DPP4GLP1SGLT2. Inwooncursus : Hormonopolis 16 april Dr. Ann Verhaegen. ZNA Jan Palfijn UZA

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1 DPP4GLP1SGLT2 Inwooncursus : Hormonopolis 16 april 2014 Dr. Ann Verhaegen ZNA Jan Palfijn UZA

2 Casus 1 Marie 54 jarige psychiatrisch verpleegkundige met wisselende werkuren (ook nachtshifts) Antecedenten: Enkele niet relevante kleine chirurgische ingrepen Type 2 diabetes sinds 3 jaar geen gekende verwikkelingen Arteriele hypertensie Dyslipidemie Huidige medicatie metformin 2x 850 mg/d Ramipril 10 mg simvastatine 40 mg Levenswijze: rookt niet drinkt in weekend enkele glazen wijn probeert sinds haar diagnose 3 x per week te sporten onder begeleiding van dietiste sinds diagnose 8 kg vermagerd

3 Casus 1 Marie 54 jarige psychiatrisch verpleegkundige met wisselende werkuren (ook nachtshifts) K.O.: G 73 kg, L 165 cm, BMI 27 kg/m² buikomtrek 93 cm Bloeddruk 128/78, P 72/min lab: HbA1c progressief lichtjes toenemend begin vorig jaar 6,6 % (59 mmol/mol) naar nu 7,8 % (62 mmol/mol) creatinine 0,78 mg/dl e GFR > 60 ml/min lipiden: totaal cholesterol 151 mg/dl HDL cholesterol 60 mg/dl Triglyceriden 173 mg/dl LDL cholesterol 56 mg/dl Voldoende of toch behandeling aanpassen? Wat is volgende stap in de behandeling?

4 Depiction of the elements of decision making used to determine appropriate efforts to achieve glycemic targets. Inzucchi S E et al. Diab Care 2012;35:

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6 Incretines algemene inleiding fysiopathologie van natief GLP-1 medicatie actief op incretinesysteem DPP-4 inhibitoren GLP-1 agonisten

7 Venous plasma glucose (mmol/l ) C-peptide (mmol/l) The incretin effect increases -cell response to oral vs IV glucose The incretin effect is demonstrated by increased C-peptide levels after oral glucose load * Oral glucose IV glucose * * * Incretin effect * * * Time (min) Time (min) Responses to an oral glucose load of 50 g and IV glucose infusion measured in 8 healthy control subjects. Mean ± SE; n=6; *P 0.05; 01 and 02 = -10 and -5 min, respectively, before glucose infusion. To convert mmol/l of glucose to mg/dl, multiply by 18. Nauck MA. J Clin Endocrinol Metab. 1986;63:492-8.

8 De effecten van GLP-1 zijn glucose-afhankelijk bij diabetes type 2 patiënten Glucose (g/l) Insuline (pmol/l) Glucagon (pmol/l) Placebo GLP-1 2, PBO GLP PBO GLP-1 20 PBO GLP-1 1,80 0,90 * * * * * * * * * * * * * * * 10 * * * * Tijd (min) Tijd (min) Tijd (min) Een gerandomiseerde, cross-over; placebo gecontroleerde trial bij patiënten met Diabetes type 2 (n=10) ; gemiddelde ±SEM ; *p <0,05. (16) Nauck MA, et al. Diabetologia. 1993;36: Reproduced with the permission of Springer-Verlag 1993.

9 Physiological actions of GLP 1 Baggio & Drucker. Gastroenterology 2007; 132:

10 Release and action of Glucagon Like Peptide-1 (GLP-1) Half-life of GLP-1 Is <2 minutes Mixed Meal Intestinal GLP-1 Release GLP-1 (7-36) Active Resistant to DPP-4 inactivation Incretine-analogen - Exenatide (Byetta) - Liraglutide ( Victoza) - Lixisenatide ( Lyxumia) - exenatide LAR ( Bydureon) DPP-4 Rapid Inactivation (>80% of pool) GLP-1(9-36) Inactive Block DPP-4 enzyme activity DPP-4 inhibitore - Vildagliptin (Galvus) - Sitagliptin(Januvia) - Saxagliptin (Onglyza) - Linagliptine ( Trajenta) Mentlein et al. in Eur J Biochem. 214(3):829-35, 1993 Eng J, et al. J Biol Chem 1992; 267:

11 producten actief via incretinesysteem GLP-1 analogen (incretine mimetica of analogen) Exenatide (Byetta ) Liraglutide (Victoza ) Exenatide LAR Lixisenatide ( Lyxumia ) DPP-4 inhibitoren Sitagliptin (Januvia ) Saxagliptin (Onglyza ) Vildagliptin (Galvus ) Linagliptin ( Trajenta )

12 Mean HbA1C (%) Sitagliptin doeltreffendheid Add-on to metformin Reductions in HbA1c comparable to glipizide when added to metformin Glipizide 5 mg/day + metformin (n=584) Sitagliptin 100 mg q.d. + metformin (n=588) Week Adapted from: Nauck MA, et al. Diabetes Obes Metab. 2007;9:

13 HbA1c (%) ± SE Saxagliptin is non-inferior to SU in lowering HbA1c as an add-on to metformin at 52 weeks1 Adjusted mean change in HbA1c from baseline (PP analysis set) 0.0 Mean Baseline HbA1c: 7.5% 7.5% MET + SAXA (n=293) MET + GPZ (n=293) Absolute difference between groups: 0.06% 95% CI to 0.16 MET+SAXA was considered non-inferior to MET+GPZ if upper confidence limit of difference in adjusted HbA1c change from baseline to week 52 was <0.35%; PP: per protocol; GPZ: glipizide; PBO: placebo; MET: metformin; SAXA: saxagliptin. 1. Göke B, et al. Int J Clin Pract. 2010;64(12):

14 Gemiddelde daling van de HbA1c* Doeltreffendheid Therapeutisch effect van verschillende DPP-4-remmers in monotherapie zoals vermeld in samenvatting van producteigenschappen. Voor placebo gecorrigeerde, gemiddelde verandering van het HbA1c na 18 / 24 weken behandeling t.o.v. beginwaarde**. Doserin g Linagliptin 1 Saxagliptin 2 Sitagliptin 3 Vildagliptin 4 5 mg QD 5 mg QD 5 mg QD 5 mg QD 100 mg QD 100 mg QD 50 mg QD 50 mg QD Baselin e HbA 1c 8,1% 8,0% 7,9% 8,0% 8,0% 8,0% 8,6% 8,4% -0,4% -0,5% -0,6% -0,7% -0,6% -0,6% -0,8% -0,7% n = p- value* < 0,0001 < 0,0001 < 0,0059 < 0,0001 < 0,0001 < 0,0001 < 0,05 < 0,05 *Gemiddelde daling HbA1c vesus placebo **Geen rechtstreekse vergelijkende studie tussen de verschillende moleculen. 1. Samenvatting van de producteigenschappen Trajenta, 2. Samenvatting van de producteigenschappen Onglyza, 3. Sam envatting van de producteigenschappen Januvia, 4. Samenvatting van producteigenschappen Galvus.

15 Difference in weight change was significant between saxagliptin vs SU as add-on to metformin Body weight (kg) ± SE Adjusted mean change in body weight from baseline to Week 52 (safety analysis set) p< MET + SAXA (n=428) MET + GPZ (n=430) GPZ: glipizide; MET: metformin; SAXA: saxagliptin. 1. Göke B, et al. Int J Clin Pract. 2010;64(12):

16 Patients (%) ± CI Significantly fewer patients experience hypoglycaemia with saxagliptin vs SU as add-on to metformin Proportion of patients with 1 hypoglycaemic episode at Week 52 (safety analysis set) p< % % 0 MET + SAXA (n=428) MET + GPZ (n=430) Severe hypoglycaemic events or events requiring medical assistance 0 with saxagliptin vs 11 for glipizide CI: confidence interval; GPZ: glipizide; MET: metformin; SAXA: saxagliptin. 1. Göke B, et al. Int J Clin Pract. 2010;64(12):

17 Characteristics of DPP-4 Inhibitors in Clinical Development Chemistry Metabolism Elimination route Sitagliptin Januvia β-amino acid-based Not appreciably metabolised Renal (~80% unchanged as parent) Vildagliptin Galvus Cyanopyrrolidine Hepatically hydrolysed to inactive metabolite (P450 enzyme independent) Renal (22% as parent, 55% as metabolite) Saxagliptin Onglyza Cyanopyrrolidine Hepatically metabolised to active metabolite (via P450 3A4/5) Renal (12-29% as parent, 21-52% as metabolite) Linagliptin Trajenta Xanthine-based Not appreciably metabolised Biliary (unchanged as parent); <6% via kidney 17

18 Sulfonylurea vs DPP-4 voordelen Sulfonylurea DPP-4 inhibitoren Bewezen effect op microvasculaire verwikkelingen Beperkte nevenwerkingen Lang bekend Effect zowel op nuchtere als PP glycemie Keuze ifv nierfunctie / leverfunctie/ werkingsduur Goedkoop Gewichtsneutraal Laag risico hypoglycemie Eenvoudig in dosering Weinig nevenwerkingen CV neutraal Kunnen gebruikt worden bij nierinsufficientie ( mits dosisaanpassing)

19 Sulfonylurea vs DPP-4 nadelen Sulfonylurea DPP-4 inhibitoren Hypo s Gewichtstoename Niet consistente gegevens op macrovasculaire verwikkelingen Betacel onder druk CI bij ernstig nier en leverfalen geen lange termijn gegevens Geen studies op microvasculaire eindpunten Duur

20 Casus 2: Francois -79 jaar Alleenstaande man, echtgenote 3 jaar geleden overleden Sindsdien gezondheid/dieet wel wat verwaarloosd Antecedenten: unieke nier na een trauma als kind waarbij nefrectomie CVA 5 jaar geleden, volledige recuperatie prostaatcarcinoom waarvoor radicale prostatectomie en hormonale therapie 10 jaar geleden myocardinfarct jarenlange arteriele hypertensie chronische nierinsufficientie hypercholesterolemie

21 Casus 2: Francois 79 jaar HZG: opname omwille van een pneumonie K.O.: na recuperatie van de acute fase ivm pneumonie, vitale man G 81 kg, L 174 cm, BMI 26 kg/m² bloeddruk 140/78 lab: glycemie 280 mg/dl bij opname tijdens opname steeds > target HbA1c 8,1% creatinine 2,64 mg/dl, e GFR 23 ml/min Behandeltarget? Welke eerste stap?

22 Depiction of the elements of decision making used to determine appropriate efforts to achieve glycemic targets. Inzucchi S E et al. Dia Care 2012;35:

23 Starttherapie Type 2 diabetes: steeds Metformin Voordelen Geen hypo s in monotherapie Gewichtsneutraal Bewezen effect op reductie van micro en macrovasculaire verwikkelingen ( UKPDS) betacelsparend tragere nood insulinetherapie vs SU ( ADOPT) Verminderde insulinenood bij combinatie met insuline Verminderd kankerrisico bij obese Type 2 diabetes (? ) nadelen GI nevenwerkingen ( traag optitreren) Geen gebruik bij nierinsufficientie ( GFR < 30 ml/min)- dosis reductie bij mildere nierinsufficientie hartinsufficientie en andere oorzaken van acidose of ischemie ( lactaatacidose) Vit B 12 en foliumzuurdeficientie

24 DPP-4 inhibitoren - aanpassing nierfunctie egfr (ml/min) > <15 Normaal Lichte NI Matige NI Ernstige NI End stage Sitagliptine Januvia Vildagliptine Galvus 100 mg 100 mg 50 mg 25 mg 25 mg 2 x 50 mg 2 x 50 mg 1 x 50 mg 1 x 50 mg 1 x 50 mg Saxagliptine Onglyza 5 mg 5 mg 2,5 mg 2,5 mg + opvolging CI Linagliptine Trajenta 5 mg 5 mg 5 mg 5 mg 5 mg

25 Terugbetaling DPP-4 (04/2014) Monotherapie Bitherapie met Metformin Januvia Onglyza: Galvus Trajenta 50 mg (30-50 ml ) 25 mg (<30 ml ) 1 x 50 mg/d (50 ml/min) X (<30 ml/min) x x x x Bitherapie met SU Bitherapie met TZD Tritherapie met Metformin + SU Tritherapie met TZD x x x x Insuline Niet vermeld Niet vermeld + metformin en gliptine ( indien GFR < 50 ml/min) Opm. combinatiepreparaten: Janumet, Komboglyze, Jentadueto: enkel in monotherapie terugbetaaald, nooit met insuline Eucreas: combinatie therapie met SU en gliptine X neen

26 Casus 3: Paul, 68 jaar Antecedenten: Myocardinfarct in 2002 CABG in 2008 Hypertensie Hartfalen op basis van ischemische CMP en hypertensie waarvoor 2 x opname in 2011 en 2012 Chronische VKF Hypercholesterolemie Perifeer vaatlijden Diabetes sinds 2004 Medicatie Novonorm 3 x 2 mg, metformin 2 x 850 Burinex 1 mg, Kredex 25, Aprovel 300, Hydralazine, Moxonidine 0,4 Atorvastatine 40 Eliquis

27 Casus 3: Paul, 68 jaar K.O.: G 81 kg, L 176 cm RR 128/78 Lab: Creatinine 1,1 mg/dl HbA1c 8,1 % Welke verdere stappen in de behandeling Triple therapie door toevoegen van een DPP-4 aan Novonorm en metformin? Toevoegen van een GLP-1 agonist Toevoegen of omschakelen naar insuline? Wat weten we van CV veiligheid?

28 DPP-4 inhibitoren CV events meta analyse Grafische compilatie van CV-veiligheidsdata tijdens onafhankelijke klinische studies met DPP-4- inhibitoren DPP-4-remmer beter Vergelijkingsproduct beter Primair eindpunt Commentaar Linagliptine1 0,15 0,34 0, CV-sterfte, MI, CVA, ziekenhuisopname wegens angina Vooraf gespecificeerde / onafhankelijke evaluatie Sitagliptine2 0,41 0,68 1, Med DRA-termen voor MACE Geen formele evaluatie Vildagliptine3 0,62 0,84 1, Acuut coronair syndroom, TIA, CVA, CV-sterfte Vooraf gespecificeerde / onafhankelijke evaluatie Saxagliptine4 0,23 0,42 0, MI, CVA, CV-sterfte Vooraf gespecificeerde / onafhankelijke evaluatie 1/8 1/4 1/ Risicoratio voor macrovasculaire events * CV-sterfte, niet-fataal MI, niet-fataal CVA, ziekenhuisopname wegens instabiele angina pectoris. Aangepast naar 1.Johansen et al. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a prespecified, prospective and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol Jan 10;11:3; 2. Sitagliptine Williams- Herman et al. 2010, BMC Endocrine disorders; 3. Vildagliptine; Schweizer et al. 2010, DOM; 4. Saxagliptine: Frederich et al. 2010, Postgraduate Medicines.

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31 SAVOR-TIMI & EXAMINE Saxagliptin SAVOR Alogliptin EXAMINE Primary MACE 1.00 ( ) 0.96 (UL 1.16) CV Death 1.03 ( ) 0.79 ( ) MI 0.95 ( ) 1.08 ( ) Stroke 1.11 ( ) 0.91 ( ) Total Mortality 1.11 ( ).88 ( ) Saxa/PBO - % Alo/Pbo - % Heart Failure Admissions 3.5/2.8* Reported as NS Hypoglycemia Mild 14.2/12.5* 6.7/6.5 Severe 2.1/1.7* 0.7/0.6 Pancreatitis n n Any 24/21 NR Acute 22/16 12/8 Chronic 2/6 5/4 Pancreatic Cancer 5/12 0/0 *<0.05

32 producten actief via incretinesysteem GLP-1 mimetica: Mimetica Exenatide (Byetta ) -BID Exenatide LAR(Bydureon ) - OW Analogen Liraglutide (Victoza ) -OD Lixisenatide ( Lyxumia ) - OD DPP-4 inhibitoren Sitagliptin (Januvia ) Saxagliptin (Onglyza ) Vildagliptin (Galvus ) Linagliptin ( Trajenta )

33 Plasma exenatide (pg/ml) BYDUREON At steady state, there are minimal peak-to-trough fluctuations in exenatide concentration Establishing steady-state exenatide levels Exenatide once-weekly injection Mean plasma level of exenatide Steady state is maintained with subsequent weekly doses Steady state achieved for continuous glycaemic control N= Microsphere diffusion over time (weeks) Kim D, et al. Diabetes Care 2007;30:

34 LS mean change in HbA1c (%) BYDUREON DURATION TRIALS EFFECT OP HBA1C Exenatide once weekly vs: Baseline (%) DURATION-2 DURATION-1 DURATION-5 DURATION-6 DURATION-3 Sitagliptin (100 mg QD) or pioglitazone (45 mg QD)1 n= weeks Exenatide BID 2 n= weeks Exenatide BID 3 n= weeks Liraglutide 1.8 mg 4 n= weeks Insulin glargine#5 n= weeks Exenatide QW Sitagliptin Pioglitazone Exenatide QW Exenatide BID Exenatide QW Exenatide BID Exenatide QW Liraglutide Exenatide QW Insulin glargine % 0.9% %* 1.2% 1.5% 1.6% 1.3% 1.5% 1.5% 1.3% % Data from Weeks. *P<0.05 vs both; P<0.01; P<0.0001; P=0.02; P=0.017; ITT population; #Modified ITT population. LS, least squares 1. Bergenstal RM, et al. Lancet 2010;376:431 9; 2. Drucker DJ, et al. Lancet. 2008;372: ; 3. Blevins T, et al. J Clin Endocrin Metab 2011;96: ; 4. Buse JB, et al. Lancet 2013;381:117 24; 5. Diamant M, et al. Lancet 2010;375:

35 LS mean change in body weight (kg) 1. Bergenstal RM, et al. Lancet 2010;376:431 9; 2. Drucker DJ, et al. Lancet 2008;372: ; 3. Blevins T, et al. J Clin Endocrin Metab 2011;96: ; 4. Buse JB, et al. Lancet 2013;381:117 24; 5. Diamant M, et al. Lancet 2010;375: Bydureon - DURATION trials: Effect op gewicht DURATION-2 DURATION-1 DURATION-5 DURATION-6 DURATION-3 Exenatide once weekly vs: Sitagliptin (100 mg QD) or pioglitazone (45 mg QD)1 Exenatide BID#2 Exenatide BID#3 Liraglutide 1.8 mg#4 Insulin glargine#5 Baseline (kg) Exenatide QW 2.3* (n=160) Sitagliptin 0.8 (n=166) +2.8 Pioglitazone (n=165) Exenatide QW 3.7 (n=148) Exenatide BID 3.6 (n=147) 2.3 (n=129) Exenatide BID 1.4 (n=123) Exenatide QW 2.7* (n=461) Liraglutide 3.6 (n=450) Exenatide QW 2.6* (n=233) Insulin glargine (n=222) +1.4 Data from Weeks. *P<0.05 vs each comparator; #ITT population. LS, least squares

36 DURATION-1: 3 jaar gegevens 20 27% Exenatide once weekly2 mg (n = 96)1,2 7% Body Weight (kg) % 7% A1C (%) LS Mean ± SE weight loss at 3 years (completer population) was -2.3 ± 0.6kg Exenatide QW 3-year completer population (n = 96) LS, least squares Macconell L, et al. Diabetes Metab Syndr Obes 2013;6: Epub 2013 Jan 21.

37 Change in SBP (mmhg) When used to treat type 2 diabetes liraglutide consistently reduces SBP 1 Monotherapy LEAD-3 Met combination LEAD-2 SU combination LEAD-1 Met + TZD combination LEAD-4 Met + SU combination LEAD-5 Met ± SU combination LEAD * 0.7 Glimepiride Glimepiride Rosiglitazone * * 4.0 * Placebo Glargine Exenatide 6 7 Liraglutide 1.2 mg Liraglutide 1.8 mg 6.6 *** 5.5 ** *p<0.05; **p<0.001; ***p< vs. baseline Colagiuri et al. Diabetes 2008;57(Suppl. 1):A16 (LEAD-1-5); Buse et al. Lancet 2009;374:39 47 (LEAD-6). 37

38 NN2211 Regulatory Submission Data Consistent minor increase in heart rate without any clear dose-response relationship in patients with type 2 diabetes *Significant difference compared to active comparator ** Significant difference compared to placebo in each trial

39 Change from baseline (mmol/l) Liraglutide improves lipid profiles in patients with type 2 diabetes LEAD-6 p<0.05 BID, twice daily; OD, once daily Buse et al. Lancet Jul 4;374:39-47.

40 Native GLP-1 improves left ventricular function in highrisk cardiac patients Data are mean±sem Post IV GLP-1 = post 72-h intravenous (IV) GLP-1 infusion ASE, American Society of Echocardiography Nikolaidis et al. Circulation 2004;109:962 5

41 Not all GLP-1 RAs are the same Mechanism of action in the fasting state Enhance insulin secretion Suppress glucagon secretion Mechanism of action in the postprandial state Enhance insulin secretion Suppress glucagon secretion Slow gastric emptying Reduce food intake Clinical effects Reduce FPG (a) Reduce PPG increment Reduce body weight Prandial GLP-1 Lyxumia/Byetta +/Neutral +/Neutral non-prandial GLP-1 Victoza Adapted from Fineman et al. 2012, Diabetes, Obesity and Metabolism 14:

42 Classification of GLP-1 RAs Based on Regimen Twice daily (BID) Once daily (QD) Once weekly (QW) Exenatide Lixisenatide Liraglutide Exenatide LAR Starting dose 5 mcg BID X 1 month 10 mcg QD X 14 days 0.6 mg QD X 7 days Maintenance dose 10 mcg BID 20 mcg QD 1.2 mg QD 2 mg QW Additional instructions Given within 1 hr before the morning and evening meal (or 2 main meals of the day, ~6 hours or more apart). Should not be given after a meal Given 1 hr prior to first or evening meal May be increased to max 1.8 mg QD given unrelated to meals at any time of day Administer same day each week; given anytime of day, with or without meals. If dosing day is changed, must be at least 24 hours after prior schedule s dosing time SmPCs for exenatide, liraglutide, lixisenatide, exenatide LAR; Rosenstock JC et al. Diabetes Care. 2009; 32:

43 Insuline vs GLP-1 agonistenvoordelen Insuline Lang bekend Zeer goed effect op nuchtere en postprandiale glycemie en op HbA1c ( > 1%) Dosistitratie mogelijk EB reductie microvasculaire verwikkelingen Verlagen triglyceriden Verlagen inflammatoire parameters Gebruik bij nierinsufficientie, leverfalen, cordecompensatie, GLP -1 Goed effect op nuchtere, postprandiale glycemie en HbA1c (1-1,5 %) Eenvoudige toediening: minder educatie, geen dosititratie Weinig hypo s Mogelijk betacelsparend Mogelijk cardioprotectief Beperkte zelfcontrole gewichtsreductie

44 Insuline vs GLP-1 agonisten: nadelen Insuline Hypo risico gewichtstoename Soms moeizame educatie Medewerking patiënt vereist GLP-1 Geen lange termijn effecten Geen lange termijn veiligheid Geen aangetoonde effecten op harde end points Duur Geen gebruik bij nierinsufficientie Alleen bij nog aanwezige endogene insuline-activiteit

45 Casus 3: Paul, 68 jaar - vervolg Medicatie Novonorm 3x 2 mg, metformin 2 x 850, Victoza 1,2 mg Burinex 1 mg, Kredex 25, Aprovel 300, Hydralazine, Moxonidine 0,4 Atorvastatine 40 Eliquis Initieel goede respons op associatie van Victoza Laatste 6 maand toch terug oplopen van het HbA1c HbA1c 6,8 in okt 2012 tot nu in december ,1 % Dagkurve Gemiddeld nuchter 180 mg/dl, middag 140 mg/dl, voor avondmaal 110 mg/dl en voor slapen 120 mg/dl Welke behandelingsopties??

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47 Rationale for combination of basal insulin plus a GLP-1 agonist Basal Insulin Analogs Simple to initiate Control nocturnal and FPG Less hypoglycemia risk vs NPH Weight Gain ~1-3 kg GLP-1 Receptor Agonists Simple to use Control PPG and some FPG No Increase in hypoglycemia Weight Loss ~1-3 kg Complementary and Potentially Synergistic Effects

48 HbA1C (%) Patients achieving targets (%) Effect of Twice-Daily Exenatide in Combination with Insulin Glargine on HbA1C p = p < p < 0.001* p < 0.001* p < Glargine + placebo Glargine + exenatide 0 HbA1C <7.0% HbA1C <6.5% *Versus baseline, between treatment groups Buse JB, et al. Ann Intern Med 2011;154:

49 Combinatie Glargine/Exenatide Change in HbA1c from baseline Exenatide first then glargine Glargine first then exenatide Treatment groups Combined % Change in A1C from baseline months 12 months 18 months 24 months ap < vs baseline, bp vs baseline Significant decreases in HbA1c were seen at 6 months and maintained, irrespective of therapy order Levin P. Endocr Pract 2011 [Epub ahead of print]

50 GetGoal-L: Study Design Objective: to evaluate the efficacy & safety of lixisenatide 20 µg QD vs. placebo as additional therapy in patients with T2DM inadequately controlled on basal insulin ± metformin. 1 wk 20 µg Basal insulin ± metformin + Lixisenatide (n=329) Key Inclusion Criteria: Type 2 DM HbA1c 7.0% 10.0% Basal insulin 30 U/day 1 wk 1 wk 10 µg R (n=496) 10 µg 15 µg 15 µg Diet & lifestyle counselling every 3 months from D 1 1 wk Screening Run-in 20 µg Basal insulin ± metformin + Placebo + (n=167) Main double-blind period Variable extension 52 weeks 3 d F/U W-3 W-1 W0 W24 W52 Primary endpoint End of treatment FU Visit Riddle et al., Diabetes Care Publish Ahead of Print, published online April 29,

51 Mean HbA1c (%) ±SE LS mean change in HbA1c (%) GetGoal-L : HbA1c at Week 24 Placebo (n=158) Lixisenatide (n=304) Baseline Week -0.38%* -0.74%* *LS mean change in HbA1c at Week 24, LOCF data mitt population (LOCF), on treatment value available LS mean difference [95%CI] vs placebo= -0.36% [-0.550, ]; p= Riddle et al., Diabetes Care Publish Ahead of Print, published online April 29,

52 % of patients GetGoal-L: HbA1c Target reached at Week Lixisenatide (n=304) Placebo (n=158) 28.3% p< % p= % 12.0% 0 HbA1c 6.5% mitt population (LOCF), on treatment value available HbA1c <7.0% Riddle et al., Diabetes Care Publish Ahead of Print, published online April 29,

53 Mean change in body weight (kg) ± SE LS mean change in body weight (kg) GetGoal-L: Body Weight Changes at Week 24 Placebo (n=161) Lixisenatide (n=311) Baseline Week *LS mean change in body weight at Week 24, LOCF data mitt population (LOCF), on treatment value available -0.5 kg* -1.8 kg* LS mean difference [95%CI] vs placebo= kg [-1.803, ]; p< Riddle et al., Diabetes Care Publish Ahead of Print, published online April 29,

54 LS mean change in basal insulin dose (U) GetGoal-L: Change in Basal Insulin Dose at Week 24 0 Lixisenatide (n=325) Placebo (n=165) LS mean difference [95%CI] vs placebo= U [-6.568, ]; p= mitt population (LOCF), on treatment value available p= Riddle et al., Diabetes Care Publish Ahead of Print, published online April 29,

55 Terugbetalingsvoorwaarden voor GLP-1 agonisten ( ) Byetta Victoza Lyxumia Bydureon Eerste aanvraag HbA1c > 7,5%, min 3 maand basis therapie Metformin + sulfonylurea Metformin + pioglitazone Basale insuline +/- perorale x x x x x x Verhogen dosis Als HbA1c > 7,5 na 6 maand Verlenging na 1 jaar als < 7 % of verschil tov voor behandeling 1 % x x x x

56 Summary of Key Benefits and Risks of Medications Metformin DPP-4 Inhibitor GLP-1 Agonist Benefits Sulfonylurea Glinide TZD Insulin PPG - lowering Mild Moderate Moderate to Marked Moderate Moderate Mild Moderate to Marked FPG - lowering Moderate Mild Mild Moderate Mild Moderate Moderate to Marked Nonalcoholic fatty liver disease (NAFLD) Mild Neutral Mild Neutral Neutral Moderate Neutral Risks Hypoglycemia Neutral Neutral Neutral Moderate Mild Neutral Moderate to Severe GI Symptoms Moderate Neutral Moderate Neutral Neutral Neutral Neutral Risk of use with renal insufficiency Severe Reduce Dosage Moderate Moderate Neutral Mild Moderate Contraindicated if liver failure or predisposition to lactic acidosis Severe Neutral Neutral Moderate Moderate Moderate Neutral Heart failure/edema Contraindicted in CHF??? Neutral Neutral Neutral Mild/ Moderate Neutral Contraindicted in class 1, 4 CHF Weight Gain Benefit Neutral Benefit Mild Mild Moderate Mild to Moderate Fractures Neutral Neutral Neutral Neutral Neutral Moderate Neutral Drug-Drug Interactions Neutral Neutral Neutral Moderate Moderate Neutral Neutral

57 SGLT-2 INHIBITOREN

58 Chao EC, et al. Nat Rev Drug Discovery. 2010;9: Targeting the Kidney

59 Changes from Baseline in A1C in Phase 3 Dapagliflozin Studies Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010;33(10): ; Bailey CJ, et al. Lancet. 2010;375(9733):

60 Canagliflozin Mean Baseline Weight (kg) SGLT2 Inhibition for Type 2 Diabetes: Metformin + Canagliflozin Dose-Ranging Study * * * * * * * Rosenstock J, et al. Abstract 77-OR. ADA *P.001 vs. placebo calculated using LS means

61 Dapagliflozin Add-on to Metformin: 2 Year Extension Study Δ from BL (SE) Placebo DAPA 2.5mg DAPA 5mg DAPA 10mg A1c, % 0.2 (0.11) (-.1) (0.1) (0.09) FPG, mg/dl (3.6) (3.2) (2.8) (2.7) Body weight, kg -0.7 (0.5) -2.2 (0.5) -3.4 (0.4) -2.8 (0.4) % Pts with 1 hypoglycemic event Events suggestive of urinary tract infection Dapagliflozin 2.5 mg: 8.0%, 5 mg: 8.8%, 10 mg: 13.3% Placebo: 8.0% Events suggestive of urinary tract infection Dapagliflozin 2.5 mg: 11.7%, 5 mg: 14.6%, 10 mg: 12.6% Placebo: 5.1% Events primarily mild or moderate in intensity and responded to standard treatment Bailey CJ et al. Abstract 988-P. ADA 2011.

62 Safety SGLT2: Malignancies Bladder cancer incidence rate: 0.16% patients (n=5,478) treated with dapagliflozin vs 0.03% patients (n- 3,156) in placebo group (p = 0.15) Breast cancer incidence rate: 0.4% patients (n=2,223) treated with dapagliflozin vs 0.09% patients (n=1,053) in placebo group (p = 0.27) Jones D. Nat Rev Drug Discov. 2011;10(9):

63 Dapagliflozin: Effect on BP and Lipids Systolic Blood Pressure (mmhg) Placebo: -0.2 Dapa 2.5mg: -2.1 Dapa 5mg: -4.3 Dapa 10mg: -5.1 Diastolic Blood Pressure (mmhg) Placebo: -0.1 Dapa 2.5mg: -1.8 Dapa 5mg: -2.5 Dapa 10mg: -1.8 HDL (% change) Placebo: +0.4 Dapa 2.5mg: +1.8 Dapa 5mg: +3.3 Dapa 10mg: +4.4 Triglycerides (% change) Placebo: +2.1 Dapa 2.5mg: -2.4 Dapa 5mg: -6.2 Dapa 10mg: -6.2 Bailey CJ, et al. Lancet

64 SGLT2 Inhibitie Mogelijke voordelen Onafhankelijk van insuline Gewichtsverlies (75g urine glucose = 300kcal/dag) Laag hypoglycemie risico bloeddrukdaling Mogelijke nadelen Polyurie electrolytenstoornissen urineweginfecties Genitale ( schimmel) infecties Blaas CA