Glycemie medicatie bij type 2 diabetes: anno 2015

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1 Glycemie medicatie bij type 2 diabetes: anno 2015 Dr. Frank Nobels Endocrinologie-Diabetologie OLV Ziekenhuis, Aalst-Asse-Ninove glycemie verlagers metformine sulfonylureum glinide acarbose glitazone DPP-4 inhibitor SGLT2 inhibitor GLP-1 analoog insuline en combinaties 1

2 ADA-EASD position statement. Inzucchi S, et al. Diabetes Care 2015;38:140 patiëntgericht 2

3 Metformine blijft 1 ste keuze goedkoop geen hypoglycemie geen gewichtstoename reduceert microvasculaire complicaties (UKPDS) reduceert macrovasculaire complicaties (UKPDS) overbelast de β-cel niet geen glycemie zelfcontrole nodig (cave nierfunctie) Metformine: cave gastro-intestinale neveneffecten (1 op 20) - op volle maag - langzaam opbouwen oppassen voor lactaatacidose (zeer zeldzaam) - dosis aanpassen bij nierinsufficiëntie - niet bij onstabiele hartdecompensatie, COPD, cirrhose - stop tijdelijk in alle acute situaties (cave deshydratatie + slechte nierfunctie + ACE-i/ARB, NSAID) - stop tijdelijk 24 u voor iv-contrast en voor heelkunde Nathan D et al. Diabetes Care 2009;32: Shaw J et al.diabet Med 2007;24: Herrington W, Levy J. Int Urol Nephrol 2008;40:

4 DM2 op metformine 48 j obees, metabool syndroom metformine 850 mg HbA1c (%) 7,2 7,8 8,6 nierfunctie nl dyslipidemie, hypertensie taxichauffeur DM2 op metformine 71 j licht obees metformine 850 mg HbA1c (%) 7,2 7,8 8,6 nierfunctie nl dyslipidemie, hypertensie alleenstaand, maar nog erg actief 4

5 metformine + sulfonylureum / glinide glitazone DPP-4 inhibitor SGLT2 inhibitor Sulfonylurea goedkoop geen hypoglycemie geen gewichtstoename reduceert microvasculaire complicaties (UKPDS) reduceert macrovasculaire complicaties (UKPDS) overbelast de β-cel niet geen glycemie zelfcontrole nodig (cave nierfunctie) 5

6 Mortaliteit: secretagogen metformine All Danish residents.20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years) Danish Registry. Schramm T et al. European Heart Journal 2011;32: Glitazones: neveneffecten gewichtstoename vochtretentie hartdecompensatie meer coronaire events en mortaliteit met rosiglitazone? atypische fracturen (distale BL en OL) macula oedeem (blaascarcinoom) 6

7 DPP-4 inhibitoren (gliptines) + metformine - alogliptine: Vipidia Vipdomet - linagliptine: Trajenta Jentadueto - saxagliptine: Onglyza Komboglyze - sitagliptine: Januvia Janumet - vildagliptine: Galvus Eucreas Incretine systeem insulinesynthese maaglediging glucagonsecretie glucose afhankelijke insulinesecretie 7

8 Metabolisme van GLP-1 Meal Intestinal GLP-1 release GLP-1 analoog Byetta, Lyxumia, Victoza, Bydurion (spuiten) Active GLP-1 DPP-4 Januvia, Galvus, Onglyza, Trajenta, Vipidia (tabletten) DPP-4 inhibitor GLP-1 inactive Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39. Rothenberg P, et al. Diabetes 2000;49(suppl 1):A39 MF + sitagliptin MF + glipizide Nauck M, et al. Diabetes, Obesity and Metabolism 2007;9:

9 MF + sitagliptin MF + glipizide 50 hypoglycemia Body weight (kg ± SE) Incidence (%) % P< % 0 Week 52 Glipizide + metformin Sitagliptin + metformin Nauck M, et al. Diabetes, Obesity and Metabolism 2007;9: incretinetherapie en pancreatitis gelinkte medische en pharmaciedata van pat, waarvan DM (6545 op exenatide, op sitagliptine) Garg R, et al. Diabetes Care 2010;33:2349 9

10 incretinetherapie en pancreatitis gelinkte medische en pharmaciedata van pat, waarvan DM (6545 op exenatide, op sitagliptine) Garg R, et al. Diabetes Care 2010;33:2349 DPP4i: cv events and heart failure US commercial insurance claims data ( ) propensity score-matched initiators of DPP4 versus non-dpp4i 79,538 Kim S, et al. Acta Diabetol 2014, online October 14 10

11 SGLT2= Sodium-GLucose cotransporter-2 genetisch defect van SGLT2 benigne renale glucosurie SGLT2 inhibitie: verwachte (neven)effecten goede nierfunctie nodig glycemie, HbA1c weinig hypoglycemie BD (natriurese, osmotische diurese) gewicht (glucosurie, diurese) urogenitale infecties (glucosurie) veilig op lange termijn ( benigne renale glucosurie ) Misra M. Journal of Pharmacy and Pharmacology 2013;65:317 11

12 Sodium Glucose Co-Transporter (SGLT) Inhibitors Compound Manufacturer Development Canagliflozin Janssen Approved in the EU & US Reimbursed in Belgium since 1 Dec 14 Dapagliflozin Astra Zeneca Approved in the EU & US Empagliflozin Boehringer Ingelheim, Lilly Approved in the EU & US Luseogliflozin Taisho, Novartis Approved in Japan Tofogliflozin Chugai, Kowa, Sanofi Approved in Japan *Other SGLT inhibitors are also in development.** Dual SGLT1/SGLT2 inhibitor Available at : ADA-EASD position statement. Inzucchi S, et al. Diabetes Care 2015;38:140 12

13 The Renal Glucose Threshold (RT G ) is increased in subjects with Type 2 Diabetes 150 Below RT G minimal glucosuria occurs Urinary Glucose Excretion (g/day) Healthy RT G ~180 mgl/dl Above RT G glucosuria occurs T2DM RT G ~240 mg/dl Plasma Glucose (mg/dl) Renal glucose reabsorption is increased in diabetes, which could contribute to further increasing plasma glucose levels RT G, renal threshold for glucose excretion. Polidori D et al Abstract 2186-PO. American Diabetes Association. June 25-29, 2010; Orlando, Florida. Polidori D et al Presented at: European Association for the Study of Diabetes. September 20-24, 2010; Stockholm, Sweden. SGLT2 Inhibition Lowers RT G Below RT G minimal glucosuria occurs Urinary Glucose Excretion (g/d) RT G 70 SGLT2itreated healthy Above RT G glucosuria occurs SGLT2itreated T2DM RT G Plasma Glucose (mg/dl) 200 Untreated healthy 240 Untreated T2DM Canagliflozin decreases RT G to the levels that have low potential to cause hypoglycaemia SGLT2, sodium glucose co-transporter 2; RTG, renal threshold for glucose excretion; UGE, urinary glucose excretion. Polidori D et al Abstract 2186-PO. Presented at. ADA Polidori D et al Abstract 875. Presented at EASD

14 HbA1 c change from baseline Placebo-controlled Phase 3 Studies Monotherapy (DIA3005) N =584 BL Mean HbA 1c (%) Metformin (DIA3006) N = 1284 SU (DIA3008) N = 127 Add-on combinations with Met/SU (DIA3002) N = 469 Met/Pio (DIA3012) N = 342 Insulin (DIA3008) N = Placebo-subtracted LS Mean Change in HbA 1c (%) (95% CI) All at 26 weeks except 18 weeks DIA3008 Insulin, SU sub-studies * p<0.001 Based on ANCOVA models, data prior to rescue (LOCF) Assessment report EMA/718531/ Dapagliflozin Versus Sulfonylurea as Add-on to Metformin: Incidence of Hypoglycemia The proportion of patients experiencing hypoglycemia was significantly lower with dapagliflozin than glipizide P< Percent with 95% CI 28 Nauck M, et al. Diabetes Care. 2011;34(9): DAPA + MET Glipizide + MET ME732BE13NP01160 NS SK

15 Body weight percent change from baseline Placebo-controlled Phase 3 Studies Add-on combinations with BL Mean Weight (kg) Monotherapy (DIA3005) N = Metformin (DIA3006) N = SU (DIA3008) N = Met/SU (DIA3002) N = Met/Pio (DIA3012) N = Insulin (DIA3008) N = Placebo-subtracted LS Mean % Change in Body Weight (95% CI) * p <0.001; p <0.05 Based on ANCOVA models, data prior to rescue (LOCF) Assessment report EMA/718531/ Summary of Systolic Blood Pressure Change from Baseline Placebo-controlled Phase 3 Studies Add-on combinations with BL Mean SBP (mmhg) Placebo-subtracted LS Mean Change in Systolic BP (mmhg) (95% CI) Pulse rate (bpm) LS mean change Monotherapy (DIA3005) N =584 Metformin (DIA3006) N = 1284 SU (DIA3008) N = CANA 100 mg CANA 300 mg No clinically meaningful changes in pulse rate Met/SU (DIA3002) N = 469 Met/Pio (DIA3012) N = 342 Insulin (DIA3008) N = 1718 Assessment report EMA/718531/2013 *p<0.001; **p<0.05 Based on ANCOVA models, data prior to rescue (LOCF) 30 15

16 Summary of Adverse Drug Reactions 2% in Four Placebo-controlled 26-week Studies (n=2313) Gastrointestinal Disorders Placebo N=646 (%) CANA 100 mg N=833 (%) CANA 300 mg N=834 (%) Constipation Thirst Nausea Renal and Urinary Disorders Polyuria or pollakiuria Urinary tract infection (UTI) Reproductive System Disorders Balanitis or balanoposthitis Vulvovaginal candidiasis The most commonly reported AEs overall were vulvovaginal candidiasis, UTI and polyuria or pollakiuria. When CANA was used in combination with insulin or insulin secretagogues the most commonly reported AEs included hypoglycaemia Janssen Briefing Materials for the January 10, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee: EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM pdf Dapaglifozin: genital and urinary tract infections GTI UTI Johnsson K, et al. J Diab Complic 2013 dx.doi.org/ /j.jdiacomp en dx.doi.org/ /j.jdiacomp

17 13/04/2015 Genital mycotic infections: consideration and management Placebo N=646 % CANA 100 mg N=833 % CANA 300 mg N=834 % Balanitis or balanoposthitis Vulvovaginal candidiasis Consideration Management Risk factors History of GMI More common in females than males Conventional treatment Topical antifungal treatments either prescribed by a healthcare professional or self-treated while continuing therapy Highest rate of occurrence observed during the first four months of treatment, followed by an attenuation in the rate of increase Low discontinuation rate Only 0,7 % for men and 0,5% for women Majority: no recurrence after treatment Invokana SmPC (Nov 2013) Available at: 33 individualiseren metformine + DPP-4 inhibitor of SGLT2 inhibitor 17

18 nierinsufficiëntie DPP4i MDRD (ml/min) sitagliptine (Januvia) vildagliptine (Galvus) saxagliptine (Onglyza) linagliptine (Trajenta) alogliptine (Vipidia) > 50 1x 100 mg 2x 50 mg 1x 5 mg 1x 5 mg 1x 25 mg x 50 mg 1x 50 mg 1x 2,5 mg 1x 5 mg 1x 12,5 mg < 30 1x 25 mg 1x 50 mg 1x 2,5 mg 1x 5 mg 1x 6,25 mg onvoldoende controle met 2 OAD Jan is 50j. Hij heeft overgewicht. Hij slaagt er niet in om te vermageren. Hij neemt Metformine 850 mg en Uni-Diamicron 60 mg 1,5. Hij heeft lang een A1c tussen 7 en 7.5% gehad, maar die is geleidelijk opgelopen tot 9,2%. Hij ziet erg op tegen spuitjes. Normale nierfunctie. 18

19 onvoldoende controle met 2 OAD Jan is 76. Hij heeft licht overgewicht. Hij neemt Metformine 850 mg en Uni-Diamicron 60 mg 1,5. Hij heeft lang een A1c tussen 7 en 7.5% gehad, maar die is geleidelijk opgelopen tot 9,2%. Hij ziet erg op tegen spuitjes. Normale nierfunctie. Hij is een maaglijder (makkelijk misselijk) MF + SU + 3 de OAD = glitazone of DPP4i of SGLT2i GLP1 analoog basale insuline 19

20 Add-on to MET + SU vs DPP4 inhibitor: Change in HbA 1c (LOCF) Triple therapy Baseline (%) LS mean change (±SE) from baseline (%) LS mean change 0.66% 1.03% 0.37% (95% CI: 0.50, 0.25) Time point (wk) CANA provided a greater reduction in HbA1c compared with SITA (upper limit of 95% CI < 0.0%) LOCF, last observation carried forward ; SITA, sitagliptin; CANA, Canagliflozin; LS, least squares; SE, standard error; CI, confidence interval. Adapted from Schernthaner G. et al. Data presented at EASD 2012 Berlin, Germany, (OP43) Schernthaner G et al. Diabetes Care Apr 5. [Epub ahead of print] 39 Add-on to MET + SU vs DPP-4 inhibitor: Percent Change in Body Weight (LOCF) Baseline (kg) 1.0 LS mean % change (±SE) from baseline Triple therapy LS mean % change 0.3% (0.1 kg) 2.5% ( 2.3 kg) 2.8% ( 2.4 kg) P < Time point (wk) LOCF, last observation carried forward; SITA, sitagliptin; CANA, Canagliflozin; LS, least squares; SE, standard error. 40 Schernthaner G. et al. Poster presented at CODHy 2012 Barcelona, Spain, (P70). Schernthaner G et al. Diabetes Care Apr 5. [Epub ahead of print] 20

21 Metabolisme van GLP-1 Meal Intestinal GLP-1 release GLP-1 analoog Byetta, Lyxumia, Victoza, Bydurion (spuiten) Active GLP-1 DPP-4 Januvia, Galvus, Onglyza, Trajenta, Vipidia (tabletten) DPP-4 inhibitor GLP-1 inactive Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39. Rothenberg P, et al. Diabetes 2000;49(suppl 1):A39 GLP1 analogen - exenatide: Byetta 2x /d - liraglutide: Victoza 1x /d - lixisenatide: Lyxumia 1x /d - exenatide LA: Bydurion 1x /wk - (albiglutide: Eperzan 1x /wk) - (dulaglutide: Trulicity 1x /wk) 21

22 Exenatide LA vs glargine MF ± SU HbA1c 8,3 ± 1,1 % Diamant M, et al. Lancet 2010;375: Exenatide LA vs glargine Diamant M, et al. Lancet 2010;375:

23 Exenatide LA vs glargine Diamant M, et al. Lancet 2010;375: Exenatide LA vs glargine Diamant M, et al. Lancet 2010;375:

24 GLP1 analogen product naam structuur T½ eliminatie frequentie reconstitutie / naald HbA1c vs lira HbA1c vs sita exenatide Byetta exendin-4 analoog 3-4u renaal 2/d - / dun <? liraglutide Victoza humaan analoog ~ VVZ 11-13u mutipel 1/d - / dun > lixisenatide Lyxumia exendin-4 analoog 3-4u renaal 1/d - / dun? = exenatide LA Bydureon exendin-4 analoog polymeer microsferen steady-state 6-7 w renaal 1/w + / dik < > albiglutide Eperzan humane analoog ~albumine 5d multipel 1/w + / dun < = dulaglutide Trulicity 2 humane analogen ~ IgG4 Fc fragment 5d multipel 1/w - / dun = > 24

25 individualiseren metformine + SU + DPP4i of SGLT2 inhibitor of GLP1 analoog of insuline conclusies 25

26 Anno 2015 geïndividualiseerde aanpak verschuiving naar nieuwe producten met beter profiel dan SU DPP4i: effectief, meer en meer gerust over veiligheid SGLT2i: effectief, ook bij gevorderde diabetes (maar niet bij nierinsufficiëntie), breed effect (G, BD) GLP1a: meer en meer vóór insuline of in combinatie met basale insuline ADA-EASD position statement. Inzucchi S, et al. Diabetes Care 2015;38:140 26