Fixed-Dose Combination: un Vantaggio o uno Svantaggio? Luigi Laviola

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1 Fixed-Dose Combination: un Vantaggio o uno Svantaggio? Luigi Laviola Medicina Interna, Endocrinologia, Andrologia e Malattie Metaboliche Dipartimento dell Emergenza e dei Trapianti di Organi Roma, 31 ottobre 2017

2 Il prof. Luigi Laviola dichiara di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche: Boehringer Ingelheim, Astra Zeneca, Johnson&Johnson, Lilly Italia, Medtronic, MOVI, Novo Nordisk, Roche, Sanofi Aventis, Takeda (consulenza scientifica) Bayer, Boehringer Ingelheim, Astra Zeneca, Guidotti, Johnson&Johnson, Lilly, Medtronic, Menarini, Movi, MSD, Novartis, Novo Nordisk, Roche, Sanofi-Aventis, Takeda (relazioni a convegni, supporto per partecipazione a congressi)

3 Dobbiamo proprio usare una combinazione precostituita? Metformina 400 mg + glibenclamide 2,5 mg Metformina 400 mg + glibenclamide 2,5 mg Metformina 400 mg + glibenclamide 2,5 mg

4 Perché una combinazione precostituita? Contro? Pro?

5 Combinazione Fissa Insulina Basale GLP-1 RA Degludec/liraglutide (IDegLira) 100 unità di insulina degludec e 3,6 mg di liraglutide. Una dose unitaria contiene 1 unità di insulina degludec e 0,036 mg di liraglutide. La dose piena di liraglutide (1,8 mg) si ottiene con 50 unità di basale. 1.8 mg Glargine/lixisenatide (IGlarLixi) 2 formulazioni: 100 unità glargine + 50 mcg lixisenatide (rapporto 2:1) La dose piena di lixisenatide (20 mcg) si ottiene con 40 unità di insulina Liraglutide Max dose 100 unità glargine + 33 mcg lixisenatide (rapporto 3:1) La dose piena di lixisenatide (20 mcg) si ottiene con 60 unità di insulina Insulin degludec 50 U

6 Quando considerare una combinazione fissa basale GLP-1 RA? Necessità di intensificare una terapia iniettiva: Pazienti già in terapia con insulina basale + OAD

7 DUAL II: study design Patients with type 2 diabetes (N=398) Randomised 1:1 Double-blind IDegLira + Met (n=199) IDeg + Met (n=199) Titrate to target FPG 4 5 mmol/l Starting dose: 16 dose steps/units Maximum dose 50 dose steps / 50 units 0 26 weeks Titration algorithm: IDegLira and IDeg Inclusion criteria Type 2 diabetes HbA 1c % BMI 27 kg/m 2 Age 18 years Basal insulin (20 40 U) + metformin ± SU or glinides Mean fasting PG Dose change mmol/l dose steps or U < > Buse et al. Diabetes Care 2014

8 DUAL II: HbA1c over time IDegLira (n=199) IDeg (n=199) HbA 1c (%) 8.0% 6.9% 0.0 Time (weeks) Buse et al. Diabetes Care 2014

9 DUAL II: percentage of patients to target IDeg (n=199) Patients reaching glycaemic targets (%) p< p< IDegLira (n=199) HbA 1c <7.0% HbA 1c 6.5% Buse et al. Diabetes Care 2014

10 DUAL II: 9P-SMBG - Post-prandial PG increment Week 0 Plasma glucose (mmol/l) 0.0 * * * * * * * * * IDeg IDegLira Week 26 IDeg IDegLira *p<0.05 p=ns p= p=ns Week 26 PG increment (mmol/l) IDeg IDegLira p-values from an ANCOVA Breakfast Lunch Evening meal Buse et al. Diabetes Care 2014

11 DUAL II: confirmed hypoglycaemia Cumulative episodes per subject Rate ratio: 0.66 p=0.13 IDegLira (n=199) IDeg (n=199) Time (weeks) IDegLira IDeg HbA 1c (%) Buse et al. Diabetes Care 2014

12 Buse et al. Diabetes Care 2014 DUAL II: Insulin Dose and Body Weight Daily Insulin Dose Body Weight

13 Riassunto: IDegLira vs IDeg Riduzione HbA1c Maggior numero di pazienti a target Miglior profilo glicemico Calo ponderale Stessa dose di insulina (circa 45 unità) Rischio di ipoglicemia simile Effetti collaterali in linea con GLP-1 RA (più lievi)

14 DUAL V Subjects with T2DM (N=557) IDegLira + metformin (n=278) IGlar + metformin (n=279) IDegLira Starting dose: 16 dose steps Maximum dose: 50 dose steps IGlar Starting dose: Pre-trial dose Maximum dose: None Screening Visit 1 randomization Visit 2 End of trial Visit 28 Follow-up Visit 29 Week Inclusion criteria T2DM Metformin + IGlar (20 50 units) HbA 1c 7 10% Age 18 years BMI 40 kg/m 2 Randomized 1:1 Open label Mean FPG a Dose change mmol/l mg/dl dose steps/units <4.0 < >5.0 >90 +2 Lingvay I et al. JAMA 2016

15 DUAL V: Change in HbA 1c over time Time (weeks) 0, Change in HbA 1c (%) -0,4-0,8-1,2-1,6-2,0 Treatment difference: 0.59% p< ,4 IDegLira IGlar HbA 1c (%) IDegLira (n=278) IGlar (n=279) Lingvay I et al. JAMA 2016

16 DUAL V: Subjects achieving HbA1c targets Proportion of subjects achieving target HbA 1c (%) ,6 Odds ratio: 3.45 p< ,0 55,4 Odds ratio: 3.29 p< ,8 IDegLira (n=278) IGlar (n=279) 0 HbA 1c <7% HbA 1c 6.5% Lingvay I et al. JAMA 2016

17 DUAL V: FPG over time FPG (mmol/l) 9,5 9,0 8,5 8,0 7,5 7,0 6,5 6,0 5, ,0 IDegLira (n=278) IGlar (n=279) 6.1 mmol/l 6.1 mmol/l Time (weeks) Lingvay I et al. JAMA 2016

18 DUAL V: Daily insulin dose over time units Treatment difference: units p<0.001 Dose (units) % of subjects on IDegLira were at maximum dose of 50 dose steps, of which 68% achieved HbA 1c <7%* 41 units IDegLira (n=278) IGlar (n=279) Time (weeks) Lingvay I et al. JAMA 2016

19 DUAL V: Change in body weight Change in body weight (kg) 2,5 2,0 1,5 1,0 0,5 0,0-0,5-1,0-1,5-2, Time (weeks) IDegLira IGlar Body weight (kg) IDegLira (n=278) IGlar (n=279) Treatment difference: 3.20 kg p<0.001 Lingvay I et al. JAMA 2016

20 DUAL V: Confirmed hypoglycaemia Number of episodes per subject 2,5 2,0 1,5 1,0 0,5 0, Time (weeks) Treatment ratio: 0.43 p<0.001 IDegLira (n=278) IGlar (n=279) Lingvay I et al. JAMA 2016

21 DUAL V: Composite outcomes Proportion of subjects (%) IDegLira IGlar Odds ratio IDegLira/IGlar 95% CI p-value HbA 1c <7% [2.36; 5.05] <0.001 HbA 1c <7%, no weight gain [3.43; 7.83] <0.001 HbA 1c <7%, no hypoglycaemic episodes HbA 1c <7%, no weight gain and no hypoglycaemic episodes [2.24; 4.70] < [3.49; 8.77] <0.001 Lingvay I et al. JAMA 2016

22 DUAL V: Subjects with nausea 10 IDegLira (n=278) IGlar (n=279) 8 Subjects (%) Time (weeks) Lingvay I et al. JAMA 2016

23 Riassunto: IDegLira vs IGlar Riduzione HbA1c Glicemia a digiuno simile Maggior numero di pazienti a target Calo ponderale Riduzione dose di insulina (66 vs 41 unità) Riduzione ipoglicemie Migliore outcome composito Effetti collaterali in linea con GLP-1 RA (più lievi)

24 LixiLan-L: Patients with T2DM not controlled on basal insulin DESIGN: Randomized, open label, parallel-group, 30-week treatment study 7% HbA1c 10% FPG 140 mg/dl 20 U iglar daily dose 50 U iglar ± metformin n=369 T2DM patients with: Basal insulin >6 months Stable dose U/day ± OADs HbA1c 7.5% 10% FPG mg/dl iglar introduced and/or titrated R iglarlixi ± metformin n=367 iglar dose adjusted to SMPG target ( mg/dl) and capped at 60 U/day in both treatment arms 6-week run-in phase Only metformin continued after the start of run-in 30-week treatment period Primary objective: Superiority of iglarlixi over iglar in HbA1c change at Week 30 Aroda VR, et al. Diabetes Care 2016

25 LixiLan-L: Mean change in HbA1c HbA1c over time (%) iglarlixi iglar Baseline iglarlixi iglar 9,0 8,5 8.5% 8.5% 8.1% Week LS mean change LS mean difference 95% CI p-value 0.5 ( 0.6 to 0.4) p< Mean ± SE 8,0 7,5 8.1% 7.5% 7,0 6.9% 6,5 6,0 S BL LOCF Week Aroda VR, et al. Diabetes Care 2016

26 LixiLan-L: Key results LS mean change (%) 0,0-0,2-0,4-0,6-0,8-1,0-1,2 HbA1c Reduction % CI: 0.6, 0.4 p< iglarlixi iglar LS mean change (mmol/l) 0,0-1,0-2,0-3,0-4,0-5,0 2-hour PPG (mmol/l) % CI: 3.9, 2.8 p=ns PPG Reduction Excursion PPG (mmol/l) % CI: 3.9, 2.9 p< Proportion of patients (%) Patients at target HbA1c % CI: 18.9, 32.1 p< HbA1c <7% HbA1c 6.5% iglarlixi iglar % CI: 13.9, 25.6 p< LS mean change (kg) 1,0 0,0-1,0-2,0 Weight change 0.7 0, % CI: 1.8, 0.9 p< Patients with events (%) 40,0 Hypoglycemia 42,5 5,0 4,5 4,0 3,5 3,0 2,5 2,0 1,5 1,0 0,5 0,0 No. of events per patient year 3,0 4,2 Aroda VR, et al. Diabetes Care 2016

27 Lixi Lan L: Composite outcomes Proportion of subjects (%) IGlarLixi IGlar p-value HbA 1c <7% <0.001 HbA 1c <7%, no weight gain <0.001 HbA 1c <7%, no hypoglycaemic episodes <0.001 HbA 1c <7%, no weight gain and no hypoglycaemic episodes <0.001 Aroda VR, et al. Diabetes Care 2016

28 Riassunto: IGlarLixi vs IGlar Riduzione HbA1c Glicemia a digiuno simile, miglior profilo glicemico Maggior numero di pazienti a target Calo ponderale Stessa dose di insulina (47 unità) Rischio di ipoglicemie simile Migliore outcome composito Effetti collaterali in linea con GLP-1 RA (più lievi)

29 Quando considerare una combinazione fissa basale GLP-1 RA? Necessità di intensificare una terapia iniettiva: Pazienti già in terapia con insulina basale + OAD Pazienti già in terapia con GLP-1 RA + OAD

30 DUAL III: IDegLira vs GLP-1 RA Linjawi et al. Diabetes Ther 2017

31 Perché una combinazione precostituita? Miglior compenso glicemico (HbA1c, profilo) Controllo del peso (vs basale) Eventi ipoglicemici correlati alla dose di insulina (pari/ridotta) Migliore outcome composito Limitata flessibilità nella titolazione Dose di GLP-1 RA non massimale ( migliore tollerabilità) Farmaco anti-inerzia!

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33 Meta-analysis of clinical trials comparing basal insulin/glp-1 RA and basal/bolus insulins HbA1c

34 Hypoglycemia Body weight

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36 Clinical trial design and results template 3 6

37 Change in systolic blood pressure over time IDegLira (n=278) IGlar (n=279) 1 Change in systolic blood pressure (mmhg) Treatment difference: 3.57 mmhg p< Time (weeks) Mean observed values with error bars (standard error mean) based on FAS and LOCF imputed data Treatment difference is estimated from an ANCOVA analysis NN ; IDegLira vs. IGlar