Gli inibitori del cotrasportatore SGLT2: efficacia clinica e profilo di tollerabilità

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1 Gli inibitori del cotrasportatore SGLT2: efficacia clinica e profilo di tollerabilità

2 Potenziali conflitti di interesse.

3 Caso Clinico - Marco Uomo di anni 59. Commerciante, viaggia molto in auto per lavoro. Sposato con due figli. Non fumatore, saltuario consumo alcol, poca attività fisica. Familiarità positiva per diabete mellito (un fratello) e per ipertensione arteriosa (il padre). Non eventi CV. Iperteso da 14 aa in trattamento con Losartan + idroclortiazide e amlodipina 5 mg/die. Altri originale trattamenti: in Simvastatina formato ppt, 40 mg/die. si prega di scrivere a Diabete tipo 2 diagnosticato 6 aa fa.

4 Caso Clinico - Marco 6 mesi fa ha eseguito i seguenti esami ematochimici mentre era in trattamento con metformina 850 mg x 2: FPG: 180 mg/dl HbA1c: 8.3 % Trattamento modificato in metformina 850 mg x 3

5 Caso Clinico - Marco Obiettivamente si riscontrano: Sintomi di affaticamento Esame Obiettivo PA: 135/90 mmhg Peso: 102 Kg, altezza 177 cm; Diapositiva Diapositiva BMI: 32.6 preparata preparata Kg/m 2 ; da da Giorgio Giorgio Sesti Sesti e e ceduta ceduta alla alla Societa Societa Italiana Cute, Italiana di Diabetologia. Per avere una versione Articolazioni, di Diabetologia. ROC, ROT: nella Per norma; avere una versione Fegato debordante dall arco costale.

6 Caso Clinico - Marco Esami di laboratorio FPG: 107 mg/dl HbA 1c : 7.9 % Creatinina: 0.9 mg/dl (egfr 92 ml/min per 1.73 m 2 con MDRD). colesterolo totale 195 mg/dl, colesterolo LDL 111 mg/dl, colesterolo HDL 47 mg/dl, trigliceridi 185 mg/dl Societa ALT (IU/mL): Italiana 62 di Diabetologia. Per avere una versione AST (IU/mL): 50 Ecografia epatica: segni di steatosi.

7 Quale target?

8 1. HbA 1c < 6% 2. HbA 1c >6 % e < 7% 3. HbA 1c > 8% e < 10% 4. HbA 1c >7 % e < 8%

9 Come modificare la terapia del Sig. Marco?

10 1. Aggiungere alla terapia con metformina un inibitore di DPP Aggiungere alla terapia con metformina una sulfonilurea. 3. Aggiungere alla terapia con metformina il pioglitazone. 4. Aggiungere alla terapia con metformina un inibitore di SGTL2.

11 T2DM anti-hyperglycaemic therapy: general recommendations Diabetes Care 2012;35: ; Diabetologia

12 T2DM anti-hyperglycaemic therapy: general recommendations SGTL2 Inhibitor Efficacy (â A1c) Hypoglycemia Weight Major side effects Costs high low risk. loss. UTI/GI high

13 Challenges in the management of type 2 diabetes Ø Consider pathophysiological basis Ø Consider efficacy (FPG, PPG, HbA1c) Ø Consider effects on body weight Ø Consider effects on CV risk factors Ø Tolerability and safety

14 Considerazioni nel trattamento del diabete tipo 2 Ø Trattamento su basi fisiopatologiche Ø Efficacia (FPG, PPG, HbA 1c ) Ø Effetto sul peso corporeo Ø Effetti sui fattori di rischio CV Ø Tollerabilità e sicurezza

15 Considerazioni nel trattamento del diabete tipo 2 Ø Trattamento su basi fisiopatologiche Ø Efficacia (FPG, PPG, HbA 1c ) Ø Effetto sul peso corporeo Ø Effetti sui fattori di rischio CV Ø Tollerabilità e sicurezza

16 Expected clinical effects of SGLT2 inhibition based on the mode of action Increased Glucose Excretion Reduced glycaemia Loss of energy (calories) â FPG â PPG â HbA 1c â Body weight Diapositiva Increased preparata da Giorgio Reduced Sesti e ceduta alla Sodium Excretion â Blood Societa Italiana di Diabetologia. sodium Per load avere una versione Pressure SGLT2: sodium-glucose transporter 2 Modified from Abdul-Ghani MA, et al. Endocr Rev. 2011; 32:515 31

17 Effetti clinici attesi dell inibizione di SGLT2 in base al meccanismo d azione Increased Glucose Excretion Reduced glycaemia Loss of energy (calories) â FPG â PPG â HbA 1c â Body weight Diapositiva Increased preparata da Giorgio Reduced Sesti e ceduta alla Sodium Excretion â Blood Societa Italiana di Diabetologia. sodium Per load avere una versione Pressure SGLT2: sodium-glucose transporter 2 Modified from Abdul-Ghani MA, et al. Endocr Rev. 2011; 32:515 31

18 Challenges in the management of type 2 diabetes Ø Consider pathophysiological basis Ø Consider efficacy Ø HbA 1c Ø FPG Ø PPG Ø Consider effects on body weight Diapositiva Ø Consider preparata effects on da CV Giorgio risk factors Sesti e ceduta alla originale Ø Tolerability in formato and safety ppt, si prega di scrivere a

19 Considerazioni nel trattamento del diabete tipo 2 Ø Trattamento su basi fisiopatologiche Ø Efficacia Ø Ø Ø HbA 1c FPG PPG Ø Effetto sul peso corporeo Ø Societa Effetti Italiana sui fattori di Diabetologia. di rischio CV Per avere una versione Ø originale Tollerabilità in formato e sicurezza ppt, si prega di scrivere a

20 Changes from baseline in HbA 1C in Phase 3 Dapagliflozin studies Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg 0-0,1-0,2-0,12-0,3-0,4-0,23-0,3-0,3-0,5-0,6-0,59-0,59-0,7-0,65-0,68-0,7-0,8-0,75-0,79 Diapositiva preparata da Giorgio Sesti -0,82 e ceduta -0,81 alla -0,9-0,85-0,89 Monotherapy -0,91-1 originale Add-on in Met formato ppt, si prega di scrivere a Add-on SU Add-on Insulin 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):

21 Empagliflozin reduced HbA 1c across different background therapy compared with placebo* Phase III pooled efficacy analysis Patients, n BL HbA 1c, % Adjusted mean (SE) difference versus placebo in change from baseline in HbA 1c (%) Pooled Monotherapy MET PIO MET+SU Insulin 78 week originale Empagliflozin in formato 10 mg ppt, QD Empagliflozin si prega 25 di mg scrivere QD a BL, baseline; MET, metformin; PIO, pioglitazone; QD, once daily; RI, renal impairment; SE, standard error; SU, sulphonylurea. *Placebo-corrected values. All statistically significant. 1. Hach T et al. Diabetes :(Suppl 1A); A21 (P69-LB); 2. Roden M et al. Lancet Diabetes Endocrin (3) ; 3. Häring H-U, et al. Diabetes 2013 (Suppl 1) (1092-P); 4. Kovacs C et al. Diab Obes Met (2) ; 5. Häring H-U et al. Diab Care (11): ; 6. Rosenstock J, et al. Diabetologia. 2013;56(Suppl 1);S372 (P931)

22 Sodium glucose cotransporter 2 inhibitors and HbA 1c Fujita Y et al, J Diabetes Invest 2014

23 Efficacy of Canagliflzoin on HbA 1c in placebo-controlled studies * : Change from baseline 8.01% 7.94% 8.13% 7.9% 8.27% 8.35% 7.7% Baseline HbA1c DIA Diet/Ex DIA MET DIA MET/SU DIA MET/Pio DIA insulin DIA SU DIA Any 0,2 0,14 0 0,01 0,04 HbA1c (%) -0,2-0,4-0,17-0,13-0,26-0,6-0,6-0,63-0,72-0,7-0,73-0,8 Societa -0,77 Italiana -0,79 di Diabetologia. Per avere -0,79 una versione -1-1,2-0,85-0,89 P <0.05 vs -0,95 PBO for both % -1, % % % -1, % % % 300 mg vs 100 mg CANA doses -1,06 in all studies -0,03 PBO CANA 100 mg CANA 300 mg * excluding the study in patients with chronic renal impairment

24 Sodium glucose cotransporter 2 inhibitors and FPG Fujita Y et al, J Diabetes Invest 2014

25 Efficacy of canagliflozin vs. glimepiride in T2DM patients inadequately controlled with metformin (CANTATA-SU): Change in FPG Cefalu WT et al. Lancet 2013;382:941-50

26 Changes from baseline in fasting plasma glucose in Phase 3 Dapagliflozin studies 10 5 Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg 3,6 0 mg/dl ,6-5,4-0, , ,6-21,6 Diapositiva -25 preparata da Giorgio -23,4 Sesti e ceduta -23,4 alla Societa -30Italiana di Diabetologia. Monotherapy Per avere una versione -28,8 originale in formato -35 Add-on Met ppt, si prega di scrivere a Add-on Insulin 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):

27 Phase III pooled efficacy and cardiovascular risk factor analysis Placebo-corrected change* from baseline in FPG (mg/dl) Adjusted mean (SE) difference versus placebo in change from baseline in FPG (mg/dl) Pooled data Pooled Mono MET PIO MET+SU BL, baseline; FPG, fasting plasma glucose ; MET, metformin; PIO, pioglitazone; QD, once daily;se, standard error; SU, sulphonylurea. *All statistically significant unless otherwise marked. Empagliflozin 10 mg QD Empagliflozin 25 mg QD Insulin 78 week Mild RI Häring H-U, et al. Diabetes Care 36: , 2013; Hach T, et al., Rosenstock J, et al., Barnett A, et al. Diabetes. 2013;(Suppl 1) (P69-LB, P1102, P1104, respectively); Kovacs C, et al. Diabetes Obes Metab , 2014; Häring H-U, et al. Diabetes Care 37: , 2014

28 Canagliflozin lowers PPG by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion Rate of oral glucose appearance Glucose absorption as a function of time after the standard meal Polidori D et al. Diabetes Care 36: , 2013

29 COME INTERVENIRE? Considerazioni Glicemia a digiuno è a target ma HbA 1c non è a target per l obiettivo terapeutico del sig. Marco. Marco viaggia molto guidando auto con possibili problemi di gestione delle ipoglicemie. Marco è obeso.

30 SGTL2 o sulfonilurea?

31 Efficacy of Canagliflozin vs. Glimepiride over time: Change in HbA 1c analyzed using mixed model repeated measures The coefficient of durability (rate of A 1C rise from Week 26 to Week 104) was lower with CANA 100 and 300 mg than GLIM (0.16%, 0.16%, and 0.37%, respectively) GLIM CANA 100 mg CANA 300 mg Baseline (%) LS mean change (±SE) from baseline (%) LS mean change 0.38% 0.58% 0.68% 0.20% (95% CI: 0.34, 0.06) 0.30% (95% CI: 0.44, 0.16) 1.0 Societa 1.2 Italiana di Diabetologia. Per avere una versione originale in formato Time point ppt, (wk) si prega di scrivere a * N = 1,450 (Baseline); N = 1,377 (Week 8); N = 1,355 (Week 12); N = 1,327 (Week 18); N = 1,264 (Week 26); N = 1,241 (Week 36); N = 1,142 (Week 44); N = 1,079 (Week 52); N = 1,019 (Week 64); N = 889 (Week 78); N = 830 (Week 88); N = 786 (Week 104). 31 Cefalu WT et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun ; Chicago, Illinois, (65-LB).

32 Efficacy of Empagliflozin vs. Glimepiride over 104 weeks : Change in HbA 1c analyzed using mixed model repeated measures Adjusted mean (SE) HbA1c (%) Glimepiride Empagliflozin Difference in change from baseline at week 104: -0.11% (95% CI -0.21, -0.01) p= Glimepiride Empagliflozin Weeks Analyzed patients Ridderstråle M et al., Lancet Diabetes Endocrinol. 2014

33 Canagliflozin vs. glimepiride in T2DM patients inadequately controlled with metformin (CANTATA-SU): Proportion of patients with documented hypoglycemia episodes 33 Cefalu WT et al. Lancet 2013;382:941-50

34 Challenges in the management of type 2 diabetes Ø Consider pathophysiological basis Ø Consider efficacy Ø Consider effects on body weight Ø Consider effects on CV risk factors Ø Tolerability and safety

35 Considerazioni nel trattamento del diabete tipo 2 Ø Trattamento su basi fisiopatologiche Ø Efficacia (FPG, PPG, HbA 1c ) Ø Effetto sul peso corporeo Ø Effetti sui fattori di rischio CV Ø Tollerabilità e sicurezza

36 Sodium glucose cotransporter 2 inhibitors and body weight Fujita Y et al, J Diabetes Invest 2014

37 Percent Change in Body Weight (LOCF)* GLIM CANA 100 mg CANA 300 mg LS mean % change (±SE) from baseline Baseline (kg) LS mean % change 0.9% (0.8 kg) 5.1% (95% CI: 5.6, 4.5) ( 4.3 kg) ([95% CI: 4.8, 3.8]) 3 4.1% 4 ( 3.6 kg) 5.2% 4.2% (95% CI: 5.7, 4.6) Diapositiva 5 preparata da Giorgio Sesti ( 3.6 e kg) ceduta ( 4.4 kg) alla ([95% CI: 4.9, 3.9]) originale in formato Time point (wk) ppt, si prega di scrivere a *N = 1,450 (Baseline); N = 1,425 (Week 4); N = 1,436 (Week 8); N = 1,438 (Weeks 12, 18, 26, 36, 44, 52, 64, 78, 88, and 104). 37 Cefalu WT et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun ; Chicago, (65-LB).

38 Efficacy of Canagliflozin on Body Weight Reduction * % LS Mean Change from Baseline 86.8 kg 87.2 kg 92.8 kg 94.1 kg 97.0 kg 97.0 kg 89.5 kg Baseline body weight DIA Diet/Ex DIA MET DIA MET/SU DIA MET/Pio DIA insulin DIA SU DIA Any Body weight (%) 0-0,5-1 -1,5-2 -0, ,7-2,1-0,1-0,1-2, ,4 P <0.05 vs -2,6 PBO for both -2,8-2,8-3Diapositiva preparata da Giorgio Sesti e ceduta CANA alla doses -3,1 in all studies -3,5 except CANA -3,5 100 mg in -3,8-4 -3,9-3,8-4,5-1,8-0,2-0,6-2,0-0,1 PBO CANA 100 mg CANA 300 mg DIA SU * Only studies enrolling patients with normal/mild chronic renal insufficiency are shown.

39 *p<0.05, **p<0.001 vs placebo CI, confidence interval; Dapa, dapagliflozin; PIO, pioglitazone; SU, sulphonylurea Bristol-Myers Squibb/AstraZeneca briefing document Dapagliflozin: Weight loss after 24 weeks Low-dose monotherapy Monotherapy Add-on to metformin Add-on to SU Add-on to PIO Add-on to insulin Baseline 86.9 kg 90.2 kg kg 81.1 kg 86.3 kg 93.8 kg ΔWeight (kg) with 95% CI ** 2.3** * 2.9** 2.7* 2.7* ** Placebo-corrected mean weight reductions over 24 weeks ranged from 0.46 to 2.16 kg * ** 0.1** 1.0** 1.0** 1.7** Dapa 1.0 mg Dapa 2.5 mg Dapa 5.0 mg Dapa 10.0 mg Placebo 0.0

40 Phase III pooled efficacy and cardiovascular risk factor analysis Placebo-corrected change* from baseline in in body weight Adjusted mean (SE) difference versus placebo in change from baseline in body weight (kg) Pooled data Societa Italiana di Diabetologia. Per avere una versione originale in formato ppt, si prega di scrivere a BL, baseline; FPG, fasting plasma glucose ; MET, metformin; PIO, pioglitazone; QD, once daily; SE, standard error; SU, sulphonylurea. *All statistically significant unless otherwise marked. Empagliflozin 10 mg QD Pooled Mono MET PIO MET+SU Häring H-U, et al. Diabetes Care 36: , 2013; Hach T, et al., Rosenstock J, et al., Barnett A, et al. Diabetes. 2013;(Suppl 1) (P69-LB, P1102, P1104, respectively); Kovacs C, et al. Diabetes Obes Metab , 2014; Empagliflozin 25 mg QD Insulin 78 week Mild RI Häring H-U, et al. Diabetes Care 37: , 2014

41 Changes in Body Composition: Canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU) DXA Analysis Subgroup N=312 Total fat mass measurement Total lean mass measurement LS mean change (Kg) Diapositiva preparata da Giorgio Sesti e ceduta alla LS mean change (Kg) Societa Societa Italiana Italiana di di Diabetologia. Diabetologia. Per Per avere avere una una versione versione originale in formato Glimepiride ppt, si prega di scrivere a Canagliflozin 100 gg Canagliflozin 300 mh Cefalu WT et al. Lancet 2013;382:941-50

42 Changes in Body Composition: Canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU) CT measurements N=312 Subcutaneous adipose tissue Visceral adipose tissue. LS mean percentage LS mean change percentage originale in formato Glimepiride ppt, si prega di scrivere a Canagliflozin 100 gg Canagliflozin 300 mh Cefalu WT et al. Lancet 2013;382:941-50

43 SGTL2 o DPP-4 inibitori?

44 Canagliflozin: HbA 1c reduction vs sitagliptin as add-on to metformin at 52 weeks LS mean change in HbA1c from baseline (%) Time point (weeks) Mean difference from baseline HbA 1c at 52 weeks SITA 100 mg -0.73% CANA 100 mg -0.73% CANA 300 mg -0.88% Difference vs SITA CANA 100mg 0.00% % CI -0.12, 0.12 CANA 300mg -0.15% 95% CI -0.27, originale in formato ppt, 34 si 42 prega 52 di scrivere a Vertical bars represent standard error. CANA, canagliflozin; CI, confidence interval; LS, least squares; SITA, sitagliptin. Lavalle-González FJ, et al. Diabetologia 56: , 2013

45 Efficacy of Canagliflozin vs. sitagliptin in T2DM patients inadequately controlled with metformin plus Sulfonylurea: Change in HbA1c Baseline (%) 8.1 Sitagliptin 100 mg Canagliflozin 300 mg LS mean change (±SE) from baseline (%) LS mean change 0.66% 1.03% Societa -1.2 Italiana di Diabetologia. Per avere una versione Time point (wk) 0.37% (95% CI: 0.50, 0.25) LOCF, last observation carried forward ; SITA, sitagliptin; CANA, canagliflozin; LS, least squares; SE, standard error; CI, confidence interval. Schernthaner G et al. Diabetes Care 36: ,

46 Canagliflozin: FPG reduction vs sitagliptin as add-on to metformin at 52 weeks 0 SITA 100 mg CANA 100 mg CANA 300 mg LS mean change in FPG from baseline (mmol/l) Time point (weeks) 1.0 mmol/l 1.5 mmol/l a 2.0 mmol/l b Vertical bars represent standard error. a Difference in LS mean change vs SITA: 0.5 mmol/l; p < b Difference in LS mean change vs SITA: 1.0 mmol/l; p < CANA, canagliflozin; CI, confidence interval; FPG, fasting plasma glucose; LS, least squares; SITA, sitagliptin. Lavalle-González FJ, et al. Diabetologia 56: , 2013

47 Esistono differenze tra SGTL2 inibitori e DDP-4 inibitori in termini di riduzione della glicemia postprandiale? 1. No inibitori di SGTL2 e inibitori di DPP-4 hanno la stessa efficacia su PPG. 2. Gli inibitori di DPP-4 sono più efficaci degli inibitori di SGTL2 su PPG. 3. Gli inibitori di SGTL2 sono più efficaci degli inibitori di DPP-4 su PPG. 4. Nessuno dei due farmaci agisce su PPG.

48 Efficacy of Canagliflozin vs. sitagliptin in T2DM patients inadequately controlled with metformin Plus Sulfonylurea: Change in FPG and PPG FPG 2-hour PPG (Week 52) Baseline (mmol/ 0 L) SITA 100 mg CANA 300 mg LS mean change Baseline (mmol/l) LS mean change (±SE) from baseline (mmol/l) mmol/l 1.3 mmol/l P <0.001 LS mean change (±SE) from baseline (mmol/l) Diapositiva preparata da Giorgio mmol/l Sesti e ceduta alla Societa 2.0 Italiana di Diabetologia. Per avere una versione SITA 100 mg CANA 300 mg Time point (wk) LOCF, last observation carried forward; FPG, fasting plasma glucose; PPG, postprandial glucose; SITA, sitagliptin;cana, canagliflozin; LS, least squares; SE, standard error Schernthaner G et al. Diabetes Care 36: ,

49 Canagliflozin lowers PPG by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion Rate of oral glucose appearance Glucose absorption as a function of time after the standard meal Polidori D et al. Diabetes Care 36: , 2013

50 Esistono differenze tra DDP-4 inibitori e SGTL2 inibitori in termini di riduzione del peso corporeo? 1. Nessuno dei due farmaci ha effetti sul peso. 2. Gli inibitori di DPP-4 sono più efficaci degli SGTL2 inibitori per indurre una riduzione di peso. 3. Gli SGTL2 inibitori sono più efficaci degli inibitori di DPP-4 per indurre una riduzione di peso. sul peso. 4. Gli inibitori di DPP-4 e SGTL2 inibitori hanno la stessa efficacia

51 Canagliflozin: body weight reduction vs sitagliptin as add-on to metformin at 52 weeks SITA 100 mg CANA 100 mg CANA 300 mg 0 LS mean % change in body weight from baseline % ( 1.2 kg) Diapositiva preparata da Giorgio Sesti e ceduta 3.8% ( 3.3 alla kg) 4 4.2% ( 3.7 kg) Vertical bars represent standard error. a Difference in LS mean change vs SITA: 2.4%; p < b Difference in LS mean change vs SITA: 2.9%; p < CANA, canagliflozin; LS, least squares; SITA, sitagliptin. Time point (weeks) Lavalle-González FJ, et al. Diabetologia 56: , 2013

52 Challenges in the management of type 2 diabetes Ø Consider pathophysiological basis Ø Consider efficacy Ø Consider effects on body weight Ø Consider effects on CV risk factors Ø Tolerability and safety

53 Considerazioni nel trattamento del diabete tipo 2 Ø Trattamento su basi fisiopatologiche Ø Efficacia (FPG, PPG, HbA 1c ) Ø Effetto sul peso corporeo Ø Effetti sui fattori di rischio CV Ø Tollerabilità e sicurezza

54 Efficacy of Canagliflozin on Systolic Blood Pressure: Change from Baseline-Placebo-controlled Phase 3 Studies * p<0.001; ** p<0.05 Based on ANCOVA models, data prior to rescue (LOCF) BL Mean SBP (mmhg) 8,0 Placebo-subtracted LS Mean Change in Systolic BP (mmhg) (95% CI) 6,0 4,0 2,0 0,0-2,0 Monotherapy (DIA3005) N = Metformin (DIA3006) N = 1284 Add-on combinations with SU (DIA3008) N = 127 Met/SU (DIA3002) N = 469 Met/Pio (DIA3012) N = 342 Insulin (DIA3008) N = ,0-1,6-2.6* -6,0-2,2-3.7* * * -8,0-4.1 Diapositiva -5.4* preparata -6.6* da Giorgio Sesti e ceduta alla -10, * -7.9* -12,0 No clinically meaningful changes in pulse rate Current Therapy in Older Subjects (DIA3010) N = 714 Societa Italiana di Diabetologia. CANA 100 mg CANA Per 300 avere mg una versione Pulse rate originale (bpm) in formato ppt, si prega di scrivere a 0.22 LS mean change 131.1

55 Empagliflozin reduced SBP across different background therapy compared with placebo* Phase III pooled efficacy analysis Adjusted mean (SE) difference versus placebo in change from baseline in SBP (mmhg) Pooled Monotherapy MET PIO MET+SU Insulin 78 week BL, baseline ; MET, metformin; PIO, pioglitazone; QD, once daily; RI, renal impairment; SBP, systolic blood pressure; SE, standard error; SU, sulphonylurea. *All statistically significant except when marked as. 1. Hach T et al. Diabetes :(Suppl 1A); A21 (P69-LB); 2. Roden M et al. Lancet Diabetes Endocrin (3) ; 3. Häring H-U, et al. Diabetes 2013 (Suppl 1) (1092-P); 4. Kovacs C et al. Diab Obes Met (2) ; 5. Häring H-U et al. Diab Care (11): ; 6. Rosenstock J, et al. Diabetologia. 2013;56(Suppl 1);S372 (P931) originale Empagliflozin in formato 10 mg ppt, QD Empagliflozin si prega 25 di mg scrivere QD a Mild RI

56 Effects of sodium-glucose co-transporter 2 inhibitors on systolic blood pressure: Meta-analysis Baker WL et al. J Am Soc Hypertens 8: , 2014

57 Effects of sodium-glucose co-transporter 2 inhibitors on diastolic blood pressure: Meta-analysis Baker WL et al. J Am Soc Hypertens 8: , 2014

58 Vasilakou D et al Ann Intern Med 159: , 2013

59 Change in lipid levels: Canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU) Adjusted mean (SE) change (mg/dl) Glimepiride Canagliflozin 100 Canagliflozin Societa Italiana LDL-C di Diabetologia. HDL-C Triglyceride Per avere una LDL/HDL-C versione ratio originale in formato ppt, si prega di scrivere a Cefalu WT et al. Lancet 2013;382:941-50

60 HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; QD, once daily; SE, standard error. *p < 0.05 ; **p < 0.001; ***p = versus placebo. LDL/HDL-C ratio does not have units. ANCOVA. TS. Hach T et al. Diabetes :(Suppl 1A): A21 (P69-LB). Change in lipids from baseline at Week 24 Phase III pooled efficacy analysis Adjusted mean (SE) change (mg/dl) *** Placebo (n = 825) Empagliflozin 10 mg QD (n = 830) Empagliflozin 25 mg QD (n = 822) 3.00 ** 3.00 ** * LDL-C HDL-C Triglyceride LDL/HDL-C Total ratio cholesterol ** 6.00

61 Vasilakou D et al Ann Intern Med 159: , 2013

62 Cardiovascular outcomes trials for GLP-1, DPP4i and SGLT2i products SUSTAIN 6 (Semaglutide, GLP-1) n=3,260; duration ~2.8 yrs end Q NCT (Omarigliptin, QW DPP4i) n=4,000; duration ~3 yrs end Q REWIND (Dulaglutide, QW GLP-1) n=9,622; duration ~8 yrs end Q CANVAS (Canagliflozin, SGLT2i) n=4,414; duration 4+yrs end Q EXAMINE (Alogliptin, DPP4i) n=5,380; follow-up ~1.5 yrs end Q RESULTS ELIXA (Lixisenatide, GLP-1) n=6,000; duration ~4 yrs end Q EMPA-REG OUTCOME (Empagliflozin, SGLT2) n=7,000; duration ~4 yrs end Q FREEDOM-CVO (ITCA 650, GLP-1 in DUROS) n=2-3,000; duration ~2 yrs end Q Pre-approval Pre + post approval SAVOR TIMI-53 (Saxagliptin, DPP4i) n=16,492; follow-up ~2 yrs end Q RESULTS Post-approval Other LEADER (Liraglutide,GLP-1) n=9,340; duration yrs end Q EXSCEL (Exenatide QW GLP-1) n=9,500; duration ~5.5 yrs end Q DECLARE-TIMI-58 (Dapagliflozin, SGLT2i) n=17,150; duration~6 yrs end Q Diapositiva ORIGIN preparata da TECOS Giorgio Sesti CARMELINA e ceduta CAROLINA alla (Glargine, basal insulin) (Sitagliptin, DPP4i) (Linagliptin, DPP4i) (Linagliptin, DPP4i vs SU) n=12,500; duration >5yrs n=14,000; duration ~4-5yrs n= 8,300; duration ~4 yrs n= 6,000; duration ~8 yrs end Q RESULTS end Q end Q end Q Source: ClinicalTrials.gov (October 2013) and LLY Investor call ADA 2013

63 Challenges in the management of type 2 diabetes Ø Consider pathophysiological basis Ø Consider efficacy Ø Consider effects on body weight Ø Consider effects on CV risk factors Ø Tolerability and safety Ø Hypoglycemia Diapositiva Ø Volume-related preparata adverse da Giorgio events/dehydration Sesti e ceduta alla Ø originale Renal in function formato ppt, si prega di scrivere a Ø Genito-urinary infections

64 Considerazioni nel trattamento del diabete tipo 2 Ø Trattamento su basi fisiopatologiche Ø Efficacia (FPG, PPG, HbA 1c ) Ø Effetto sul peso corporeo Ø Effetti sui fattori di rischio CV Ø Tollerabilità e sicurezza Ø Ipoglicemia Societa Ø Eventi Italiana avversi di Diabetologia. legati al volume/disidratazione Per avere una versione Ø Funzione renale Ø Infezioni genito-urinarie

65 Considerazioni nel trattamento del diabete tipo 2 Ø Trattamento su basi fisiopatologiche Ø Efficacia (FPG, PPG, HbA 1c ) Ø Effetto sul peso corporeo Ø Effetti sui fattori di rischio CV Ø Tollerabilità e sicurezza Ø Ipoglicemia Societa Ø Eventi Italiana avversi di Diabetologia. legati al volume/disidratazione Per avere una versione Ø Funzione renale Ø Infezioni genito-urinarie

66 Phase III pooled safety and tolerability analysis Low incidence of hypoglycaemia with empagliflozin if used without SU Percentage of patients with confirmed hypoglycaemia (%) Placebo Pooled data excl. SU background Pooled data Empagliflozin 25 mg QD 0.0 Monotherapy MET, metformin; PIO, pioglitazone; QD, once daily; SU, sulphonylurea. Add-on to MET Empagliflozin 10 mg QD Add-on to PIO Pooled data incl. SU background Add-on to MET + SU Placebo Empagliflozin originale 10 mg QD in 1.2 formato 0.4 ppt, 1.8 si prega 1.2 di scrivere 5.2 a 16.1 Empagliflozin 25 mg QD Pooled data adapted from Hach T, et al. Abstract no 69-LB; 2. Individual studies adapted from abstracts 1085, Presented at the 73rd Scientific Sessions of the American Diabetes Association. June 21 25, Chicago, Illinois; Kovacs C, et al. Diabetes Obes Metab , 2014; Häring H-U, et al. Diabetes Care 37: , 2014

67 Vasilakou D et al Ann Intern Med 159: , 2013

68 Challenges in the management of type 2 diabetes Ø Consider pathophysiological basis Ø Consider efficacy Ø Consider effects on body weight Ø Consider effects on CV risk factors Ø Tolerability and safety Ø Hypoglycemia Diapositiva Ø Volume-related preparata adverse da Giorgio events/dehydration Sesti e ceduta alla Ø originale Renal in function formato ppt, si prega di scrivere a Ø Genito-urinary infections

69 Considerazioni nel trattamento del diabete tipo 2 Ø Trattamento su basi fisiopatologiche Ø Efficacia (FPG, PPG, HbA 1c ) Ø Effetto sul peso corporeo Ø Effetti sui fattori di rischio CV Ø Tollerabilità e sicurezza Ø Ipoglicemia Societa Ø Eventi Italiana avversi di legati Diabetologia. al volume/disidratazione Per avere una versione Ø Funzione renale Ø Infezioni genito-urinarie

70 Summary of overall safety and selected AEs over 104 weeks* GLIM (n = 482) Subjects, n (%) CANA 100 mg (n = 483) CANA 300 mg (n = 485) Any AE 378 (78.4) 354 (73.3) 378 (77.9) AEs leading to discontinuation AEs related to study drug 35 (7.3) 30 (6.2) 46 (9.5) 134 (27.8) 138 (28.6) 159 (32.8) Serious AEs 69 (14.3) 47 (9.7) 47 (9.7) Deaths 2 (0.4) 3 (0.6) 3 (0.6) Osmotic diuresisrelated AEs # 10 (2.1) 28 (5.8) 32 (6.6) Volume-related Diapositiva AEs** preparata 11 (2.3) da Giorgio 8 (1.7) Sesti e ceduta 12 (2.5) alla *All AEs are reported for regardless of rescue medication. Societa Possibly, probably, or very likely related study drug, as assessed by investigators. Italiana di Diabetologia. Per avere una versione GLIM, n = 263; CANA 100 mg, n = 252; CANA 300 mg, n = 241. Including balanitis, balanitis candida, balanoposthitis, genital candidiasis, genital infection fungal, and posthitis. GLIM, n = 219; CANA 100 mg, n = 231; CANA 300 mg, n = 244. # Including dry mouth, micturition urgency, nocturia, pollakiuria, polydipsia, polyuria, thirst, and urine output increased. **Including BP decreased, dehydration, dizziness postural, hypotension, orthostatic hypotension, presyncope, and syncope. 70 Cefalu WT et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun ;Chicago, (65-LB)

71 Volume depletion events occurred at a similar rate between placebo and the empagliflozin groups N, (%) Events consistent with volume depletion QD, once daily; AE, adverse event Data were pooled from three Phase I trials, five dose-finding Phase II trials and 13 Phase IIb/III trials (including extension trials) that investigated empagliflozin 10 mg and empagliflozin 25 mg compared with placebo in patients with T2DM. Analyses were descriptive in nature and performed in the treated set (all patients treated with 1 dose of randomized trial medication. Investigator-defined based on 8 prospectively defined preferred terms: blood pressure (BP) decreased, BP- ambulatory decreased, BP systolic decreased, dehydration, hypotension, orthostatic hypotension, hypovolemia and syncope. Toto R et al. J Am Soc Nephrol. 24: A (SA-PO373) Placebo (n=3522) 10 mg QD (n=3630) Empagliflozin 25 mg QD (n=4602) 49 (1.4) 52 (1.4) 67 (1.5) Hypotension 28 (0.8) 22 (0.6) 25 (0.5) Orthostatic hypotension 6 (0.2) 8 (0.2) 11 (0.2) Blood pressure decrease 1 (<0.1) 0 (0.0) 2 (<0.1) Hypovolemia 2 (<0.1) 0 (0.0) 1 (<0.1) Dehydration 4 (0.1) 9 (0.2) 8 (0.2) Syncope 11 (0.3) 16 (0.4) 22 (0.5) Events consistent with volume depletion leading to discontinuation Events consistent with volume depletion, serious AEs Pooled* safety and tolerability analysis 4 (0.1) 1 (<0.1) 4 (0.1) 12 (0.3) 9 (0.2) 11 (0.2)

72 Vasilakou D et al Ann Intern Med 159: , 2013

73 Challenges in the management of type 2 diabetes Ø Consider pathophysiological basis Ø Consider efficacy Ø Consider effects on body weight Ø Consider effects on CV risk factors Ø Tolerability and safety Ø Hypoglycemia Diapositiva Ø Volume-related preparata adverse da Giorgio events/dehydration Sesti e ceduta alla Ø originale Renal in function formato ppt, si prega di scrivere a Ø Genito-urinary infections

74 Considerazioni nel trattamento del diabete tipo 2 Ø Trattamento su basi fisiopatologiche Ø Efficacia (FPG, PPG, HbA 1c ) Ø Effetto sul peso corporeo Ø Effetti sui fattori di rischio CV Ø Tollerabilità e sicurezza Ø Ipoglicemia Societa Ø Eventi Italiana avversi di Diabetologia. legati al volume/disidratazione Per avere una versione Ø Funzione renale Ø Infezioni genito-urinarie

75 Efficacy of canagliflozin vs. glimepiride in T2DM patients inadequately controlled with metformin (CANTATA-SU): Change in egfr Cefalu WT et al. Lancet 2013;382:941-50

76 Challenges in the management of type 2 diabetes Ø Consider pathophysiological basis Ø Consider efficacy Ø Consider effects on body weight Ø Consider effects on CV risk factors Ø Tolerability and safety Ø Hypoglycemia Diapositiva Ø Volume-related preparata adverse da Giorgio events/dehydration Sesti e ceduta alla Ø originale Renal in function formato ppt, si prega di scrivere a Ø Genito-urinary infections

77 Sfide aperte nel trattamento del diabete tipo 2 Ø Trattamento su basi fisiopatologiche Ø Efficacia (FPG, PPG, HbA 1c ) Ø Effetto sul peso corporeo Ø Effetti sui fattori di rischio CV Ø Tollerabilità e sicurezza Ø Ipoglicemia Societa Ø Eventi Italiana avversi di Diabetologia. legati al volume/disidratazione Per avere una versione Ø Funzione renale Ø Infezioni genito-urinarie

78 Canagliflozin 100 mg and 300 mg were generally well tolerated as add-on to metformin at 52 weeks Placebo (n = 183) SITA 100 mg (n = 366) Subjects, n (%) CANA 100 mg (n = 368) CANA 300 mg (n = 367) Any AE 122 (66.7) 236 (64.5) 266 (72.3) 230 (62.7) AEs leading to discontinuation 8 (4.4) 16 (4.4) 19 (5.2) 12 (3.3) AEs related to study drug 23 (12.6) 72 (19.7) 97 (26.4) 73 (19.9) Serious AEs 7 (3.8) 18 (4.9) 15 (4.1) 12 (3.3) Deaths 1 (0.5) 1 (0.3) 0 1 (0.3) UTI 12 (6.6) 23 (6.3) 29 (7.9) 18 (4.9) Genital mycotic infection Male 1 (1.1) 2 (1.2) 9 (5.2) 4 (2.4) Female 1 (1.1) 5 (2.6) 22 (11.3) 20 (9.9) Osmotic diuresis-related AEs Pollakiuria (increased frequency) 1 (0.5) 2 (0.5) 21 (5.7) 11 (3.0) Societa Polyuria (increased Italiana volume) di Diabetologia. 0 0 Per avere 2 (0.5) una versione 2 (0.5) Volume-related AEs Postural dizziness 1 (0.5) 1 (0.3) 2 (0.5) 2 (0.5) Orthostatic hypotension (0.3) Data presented as n (%). AE, adverse event, CANA, canagliflozin; GLIM, glimepiride; UTI, urinary tract infection; SITA, sitagliptin. Lavalle-González FJ, et al. Diabetologia 56: , 2013

79 Summary of genital mycotic and urinary tract infections over 104 weeks* Genital mycotic infection GLIM (n = 482) Male, 5 (1.9) Female, 6 (2.7) Subjects, n (%) CANA 100 mg (n = 483) 24 (9.5) 32 (13.9) CANA 300 mg (n = 485) 22 (9.1) 38 (15.6) UTI 33 (6.8) 51 (10.6) 42 (8.7) UTI, urinary tract infection. *All AEs are reported for regardless of rescue medication. Including balanitis, balanitis candida, balanoposthitis, genital candidiasis, genital infection fungal, and posthitis. GLIM, n = 219; CANA 100 mg, n = 231; CANA 300 mg, n = 244. Including originale genital infection in fungal, formato vaginal infection, ppt, vulvitis, si vulvovaginal prega candidiasis, di scrivere vulvovaginal a mycotic infection, and vulvovaginitis. 79 Cefalu WT et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun ;Chicago, (65-

80 Vasilakou D et al Ann Intern Med 159: , 2013

81 Phase III pooled safety and tolerability analysis Events consistent with UTI Patients with events consistent with UTI (%) With/without history of chronic/ recurrent UTI 20.8 originale 0.0 in formato ppt, si prega di scrivere a All patients with events With a history of chronic/ Without a history of recurrent UTI chronic/recurrent UTI Placebo (n = 825) Empagliflozin 10 mg QD (n = 830) Empagliflozin 25 mg QD (n = 822) QD, once daily; UTI, urinary tract infection. Kim G, et al. Diabetes. 2013;(Suppl 1) (P74-LB).

82 Phase III pooled safety and tolerability analysis Events consistent with genital infection 60.0 With/without history of chronic/ recurrent genital infection Patients with events consistent with genital infection (%) Societa Italiana di Diabetologia. 3.6 Per avere una 4.0 versione originale 0.0 in formato ppt, si prega di scrivere a All patients with events With history of chronic/ Without history of recurrent genital chronic/recurrent genital infection infection Placebo (n = 825) Empagliflozin 10 mg QD (n = 830) Empagliflozin 25 mg QD (n = 822) QD, once daily; UTI, urinary tract infection. Kim G, et al. Diabetes. 2013;(Suppl 1) (P74-LB).

83 Phase III pooled safety and tolerability analysis Events consistent with genital infection Placebo (n = 825) 10 mg QD (n = 830) Empagliflozin 25 mg QD (n = 822) Patients with events, n (%) 6 (0.7) 35 (4.2) 30 (3.6) Male, n/n (%) 2/424 (0.5) 12/463 (2.6) 5/464 (1.1) Female, n/n (%) 4/401 (1.0) 23/367 (6.3) 25/358 (7.0) Patients without history of chronic or recurrent genital infections, n/n (%) Patients with history of chronic or recurrent genital infections, n/n (%) Number of episodes per patient, n (%) 5/818 (0.6) 33/826 (4.0) 27/809 (3.3) 1/7 (14.3) 2/4 (50.0) 3/13 (23.1) (99.3) 795 (95.8) 792 (96.4) 1 5 (0.6) 30 (3.6) 25 (3.0) 2 1 (0.1) 3 (0.4) 4 (0.5) (0.2) 1 (0.1) Intensity of worst episode, n (%) Mild 5 (0.6) 24 (2.9) 20 (2.4) Societa Moderate Italiana di Diabetologia. 1 (0.1) Per 11 (1.3) avere una 10 versione (1.2) 0 1 (0.1) 2 (0.2) Severe Patients with events leading to treatment discontinuation, n (%) QD, once daily; UTI, urinary tract infection. Kim G, et al. Diabetes. 2013;(Suppl 1) (P74-LB).

84 Kim G, et al. Diabetes. 2013;(Suppl 1) (P74-LB). Events consistent with UTI stratified by gender Phase III pooled safety and tolerability analysis Male versus female patients Patients with events consistent with UTI (%) Diapositiva preparata da Giorgio Sesti e ceduta alla 0.0 QD, once daily; UTI, urinary tract infection Placebo (n=825) Empagliflozin 10 mg QD (n=830) Empagliflozin 25 mg QD (n=822) All patients with events Female patients Male patients

85 Kim G, et al. Diabetes. 2013;(Suppl 1) (P74-LB). Events consistent with genital infection stratified by gender Phase III pooled safety and tolerability analysis Male versus female patients Patients with events consistent with genital infection (%) Diapositiva preparata da Giorgio 1.0 Sesti e ceduta alla 0.0 All patients with events Female patients Male patients QD, once daily; UTI, urinary tract infection. Placebo (n=825) Empagliflozin 10 mg QD (n=830) Empagliflozin 25 mg QD (n=822)

86 Flow-chart per la terapia del diabete mellito di tipo 2 Diapositiva Diapositiva preparata preparata da da Giorgio Giorgio Sesti Sesti e e ceduta ceduta alla alla Societa Societa Italiana Italiana di di Diabetologia. Diabetologia. Per Per avere avere una una versione versione

87 Caso Clinico - Marco A Marco veniva proposta terapia con: Metformina 850 mg x 3 + Canagliflozin Al primo controllo dopo 4 mesi HbA 1c = 7,1 % FPG = 98 mg/dl PPG = mg/dl PA: 125/85 mmhg Diapositiva Diapositiva preparata preparata da da Giorgio Giorgio Sesti Sesti e e ceduta ceduta alla alla Societa Societa Italiana Italiana di di Diabetologia. Diabetologia. Per Per avere avere una una versione versione Peso originale -2.4 in Kg formato ppt, si prega di scrivere a Nessun episodio ipoglicemia sintomatica. Nessun effetto indesiderato della terapia.

88 SGLT2-inhibitors: For which Patients? At What Stage of the Disease? Injections Step 4 Yes: on the top of insulin to reduce its doses Lifestyle changes Two oral agents Step 3 Yes: in dual therapy Step 2 (particularly in obese or Step 1 Diabetes progression Yes: in triple oral therapy (when you want to avoid injections) hypertensive patients) Societa Italiana One di oral Diabetologia. Per avere una versione originale in agent formato ppt, si prega di scrivere a No in monotherapy

89 THANK YOU! Now it s time for discussion. Sesti lecture