Insulin 101. An Introduction to Insulin Therapy in the 21 st Century. titration. premixed T1DM T2DM. glycemic control. Basal-bolus

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1 Insulin An Introduction to Insulin Therpy in the st Century glycemic control titrtion AC levels Bsl-bolus premixed TDM TDM hypog November, Boston, Msschusetts Eduction Prtner

2 Session : Insulin : An Introduction to Insulin Therpy in the st Century Lerning Objectives. Clculte pproprite insulin doses for inititing bsl nd bsl-prndil insulin regimens in type dibetes mellitus.. Demonstrte best prctices in insulin injection nd self-monitoring of blood glucose (SMBG) techniques to improve tretment dherence nd potentilly impct ptient outcomes. 3. Apply pttern recognition to SMBG dt to ppropritely titrte insulin doses nd djust insulin regimens to specific ptient needs.. Summrize the efficcy nd sfety findings from clinicl trils of investigtionl insulins nd the combintion of incretin-bsed therpies with insulin. Fculty Jmes R. Gvin III, MD, PhD Progrm Chir Clinicl Professor of Medicine Emory University School of Medicine CEO nd Chief Medicl Officer Heling Our Villge, Inc. Atlnt, Georgi Dr Gvin is clinicl professor of medicine t Emory University School of Medicine in Atlnt, Georgi, nd clinicl professor of medicine t the Indin University School of Medicine, Indinpolis, Indin. He currently serves s chief executive officer nd chief medicl officer of Heling Our Villge, Inc. He served s president nd chief executive officer of MicroIslet, Inc., Sn Diego, Cliforni, from Jnury 6 to July 7 nd ws president of the Morehouse School of Medicine in Atlnt from to. He served s senior scientific officer t the Howrd Hughes Medicl Institute (HHMI) from 99 to nd s director of the HHMI Ntionl Institutes of Helth (NIH) Reserch Scholrs Progrm from to. joining the senior stff of HHMI, Dr Gvin ws professor nd chief of the dibetes section, cting chief of the section on endocrinology, metbolism, nd hypertension, nd Willim K. Wrren Professor for Dibetes Studies t the University of Oklhom Helth Sciences Center, Oklhom City, Oklhom. He previously served s n ssocite professor of medicine t Wshington University School of Medicine in St Louis, Missouri. Dr Gvin is member of numerous orgniztions, including the Institute of Medicine of the Ntionl Acdemy of Sciences, the Americn Dibetes Assocition (ADA), the Americn Assocition of Clinicl Endocrinologists, The Endocrine Society, the Americn Society for Clinicl Investigtion, the Americn Assocition of Physicins, the Alph Omeg Alph Honor Medicl Society, the Sigm Pi Phi Ledership Frternity, nd the Downtown Atlnt Rotry Club. He is life member of Alph Phi Alph Frternity, Inc. He is pst president of the ADA nd ws voted Clinicin of the Yer in Dibetes by the ADA in 99. He hs served on mny dvisory bords nd on the editoril bords of the Americn Journl of Physiology nd the Americn Journl of the Medicl Sciences. He is on the bord of trustees for Emory University, Livingstone College, nd is trustee emeritus for the Robert Wood Johnson Foundtion. In ddition, he is ntionl progrm director of the Hrold Amos Medicl Fculty Development Progrm of the Robert Wood Johnson Foundtion. He is member of the Ntionl Advisory Bord for the Institute of Medicine s Helth Policy Fellows Progrm. He is lso chirmn emeritus of the Ntionl Dibetes Eduction Progrm. He serves s chirmn of the dt sfety monitoring bord for the Veterns Affirs Coopertive Dibetes Study. He is chirmn of the bord of directors for the Prtnership for Helthier Americ, n independent, nonprtisn foundtion formed to support the childhood obesity prevention inititive nd the Let s Move! inititive of First Ldy Michelle Obm. Dr Gvin hs published more thn rticles nd bstrcts in such publictions s Science, Journl of Applied Physiology, Dibetes, nd the Americn Journl of Physiology. He is couthor of two books: Heling Our Villge: A Self-Cre Guide to Dibetes Control (written with L. Colemn) nd Dr. Gvin s Helth Guide for Africn Americns (written with S. Lndrum). He hosted the PowerPoint helth tlk-rdio shows for public rdio sttion WCLK, 9.9 FM in Atlnt from to 6. Among the mny honors Dr Gvin hs received re the Dniel Hle Willims Awrd, the EE Just Awrd, the Herbert Nickens Awrd, the Dniel Svge Memoril Awrd, the Emory University Medl for Distinguished Achievement, the Bnting Medl for Distinguished Service from the ADA, the Distinguished Alumni Awrd from Duke University School of Medicine, the FC Greenwood Awrd from the Reserch Centers in Minority Institutions of the former Ntionl Center for Reserch Resource t the NIH, the Bernrdo Houssy Awrd from the Ntionl Minority Qulity Forum nd the Congressionl Blck Cucus, nd the Internist of the Yer Awrd from the Ntionl Medicl Assocition. He ws recipient of the 9 Living Session

3 Legend in Dibetes Awrd from the Americn Assocition of Dibetes Eductors. He is lso recipient of the Public Policy Awrd from the ADA for contributions to dvoccy on behlf of persons with dibetes. Dr Gvin grduted from Livingstone College (My 966) in Slisbury, North Crolin, with degree in chemistry. He erned his PhD in biochemistry from Emory University (December 97) nd his MD from Duke University School of Medicine (December 97), Durhm, North Crolin. He completed his internship, residency, nd clinicl fellowship trining t Brnes-Jewish Hospitl of Wshington University in St. Louis. He nd his wife, Dr Annie Gvin, re the prents of three dult sons. Dvid F. Kruger, MSN, APRN-BC, BC-ADM Certified Nurse Prctitioner Henry Ford Helth System Division of Endocrinology, Dibetes, Bone nd Minerl Disorders Detroit, Michign Ms Kruger hs been certified nurse prctitioner in dibetes for the pst 7 yers t Henry Ford Helth System in Detroit, Michign. Her role includes both clinicl prctice nd reserch. She is bord certified by the Americn Nurses Assocition Credentiling Center in both Primry Cre nd Advnced Dibetes Mngement. She is pst chir of the Americn Dibetes Assocition (ADA) s Reserch Foundtion nd hs served on the ADA 's Reserch Policy Committee. She is lso pst president of Helth Cre & Eduction of the ADA. She served s editor of Dibetes Spectrum from to 8. Presently, she serves s n ssocite editor of Clinicl Dibetes. Ms Kruger hs been principl investigtor on numerous reserch projects nd hs written widely on dibetes cre, uthoring the second edition of The Dibetes Trvel Guide (6). Her wrds include the Florence Nightingle Awrd for excellence in reserch, the ADA s Rchmiel Levine Awrd for Distinguished Service, the ADA s Outstnding Service in Dibetes Reserch Funding Awrd, nd the ADA s Wendell Myes Awrd. Thoms B. Reps, DO, FACP, FACOI, FNLA, FACE, CDE Clinicl Assistnt Professor Deprtment of Internl Medicine Snford School of Medicine The University of South Dkot Rpid City, South Dkot Dr Reps is n endocrinologist, lipidologist, nd physicin nutrition specilist in prctice t the Regionl Medicl Clinic, Endocrinology nd Dibetes Eduction in Rpid City, South Dkot. He is clinicl ssistnt professor with the deprtment of medicine, Snford School of Medicine t The University of South Dkot. Dr Reps completed his undergrdute studies t Frnklin nd Mrshll College in Lncster, Pennsylvni, nd received his DO degree from Des Moines University in Des Moines, Iow. He completed his postgrdute residency in internl medicine from the University of Nevd-Reno nd his fellowship in endocrinology, dibetes nd metbolism t the University of Wisconsin Hospitl nd Clinics, Mdison, Wisconsin. Dr Reps is bord certified in four medicl subspecilties: endocrinology, dibetes nd metbolism; clinicl lipidology; internl medicine; nd nutrition. Dr Reps lso hs been wrded numerous other certifictions including: Endocrine Certifiction in Neck Ultrsound (ECNU), Certified Clinicl Densitometrist (CCD), Certified Dibetes Eductor (CDE), nd Certified Physicin Investigtor (CPI). Dr Reps serves s principl investigtor nd sub investigtor for multiple clinicl reserch trils for type nd type dibetes mellitus. Dr Reps is member of the South Dkot Dibetes Colition nd is the former chirmn of the professionl dibetes dvisory committees of the Dibetes Prevention nd Control Progrms of Wyoming nd Wisconsin. He holds membership in severl professionl societies, including the Americn Assocition of Clinicl Endocrinologists, the Americn College of Physicins, the Americn College of Osteopthic Internists, the Assocition of Clinicl Reserch Professionls, the Americn Hert Assocition, the Interntionl Atherosclerosis Society, the Ntionl Lipid Assocition, nd the Wilderness Medicl Society. Dr Reps gretly enjoys teching nd hs been honored to be n invited lecturer t regionl nd ntionl meetings. Dr Reps hs been n uthor of rticles nd editorils published in peer-reviewed journls. He lso writes regulr weekly column Session

4 published s blog on the website of the journl Endocrine Tody. Outside of medicine, he enjoys pursuing vriety of outdoor ctivities, including running ultrmrthons of up to miles. Fculty Finncil Disclosure Sttements The presenting fculty reports the following: Jmes R. Gvin III, MD, PhD, receives honorri s consultnt nd speker from Eli Lilly nd Compny nd snofiventis US LLC. Dr Gvin is lso n dvisor for Amylin Phrmceuticls, Inc. Dvid F. Kruger, MSN, APRN-BC, BC-ADM, reports tht she prticiptes in n dvisory bord for Abbott Lbortories, Anims Corportion, Council for the Advncement of Dibetes Reserch nd Eduction, Eli Lilly nd Compny, GlxoSmithKline plc, Merck & Co., Inc., Ptton Medicl Devices, LP, nd Tethys Bioscience, Inc. She receives honorri from Abbott Lbortories, Amylin Phrmceuticls, Inc., Anims Corportion, Clibr Medicl, Inc., Eli Lilly nd Compny, nd Novo Nordisk Inc. She receives grnt reserch support from Amylin Phrmceuticls, Inc., Clibr Medicl, Inc., Eli Lilly nd Compny, F. Hoffmnn-L Roche Ltd., Hlozyme Therpeutics, nd the Ntionl Institutes of Helth. She receives honorri s member of the spekers bureus for Amylin Phrmceuticls, Inc., Eli Lilly nd Compny, nd Novo Nordisk Inc. She lso holds stock with Amylin Phrmceuticls, Inc., Dexcom, Inc., Hygiei, Inc., nd Ptton Medicl Devices, LP. Thoms Reps, DO, FACP, FACOI, FNLA, FACE, CDE, reports tht he receives honorri s member of the spekers bureus for Abbot Lbortories, Amgen Inc., GlxoSmithKline, Novrtis AG, Novo Nordisk, Inc., nd Tked Phrmceuticls North Americ, Inc. He receives grnt/reserch support from Dimyd Medicl AB, Novo Nordisk Inc., snofi-ventis U.S. LLC, Tolerx, Inc., nd Vercyte, Inc. Eduction Prtner Finncil Disclosure Sttements The content collbortors t the Institute for Medicl nd Nursing Eduction, Inc., report the following: Amy Crbonr, Director of Progrm Development, hs no finncil reltionships to disclose. Robin Devine, DO, Medicl Writer, hs no finncil reltionships to disclose. Angel McIntosh, PhD, Scientific Director, hs no finncil reltionships to disclose. Mrge Tms, Editoril Mnger, hs no finncil reltionships to disclose. Steve Weinmn, RN, Executive Director, hs no finncil reltionships to disclose. Acronym List Acronym Definition AC glycosylted hemoglobin AC AACE Americn Assocition of Clinicl Endocrinologists AADE Americn Assocition of Dibetes Eductors ACE Americn College of Endocrinology ADA Americn Dibetes Assocition AE dverse event ASP insulin sprt B brekfst BBT bsl bolus therpy BG blood glucose Bi-ASP biphsic sprt BID twice dily BMI body mss index CGM continuous glucose monitoring CKD chronic kidney disese CSII continuous subcutneous insulin infusion CVD crdiovsculr disese D dinner DEG insulin degludec DET insulin detemir DPP- dipeptidyl peptidse- Acronym Definition EPM events/ptient-month EXN exentide FBG fsting blood glucose FPG fsting plsm glucose FPG LL fsting plsm glucose lower limit FPG UL fsting plsm glucose upper limit GLAR insulin glrgine GLP- glucgon-like peptide- GLU insulin glulisine HS t bedtime IFG impired fsting glucose IGT impired glucose tolernce ILPS insulin lispro protmine suspension ITT intention-to-tret L lunch LIRA lirglutide LIS insulin lispro LM/ insulin lispro protmine (%)/insulin lispro (%) LM7/ insulin lispro protmine (7%)/insulin lispro (%) LY pegylted insulin lispro MDI multiple dily injections MET metformin Session

5 NA NPH NPL OAD OD PBO PCP PD PH PIO PK PPG PPG UL QHS QOL not pplicble neutrl protmine Hgedorn insulin lispro protmine suspension orl ntidibetes gent once dily plcebo primry cre physicin phrmcodynmics recombinnt humn hyluronidse pioglitzone phrmcokinetics postprndil glucose postprndil glucose upper limit every night t bedtime qulity of life R RA RHI SAXA SC SITA SMBG STeP SU TDM TDM TDD TZD U recombinnt receptor gonist regulr humn insulin sxgliptin subcutneous sitgliptin self-monitoring of blood glucose Structured Testing Progrm sulfonylure type dibetes mellitus type dibetes mellitus totl dily dose thizolidinedione unit Suggested Reding List Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. Alexndri, VA: Americn Dibetes Assocition, Inc; :-68. Freemn JS. Insulin nlog therpy: improving the mtch with physiologic insulin secretion. J Am Osteopth Assoc. 9;9():6-36. Frid A, Hirsch L, Gspr R, et l. New injection recommendtions for ptients with dibetes. Dibetes Metb. ;36(suppl ):S3-S8. Hndelsmn Y, Mechnick JI, Blonde L, et l; for the AACE Tsk Force for Developing Dibetes Comprehensive Cre Pln. Americn Assocition of Clinicl Endocrinologists Medicl Guidelines for Clinicl Prctice for developing dibetes mellitus comprehensive cre pln. Endocr Prct. ;7(suppl ):-3. Hinnen D, Tomky D. In: Mensing C, et l, eds. The Art nd Science of Dibetes Self-Mngement: A Desk Reference for Helthcre Professionls. Chicgo, IL: Americn Assocition of Dibetes Eductors; :3-76. Hirsch E, Bergenstl RM, Prkin CG, et l. A rel-world pproch to insulin therpy in primry cre prctice. Clin Dibetes. ;3(): Inzucchi SE, Bergenstl RM, Buse JB, et l. Mngement of hyperglycemi in type dibetes: ptient-centered pproch: position sttement of the Americn Dibetes Assocition (ADA) nd the Europen Assocition for the Study of Dibetes (EASD). Dibetes Cre. ;3(6): Nthn DM, Buse JB, Dvidson MB, et l. Medicl mngement of hyperglycemi in type dibetes: consensus lgorithm for the initition nd djustment of therpy: consensus sttement of the Americn Dibetes Assocition nd the Europen Assocition for the Study of Dibetes. Dibetes Cre. 9;3():93-3. Prkin CG, Dvidson JA. Vlue of self-monitoring blood glucose pttern nlysis in improving dibetes outcomes. J Dibetes Sci Technol. 9;3(3):-8. Rodbrd HW, Jellinger PS, Dvidson JA, et l. Sttement by n Americn Assocition of Clinicl Endocrinologists/Americn College of Endocrinology consensus pnel on type dibetes mellitus: n lgorithm for glycemic control. Endocr Prct. 9;(6):-9. Skyler JS. In: Lebovitz HE, ed. Therpy for Dibetes Mellitus nd Relted Disorders. Alexndri, VA: Americn Dibetes Assocition, Inc.; :7-3. Session

6 Drug List Acronym Definition Asprt NovoLog Biphsic sprt 7/3 Novolog Mix 7/3 Detemir Levemir Exentide BID Byett Exentide ER Bydureon Glrgine Lntus Glulisine Apidr Glyburide glycosylted hemoglobin AC Lingliptin Trdjent Lirglutide Victoz Lispro Humlog Metformin Fortmet, Glucophge, Glumetz, Riomet NPH Humulin N, Novolin N Regulr insulin Humulin R, Novolin R Sxgliptin Onglyz Sitgliptin Jnuvi 7% NPH/3% regulr Humulin 7/3, Novolin 7/3 7% NPL/% lispro Humlog Mix7/ % NPL/% lispro Humlog Mix/ 7% sprt protmine/ 3% sprt Novolog Mix7/3 Insulin : Bsl Insulin Therpy Dvid F Kruger, MSN, APN BC, BC ADM Certified Nurse Prctitioner Henry Ford Helth System Division of Endocrinology, Dibetes, Bone nd Minerl Disese Detroit, Michign Insulin : Course Syllbus Prt : Bsl insulin therpy Bsics of insulin therpy Currently vilble bsl insulins Inititing bsl insulin therpy Optimizing insulin injection techniques Glucose (mg/dl) Reltive Amount Clinicl fetures Type Dibetes is Progressive 3 Predibetes 3 (Obesity, IFG, IGT) Dibetes dignosis Yers Fsting glucose Insulin resistnce Insulin level 3 Onset dibetes Mcrovsculr chnges β-cell filure Microvsculr chnges Postmel Glucose Kendll DM, et l. Am J Med. 9;:S37-S; Kendll DM, et l. Am J Mng Cre. ;7( suppl):s37-s33. Dily Plsm Insulin Profiles In Individuls With nd Without Type Dibetes Types of Insulin Therpies Men Insulin Level ( U/mL) Without Dibetes With Type Dibetes 8 B L D 6 Insulin Effect Insulin Effect Time Bsl Premixed/Biphsic h Insulin Effect Insulin Effect Time Bsl Plus Bsl Bolus h 6 8 Time of Dy 6 Brs denote stndrd error of the men. Polonsky KS, et l. N Engl J Med. 988;38:3-39. Time = insulin injection h h Del Prto S et l, Dibetes Technol Ther, ; : 7-8; Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68.

7 Bsl Insulin Therpy in TDM Cn be initited t ny point in the TDM spectrum AC > 7.% despite the use of or 3 OADs AC > 9.% despite previous TDM phrmcologic therpy AC > 9.% plus symptoms in newly dignosed TDM Erly initition is ssocited with improved β cell function nd higher probbility of ttining AC < 7% Combintion with other gents including OADs, prndil insulin, nd some incretin bsed therpies cn improve glycemic control Rodbrd H, et l. Endocr Prct. 9;:-9; McFrlne SI. Dibet Med. ;8:-6; Nichols GA, et l. Dibetes Cre. ;3:9-97. Δ in AC, from bseline, %.. Bsl Insulin Added to OADs Improves Glycemic Control week non inferiority tril of 973 insulin nive TDM ptients indequtely controlled on OADs Insulin glrgine QD Insulin detemir BID.6 P =.9. Similr hypoglycemi rtes (< 3% symptomtic) Chnge in body weight (kg): Insulin glrgine:. Insulin detemir:.6 (P <.) Finl insulin doses (U/dy): Insulin glrgine: 3. Insulin detemir: 76. (P <.) Swinnen S, et l. Dibetes Cre. ;33: Insulin : Course Syllbus Currently Avilble Bsl Insulins Prt : Bsl insulin therpy Bsics of insulin therpy Currently vilble bsl insulins Inititing bsl insulin therpy Optimizing insulin injection techniques Insulin Type NPH Insulin Insulin Glrgine Insulin Detemir Humn; intermedite cting Anlogue; long cting Anlogue; long cting Onset hours N/A N/A Pek hours No pronounced pek Reltively flt Effective Durtion 6 hours Up to hours Up to hours Lucidi D, et l. Dibetes Cre. ;3:3-3. Niswender K, et l. Clin Dibetes. 9;7:6-68. GIR to Mintin Constnt BG Level (mg/kg/min) Time-Action Profiles Illustrte Vribility in NPH Insulin vs Bsl Insulin Anlogues Long cting insulin nlogues re preferred over NPH insulin becuse they: Do not exhibit pronounced pek in ctivity Hve more predictble time ction profiles nd less within/between ptient vribility Are ssocited with less nocturnl hypoglycemi NPH Subject Glrgine Subject Detemir Subject 8 6 Insulin : Course Syllbus Prt : Bsl insulin therpy Bsics of insulin therpy Currently vilble bsl insulins Inititing bsl insulin therpy Optimizing insulin injection techniques Elpsed Time (hours) N = TDM ptients. Euglycemic glucose clmp study, trils/subject. Heise T, et l. Dibetes. ;3:6-6. Rodbrd H, et l. Endocr Prct. 9;:-9.

8 Current Authorittive Guidelines on Inititing Bsl Insulin Therpy ADA Titrte to FPG 7 3 mg/dl FPG < 7: reduce dose by Uor % TDD FPG > 3: increse dose by Uevery 3 dys ADA/AACE/AADE Initite t U/dy or Use weight bsed pproch:.. U/kg/dy Monitor FPG to determine dosge djustments AADE Increse dose by Uevery 3 dys until FPG is 7 to mg/dl or Increse by U/dy until FPG < mg/dl Nthn DM, et l. Dibetes Cre. 9;3:93-3; Hndelsmn Y, et l. Endocr Prct. ;7(suppl ):-3; Hinnen D, et l. Combting clinicl inerti through pttern mngement nd intensifying therpy. In: Mensing C, et l, eds. The Art nd Science of Dibetes Self-Mngement Desk Reference. :3-76. Insulin Self-Titrtion Is s Effective nd Sfe s Physicin-Adjusted Dosing Sfety nd efficcy hve been demonstrted in 3 trils AT.LANTUS (glrgine) PREDICTIVE 33 (detemir) INITIATE Plus (biphsic sprt 7/3) Anticipted benefits Cost svings Fewer office visits Equivlent or fewer hypoglycemic episodes Greter ptient stisfction (incresed utonomy) Confirming benefits Ptient centered outcomes study is in progress (Di@log) Grber AJ. Dibetes Obes Metb. 9;(suppl ):-3; Oyer DS, et l. Am J Med. 9;:3-9; Roek MG, et l. BMC Fm Prct. 9;:. AACE nd ADA Recommended Glycemic Trgets Idel Glycemic Control AACE ADA AC 6.% < 7.% SMBG Redings Fsting Plsm Glucose < mg/dl 7 3 mg/dl Preprndil N/A Postprndil < mg/dl b < 8 mg/dl c Blood Glucose (mg/dl) 3 PPG UL FPG UL FPG LL Bedtime N/A mg/dl Both orgniztions recognize tht more or less stringent gols my be pproprite for some individuls brekfst h fter brekfst lunch h fter lunch dinner h fter dinner bed mg/dl More thn hlf of the redings should fll within this rnge. b -hour PPG reding. c to -hour PPG reding. Hndelsmn Y, et l. Endocr Prct. ; 7(suppl ): -3; Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68. ADA stndrds shown. Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68. Accu-Chek Connect: Quick Reference Guide: Bsl Dose Too Low Bsl Dose Too High 3 3 Blood Glucose (mg/dl) PPG UL FPG UL FPG LL Blood Glucose (mg/dl) PPG UL FPG UL FPG LL brekfst h fter brekfst lunch h fter lunch dinner h fter dinner bed mg/dl brekfst h fter brekfst lunch h fter lunch dinner h fter dinner bed mg/dl ADA stndrds shown. Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68. Accu-Chek Connect: Quick Reference Guide: ADA stndrds shown. Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68. Accu-Chek Connect: Quick Reference Guide: 3

9 Bsl Dose Too High Insulin : Course Syllbus Blood Glucose (mg/dl) 3 PPG UL FPG UL FPG LL Prt : Bsl insulin therpy Bsics of insulin therpy Currently vilble bsl insulins Inititing bsl insulin therpy Optimizing insulin injection techniques 3: AM h fter h fter h fter brekfst brekfst lunch lunch dinner dinner bed mg/dl ADA stndrds shown. Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68. Accu-Chek Connect: Quick Reference Guide: Encourging Proper Insulin Injection Technique: Step by Step Instructions Pen. Prime pen to check for flow ( drop of insulin should be visible t the tip of the needle). Ensure dosing dil is set to nd dil in dose of insulin to be delivered 3. Insert needle quickly into the SC tissue. Fully depress thumb button. Count slowly to before withdrwing the needle 6. Following injection, remove needle nd discrd properly 7. Never leve needles ttched to the pen Syringe. Drw up equivlent mount of ir into syringe nd inject into vil prior to drwing up insulin. Tp brrel nd push plunger to remove ir bubbles 3. Insert needle quickly into the SC tissue. Depress plunger fully. Following injection, remove needle nd discrd properly 6. Never use syringe needles more thn once Upper Arm Abdomen Thigh Buttocks Insulin Injection Sites My need longer time when using high doses of insulin. Frid A, et l. Dibetes Metb. ; 36 (suppl):s3-s8. Becton Dickinson Dibetes. Step by step injection guide. ; King et l. Nurs Stnd. 3;7:-. Becton Dickinson Dibetes. Step by step injection guide. ; Lipohypertrophy Cn Result from Poor or Improper Site Rottion Results from the growth effects of insulin nd induction of locl growth fctors due to repeted injection Often less pinful to inject into res of lipohypertrophy BUT bsorption of insulin is ltered nd cn led to hypo or hyperglycemi It is recommended tht ptients do not to inject into these sites Prevention: Rotte sites void repeted injection into the sme re Use new needle with every injection Tips for Reducing Discomfort From Insulin Injections Ensure injection into subcutneous tissue, not intrmusculrly Penetrte skin quickly, but inject slowly Allow newly opened insulin to come to room temperture If using lcohol, llow to dry before injecting insulin Het/cold is not recommended s it cn lter bsorption Use shorter length needles (,, or 6 mm) If longer needles( 8 mm) re being used, skin pinch technique should be employed Use new needle with every injection Repeted use blunts needles New needles re coted with silicone lubriction King L, et l. Nurs Stnd. 3;7:-; Wllymhmed ME, et l. Postgrd Med. ;8: Clening with sop nd wter is preferred. King L, et l. Nurs Stnd. 3;7:-; Frid A, et l. Dibetes Metb. ; 36 (suppl ):S3-S8.

10 Needle Size Considertion Conveniences of Insulin Pen Therpy Esy to use/store/crry Discreet Smll needle size mm x 3G mm x 3G 8 mm x 3G.7 mm x 9G /3 3/6 /6 / Use the shortest needle possible when inititing insulin therpy There is no medicl reson to use needle longer thn 8 mm Becton Dickinson Dibetes. Step by step injection guide. ; Becton Dickinson Dibetes. BD pen needles fit these pens. Frid A, et l. Dibetes Metb. ;36(suppl ):S3-S8. Molife C, et l. Dibetes Technol Ther. 9;:9-38. A Prescriber s Checklist For Insulin Therpy Insulin prescription should include: Type of insulin Number of units, vils/pens Frequency of dosing Dignosis code Supplies Pen needles or syringe/needles SMBG supplies (lncets, test strips, control solution, log) Insulin titrtion instructions Needle disposl ptient resources Hypoglycemi tretment protocol Glucgon kit (if ptient is t significnt risk for hypoglycemi) Dibetes eduction referrl Bsl Insulin Therpy: Summry Bsl insulin cn be initited throughout the TDM spectrum Insulin injection is simple nd strightforwrd Alwys inject into subcutneous tissue, not muscle Be sure to rotte injection sites Anlogue bsl insulins re often preferred over humn insulins (NPH/regulr) becuse of their more physiologic profiles Bsl insulin is generlly initited t U/dy or.. U/kg/dy nd titrted to chieve FPG glucose trgets Proper injection technique should be reinforced periodiclly nd injection sites should be exmined regulrly Joslin Dibetes Center. Writing Prescriptions for Dibetes Medictions nd Devices. Accessed Jnury 8,. INSULIN : BASAL-PRANDIAL INSULIN THERAPY Thoms Reps, DO, FACP, FACOI, FACE, CDE Clinicl Assistnt Professor Deprtment of Medicine Snford School of Medicine University of South Dkot Rpid City, South Dkot Insulin : Course Syllbus Prt : Bsl prndil insulin therpy Indictions for bsl prndil insulin therpy Currently vilble prndil insulins Inititing bsl prndil insulin therpy Insulin titrtion using SMBG dt

11 When Is Prndil Insulin Therpy Indicted in TDM? The individul is not meeting glycemic trgets on bsl insulin Elevted AC despite norml FPG (in the bsence of vilble PPG redings) with bsl insulin FPG with bsl insulin is within trgeted rnge, but PPG is persistently bove gol Further increses in bsl insulin result in hypoglycemi Some ptients my only require prndil insulin with their lrgest mel Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68; Skyler JS. In: Lebovitz HE, ed. Therpy for Dibetes Mellitus nd Relted Disorders. Alexndri, VA: Americn Dibetes Assocition, Inc.; :7-3; Holmn RR, et l. N Engl J Med. 7;37:76-73; Dvidson MB, et l. Endocr Prct. ;7:39-3. Reltive Contribution of Postprndil Hyperglycemi to Overll Glycemic Control Contribution to Diurnl Hyperglycemi (%) 8 6 Postprndil hyperglycemi b,b < 7.3% 7.3% to 8.% 8.% to 9.% AC Quintile Fsting hyperglycemi 9.3% to.% >.% The reltive contribution of postprndil hyperglycemi to overll hyperglycemi is greter t AC levels ner 7%. Significntly different between fsting nd postprndil. b Significntly different from ll other quintiles. Monnier L, et l. Dibetes Cre. 3;6: Insulin : Course Syllbus Prt : Bsl prndil insulin therpy Indictions for bsl prndil insulin therpy Currently vilble prndil insulins Inititing bsl prndil insulin therpy Insulin titrtion using SMBG dt Insulin type Currently Avilble Short-Acting Prndil Insulins Regulr Insulin Humn; short cting Insulin Lispro Anlogue; rpid cting Insulin Asprt Anlogue; rpid cting Insulin Glulisine Anlogue; rpid cting Onset, h. <.3. <. <. Pek, h Effective durtion, h Injection: mel timing, min 3 to to immeditely fter to to + Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68. Insulin : Course Syllbus Prt : Bsl prndil insulin therpy Indictions for bsl prndil insulin therpy Currently vilble prndil insulins Inititing bsl prndil insulin therpy Insulin titrtion using SMBG dt Insulin Effect Introducing Bsl-Prndil Insulin Therpy in Ptients With TDM Bsl Bolus Insulin Insulin injection Insulin Effect Premixed/Biphsic Insulin Insulin injection h h Time Time Prndil insulin cn be given with,, or ll 3 mels of the dy Hirsch IB, et l. Clin Dibetes. ;3:78-86; Skyler JS. In: Lebovitz HE, ed. Therpy for Dibetes Mellitus nd Relted Disorders. Alexndri, VA: Americn Dibetes Assocition, Inc.; :7-3; Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68. 6

12 Inititing Bsl-Prndil Insulin Therpy: Dosing According to Ptient Needs Assumes ptient is lredy using bsl insulin Method : weight bsed Totl dily dose (TDD).. U/kg/dy Bsl dose is % of TDD Divide the remining % mong mels Assumes consistent crbohydrte content with ech mel Method : insulin: crbohydrte rtio bsed Initilly estimte prndil doses t.. U/ g crbohydrte Bsl-Prndil Dose Budget : Equl Crbohydrte Intke Among Mels Totl Dily Dose (TDD) Insulin = Bsl (%) + Prndil (%; divided mong mels) 3 U U U U Bsl Brekfst ( g CHO) Lunch ( g CHO) Dinner ( g CHO) Skyler JS. In: Lebovitz HE, ed. Therpy for Dibetes Mellitus nd Relted Disorders. :7-3; Hinnen D, Tomky D. In: Mensing C, et l, eds. The Art nd Science of Dibetes Self-Mngement: A Desk Reference for Helthcre Professionls. :3-76. lb ( kg) ptient,.6 U/kg, 6 U totl dily insulin; ssumes unit of insulin covers g crbohydrte nd isocloric mels. Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68. Bsl-Prndil Dose Budget : Vrying Meltime Crbohydrte Intke Totl Dily Dose (TDD) Insulin = Bsl (%) + Prndil (%; divided mong mels) 3 U U U U Bsl Brekfst ( g CHO) Lunch ( g CHO) Dinner ( g CHO) BG (mmol/l) 8 6 Timing of Prndil Insulin Injections Differs Between Humn nd Anlogue Insulins In TDM 8 6 Fsting Effects of Glulisine Injection Premel vs Postmel Premel Postmel Bseline Week Postbrekfst Prelunch Postlunch Predinner Postdinner Bedtime BG (mg/dl) Regulr humn insulin needs to be injected 3 minutes before mels Less convenient for ptient Rpid cting insulin nlogues (sprt, glulisine, lispro) cn be injected minutes before mels Insulin lispro nd insulin glulisine cn be sfely injected immeditely fter mel lb ( kg) ptient,.6 U/kg, 6 U totl dily insulin. Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68. Bckground of insulin glrgine bsl insulin. Rtner R, et l. Dibetes Obes Metb. ;3:-8; Luijf YM, et l. Dibetes Cre. ;33:-; Cobry E, et l. Dibetes Technol Ther. ;:73-77; Rssm AG, et l. Dibetes Cre. 999;:33-36; Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68. Insulin : Course Syllbus Prt : Bsl prndil insulin therpy Indictions for bsl prndil insulin therpy Currently vilble prndil insulins Inititing bsl prndil insulin therpy Insulin titrtion using SMBG dt Self-Monitored Blood Glucose Cn Improve Glycemic Control In TDM Ptients SMBG enbles pproprite mngement of glycemi Detecting/voiding hyperglycemi Detecting/voiding hypoglycemi SMBG frequency nd schedule cn be vried to meet individul needs Clinicin review of SMBG logs is essentil Helps ssess efficcy nd sfety of ntidibetic regimen Fcilittes provider ptient prtnership 7

13 Blood Glucose Monitor Fetures Disply Lrge numericl disply Bcklit disply or glow in the drk disply Grphing cpbility Size Compct, medium, or lrge Lrge memory cpcity Audio reporting of SMBG results Computer uplod Compring Two Methods of Stepwise Prndil Insulin Intensifiction in TDM Prmeter/ Chrcteristic SimpleSTEP ExtrSTEP Bsl insulin titrtion Bsed on verge of 3 pre brekfst PG mesurements Prndil dose ddition Every wks, if needed Every wks, if needed To lrgest perceived To mel with highest mel postmel PG increse Prndil insulin titrtion Bsed on premel PG Bsed on post mel PG SMBG 3 X point profiles 3 X6 point profiles ech mel ech mel Bedtime h fter ech mel Prticipnt djustments? Yes Yes PG, plsm glucose; SMBG, self monitoring of blood glucose. Meneghini L, et l. Endocr Prct. ;7: ΔAC (%) Outcomes for Two Methods of Stepwise Prndil Insulin Intensifiction in TDM Efficcy BL AC: 8.7% 8.9%. Wt:.7 kg SimpleSTEP (n = ) ExtrSTEP (n = 6).3. kg Hypo Event Rte (EPY) Hypoglycemi (BG < 6 mg/dl) Minor Nocturnl Mjor SMBG Alone My Not Led to Improved Glycemic Control Ptient Eduction Needs Approprite glycemic trgets (fsting, postprndil) When to test Wht the results men When to tke ction Clinicin Needs Must review SMBG logs Must tke ction bsed on SMBG dt Lck of clinicin review/ction my render SMBG ineffective Finl insulin doses (U/kg/d): SimpleSTEP,. ±.9; ExtrSTEP,.37 ±.7. Hypoglycemi definitions: minor, self-treted; mjor, ssistnce required. Meneghini L, et l. Endocr Prct. ;7: Diley G, et l. Myo Clin Proc. 7;8:9-36. Clr C, et l. Helth Technol Assess. ;:-. Prkin CG, Dvidson JA. J Dibetes Sci Technol. 9;3:-8. Frmer AJ, et l. Helth Technol Assess. 9;3:iii-iv, ix-xi, -. Pttern Recognition nd Principles of Insulin Dose Adjustment SMBG Pttern All redings bove trgets PPG redings bove trgets Hypoglycemi Frequent, unpredictble glycemic fluctutions Action Increse bsl dose Add/increse prndil dose Decrese insulin dose My be pump cndidte If glucose levels re out of trget t: Adjust this insulin component: Postbrekfst/prelunch Prebrekfst prndil Postlunch/predinner Prelunch prndil nd/or morning bsl insulin Midfternoon Morning bsl insulin Postdinner/bedtime Predinner prndil Erly morning Evening bsl insulin Bsl-Prndil Insulin Therpy: Summry Prndil insulin cn be initited with bsl insulin or when FPG is controlled with bsl insulin nd AC or PPG levels remin high Prndil insulin is vilble in humn or synthetic nlogue forms Anlogue prndil insulins re often preferred becuse of their more physiologic profiles compred with humn prndil insulin Prndil insulin is initited s % of the TDD of insulin nd divided mong mels or with n insulin: crbohydrte rtio SMBG plys n importnt role in determining the efficcy nd sfety of ptient s ntidibetic regimen Hinnen D, Tomky D. In: Mensing C, et l, eds. The Art nd Science of Dibetes Self-Mngement Desk Reference. ;: Americn Dibetes Assocition. Prcticl Insulin. 3rd ed. :-68. 8

14 INSULIN : ELECTIVES Elective : Overcoming Ptient Brriers to Insulin Therpy nd Pttern Mngement Dvid Kruger, MSN, APN BC, BC ADM Certified Nurse Prctitioner Henry Ford Helth System Division of Endocrinology, Dibetes, nd Bone Minerl Disorders Detroit, Michign Brriers to Inititing Insulin Therpy Among Privtely Insured Ptients New Jersey, Eductionl Brriers Risks/benefits not well explined Indequte helth litercy Side effects of injection Hypoglycemi Doubt bility to djust dose Negtive socil impct Negtive job impct Too pinful Initited (n = ) Did not initite (n = 69) 3 6 Ptients With TDM With Moderte to Extreme Concerns (%) Physicl complints Socil worries Worries bout future Fer of hypoglycemi Dietry restrictions Dily struggles Insulin Initition Improves Qulity of Life in TDM 6 months fter insulin initition insulin initition QOL 6 8 QOL Score (Higher Scores Indicte Better QOL) b Sttisticlly significnt fctors influencing insulin use from survey of 69 privtely insured, insulin-nive ptients with poorly controlled TDM; P <., not dherent vs dherent for ll fctors shown. Percentges of omitted responses not shown. Krter AJ, et l. Dibetes Cre. ;33: Results from insulin-nive older (men ge 68. y) Germn dults with TDM who initited insulin with structured dibetes eduction progrm. P <.; b P <.. Brun A, et l. Ptient Educ Couns. 8;73:-9. Fcilitting Ptient Acceptnce of nd Adherence to Insulin Therpy Educte ptients from the beginning of the disese process bout The progressive nture of TDM The complictions ssocited with poor glycemic control The short nd long term effects of improved glycemic control Avoid thretening ptients with insulin therpy Use simple insulin regimen to strt Allow ptients to prticipte in their insulin dose titrtion Ptients who receive eduction bout their glycemic gols re more likely to ccept insulin therpy But I Relly Don t Hve Enough Time to Explin All of This To My Ptients Strtegies to help you communicte this criticl informtion with limited time: Utilize the dibetes tem to deliver/reinforce your messges Nursing ssistnts cn sfely tech insulin use nd titrtion Dibetes eductors nd comprehensive eduction cn help with initition nd titrtion of insulin, hypoglycemi wreness, nd glucgon use Consider group visits Efficient, but optiml group size hs not yet been defined My be reimbursed by third prty pyors Develop or obtin comprehensive hndouts for ptients nd reinforce eduction in smll mounts t ech visit Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68; Cobble M, et l. J Fm Prct. 9; 8(suppl ): S7-S. Unger J, et l. Dibetes Metb Synd Obes. ;:3-6. Burke RE, O Grdy ET. Helth Aff (Millwood). ;3:3-9. 9

15 Structured SMBG Reduces AC in TDM: STeP Tril Dose Adjustment PATTERN MANAGEMENT 7 point BG profiles collected over 3 dys Dt used by ptient AND provider Pttern mngement priorities:. Hypoglycemi. Fsting/preprndil hyperglycemi 3. Postprndil hyperglycemi Abnormlity occurring on of 3 dys t the sme time of dy must be ddressed AACE/ACE titrtion nd gols recommended Bsl dose djustment Initite t units/dy t bedtime or units every 3 dys until FBG gols met Prndil dose djustment Initite t units/mel or 3 units every 3 dys until gols met, considering both h PBG nd preprndil BG Polonsky W, et l. BMC Fmily Prctice. ;:37. Rodbrd HW, et l. Endocr Prct. 9;:-9. Priority Correct Hypoglycemi Priority Fix the Fstings ( > mg/dl) Priority 3 Postprndil Hyperglycemi Hypoglycemi 7/ 7/ 7/6 Dte Fsting After brekfst lunch After lunch dinner After dinner Bedtime // 8 9 // /6/ /8/ // /3/ /6/ /8/ /3/ // /3/ /6/ /8/

16 Fix the Fsting Postprndil Hyperglycemi Elective : Premixed/Biphsic Insulin Therpy Thoms Reps, DO, FACP, FACOI, FACE, CDE Clinicl Assistnt Professor Deprtment of Medicine Snford School of Medicine University of South Dkot Rpid City, South Dkot Premixed/Biphsic Insulin Regimens Combintion of different types of insulin, usully up to injections/dy For ptients with TDM or TDM Requires consistent meltimes nd crbohydrte counting My or my not cuse more weight gin thn BBT My result in poorer glycemic control thn BBT For ptients with TDM trnsitioning from bsl only regimens Premixed/biphsic insulin does not gurntee reduced AC My increse risk of hypoglycemi My cuse more weight gin Roch P, et l. Clin Ther. 999;:3-3. Grber AJ, et l. Dibetes Obes Metb. 6;8:8-66. Tnk M, Ishii H. J Dibetes Complictions. ;: Shrplin P, et l. Crdiovsc Dibetol. 9;8:9. Miser WF, et l. Clin Ther. ;3: Holmn RR, et l. N Engl J Med. 9;36: Premixed Insulin Added to Any Combintion of OADs Improves Glycemic Control in Insulin-Nïve Ptients With TDM (DURABLE Study) AC (%) P <. vs bseline. 9. Lispro 7/ (n = ) Glrgine (n = 6) Bseline Week 7.3 OADs kept t bseline dose(s) throughout the study AC gols were mintined medin of 6.8 months with lispro 7/ nd. months with glrgine (P =.) Buse JB, et l. Dibetes Cre. 9;3:7-3. Buse JB, et l. Dibetes Cre. ;3:9-. Premixed Insulin Added to MET ± PIO Improves Glycemic Control t 8 Weeks INITIATE Study Rndomized Popultion Bseline Bseline AC = 9.7 ±.% 9.8 ±.% AC > 8.% AC 8.% n = Biphsic sprt 7/ Glrgine...8 b P <.; b P <., biphsic vs glrgine. All orl drugs except MET ± PIO discontinued t bseline; ptients were insulin-nive t bseline. Rskin P, et l. Dibetes Cre. ;8:6-6. Chnge in AC (%)

17 Ptients Meeting Trget (%) Comprison of Biphsic nd Bsl Bolus Therpy: PREFER Study Detemir-sprt Biphsic sprt 7/3 Insulin Nive 6 AC 7% Men AC Reduction From bseline (%).69 P =.6 Minor hypoglycemi occurred in 3% of ptients in the detemir sprt group nd 8% in the biphsic sprt group Weight gin ws similr in both groups (. kg vs. kg)... Previously Treted With Bsl Insulin..7 P =.9 Inititing nd Adjusting Premixed/Biphsic Insulin in TDM AACE Recommendtions, Expert Consensus, nd INITIATE Study AACE Administer t lrgest mels twice dily OR dminister t lrgest mel once dily Adjust prebrekfst dose bsed on predinner glucose level Adjust predinner dose bsed on prebrekfst (fsting) glucose level Hirsch et l () Trnsitioning from once dily bsl insulin to twice dily premixed/biphsic: Divide TDD by to compute the dose of ech injection (before brekfst nd dinner) If mels re not of equl size, lrger mel requires lrger proportion of insulin Adjust doses ccording to SMBG nd diet history Reduce TDD by % if there is recurrent hypoglycemi INITIATE Begin t units/dy if FPG < 8 mg/dl OR begin t units/dy if FPG 8 mg/dl Begin with TDD eqully divided between brekfst nd dinner Administer doses minutes before mels Adjust ccording to titrtion schedule shown in bck of progrm book N = 7 TDM ptients. Insulin ws titrted to fsting, predinner, nd postprndil plsm glucose trgets. Liebl A, et l. Dibetes Obes Metb. 9;:-. Hndelsmn Y, et l. Endocr Prct. ;7(suppl ):-3. Hirsch IB, et l. Clin Dibetes. ;3: Rskin P, et l. Dibetes Cre. ;8:6-6. Avilble Premixed/Biphsic Insulins Product Onset (h) Pek (h) Effective Durtion (h) Humn Biphsic Insulin 7% NPH/3% regulr. Dul 6 Anlogue Biphsic Insulin 7% NPL/% lispro <. Dul 6 % NPL/% lispro <. Dul 6 7% sprt protmine/ 3% sprt <. Dul 8 Preprtion Points for Considertion When Using Premixed Insulin Must be rolled nd/or tipped (NOT SHAKEN) for cycles Site selection Considertion must be given to injection site when using mixes contining NPH AM injection is best given in the bdomen becuse of more rpid bsorption (coverge for brekfst) PM injection should be given in the buttocks or thigh becuse of slower bsorption (prevention of nocturnl hypoglycemi) Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68. Frid A, et l. Dibetes Metb. ;36(suppl ):S3-S8. Elective 3: Insulin Therpy in TDM Jmes R Gvin, III, MD, PhD Progrm Chir Clinicl Professor of Medicine Emory University School of Medicine CEO nd Chief Medicl Officer Heling Our Villge, Inc. Atlnt, Georgi Insulin Therpy Considertions in TDM TDM is chrcterized by bsolute insulin deficiency insulin dministrtion is required for ptient survivl Glycemic vribility tends to be greter in ptients with TDM thn in TDM ptients treted with insulin The occurrence of hypoglycemi is greter in TDM ptients thn TDM ptients TDM demnds bsl + multiple prndil insulin injections/dy Experts recommend SMBG mesurements 3 times dily in individuls with TDM Americn Dibetes Assocition. Dibetes Cre. 3(suppl ); :S-S3; Kto T, et l. Dibetes Res Clin Prct. ;9:e6-66; Greven WL, et l. Dibetes Technol Ther. ;:69-699; Mrre M, et l. Dibetes Metb. 9;3:69-7.

18 Mintining Physiologic Insulin Delivery : Bsl Bolus Correction or Supplementl insulin Clculting Insulin Dose for Adult Ptient With TDM Obtin ptient weight in kg Clculte totl dily dose (TDD) s.. U/kg/dy Insulin Bsl insulin Norml Secretory Pttern of Insulin Brekfst Lunch Dinner Bedtime Choose the dosing schedule Give % of TDD s bsl insulin Give % of TDD s bolus (premel ) insulin Adjust ccording to results of BG monitoring Hirsch IB. N Engl J Med. ;3:7-83. Dose my vry depending on whether ptient is child or dult nd on ptient s clinicl sitution. Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68; Silverstein J, et l. Dibetes cre. ;8:86-; Hirsch I. Am Fm Physicin. 999;6:3-36. Insulin Options for TDM Efficcy nd Sfety in TDM: Bsl Insulin Anlogues vs NPH Bsl Anlogues Insulin glrgine Insulin detemir Humn NPH Prndil (Nutritionl) Anlogues Insulin sprt Insulin glulisine Insulin lispro Humn Regulr Efficcy or Sfety Prmeter Weighted Men Difference (9% CI) Interprettion AC.8 (. to.) Fvors nlogues Fsting plsm glucose.63 (.86 to.) Fvors nlogues Fsting blood glucose.86 (. to.7) Fvors nlogues Weight gin.67 (.87 to.) Fvors nlogues Hypoglycemi Odds Rtio (9% CI) Interprettion Any.93 (.8 to.8) Equivlent Severe.73 (.6 to.87) Fvors nlogues Nocturnl.7 (.63 to.79) Fvors nlogues Americn Dibetes Assocition. Prcticl Insulin: A Hndbook for Prescribing Providers. 3rd ed. :-68. P <.. Results bsed on 3 studies in dults with TDM, 387 on bsl insulin nlogues, 9 on NPH insulin. Vrdi M, et l. Cochrne Dtbse Syst Rev. 8;(3):CD697. Efficcy nd Sfety in TDM: Rpid Insulin Anlogues vs RHI Anlogues Are Associted With Lower Hypoglycemi Rtes Thn Humn Insulins for the Sme Degree of Control in TDM Tretment Tretment Trils (N) Trils (N) Adults With TD (N) Adults With TD (N) Chnge in AC % (9% CI) Severe Hypoglycemi Reltive Risk Rtio % (9% CI) Interprettion Asprt (. to.7) Fvors nlogue Lispro 6.9 (.6 to.) Fvors nlogue Interprettion Asprt 8.83 (.6 to.) Equivlent Lispro.8 (.67 to.96) Fvors nlogue Frequency of Mild Hypoglycemi (Episodes/Ptient Month) Lispro RHI Rte of Hypoglycemi (Events/ Ptient Yers) NPH insulin Insulin glrgine 9.. AC (%) AC (%) P <.. Glulisine ws not licensed in Cnd during the period covered by the nlysis. Singh SR, et l. CMAJ. 9;8: Llli C, et l. Dibetes Cre. 999;: Mullins P, et l. Clin Ther. 7;9:

19 Insulin Pump Therpy Up to % of TDM ptients in the US utilize continuous subcutneous insulin infusion (CSII), CSII uses rpid cting insulin to deliver both bsl nd bolus therpy Advntges of pump therpy in TDM include:,,3,, Improved glycemic control A reduction in hypoglycemi Improved qulity of life Reduced frequency of dibetic ketocidosis CSII cn be pired with continuous glucose monitoring (CGM):, To provide more frequent glucose redings To reduce the incidence of hypoglycemi CGM does not replce SMBG 3 Prerequisites for CSII Motivted to improve glycemic control Intellectully nd physiclly ble to mnge insulin pump therpy Experience with frequent SMBG Fluent in crbohydrte counting nd insulin correction Willingness to communicte with the dibetes tem. Hndelsmn Y, et l. Endocr. Prct. ;7(suppl ):-3;. Pickup J, et l. Int J Clin Prct. ;6:6-9; 3. Hinnen D, Tomky D. In: Mensing C, et l, eds. The Art nd Science of Dibetes Self-Mngement: A Desk Reference for Helthcre Professionls. :3-76;. Blevins T, et l. Endocr Prct. ;6:73-7;. Klonoff D, et l. J Clin Endocrinol Metb. ;96: Hndelsmn Y, et l. Endocr. Prct. ;7(suppl ):-3. Insulin in TDM: Summry Insulin therpy considertions differ for ptients with TDM nd ptients with TDM Similrly to TDM, insulin nlogues re preferred in the tretment of TDM due to their more physiologic profile The time ction profiles of insulins my differ in individuls with TDM compred to TDM Insulin pump therpy cn contribute to improved glycemic control nd less hypoglycemi in TDM Insulin pump therpy requires motivted, complint ptient willing to communicte with the dibetes tem Insulin : New Insulin Combintions nd Investigtionl Insulins * Jmes R Gvin, III, MD, PhD Progrm Chir Clinicl Professor of Medicine Emory University School of Medicine CEO nd Chief Medicl Officer Heling Our Villge, Inc. Atlnt, Georgi * Some of the gents nd/or combintions to be discussed re not US FDA-pproved t this time. Insulin : Course Syllbus New Insulin Combintions Insulin + DPP inhibitors Insulin + GLP receptor gonists Investigtionl Insulins Limittions of current insulins nd future needs Investigtionl bsl insulins Investigtionl prndil insulins US FDA-Approvl Sttus: Incretin-Bsed Therpies Combined With Insulin Clss DPP inhibitors Sitgliptin Sxgliptin Lingliptin Agents With FDA Approvl for Use in Combintion With Insulin Exentide BID Tril in combintion with insulin glrgine GLP RAs Not studied in combintion with prndil insulin Lirglutide Tril in combintion with insulin detemir Not studied in combintion with prndil insulin Clinicl trils re in progress for the GLP RA, exentide ER.. US FDA. Drugs@FDA Web site. US Ntionl Institutes of Helth.

20 AC (%) DPP- inhibitors s Add-On Therpy to Insulin: Glycemic Efficcy nd Hypoglycemi Hypoglycemi (Reported, %)... INS + PBO (n = 39) week tril.6 6. Long- or intermedite-cting (73-7%), premixed (6-7%); men BL dose = -7 U/d ± MET. b Premixed (6%), intermedite cting (%), long cting (9%); men BL dose = 9 U/d ± MET. INS + SITA (n = 3) INS b + SAXA (n = 3) P <. P =.3 8 INS b + PBO (n = ) week tril Vilsboll T, et l. Dibetes Obes Metb. ;: Brnett A, et l. Curr Med Res Opin. ; 8:-. Δ AC (%) Exentide BID Added to Insulin Glrgine EXN BID or PBO Added to GLAR 3 week tril GLAR + EXN BID (n = 37) P <. GLAR + PBO (n = ) Similr rtes of minor hypoglycemi in EXN BID (%) nd PBO (9%) groups More discontinued due to AEs in EXN BID (9%) vs PBO (%) group (P <.). Buse JB, et l. Ann Intern Med. ;:3-. Δ Weight (kg) Insulin Detemir Added to Lirglutide Insulin : Course Syllbus.. Tretment Period (Weeks ). Run in: Weeks to.8 mg LIRA + MET Ptients not chieving AC < 7% rndomized to study tretments New Insulin Combintions Insulin + DPP inhibitors Insulin + GLP receptor gonists AC Chnge (%) P <.. Study + extension: Weeks to 6 week study + 6 week extension Added insulin detemir or nothing Men strting AC = 7.6% MET + LIRA.8 mg control (n = 6) MET + LIRA.8 mg + insulin detemir (n = 6) Bin SC, et l. EASD 7th Annul Meeting. ;73. Investigtionl Insulins Investigtionl bsl insulins Investigtionl prndil insulins Why Do We Need New Insulins? Chrcteristics of An Idel Bsl Insulin Flt, pekless time ction profile Low vribility within nd between individuls Long durtion of ction Low risk of hypoglycemi Glucose infusion Rte (mg/kg/min) Insulin Action Profiles for Detemir nd Glrgine in Ptients With TDM Time ction profiles re dose dependent for cliniclly relevnt doses of detemir nd glrgine,b Detemir (. U/kg) Glrgine (. U/kg) Detemir (.8 U/kg) Glrgine (. U/kg) Time (h) -h rndomized, double-blind, prllel-group comprison under glucose clmp conditions (N = 7). b. U/kg doses yielded similr phrmcodynmic profiles. Klein O et l. Dibetes Obes Metb. 7;9:9-99. Philis-Tsimiks A et l. Clin Ther. 6;8:69-8.

21 Are Current Bsl Insulins Being Used As -Hour Therpies? Lte-Stge Investigtionl Bsl Insulins Injection time nd frequency of insulin glrgine in TDM (n=9) Insulin Administrtion Sttus Pek Effective Durtion Twice dily 36% Morning % Evening 3% Degludec - (NN) PEGylted insulin lispro -6 (LY6) Once dily Once dily Filed for pprovl Phse 3 clinicl trils Pekless Pekless > h h Also in development re new glrgine nlogue nd new glrgine formultion. Grg S, et l. Dibetes Res Clin Prct. ;66:9-6.. Zinmn B, et l. Lncet. ;377:9-93;. Birkelnd KI, et l. Dibetes Cre. ;3:66-66; 3. FDA delys decision on Novo Nordisk s degludec. Heise T, et l. Dibetes Obes Metb. Jun. [Epub hed of print];. US Ntionl Institutes of Helth Heise T, et l. ADA 7nd Annul Scientific Sessions. :-P. Insulin Degludec Time-Action Profile Degludec vs Glrgine in Adults With TDM: Efficcy, Hypoglycemi, nd Weight Chnge t Yers DEG QD (n = ;.63 U/kg) GLAR QD (n = ;.63 U/kg) Glucose Infusion Rte (mg/kg/min) 3.8 units/kg.6 units/kg. units/kg 8 6 Time (h) ΔAC (%) Efficcy BL AC: 8.% P = NS. Rte (EPY) 3 Hypoglycemi Overll Nocturnl Severe P = NS P <. P = Weight Chnge ΔWeight (kg) DEG reduced men FPG more thn GLAR ( 6.8 mg/dl vs 7.6 mg/dl, P =.) 3.7 P = NS. Heise T, et l. Dibetes Obes Metb. ;:9-9. MET ± DPP- inhibitor used in both study rms. Hypoglycemi, plsm glucose < 6 mg/dl or severe. Insulin degludec is not FDA pproved for clinicl use. Rodbrd HW, et l. Dibetologi. ;(suppl ) [bstrct 9]. Degludec /Asprt BBT vs Glrgine/Asprt BBT in Adults With TDM: Efficcy, Hypoglycemi, nd Weight Chnge t Yer DEG/ASP (n = 7) GLAR/ASP (n = ) 6 P = NS P = NS P = BL AC: 8.3% 8.%. P =. BL ΔAC:.%.3%..8 Wt: Ptients Attining AC < 7% Confirmed Nocturnl Overll Insulin degludec is not FDA pproved for clinicl use. Hypoglycemi, plsm glucose < 6 mg/dl or severe per ADA definition; nocturnl, occurring between h nd 9 h. Finl insulin dose: DEG =.6 U/kg, GLAR =. U/kg. Grber AJ, et l. Lncet. ;379:98-7. Ptients (%) Efficcy Hypoglycemi Rte (EPY) Hypoglycemi ΔWeight (kg) Weight Chnge Nocturnl Hypoglycemi in 7 Phse 3 Tret-to-Trget RCTs: Rte Rtios for Degludec Reltive to Glrgine Estimted Rte Rtio (men [9% CI]) TDM BBT (N = 69).6.7 P <.. B, bsl; BBT, bsl-bolus therpy; B+OADs, bsl plus OADs; FLEX, flexible bsl degludec dosing, 8- h. TDM BBT FLEX (N = 38) TDM BBT (N = 99) TDM B+OADs (N = 3) TDM B+OADS (N = 7) TDM B+OADs (N = 3).77 TDM B FLEX+OADs (N = 9) Russell-Jones DL, et l. Dibetes.. 6(suppl ):A63 [bstr 39-PO]. 6