GLP-1 analogs and DPP-4 inhibitors - Denver, Colorado

1 GLP-1 analogsand DPP-4 inhibitorsSaturday 16 July, 2011 Keystone, ColoradoMatthew C. Riddle Professor of MedicineOregon Health & Science University OregonPresenter DisclosureI have received the following forms of support:Research grantsAmylin, GSK, Lilly, sanofi-aventisHonoraria for consultingAmylin, Lilly, NovoNordisk, Roche, sanofi-aventisHonoraria for speakingLilly, sanofi-aventisHours after beginning a meal1234560 Toft-NeilsenM-B et al. J ClinEndocrinolMetab2001;86: 3717-3723 Cummings DE et al. Diabetes 2001;50: 1714-1719 Patterns of hormones which regulateplasma glucose and food intakeAmylinInsulinGhrelinGLP-1 MealGlucagonIt s not just insulin !Ways to enhance GLP-1 receptor stimulationGLP-1 chronic infusionOral DPP-4 inhibitorsVildagliptin(Galvus)Sitaglipti n(Januvia)Saxagliptin(Onglyza)Linaglipti n(Tradjenta)Short-acting GLP-1 agonistExenatide (Byetta)Long-acting GLP-1 agonistsLiraglutide(Victoza)Exenatide Q weekly (Bydureon)Intermediate-acting agonistLixisenatide(Lyxumia)Effects of GLP-1 infusionLarsen J et al.

2 Diabetes Care2001; 24: 1416-2124-h GLP-1 sc infusion16-h GLP-1 sc infusionDay 7 Day 0100150200250300350400060810121416182022 0002044001001502002503003500608101214161 82022000204mg/dlTime of daymg/dlEffect gone in 4 hoursGlucose profiles in 40 patients with T2 DMMain effect on basal glycemia6-week GLP-1 sc infusion by pumpGLP-1 Salinemg/dL45036027018090001234567845036 0270180900012345678 ZanderM et al. Lancet 2002; 359: 824-30 Week 6 --on sc infusionsGlucose profiles in 20 patients with T2 DMHoursWeek 0 --off OAD 3 wks4-weeks vildagliptinorallyResponses to breakfast5,08,011,014,0 Glucose mmol/L0255075-303090150210 MinutesInsulin pmol/L5075100125-300306090120 PlaceboVilda100mgGlucagon pg/mL0510152025 GLP-1 pmol/LAhr nB et al.

3 J Clin Endocrinol Metab2004;89:2078-84 MinutesEffects of DP-4 InhibitorsSitagliptin is as effective as dose metformin1091 patients randomized to PLBO, sitagliptin, or bothGoldstein BJ et al. Diabetes Care 2007;30: reduction of A1c from baseline (%)Metformin2000 mgMetformin1000 mgSitagliptin100 of GLP-1 agentsAgonistsDPP-4 inhibitorsPotentiate insulin secretion+++Suppress glucagon+++Reduce calorie intake+++Slow gastric emptying+ or ++-Tachphylaxisto GLP-1 effectsReduced effect with ongoing RxPotentiate insulin secretionNoSuppress glucagonNoReduce calorie intakeNoSlow gastric emptyingYesTachyphylaxisto GLP-1 effects9 healthy hour GLP-1 or placebo infusionsMeal tests as 0 and 4 hoursResponses to meals vsplacebo0 hours4 hoursGlucoseNo increaseBluntedGastric emptyingMarkedly slowedLess slowedInsulinMuch reducedLess reducedNauckMA et al.

4 Diabetes 2011;60: (on-line 24 March)Plasma glucosemg/dLTime of day/Hours1802602201401000800120016002000 24000400080018014022010004812241620 Degn KB et al. Diabetes 2004;53: 1187-94 Ahr n B et al. J Clin Endocrinol Metab2004;89:2078-84 LiraglutidevsplaceboVildagliptinvsplaceb oWays to enhance GLP-1 receptor stimulationGLP-1 chronic infusionOral DPP-4 inhibitorsVildagliptin(Galvus)Sitaglipti n(Januvia)Saxagliptin(Onglyza)Linaglipti n(Tradjenta)Short-acting GLP-1 agonistExenatide (Byetta)Long-acting GLP-1 agonistsLiraglutide(Victoza)Exenatide Q weekly (Bydureon)Intermediate-acting agonistLixisenatide(Lyxumia)Single-dose lixisenatide:Effect on postprandial glucose Drug na ve T2DM patients, standard meal 1 hour after injectionChristensen M et al, IDrugs2009 12(8).

5 503-513 Bloodglucose(mg/dL)Hours after injection0100200300400 InjectionMeal01234501002003004001 g (n=4)3 g (n=4)10 g (n=4)20 g (n=4)40 g (n=4)Placebo(n=10)Not approved by FDA28-day treatment with lixisenatide:Effect on fasting and postprandial glucoseT2DM patients on metformin and/or SU, subgroup treated withup to 20 mcg taken in AMBaseline28 days of treatmentBreakfastLunchDinnerHours after morning injectionBloodglucose(mg/dL)-10123456789 1011121314151630025020015010050 DistillerLA, RuusR. Diabetologia 2008; 51 (Suppl1): A155 Strong effect on postprandial increment after breakfast,less after lunch and none after ** * *0n = 107n = 55n = 50n = 53n = 51LS mean changeof A1c (%) g30 g10 g5 gLixisenatideQD *p< , **p< , p< vs.

6 *n = 51n = 53n = 52n = g30 g10 g5 * * * *n = 51n = 54n = 52n = 5320 g30 g10 g5 gLixisenatideBID LixisenatideBID = 108n = 54n = 50n = 52n = 51LS mean changeof weight (kg) * g30 g10 g5 gLixisenatideQD 88 R et al. Diab Med2010; 27:1024-32 Lixisenatidedose-ranging studyReduction of A1c and weightA family of GLP-1 agonistswith different durations of action?Danne T et al. Diabetes ;26:3087-3092. Hirsch IB. Medscape Gen ;7:49. Available at: Rave K et al. Diabetes Care. 2005;28:1077-1082. 0125346789101112131415161718192021222324 Insulin actionHoursLixisenatide8 16 h ?Exenatide4-8 hr ?Native GLP-1 <1 hr ?Liraglutide>24 hExenatideQW > 1 wkA family of GLP-1 agonistswith different durations of action?

7 Danne T et al. Diabetes ;26:3087-3092. Hirsch IB. Medscape Gen ;7:49. Available at: Rave K et al. Diabetes Care. 2005;28:1077-1082. 0125346789101112131415161718192021222324 Insulin actionHoursLixisenatide8 16 h ?Exenatide4-8 hr ?Liraglutide>24 hAction profiles of insulin formulationsDanne T et al. Diabetes ;26:3087-3092. Hirsch IB. Medscape Gen ;7:49. Available at: Rave K et al. Diabetes Care. 2005;28:1077-1082. 0125346789101112131415161718192021222324 Insulin actionHoursNPH 12 16 hRegular 6 8 hAspart, glulisine, lispro4 5 hDetemir6-18 hGlargine~24 hBlevins T et al. JCEM 2011;96:1301-1310 Effects of Exenatide BID vsExenatide QW 252 T2DM patients on one or more OAD24 weeks randomized open-label treatment A1c % FPG mg/dL A1cP< vsBID -23 mg/dLp< kg(NS)DruckerDJ et al.

8 Lancet 2008;372: 1240-50 Effects of Exenatide BID vsExenatide QW 295 T2DM patients on diet OAD30 weeks randomized open-label treatmentSMBG profile FPG mmol/L A1cP= vsBID Mainlybasal vsPPeffectSame wt reduction( kg)Buse J et al. Lancet 2009;374:39-47 Effects of LiraglutidevsExenatide BID464 T2DM patients on 1-2 OAD26 weeks randomized open-label A1cP= vsEx BIDM orebasal vsPPeffectSame wt reduction( kg) A1c %% to A1ctargets< < %Effects of Exenatide BID vsGlargine551 T2DM patients on metformin+ sulfonylurea26 weeks Rx with titrated glargineor exenatide 10 mcgBIDA1c and weight: changes from baselineA1c % Wt kgExenatideGlargineHeine RJ et al. Ann Intern Med 2005;143:559-569 Heine RJ et al. Ann Intern Med 2005;143:559-569 Effects of Exenatide vsGlargine551 T2DM patients on metformin+ sulfonylurea26 weeks Rx with titrated glargineor exenatide 10 mcgBIDSMBG and BG after test meal: changes from baselineExenatideGlargineSMBGMeal testBuse JB et al.

9 Ann Intern Med 2011;154:103-112*p< , ** p< weeksPlacebo30 weeks7-point glucose profilesLS Means SEExenatide BID added to titrated glargine OADA1c ~ , weight difference kgNot approved by FDAR iddle MC et al. ADA Annual Scientific Sessions 2010, Late-breaking abstract , Poster 18-LB678A1c %9 Met + glargine+ exenatiden=16 Met + glargine+ placebon=178/17 randomized47% < A1c2/17 randomized12% < A1cp= of A1c after 24 weeksTitrated glargineadded to exenatide+metforminNot approved by FDAA1c lowering power of GLP-1 agentsPlacebo-adjusted reductions (A1c%)DPP-inhibitorsAdded to MetAdded to Met+ receptor vsbaselinePreliminary safety concerns with GLP-1 agents Pancreatitis, pancreatic and thyroid cancerwith glucagon-like peptide-1 based therapies ElashoffM et al.

10 Gastroenterology 2011;141: 150-6 Springer J & StammschulteU. Gastroenterology 2011;141:20-3 Review of FDA adverse event reporting system database 2004-2009 Odds Rations from case-control analysis of pancreatitis and cancers. Exenatide cancerThyroid cancerOther cancersExenatide CV findings with a DPP-4 inhibitor Linagliptinhas simlarefficacy to glimepiridebut improved cardiovascular safety over 2 years in patients with type 2 diabetes inadequately controlled by metformin 1519 patients with T2DM treated with metforminRandomized double-masked to linagliptin5 mg or glimepirideup to 5 mgBaseline A1c reduction % of weight kg+ death, MI, stroke, % %RR B et al. ADA annual scientific sessions, June 2011, poster presentation 39-LBPreliminary CV findings with GLP-1 agonistsCV benefit in animal modelHuber J et al.