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10 Incidence of myocardial infarction (rate per 1000 patients) Incidence of mortality (rate per 1000 patients) p=ns p<0, p=ns p<0, FPG PPG 0 FPG PPG Binnen de waarden Op de grens van normaalwaarde Te hoog Hanefeld et al. Diabetologia 1996;39: Yu et al. Diabetes Res Clin Pract 2010;89: Hanefeld et al. Diabetologia 1997;20 (Suppl. 2):S German Diabetes Intervention Study

11 Diabetes mellitus regulatie 11 Target FPG Target PPG Langwerkend insuline Metformine SU Thiazolinides Glucagon-like peptide-1 agonisten DPP-4 inhibitoren Meglitiniden α-glucosidase inhibitoren Kortwerkend insuline

12 FPG PPG FPG PPG 12

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15 Glycerophosphate dehydrogenase 15

16 16 Properties of anti-hyperglycemic agents. Available from:

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18 Minder macrovasculaire eindpunten NNT 1:16 Niet minder macrovasculaire + microvasculaire eindpunten 18

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20 Glucosespiegel onafhankelijke insuline productie! 20

21 Properties of anti-hyperglycemic agents. Available from: _of_anti-hyperglycemic_agents_may_2012.pdf 21

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35 Bron: 35

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37 SGLT1 SGLT2 Kidney Sugar specificity Main role μ μ 37 Modified from Lee YJ. et al. Kidney Int Suppl. 2007;72:S27-S35.

38 Urinary Glucose Excretion (g/day) Below RT G minimal glucosuria occurs Above RT G glucosuria occurs ~10 mmol/l ~13.8 mmol/l RT G = Renal threshold for glucose; T2DM = type 2 diabetes mellitus. Plasma Glucose (mmol/l) 1. Polidori D., et al. (

39 Glomerulus Proximal Convoluted Tubule Early Distal Glucose reabsorption into tissue Adapted with permission from Rothenberg PL et al. SGLT = sodium-glucose co-transporter Glucose SGLT2 SGLT1 39

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41 SANL.DIA Properties of anti-hyperglycemic agents. Available from: rties_of_anti-hyperglycemic_agents_may_2012.pdf 2. Zinman B et al. N Engl J Med DOI: /NEJMoa

42 HbA1c (%) SGLT2 Remmers Baseline HbA1c 0,2 0,14 0-0,2-0,4-0,17-0,13-0,26 PBO CANA 100 mg CANA 300 mg -0,6-0,8-1 -1,2-0,77-1,03-0,79-0,94-0,85-1,06-0,89-1, mg vs 100 mg * excluding the study in patients with chronic renal impairment Stenlof et al. Diabetes Obes Metab. 2013;15(4): Lavalle-González FJ et al. Diabetologia Sep 13. [Epub ahead of print] For all studies: P <0.001 vs PBO for both CANA doses Wilding JP et al. Int J Clin Pract. 13 okt [Epub ahead of print] Forst T et al. Diabetes Obesity Metab 2014; 16(5):

43 FPG (mg/dl) with 95% CI Monotherapy (N = 558) Add-on to MET (N = 546) Add-on to SU (N = 596) Add-on to PIO (N = 420) Add-on to Insulin (N = 807) BL (mg/dl) , ,2-24.1* -4,1-21.5* -6,0-2,0-24.9* -5,5-12.5** (mmol/l) ,1-28,8-16.8* -17,8-21.5** 21.2** -23.5** 28.5** -24,9-29, Dapa 2.5 mg Dapa 5 mg Dapa 10 mg Placebo *P <.05 vs placebo. 43 Abbreviations: BL, baseline; MET, metformin; PIO, pioglitazone; SU, sulfonylurea. FDA Advisory Committee 19th July 2011:

44 Empagliflozin Systolic BP Change from Baseline at Week 24 N Baseline SBP (mmhg)

45 Empagliflozin Bodyweight Change from Baseline at Week 24 N Baseline body weight (Kg) ^ P< vs PBO * P <0.001 vs PBO ^ ^ * * * * * * * * 45

46 Dapagliflozin 5 mg (n = 1145) Dapagliflozin 10 mg (n = 1193) Placebo (n = 1393) HDL-C (n) Mean BL (mg/dl) Mean change % % % LDL-C (n) Mean BL (mg/dl) Mean change % % % TC (n) Mean BL (mg/dl) Mean change % % % TG (n) Mean BL (mg/dl) Mean change % % % FFA (n) Mean BL (mg/dl) Mean change % % % 46

47 Invokana EPAR 2013 Available at: _Public_assessment_report/human/002649/WC pdf 47 PHNL/CAN/0614/0001c

48 Nierfunctie SGLT2 Positief effect op albuminurie Negatief effect op klaring 48

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52 Simvastatin 1 for 5.4 years Ramipril 2 for 5 years Empagliflozin for 3 years 52

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56 Hartbeschermend effect Cardiaal debiet (CO) Neuroprotectie Eetlust Maaglediging GLP-1 geproduceerd door L-cellen in de dunne darm GLP-1 Synthese van insuline Proliferatie van β-cellen Apoptose van β-cellen Gevoeligheid voor insuline Uitscheiding van insuline Glucagonuitscheiding 56 Glucoseproductie

57 Gewichtsverlies + Glucagon-like peptide-1 (GLP-1) Snelle inactivatie GLP-1 mimetica Exenatide (Byetta ) Exenatide LAR (Bydureon ) Lixisenatide (Lyxumia ) Liraglutide (Victoza ) Dulaglutide (Trulicity ) Dipeptidyl peptidase DPP-4 remmers Sitagliptine (Januvia ) Vildagliptine (Galvus ) Saxagliptine (Onglyza ) Linagliptine (Trajenta )

58 Action GLP-1 Receptor Agonists 1,2 DPP-4 Inhibitors 1,2 Insulin production First-phase insulin response Glucagon; glucose output Gastric emptying Delayed No effect Food intake Decreased No effect 58

59 Properties of anti-hyperglycemic agents. Available from: properties_of_anti-hyperglycemic_agents_may_2012.pdf 59

60 endogeen actief SC injecteerbare vormen Niet afgebroken door DPP-4 Imiteren de effecten van humaan GLP-1 Orale vormen Biologische effecten van GLP-1 60

61 Verandering t.o.v. baseline (%) Verandering t.o.v. baseline (kg) Verandering in HbA1c Verandering in gewicht 61

62 Russell-Jones. Diabetologia 2009 (52) 62

63 Data are number (%) of patients exposed to treatment (safety population) Blonde et al. Can J Diabetes 2008;32(Suppl): A107 (LEAD 6). 63

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65 2 weeks Duration years 30 days Screening Randomisation (1:1) End of treatment Key inclusion criteria T2DM, HbA 1c 7.0% Antidiabetic drug naïve; OADs and/or basal/premix insulin Age 50 years and established CV disease or chronic renal failure or Age 60 years and risk factors for CV disease Key exclusion criteria T1DM Use of GLP-1RAs, DPP-4i, pramlintide, or rapid-acting insulin Familial or personal history of MEN-2 or MTC Marso SP et al. N Engl J Med DOI: /NEJMoa

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67 Patients with an event (%) P la c e b o L ir a g lu t id e Time from randomisation (months) Patients at risk Liraglutide Placebo The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio. Marso SP et al. N Engl J Med DOI: /NEJMoa

68 Hazard ratio (95% CI) Favours Liraglutide Favours Placebo Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate. %, percentage of group; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; N, number of patients; R, incidence rate per 100 patient-years of observation. Marso SP et al. N Engl J Med DOI: /NEJMoa

69 Patients with an event (%) P la c e b o 5 L ir a g lu t id e Patients at risk Liraglutide 4668 Placebo Time from randomisation (months) The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI, confidence interval; HR, hazard ratio. Marso SP et al. N Engl J Med DOI: /NEJMoa

70 *95.02% CI. CV: cardiovascular; Empa: empaglifloin; Lira: liraglutide; MACE: major adverse cardiovascular event; MI: myocardial infarction; Pbo: placebo. Zinman B et al. N Engl J Med 2015;373: ; Marso SP et al. N Engl J Med DOI: /NEJMoa

71 MACE All-cause death MACE, major adverse cardiovascular event. Marso SP et al. N Engl J Med DOI: /NEJMoa voor 3 jaar

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73 Bailey CJ; Krentz AJ. Textbook of diabetes 2010; 4 th edition (Holt ed.). 73

74 2. Holt R et al. Textbook of diabetes (4 th edition) White WB et al. N Engl J Med 2013;369: Green JB et al. N Engl J Med 2015;373: Scirica BM et al. N Engl J Med 2013;369:

75 Lancet 2012; 380:

76 SANL.DIA White (2013) N Engl J Med ;369: Scirica N Engl J Med 2013;369:

77 Vooralsnog zijn er voor DPP-4 remmers geen uitkomsten van lange termijnonderzoek 1. De EXAMINE 2 (alogliptine) en TECOS 3 (sitagliptine) studie laten zien dat deze DPP4-remmers geen verhoogd risico geven op cardiovasculaire gebeurtenissen. De SAVOR-TIMI 53 4 (saxagliptine) studie laat zien dat er mogelijk een verhoogd risico bestaat op hartfalen bij het gebruik van saxagliptine. ¹ 77

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79 ¹ ² Geen verschillen in hypoglykemie tussen SGLT2, GLP1 en DPP4 ¹ ² 80% van de genitale infecties met canagliflozin treden op in de eerste 26 weken van de behandeling² ¹Lancet 2010; 375: lira vs sita in combi met metformine ²Diabetologia 2013; 56: cana vs sita combi met metformine 79

80 SANL.DIA Klaring ml/min <15 <25 <30 <45 <50 <60 <70 <90 Metformine DPP-remmers Linagliptin Sitagliptin 25mg 1dd 25mg 1dd 50mg 1dd Vildagliptin 50mg 1dd 50mg 1dd GLP-1 analogen Lixisenatide Liraglutide Exenatide weinig ervaring weinig ervaring Voorzichtig ophogen SU-derivaten Gliclazide (lage nierfunctie hypo) Glimepiride Tolbutamide Thiazolidinederivaten Pioglitazon (staken bij dialyse) Acarbose SGLT-2 remmers Dapagliflozine (SGLT2) Canagliflozine (SGLT2) 100mg 1dd Bron: farmacotherapeutisch kompas 07/

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82 * Volledig vergoed 82 Hirsch N Engl J Med 2005; 352:174-83

83 * Volledig vergoed binnen het GVS 83

84 Hirsch IB. Insulin analogues. N Engl J Med Jan 13;352(2):

85 Conclusie (n=3181): Eight (pool 1) or five (pool 2) people with T2DM needed to use glargine rather than NPH to avoid one person from experiencing a nocturnal symptomatic hypoglycaemic event within a median of about 25 weeks of starting insulin. 85

86 86 Home et al. Diabetes, Obesity and Metabolism 12: , 2010.

87 Hypoglycaemie (aantal incidenten) Insuline detemir 2dd (n = 237) NPH insuline 2dd (n = 238) alle Minor bevestigd Symptomatisch onbevestigd 87

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89 Becker et al. Diabetes Care 2015;38: Toujeo SmPC 27 april

90 Nieuwe ultra-langwerkende insulineanalogen 90 Heise et al. Diabetes Obesity Metabolism 2012; 14: Tresiba SmPC januari

91 Nieuwe ultra-langwerkende insuline-analogen # bevestigde nachtelijke hypoglykemieën bij DM2 * Ten opzichte van insuline glargine 100 E/ml 91

92 1) SmPC Tresiba januari ) # Bevestigde nachtelijke hypoglykemieën * Ten opzichte van insuline glargine 100 E/ml 92

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94 CASUS 1 Man, 52 jaar BMI 33 Hypertensie sinds 20 jaar waarvoor ACEi, calciumantagonist 2 dd 1000 mg metformin, 3 dd 80 mg gliclazide Klaring 48 ml/min Alcohol 3-4 EH Woont alleen HbA1c 60 mmol/mol (7,7%) Pre-lunch 9 mmol/l Nuchter rond de 7-8mmol/l, soms hypo in ochtend Wat is uw beleid? SANL.DIA

95 Vrouw, 63 jaar 7 jaar diabetes BMI 31 Simvastatine 40 mg Ramipril 2 dd 2,5 mg Hydrochloorthiazide 12,5 mg Metformin 3dd 850 mg, mix-insuline (21 ochtend, 14 avond) Wordt regelmatig zwetend wakker Nuchtere glucose 4,1 mmol/l HbA1C 69 mmol/mol (8,5%) SANL.DIA

96 Metformine DPP-4 remmer GLP-1 agonist SU TZD Insuline Risico op lactaat acidose Contra-indicatie bij GFR <30 ml/min Dosis aanpassen* Renale functie monitoren* In aanwezigheid van Nierinsufficientie Voorzichtig gebruiken Niet gebruiken bij CKD IV & V Dosis aanpassen Renale functie monitoren Contra-indicatie bij afgenomen nierfunctie Vochtretentie Dosis aanpassen Toename in gewicht Algemeen: HbA1c: % HbA1c: % HbA1: % HbA1c: % HbA1c: % HbA1c: % Hypo risico: laag Hypo risico: laag Hypo risico: laag Hypo risico: hoog Insulineresistentie Hypo risico: hoog * excl. Linagliptine 3 1. Rodbard HW, et al. Endocr Pract National Kidney Foundation. Am J Kidney Dis Linagliptine is sinds sept 2011 geregistreerd voor gebruik in de EU en is eigendom van de sponsoren van deze nascholing.. Linagliptine staat niet in de vigerende richtlijnen.

97 Samenvatting van de registratie en vergoedingsvoorwaarden Type 2 diabetes (status juni 2014) 1 Mono therapie * Duo therapie * Triple therapie * Combi insuline NHG Reg. Verg. Reg. Verg. Reg. Verg. Reg. Verg. Metformine SU TZD , pio Insuline DPP-4 R 1, sit sit GLP-1 RA 1,2, exe 1 1,2, exe SGLT2-i 1 Dapa + Cana * Mono-therapie: enkelvoudige therapie Duo-therapie: combinatie therapie met metformine óf SU Triple-therapie: combinatie therapie met metformine én SU 1: indien metformine + SU niet volstaat 2: alleen indien BMI 35 kg/m 2 1. dossiers op: d.d

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