/l 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):S Bseline Hypoglycemi Euglycemi End of Clmp Dy 1 Dy 7 Bseline End of Dy 1 Dy 7 Clmp Timepoint Hypoglycemi Risks of Crdic Arrhythmis Risks of Events During Hypoglycemi 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 Hypoglycemi With Antidietes Therpies Estimted A1c Reduction, % Hypoglycemi 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 *Hypoglycemi 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: Initil Tretment Trget A1c 6.5% His PCP engges in discussion round lifestyle modifictions, including smoking cesstion nd weight loss Suggests Certified Dietes Eductor Ptient eduction Detiled dietry nd exercise recommendtions Provided medicl nutrition therpy nd his PCP lso review the possiility of inititing therpy with 2 ntihyperglycemic gents 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 Hypoglycemi Risks c d GLP-1 Receptor Agonist e Potentil Comintions Not Recommended Metformin f Comintions With Agents Associted With Hypoglycemi 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].

5 c d GLP-1 Receptor Agonist e Potentil Comintions Not Recommended Noninsulin Dul Therpy Avoiding Agents With Risks of Weight Gin or Hypoglycemi Metformin f 51 Remining Possile Noninsulin 2-Drug Regimens 2 Not recommended in comintion Comintions With Agents Associted With Hypoglycemi 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]. 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): 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):

6 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 P<.1 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 ( 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): 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]) Phrmcologic Tretment nd his PCP decide to strt therpy with metformin BID nd n inhiitor is educted on risks with oth drugs He is ssessed for volume sttus Both medictions titrted up over next 2 weeks At 3-month follow-up, s A1c hs fllen to 7.4% Previous vlue, 8.7% often forgets which drugs he hs tken ech dy Frequently skips doses for T2DM or hypertension His weight is reltively unchnged He reports continued d eting hits during tx seson How cn the PCP help improve s dherence to lifestyle recommendtions nd his medictions?

7 Adherence, % Dily Dosing Frequency nd Adherence x 2x 3x 4x Dily Dosing Frequency 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! Clxton AJ, et l. Clin Ther. 21;23: ; Lufs U, et l. Eur Hert J. 211;32: 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 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 Aville t decision-ids-for-chronic-disese/dietes-mediction-mngement/.

8 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 Key Points Individulize tretment gols for ptients with 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 When necessry, promptly intensify ntihyperglycemic therpy Consider erly multidrug regimens tht reflect the seline degree of hyperglycemi nd other clinicl prmeters Minimize risks of hypoglycemi Use comintion formultions to ddress multiple pthologic mechnisms in T2DM nd to simplify tretment regimens