Nuovi approcci alla terapia personalizzata del paziente con diabete di tipo 2 Riccardo C. Bonadonna

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1 Nuovi approcci alla terapia personalizzata del paziente con diabete di tipo 2 Riccardo C. Bonadonna Dipartimento di Medicina Università di Verona e AOUI di Verona

2 Presenter Disclosure Information Riccardo C. Bonadonna Research Support: None Speaker s Bureau: Sanofi Aventis, MSD, BMS, Eli Lilly Ltd Board Member/Advisory Panel: MSD, Eli Lilly Ltd, Amgen, Sanofi Aventis Stock/Shareholder: None Consultant: None Employee: None Other: None

3 The position statement of ADA and EASD Individualisation of treatment is the cornerstone of success Patient-centered care is an approach to providing care that is respectful of and responsive to individual preferences, needs, and values and ensuring that patient values guide all clinical decisions Inzucchi SE et al.; Diabetologia 2012

4 Alcuni bisogni di questo paziente Rieducazione nutrizionale Rieducazione motoria Tre cali: Peso Appetito Glicemia post-prandiale Limitare il rischio delle ipoglicemie Limitare il numero di iniezioni Dipendenza psicofisica

5 A classification of GLP-1 RAs Comparison of prandial vs. non-prandial GLP-1 receptor agonists Parameters Prandial GLP-1 Ras (short-acting, exendin-4 derived) Non-prandial GLP-1 Ras (short-acting, GLP-1 derived*) Compounds Exenatide, Lixisenatide Albiglutide*, Dulaglutide*, Exenatide-LAR, Liraglutide* Half-life 2-5h 12h-several days Effects Fasting blood glucose levels Modest reduction Strong reduction Post-prandial glucose levels Strong reduction Modest reduction Fasting insulin secretion Modest stimulation Strong stimulation Post-prandial insulin secretion Reduction Modest stimulation Glucagon secretion Reduction Reduction Gastric emptying rate Deceleration No effect Blood pressure Reduction Reduction Heart rate No effect or small increase (0-2 bpm) Moderate increase (2-5 bpm) Body weight reduction 1-5kg 2-5kg Induction of nausea 20-50%, attenuates slowly (weeksmany months) 20-40%, attenuates quickly (~4-8 weeks) Meier J et al.; Nat Rev Endocrinol 2012

6 Time (min) Lixisenatide prolongs gastric emptying time and blunts aftermeal glucose excursions in patients with type 2 diabetes Placebo Lixisenatide P=0.003 Lixisenatide vs Placebo Change from baseline in gastric emptying t 1/2 Lorenz M et al.; Regulat Pept, 2013

7 Post-breakfast AUC (h. pmol/l) Post-breakfast change AUC (h. pmol/l) Lixisenatide decreases the absolute amounts of insulin and glucagon released after breakfast in patients with type 2 diabetes Placebo Lixisenatide P=0.004 Lixisenatide vs Placebo Placebo Lixisenatide P=0.007 Lixisenatide vs Placebo Insulin AUC 0 Delta Glucagon AUC Lorenz M et al.; Regulat Pept, 2013

8 Domanda Exenatide e lixisenatide sono due farmaci sovrapponibili?

9 Lixisenatide vs Exenatide. The GetGoal-X study. Lixisenatide vs Exenatide in addition to: 1 wk 20 µg qd Metformin 1.5 g/day Lixisenatide Key Inclusion Criteria: Type 2 DM HbA 1c 7.0% 10.0% Stratified by A1c (<8.0%/ 8.0%) 1 wk 4 wks 15 µg 10 µg R 5 µg bid All patients: background treatment at a stable dose Diet & lifestyle counselling every 3 months from D1 Screening Single-blind run-in 10 µg bid Exenatide Main double-blind treatment period Variable extension period 3 d F/U W-3 W-1 W0 W4 W12 W24 W44 Rosenstock J et al.; Diabetes Care 2013 Primary endpoint End of treatment F/U Visit

10 Lixisenatide has similar glucose lowering efficacy and somewhat less weight lowering efficacy compared to exenatide. The GetGoal-X study. Glucose control Body weight Rosenstock J et al.; Diabetes Care 2013

11 Lixisenatide causes nausea and hypoglycemia significantly less frequently than exenatide. The GetGoal-X Study. P < 0.05 or less for Lixisenatide vs Exenatide Rosenstock J et al.; Diabetes Care 2013

12 GetGoal program: Lixisenatide in patients uncontrolled on 1 or 2 OADs Placebo-controlled trials Active comparator-controlled trial Basal insulin OADs 2 OADs GetGoal-L Diet and exercise GetGoal-Mono Monotherapy GetGoal-Mono Japan Monotherapy 1 OAD GetGoal-M Add-on to MET GetGoal-F1 Add-on to MET GetGoal-X Add-on to MET GetGoal-S Add-on to SU ± MET GetGoal-P Add-on to pioglitazone ± MET GetGoal-M-Asia Add-on to MET± SU Add-on to basal insulin ± MET GetGoal-L-Asia Add-on to basal insulin ± SU GetGoal-Duo1 Add-on to insulin glargine +MET ±TZD

13 Lixisenatide in aggiunta alla terapia con insulina basale: le evidenze

14 Lixisenatide added to basal insulin. The GetGoal-L study. Lixisenatide vs Placebo in addition to: 1 wk 20 µg Basal insulin ± metformin Lixisenatide Key Inclusion Criteria: Type 2 DM HbA 1c 7.0% 10.0% Stratified by A1c (<8.0%/ 8.0%) 1 wk 15 µg 10 µg R 10 µg All patients: background treatment at a stable dose Diet & lifestyle counselling every 3 months from D1 1 wk 15 µg 1 wk Screening Single-blind run-in 20 µg Placebo Main double-blind treatment period Variable extension period 3 d F/U W-3 W-1 W0 W4 W12 W24 W44 Riddle MC et al.; Diabetes Care 2013 Primary endpoint End of treatment F/U Visit

15 Lixisenatide added on basal insulin (±metformin) reduces HbA 1c, body weight and daily insulin dose. The GetGoal-L study Riddle MC et al.; Diabetes Care 2013

16 After-meal glucose excursion (mmol/l) Lixisenatide added on basal insulin (± metformin) reduces post-prandial glucose excursions. The GetGoal-L study P< Lixisenatide vs Placebo Basal insulin (±metformin) + placebo (n=204) Basal insulin (±metformin) + lixisenatide (n=194) -4-6 Baseline Week 24 LOCF LS mean change Riddle MC et al.; Diabetes Care 2013

17 Lixisenatide added to basal insulin + metformin. The GetGoal-Duo study. Lixisenatide in addition to:: 1 wk 20 µg Basal insulin + metformin (±TZDs) Lixisenatide Key Inclusion Criteria: Type 2 DM HbA 1c 7.0% 10.0% Stratified by A1c (<8.0%/ 8.0%) 1 wk 15 µg 10 µg R 10 µg All patients: background treatment at a stable dose Diet & lifestyle counselling every 3 months from D1 1 wk 15 µg 1 wk Screening Single-blind run-in 20 µg Placebo Main double-blind treatment period Variable extension period 3 d F/U W-3 W-1 W0 W4 W12 W24 W44 Riddle MC et al.; Diabetes Care 2013 Primary endpoint End of treatment F/U Visit

18 Lixisenatide added on basal insulin + metformin reduces HbA1c, body weight and insulin doses. The GetGoal-Duo study Riddle MC et al.; Diabetes Care 2013

19 After-meal glucose excursion (mmol/l) Lixisenatide added on basal insulin + metformin reduces post-prandial glucose excursions. The GetGoal-Duo study P< Lixisenatide vs Placebo Basal insulin + metformin (±TZDs) + placebo (n=211) Basal insulin + metformin (±TZDs) + lixisenatide (n=194) -4-6 Baseline Week 24 LOCF LS mean change Riddle MC et al.; Diabetes Care 2013

20 Conclusioni Gli agonisti del GLP1-R sono ulteriormente classificabili in agonisti prandiali (breve durata d azione, derivati da exendin-4) e non-prandiali (lunga durata d azione) Lixisenatide ed exenatide, i due GLP1-R prandiali, presentano sensibili differenze in effetti terapeutici e collaterali e in facilità d uso Lixisenatide, in virtù dei suoi spiccati effetti nel periodo post-prandiale, si presta a essere usata in combinazione/aggiunta all insulina basale per raggiungere un controllo ottimale anche delle iperglicemie post-prandiali, con ulteriori effetti benefici su peso, appetito e pressione arteriosa

21 Grazie per l attenzione

22 % Area Weight (g) Human pancreas and incretin therapy Nondiabetic Controls DM DM on Incretins Nondiabetic Controls 2,5 DM DM on Incretins , , Beta cell area Alpha cell area 0 Pancreas weight Butler AE et al.; Diabetes (in press)

23 Human pancreas and incretin therapy. Diabetic patients not on incretin therapy ID Code Age Diabetes duration Age at diabetes diagnosis BMI Rx Cause of Death Insulin Gunshot None CV Met ICH/Stroke None ICH/DKA None ICH/DKA Met Asphyxia Met ICH/Stroke Insulin ICH/Stroke Insulin CV None Seizure None Meningitis Insulin ICH/Stroke Butler AE et al.; Diabetes (in press)