XIX Congresso Nazionale AMD Innovazione nella terapia e nei modelli assistenziali. Dipartimento di Medicina Interna Università di Perugia

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1 XIX Congresso Nazionale AMD Innovazione nella terapia e nei modelli assistenziali Gabriele Perriello Dipartimento di Medicina Interna Università di Perugia SITAGLIPTIN: nuove evidenze scientifiche disponibili Roma, 30 maggio 2013

2 Use DPP4-I for treatment of T2DM Meal No DPP-4 inhibitor present Active GLP-1 & GIP Intestinal GLP-1 & GIP release Active GLP-1 & GIP DPP-4 inhibitor present DPP-4 DPP-4 DPP-4 inhibitor GLP-1 & GIP inactive (>80% of pool) DPP-4=dipeptidylpeptidase-4; GLP-1=glucagon-like peptide-1. Ahrén et al. Diabetes Care 2003; 26: ; Deacon et al. Diabetes 1995;44: ; Deacon, Holst. Biochem Biophys Res Commun 2002;294:1 4; Demuth et al. Biochem Biophys Res Commun 2002;296: ; Drucker. Diabetes Care 2003;26: GLP-1 & GIP inactive

3 Chemical structure of sitagliptin (β-amino amide derivative) The first DPP-4 inhibitor approved in 17 th October 2006 for the treatment of type 2 diabetes

4 Substrate-like and Competitive DPP4 Inhibition Substrato naturale (GLP-1, GIP) GLP-1 or GIP + DPP-4 K 1 K -1 K 2 Fast (~1 sec) Complesso GLP-1/DPP-4 + Inattivo GLP-1 o GIP DPP-4 Substrate-like (Vildagliptin, Saxagliptin) + K 1 K -1 K 2 Slow (~1 h) + Inibitore-substrato DPP-4 Complesso Inibitoresubstrato ed enzima DPP-4 Inibitoresubstrato inattivo DPP-4 Inibitore competitivo (Sitagliptin, Linagliptin) Inibitore + DPP-4 DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1. Burkey BF, et al. Poster 0788 presented at EASD 2006; Deacon CF, Holst JJ. Adv Ther. 2009; 26: ; Miller SA, St Onge EL. Ann Pharmacother. 2006; 40: ; Neumiller JJ. J Am Pharm Assoc. 2009; 49: S16 S29; White JR. Clin Diabetes. 2008; 26: Carolyn F Deacon et al. Expert Opin. Investig. Drugs (2010) 19(1): K 1 K -1 Complesso inibitore/enzima DPP-4

5 Selectivity for DPP-4 compared to the DPP gene family (QPP/DPP-2, DPP-8 and DPP-9) QPP*/DPP-2 DPP-8 DPP-9 Linagliptin > 100,000 40,000 > 10,000 Sitagliptin > 5,500 > 2,660 > 5,500 Vildagliptin > 100, Saxagliptin > 50, * Quiescent cell proline dipeptidase Modified from Deacon CF. Diabetes, Obes Metab. 2011;13(1):7 18.

6 6 Absorption, availability, half-life and distribution of DPP4-I sitagliptin 1 vildagliptin 2 saxagliptin 3-4 linagliptin 5 Absorption t max 1 4 h 1.7 h 2 h (4 h for active metabolite) 1.5 h Bioavailability ~87% 85% >75 % 4 ~30% Half-life (t 1/2 ) at clinically relevant dose 12.4 h ~2 3 h 2.5 h (parent) 3.1 h (metabolite) 12 h Distribution 38% protein bound 9.3% protein bound Low protein binding 95% protein bound DPP-4=dipeptidyl peptidase JANUVIA EU-SPC Galvus EU-SPC Onglyza EU-SPC European Public Assessment Report for Onglyza. document_library/epar_-_public_assessment_report/human/001039/wc pdf. Accessed October 14, Christopher R et al. Clin Ther. 2008;30(3):

7 Percentuale di pazienti con DM2 con HbA1c 7.0% al follow-up Grado di scompenso al basale (HbA1c) FUP A 4 MESI EXENATIDE FUP A 8 MESI N. TOT % N TOT % Tra 7.1 e 8.0% , ,6 Tra 8.1 e 9.0% , ,4 9.1% , ,5 Totale , ,3 Grado di scompenso al basale (HbA1c) FUP A 4 MESI SITAGLIPTIN FUP A 8 MESI N TOT % N TOT % Tra 7.1 e 8.0% , ,9 Tra 8.1 e 9.0% , ,8 9.1% , ,1 Totale , ,7 Registro Farmaci Antidiabetici sottoposti a Monitoraggio; 3 report quedrimestrale; marzo 2009

8 Appropriatezza d uso dei farmaci incretinici in Italia Trattamen to In associazione solo con Metformina In associazione solo con Sulfaniluree In associazione con Met+Sulf Senza associazione Totale pazienti Byetta/ Exenatide % Trattamento In associazione con Metformina In associazione con Glitazoni Senze associazione Totale pazienti Januvia Xelevia Tesavel Totale Sitagliptin % Registro Farmaci Antidiabetici sottoposti a Monitoraggio; 3 report quedrimestrale; marzo 2009

9 L associazione Sitagliptin/Metformina ha un effetto additivo sull attività del GLP-1 nativo Data on file MSD

10 Efficacia di Sitagliptin in diverse condizioni sperimentali controllate TRIAL DURATION Δ HbA1c

11 L associazione Sitagliptin/Metformina determina una riduzione di 1,7% della HbA1c a 2 anni HbA 1c (mean change, %) Week Phase* Continuation Phase** Extension Phase*** Time (weeks) Sita 100 mg q.d. (n=50) Met 1000 mg b.i.d. (n=87) Sita = sitagliptin; Met = metformin Sita 50 mg b.i.d. + Met 1000 mg b.i.d. (n=105) *Goldstein et al, Diabetes Care 2007;30: **Williams-Herman et al. Curr Med Res Opin.2009; 25: ***Qi et al, presented at EASD, September 2008

12 Similar Proportions of Patients Receiving Sitagliptin or Glipizide Achieved HbA1c Levels <7.0% at 104 Weeks 12 2-Year Per-Protocol Population (Patients Inadequately Controlled on Metformin) Patients With HbA 1c <7%, % Sitagliptin + metformin Glipizide + metformin n=248 n=256 n=193 n=196 Seck T et al. Int J Clin Pract. 2010;64(5):

13 Sitagliptin vs Glipizide: Weight Change and Incidence of Hypoglycemia Body weight at week 104 Between-groups difference = 2.3 kg (95% CI: 3.0, 1.6) Hypoglycemia over 104 weeks Between-groups difference = 28.8% (95% CI: 33.0, 24.5) LS Mean (±95% CI) Body Weight Change From Baseline, kg Patients With at Least 1 Episode, % Sitagliptin + metformin Glipizide + metformin n=588 n=584 Seck T et al. Int J Clin Pract. 2010;64(5):

14 Effetti metabolici dell aggiunta di sitagliptin all insulina Variazione media della HbA1c dal basale, % - LS(95% CI) ,6 ( 0,7; 0,5) Popolazione FAS a settimana 24 (LOCF) a 0,0 ( 0,1, 0,1) Differenza = 0,6% (P<0.001) Pazienti a goal di HbA 1c, % P<0,001 Sitagliptin (n=305) Placebo (n=312) HbA 1c Goal <7% a Esclusi I dati dopo terapia rescue. FAS=full analysis set; LOCF=last observation carried forward. Vilsbøll T et al. Diabetes Obes Metab. 2010;12(2):

15 Aggiunta di sitagliptin all insulina 15 Ipoglicemie nelle 24 ore Differenza in Peso Corporeo a 24 se1 PazienJ con numero di ipoglicemie >1 (%) P < ,5 8,2 Hypoglycemia Ipoglicemia * Hong ES et al. Diabetes Obes Metab Aggiunta di Sitaglip8n (n=61) Dose Crescente di Insulina (n=63) P <0.05 1,6 4,8 Severe Ipoglicemia Hypoglycemia Severa LS media della variazione in perso corporeo (kg) Δ = 1.7 kg (95% IC, 2.5, 0.5; P <0.05) 0.7 (95% CI, 1.4, 0.1) 1.1 (95% CI, 0.2, 1.8)

16 Sitagliptin in Older Patients With Type 2 Diabetes: Change in HbA1c From Baseline at 24 Weeks 16 Full Analysis Set HbA 1c LS Mean (± SE) Change From Baseline, % % LS mean difference 0.7%; P< % Week Placebo (n=91) Sitagliptin (n=101) Mean baseline HbA 1c =7.71% Mean baseline HbA 1c =7.82% LS=least-squares; SE=standard error. Curr Med Res Opin 2011, vol 27, 5:

17 Sitagliptin vs Glipizide in Patients With Type 2 Diabetes Mellitus and Moderate-to-Severe Chronic Renal Insufficiency: HbA1c Results at 54 Weeks LS Mean Change From Baseline, % (95% CI) Per Protocol Population Baseline HbA 1c ; sitagliptin = 7.8%; glipizide = 7.8% Week Sitagliptin (n=135) CI=confidence interval. a Mean dose of glipizide was 7.7 mg per day. 1. Arjona Ferreira JC et al. Diabetes Care December 17. [Epub ahead of publication]. LS Mean Between-Groups Difference (95% CI): 0.1% ( 0.3, 0.1) Noninferiority: upper bound of the 95% CI around the between-group difference < 0.4%. Glipizide a (n=142) 0.6% 0.8%

18 Symptomatic Hypoglycaemia AEs (-17.1, -4.8) p=0.001 Percent of Patients -1.4 (-4.8, 1.5) -1.5 (-4.2, 0.3) -0.9 (-4.2, 2.0) All Hypoglycaemia AEs Severe Hypoglycaemia AEs Required Non-medical Assistance Required Medical Assistance Δ (95% CI) Sitagliptin (N=210) Glipizide (N=212) 1. Arjona Ferreira JC et al. Diabetes Care December 17. [Epub ahead of publication].

19 Change from Baseline in Body Weight Week 54 Δ = -1.8 kg; p<0.001 Body Weight (kg) Change from Baseline (LS Mean ±SE) Week Sitagliptin Glipizide Body Weight (kg) Change from Baseline (LS Mean, 95% CI) Sitagliptin (N=143) Glipizide (N=148) 1. Arjona Ferreira JC et al. Diabetes Care December 17. [Epub ahead of publication].

20 Exposure-adjusted Incidence Rate of Confirmed, Adjudicated CV Serious AEs and Heart Failure During Week 0 to Week Days Number of Patients With 1 Event/ Patient-Years Follow-up Time (100- Patient-Years Incidence Rate) Difference in Incidence Rate vs. Glipizide Sitagliptin N=64 Glipizide N=65 Estimate (95% CI) Cardiovascular death or sudden death 2/69.2 (2.9) 4/71.0 (5.6) -3.2 (-12.8, 5.2) Cardiovascular death 2/69.2 (2.9) 1/72.1 (1.4) 1.1 Sudden death 0/71.3 (0.0) 3/71.6 (4.2) -4.4 Cardiac events, excluding heart failure 2/69.5 (2.9) 1/72.1 (1.4) 1.9 (-5.1, 10.2) Resuscitated cardiac arrest 1/70.3 (1.4) 1/72.1 (1.4) 0.3 Unstable angina pectoris 1/70.5 (1.4) 0/72.7 (0.0) 1.6 Cerebrovascular events 0/71.3 (0.0) 1/71.7 (1.4) -1.5 (-8.4, 4.0) Stroke, unknown mechanism 0/71.3 (0.0) 1/71.7 (1.4) -1.5 Peripheral vascular events (peripheral arterial thrombosis/thromboembolism) 0/71.3 (0.0) 0/72.7 (0.0) 0.0 (-5.6, 5.5) Heart failure 2/69.9 (2.9) 2/71.0 (2.8) -1.5 (-10.5, 5.8) Arjona Ferreira JC et al. Am J Kidney Dis 2013

21 Safety and tolerability of sitagliptin in T2DM: pooled analysis of 25 clinical studies Engel et al. Diabetes Ther (published online 23 may 2013)

22 7 years later.. Sitagliptin is a highly-selective DPP-4 inhibitor Sitagliptin has a favorable PK/PD profile Sitagliptin combination therapy with metformin provided substantial and durable glucoselowering efficacy Sitagliptin is advantageous when combined to insulin Sitagliptin should be preferred in older individuals Sitagliptin may be safely used in moderate-tosevere chronic renal insufficiency Sitagliptin has been shown to have a favorable risk-to-benefit profile

23 Effect of Sitagliptin on Myocardial Response to Dobutamine Stress in Patients with Coronary Artery Disease A single 100 mg sitagliptin or P and 75 g of glucose Ejection Fraction (%) Read PJ, Circ Cardiovasc Imaging Mar;3(2):

24 LEADER Jan 2016 Liraglutide 1.8 mg QD vs Placebo EXSCEL Mar 2017 Exenatide LAR 2 mg OW vs Placebo ELIXA - Lixisenatide 20 µg QD vs Placebo REWIND - Dulaglutide 20 µg OW vs Placebo SAVOR-TIMI Jun 2015 Saxagliptin 5 mg or 2.5 mg vs Placebo TECOS Dec 2014 Sitagliptin 100 mg (50 mg in CDK) vs Placebo CAROLINA Sep 2018 Linagliptin 5 mg vs Glimepiride 1-4 mg 8,754 CV death, nonfatal MI or stroke; expanded composite CV 9,500 All-cause mortality, MACE, or hospitalization for ACS or heart failure 6,000 Nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or CV death 9,600 Nonfatal MI, nonfatal stroke, or CV death 16,000 CV death, nonfatal MI or ischemic stroke; hospitalization for heart failure, unstable angina pectoris, or coronary Revascularization 14,000 CV-related death, nonfatal MI or stroke, or unstable angina requiring hospitalization 6,000 CV death, non-fatal MI or stroke, or hospitalisation for unstable angina pectoris

25 XIX Congresso Nazionale AMD Innovazione nella terapia e nei modelli assistenziali Gabriele Perriello Dipartimento di Medicina Interna Università di Perugia Grazie per la vostra attenzione Roma, 30 maggio 2013