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2 da fecha  no todos los inh dpp4 son iguales (2)
 

2 da fecha no todos los inh dpp4 son iguales (2)

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Esta ha sido una de las conferencias que mas me ha gustado darla por lo moderno en el tratamiento de la DBM tipo 2 ,con el uso de la Linagliptina completamos el cuadro

Esta ha sido una de las conferencias que mas me ha gustado darla por lo moderno en el tratamiento de la DBM tipo 2 ,con el uso de la Linagliptina completamos el cuadro

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  • 4 inhibidores de DPP-difieren en estructuras moleculares y propiedades farmacológicas, Varios inhibidores de DPP-4 o bien han sido aprobados o están en espera de aprobación para su uso en pacientes con diabetes tipo 2. Las estructuras moleculares y propiedades farmacológicas diferentes a través de la clase de tratamiento inhibidor DPP-4. La sitagliptina es un miembro de la β-fenetilamina clase1 química y tiene una concentración inhibitoria (IC50) de 9,96 ± 1,03 nM en contra de su DPP-4.2 vida media es de aproximadamente 12,4 horas.3 Vildagliptina es un miembro de la clase química cyanopyrrolidine, 4 y tiene una IC50 de 5,28 ± 1,04 nM frente a la DPP-4.2 Se tiene una vida media de aproximadamente 2 a 3 horas.5 La saxagliptina es también un miembro de la class6 cyanopyrrolidine química y su IC50 contra la DPP-4 es 3,37 ± 0,90 nm.2 saxagliptina y su metabolito activo tiene una vida media de 2,5 y 3,1 horas, respectivamente.7 Alogliptina, un miembro de la clase aminopiperidina química, 8 tiene un IC50 de 6,9 ± 1,5 nM, 9 y es su vida media de aproximadamente 12,4 a 21,4 horas.10 Linagliptina, un miembro de la clase química xantina, tiene una IC50 de ~ 1 nM, 11 y su vida media es de aproximadamente 113 a 131 hours.12 Las diferencias en las propiedades farmacológicas no proporcionan ninguna evidencia de diferencias en la eficacia clínica o de seguridad, que deben establecerse a través de ensayos de cabeza a cabeza clínicos. Deshacer cambios DPP-4 Inhibitors Differ in Molecular Structures and Pharmacologic Properties Several DPP-4 inhibitors either are approved or are awaiting approval for use in patients with type 2 diabetes. The molecular structures and pharmacologic properties differ across the DPP-4 inhibitor treatment class. Sitagliptin is a member of the β -phenethylamine chemical class 1 and has an inhibitory concentration (IC 50 ) of 9.96 ± 1.03 nM against DPP-4. 2 Its half-life is approximately 12.4 hours. 3 Vildagliptin is a member of the cyanopyrrolidine chemical class, 4 and has an IC 50 of 5.28 ± 1.04 nM against DPP-4. 2 It has a half-life of approximately 2 to 3 hours. 5 Saxagliptin is also a member of the cyanopyrrolidine chemical class 6 and its IC 50 against DPP-4 is 3.37 ± 0.90 nM. 2 Saxagliptin and its active metabolite have a half-life of 2.5 and 3.1 hours, respectively. 7 Alogliptin, a member of the aminopiperidine chemical class, 8 has an IC 50 of 6.9 ± 1.5 nM, 9 and its half-life is approximately 12.4 to 21.4 hours. 10 Linagliptin, a member of the xanthine chemical class, has an IC 50 of ~1 nM, 11 and its half-life is approximately 113 to 131 hours. 12 Differences in pharmacologic properties do not provide any evidence of differences in clinical efficacy or safety, which need to be established through head-to-head clinical trials. 1. Kim D et al. J Med Chem. 2005;48:141–151. 2. Matsuyama-Yokono A et al. Biochem Pharmacol . 2008;76:98–107. 3. JANUVIA European Summary of Product Characteristics. 2010. 4. Villhauer EB et al. J Med Chem . 2003;46:2774–2789. 5. Galvus European Summary of Product Characteristics. 2010. 6. Augeri DJ et al. J Med Chem. 2005;48(15):5025–5037. 7. Onglyza European Summary of Product Characteristics. 2010. 8. Feng J, et al. J Med Chem . 2007;50:2297–2300. 9. Lee B et al. Eur J Pharmacol . 2008;589:306–14. 10. Christopher R et al. Clin Ther . 2008;30:513–527. 11. Thomas L et al. J Pharmacol Exp Ther . 2008;325:175–182. 12. Heise T et al. Diabetes Obes Metab . 2009;11:786–794. Purpose To outline characteristics of various dipeptidyl peptidase-4 (DPP-4) inhibitors that have been approved or that are awaiting approval. Takeaway Pharmacologic properties differ across the DPP-4 inhibitor treatment class. Thomas 2008 p.176, A Thomas 2008 p.176, Fig. 1A Thomas 2008 p.177, A Content on first 4 compounds from the left (sitagliptin through alogliptin) already approved: see slide 10 of DPP-4 deck JAN-2010-W-1339612-SS Heise 2009 p.789, Table 1 Thomas 2008 p.176, A p.177,A Heise 2009 p.789, Table 1
  • 4 inhibidores de DPP-difieren en estructuras moleculares y propiedades farmacológicas, Varios inhibidores de DPP-4 o bien han sido aprobados o están en espera de aprobación para su uso en pacientes con diabetes tipo 2. Las estructuras moleculares y propiedades farmacológicas diferentes a través de la clase de tratamiento inhibidor DPP-4. La sitagliptina es un miembro de la β-fenetilamina clase1 química y tiene una concentración inhibitoria (IC50) de 9,96 ± 1,03 nM en contra de su DPP-4.2 vida media es de aproximadamente 12,4 horas.3 Vildagliptina es un miembro de la clase química cyanopyrrolidine, 4 y tiene una IC50 de 5,28 ± 1,04 nM frente a la DPP-4.2 Se tiene una vida media de aproximadamente 2 a 3 horas.5 La saxagliptina es también un miembro de la class6 cyanopyrrolidine química y su IC50 contra la DPP-4 es 3,37 ± 0,90 nm.2 saxagliptina y su metabolito activo tiene una vida media de 2,5 y 3,1 horas, respectivamente.7 Alogliptina, un miembro de la clase aminopiperidina química, 8 tiene un IC50 de 6,9 ± 1,5 nM, 9 y es su vida media de aproximadamente 12,4 a 21,4 horas.10 Linagliptina, un miembro de la clase química xantina, tiene una IC50 de ~ 1 nM, 11 y su vida media es de aproximadamente 113 a 131 hours.12 Las diferencias en las propiedades farmacológicas no proporcionan ninguna evidencia de diferencias en la eficacia clínica o de seguridad, que deben establecerse a través de ensayos de cabeza a cabeza clínicos. Deshacer cambios DPP-4 Inhibitors Differ in Molecular Structures and Pharmacologic Properties Several DPP-4 inhibitors either are approved or are awaiting approval for use in patients with type 2 diabetes. The molecular structures and pharmacologic properties differ across the DPP-4 inhibitor treatment class. Sitagliptin is a member of the β -phenethylamine chemical class 1 and has an inhibitory concentration (IC 50 ) of 9.96 ± 1.03 nM against DPP-4. 2 Its half-life is approximately 12.4 hours. 3 Vildagliptin is a member of the cyanopyrrolidine chemical class, 4 and has an IC 50 of 5.28 ± 1.04 nM against DPP-4. 2 It has a half-life of approximately 2 to 3 hours. 5 Saxagliptin is also a member of the cyanopyrrolidine chemical class 6 and its IC 50 against DPP-4 is 3.37 ± 0.90 nM. 2 Saxagliptin and its active metabolite have a half-life of 2.5 and 3.1 hours, respectively. 7 Alogliptin, a member of the aminopiperidine chemical class, 8 has an IC 50 of 6.9 ± 1.5 nM, 9 and its half-life is approximately 12.4 to 21.4 hours. 10 Linagliptin, a member of the xanthine chemical class, has an IC 50 of ~1 nM, 11 and its half-life is approximately 113 to 131 hours. 12 Differences in pharmacologic properties do not provide any evidence of differences in clinical efficacy or safety, which need to be established through head-to-head clinical trials. 1. Kim D et al. J Med Chem. 2005;48:141–151. 2. Matsuyama-Yokono A et al. Biochem Pharmacol . 2008;76:98–107. 3. JANUVIA European Summary of Product Characteristics. 2010. 4. Villhauer EB et al. J Med Chem . 2003;46:2774–2789. 5. Galvus European Summary of Product Characteristics. 2010. 6. Augeri DJ et al. J Med Chem. 2005;48(15):5025–5037. 7. Onglyza European Summary of Product Characteristics. 2010. 8. Feng J, et al. J Med Chem . 2007;50:2297–2300. 9. Lee B et al. Eur J Pharmacol . 2008;589:306–14. 10. Christopher R et al. Clin Ther . 2008;30:513–527. 11. Thomas L et al. J Pharmacol Exp Ther . 2008;325:175–182. 12. Heise T et al. Diabetes Obes Metab . 2009;11:786–794. Purpose To outline characteristics of various dipeptidyl peptidase-4 (DPP-4) inhibitors that have been approved or that are awaiting approval. Takeaway Pharmacologic properties differ across the DPP-4 inhibitor treatment class. Thomas 2008 p.176, A Thomas 2008 p.176, Fig. 1A Thomas 2008 p.177, A Content on first 4 compounds from the left (sitagliptin through alogliptin) already approved: see slide 10 of DPP-4 deck JAN-2010-W-1339612-SS Heise 2009 p.789, Table 1 Thomas 2008 p.176, A p.177,A Heise 2009 p.789, Table 1
  • Sitagliptin Provides the Right Dose for the Right Patient With Renal Insufficiency La sitagliptina proporciona la dosis adecuada para el paciente adecuado con insuficiencia renal Esta diapositiva resume el fundamento de las recomendaciones de dosificación para los pacientes con insuficiencia renal moderada a severa. Una dosis única, de etiqueta abierta estudio evaluó la farmacocinética de 50 mg de sitagliptina en pacientes con diferentes grados de insuficiencia renal crónica en comparación con la de los sanos (control) de los sujetos. Además, los efectos de la insuficiencia renal sobre la farmacocinética de sitagliptina en pacientes con diabetes tipo 2 e insuficiencia renal leve o moderada se evaluó a través de farmacocinética poblacional analyses.1 Los pacientes con insuficiencia renal leve (depuración de creatinina [CrCl]: 50 a <30 mL/min) and in patients with end-stage renal disease (ESRD) on hemodialysis. 1 To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency as well as in patients with ESRD requiring hemodialysis or peritoneal dialysis. 1 Sitagliptin has been well tolerated in studies of 200 mg. 1 Because there is a recommendation for different dosage based on renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter, per label guidance. 1 Purpose To show that sitagliptin p rovides the right dose for the right patient with renal insufficiency. Takeaway Patients with mild renal insufficiency receive the full 100-mg dose of sitagliptin. The dose of sitagliptin in patients with moderate or severe renal insufficiency is recommended to be reduced to 50 mg and 25 mg, respectively, to achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function. Sitagliptin has been well tolerated in studies of 200 mg. 1. Data on file, MSD.
  • Sitagliptin vs Glipizide in Patients With Type 2 Diabetes Mellitus and Chronic Renal Insufficiency: Change From Baseline in Estimated GFR This slide presents the change from baseline in GFR estimation MDRD (mL/min/1.73m 2 ) over time by treatment group in the APaT population (excluding data after initiation of glycemic rescue therapy). 1 In the sitagliptin group, a decrease from baseline in eGFR was observed at Week 6 and continued to decrease relative to baseline through Week 54 when a change from baseline of -3.9 mL/min/1.73 m 2 was observed. Similar changes were observed in the glipizide group, with a change from baseline at Week 54 of -3.3 mL/min/1.73 m 2 . 063 CSR p.229, Fig 12-11 Purpose To show the change in estimated GFR (eGFR) over 54 weeks. Takeaway Similar decreases in eGFR were observed in both groups. 063 CSR p.228, A, Table 12-39; p.229, Fig 12-11 1. Data on File, MSD. 063 CSR p.139, Table 12-3
  • 24 horas de medias ponderada glucosa? Cambio desde el inicio en el día 28? Sitagliptina, Linagliptina en comparación con placebo
  • Glucosa plasmática en ayunas? Cambio desde el inicio en el día 28? Sitagliptina, Linagliptina en comparación con placebo
  • Frente a Frente de Estudio? Linagliptina contra glimepride, tanto en la parte superior de la metformina
  • OPTIMA: Optimized Glycemic Control With Vildagliptin vs. Sitagliptin - Study Design This slides reviews the design of the trial. To be included in this trial, patients must have been older than 18 years old, have a HbA 1c between 6.5 and 8.0%, have a BMI between 22 and 45 kg/m 2 , and be on a stable maximum tolerated dose of metformin. Prior to randomization, patients underwent continuous glucose monitoring (CGM) by holter for 72 hours. Patients were then randomized to receive 100 mg sitagliptin QD (N=19) or 50 mg vildagliptin BID (N=19) in addition to maximum tolerated metformin dose for 8 weeks. Following the treatment period, patients underwent a 2 nd CGM for 72 hours. 1 Purpose To review the design of the OPTIMA trial. Takeaway Patients with type 2 diabetes already on metformin with HbA 1c levels between 6.5 and 8.0% underwent CGM for 72 hours prior to randomization. Patients were then randomized to receive sitagliptin or vildagliptin in addition to metformin for 8 weeks. Another 72 hour CGM was conducted following the treatment period. 1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.
  • OPTIMA: Optimized Glycemic Control With Vildagliptin vs. Sitagliptin - Study Objectives The objectives of the study were 1 : Primary Objective: Change in mean amplitude of glycemic excursions (MAGE) after 8 weeks of treatment Secondary Objectives: Time spent in the optimal glycemic range, ≥ 70 and ≤ 140 mg/dL Time spent in hyperglycemic range, ≥140 and ≥180 mg/dL Time spent in hypoglycemic range, < 70 mg/dL Purpose To review the study objectives. Takeaway The primary objective of this study was to observe the mean amplitude of glycemic excursions before and after treatment with a DPP-4 inhibitor. Secondary objectives included time spent in the optimum glycemic range, below optimum levels, and above optimum levels. 1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.
  • OPTIMA: Optimized Glycemic Control With Vildagliptin vs. Sitagliptin - Patient Characteristics This slide shows baseline patient characteristics in each treatment arm. Characteristics were similar across treatment groups. The mean HbA 1c was around 7.1% and patients received an average daily metformin dose of greater than 2 g. 1 Purpose To review the baseline patient characteristics. Takeaway Baseline characteristics between the treatment groups were similar. 1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.
  • OPTIMA: Glycemic Variability Results Were Similar Between Sitagliptin and Vildagliptin Treated Groups This study was a multi-center, prospective, randomized, open-label study to compare the glycemic profile of patients treated with a DPP-4 inhibitor as an add-on to metformin in patients with HbA 1c levels between 6.5% to 8.0%. Glycemic profiles were obtained by continuous glucose monitoring (CGMs) for 72 hours on metformin alone. Patients were then randomized to receive either 100 mg QD of sitagliptin (n=16) or 50 mg BID of vildagliptin (n=14) for 8 weeks and underwent another 72 hours of CGMs at the end of the study period. 1 This slide shows the glycemic variability endpoints for the study. Both treatment groups experienced a significant reduction in MAGE from baseline, P =0.02 for sitagliptin and P =0.03 for vildagliptin. There was no between-group difference at 8 weeks ( P =0.83). Similarly, there were no significant between-group differences for the standard deviation of 24 hour glycemia ( P =0.61) or MODD ( P =0.89) at weeks. 1 Purpose To show the results of the measures of glycemic variability examined between Vildagliptin and Sitagliptin. Takeaway There were no significant between group differences in the mean amplitude of glycemic excursions (MAGE), the standard deviation of 24 hour mean glycemia, or the mean of daily differences (MODD) measured between Sitagliptin and Vildagliptin. 1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.
  • Glycemic Variability Results Were Similar Between Sitagliptin and Vildagliptin Treated Groups This study was a multicenter, prospective, randomized, open-label study to compare the glycemic profile of patients treated with a DPP-4 inhibitor as an add-on to metformin in patients with HbA 1c levels between 6.5% to 8.0%. Glycemic profiles were obtained by continuous glucose monitoring (CGMs) for 72 hours on metformin alone. Patients were then randomized to receive either 100 mg QD of sitagliptin (n=16) or 50 mg BID of vildagliptin (n=14) for 8 weeks and underwent another 72 hours of CGMs at the end of the study period. 1 This slide shows the glycemic variability endpoints for the study. Both treatment groups experienced a significant reduction in MAGE from baseline, P =0.02 for sitagliptin and P =0.03 for vildagliptin. There was no between-group difference at 8 weeks ( P =0.83). Similarly, there were no significant between-group differences for the standard deviation of 24 hour glycemia ( P =0.61) or MODD ( P =0.89) at weeks. 1 Purpose To show the measures of glycemic variability examined. Takeaway There were no significant between group differences in the mean amplitude of glycemic excursions (MAGE), the standard deviation of 24 hour mean glycemia, or the mean of daily differences (MODD). 1 . Guerci B et al. Poster .
  • Sitagliptin and Vildagliptin Increased the Time Patients Spent in the Ideal Glycemic Range at 8 Weeks Patients in both treatment groups experienced an increase from baseline in the amount of time spent in the ideal glycemic range between 70 to 140 mg/dL. This increase was significant only for the vildagliptin group ( P =0.02). However, there was no significant between-group difference for euglycemia ( P =0.11). 1 Patients in both treatment groups experienced a reduction in the amount of time spent at hyperglycemic levels. Only patients in the vildagliptin group had a significant decrease ( P =0.02). The between-group difference did not achieve statistical significance ( P =0.09). 1 1 . Guerci B et al. Poster . Purpose To show the amount of time patients spent at euglycemic or hyperglycemic levels. Takeaway Patients in the vildagliptin group experienced a significant increase from baseline in the amount of time spent in euglycemia and a significant decrease from baseline in the amount of time spent in hyperglycemia. However, no significant between-group differences were detected.
  • Sitagliptin Reduced HbA 1c Levels at a Similar Rate From Baseline Compared With Vildagliptin This slide shows the mean change in HbA 1c from baseline at 8 weeks. Both treatment groups had similar baseline HbA 1c levels of 7.1%. 1 Sitagliptin reduced HbA 1c levels –0.34% from baseline ( P =0.09). Vildagliptin significantly reduced HbA 1c levels –0.49% from baseline ( P <0.01). There was no significant between-group difference ( P =0.42). 1 1 . Guerci B et al. Poster . Purpose To show the HbA 1c change from baseline in both treatment groups at 8 weeks. Takeaway Both sitagliptin and vildagliptin reduced HbA 1c levels from baseline at 8 weeks. There was no significant between-group difference.
  • Saxagliptin Was Noninferior to Sitagliptin in Reducing HbA 1c at 18 Weeks The primary end point of this study was change from baseline in adjusted mean HbA 1c at 18 weeks. The mean baseline HbA 1c was 7.69% for sitagliptin 100 mg plus metformin and 7.68% for saxagliptin 5 mg plus metformin. The prespecified noninferiority margin was 0.30% ( a numerical difference in the HbA 1c reduction of <0.3% for the upper limit of the 95% confidence interval (CI) was needed to satisfy the noninferiority end point) . 1 The results showed that saxagliptin 5 mg plus metformin was noninferior to sitagliptin 100 mg plus metformin; however, sitagliptin demonstrated numerically greater reductions in HbA 1c at 18 weeks. Sitagliptin 100 mg plus metformin resulted in a –0.62% change from baseline in HbA 1c compared with a –0.52% change from baseline observed with saxagliptin 5 mg plus metformin in the per-protocol analysis set ( difference vs sitagliptin plus metformin: 0.09 ; 95% CI: –0.01, 0.20). 1 Noninferiority of saxagliptin to sitagliptin was confirmed in the full cohort analysis set. In this population, however, numerically greater HbA 1c reductions from baseline were observed for sitagliptin 100 mg plus metformin compared with saxagliptin 5 mg plus metformin and the 95% CI of the between-groups difference did not include zero (difference vs sitagliptin plus metformin: 0.17%; 95% CI: 0.06, 0.28). 1 Purpose To examine the mean HbA 1c -lowering efficacy of sitagliptin 100 mg vs saxagliptin 5 mg at 18 weeks. Takeaway Saxagliptin 5 mg plus metformin was noninferior to sitagliptin 100 mg plus metformin in reducing HbA 1c levels at 18 weeks. Numerically greater reductions were observed with sitagliptin 100 mg plus metformin at 18 weeks. Reference 1. Scheen AJ, Charpentier G, Östgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev . 2010;26(7):540–549.

2 da fecha  no todos los inh dpp4 son iguales (2) 2 da fecha no todos los inh dpp4 son iguales (2) Presentation Transcript

  • No todos los Inhibidores de la DPP4 son iguales Dr. Luis More Saldaña Hospital Santa Rosa /Clínica San Felipe Endocrinólogo
  • Conflicto de Interés  Advisory: Eli Lilly  Speaker: MSD,Eli Lily,Novartis. Investigador Principal : Novartis , Covance. Takeda , Sanofi Aventis PPD, Roche , Johson&Johnson Astrazeneca, GSK.
  • DPP-4 Inhibitors Differ in Molecular Structures and Pharmacologic Properties Chemical β-Phenethylamines1 Cyanopyrrolidines Aminopiperidine8 Xanthine Class Generic Sitagliptin2,3 Vildagliptin2,4,5 Saxagliptin2,6,7 Alogliptin9,10 Linagliptin11,12 Name O F FNH2O H O CN Molecular H NH2 N N N N N H3C N N N Structure F N N H N N N N N N NC O O N O CF3 HO NC O NH2 HO NH2 DPP-4 Inhibitory 9.96 ± 1.03 nM 5.28 ± 1.04 nM 3.37 ± 0.90 nM 6.9 ± 1.5 nM ~1 nM Activity (IC50) 2.5 h (parent) Half-life 12.4 h ~2–3 h 12.4–21.4 h 113–131 h 3.1 h (metabolite)DPP-4=dipeptidyl peptidase-4. IC50 =half maximal inhibitory concentration1. Kim D et al. J Med Chem. 2005;48:141–151. 2. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76:98–107. 3. JANUVIA EU-SPC 2010.4. Villhauer EB et al. J Med Chem. 2003;46:2774–2789. 5. Galvus EU-SPC 2010. 6. Augeri DJ et al. J Med Chem. 2005;48:5025–5037. 7. OnglyzaEU-SPC 2010. 8. Feng J et al. J Med Chem. 2007;50:2297–2300. 9. Lee B et al. Eur J Pharmacol. 2008;589:306–14. 10. Christopher R et al. ClinTher. 2008;30:513–527. 11. Thomas L et al. J Pharmacol Exp Ther. 2008;325:175–182. 12. Heise T et al. Diabetes Obes Metab. 2009;11:786–794.
  • Características de los inhibidores DPP-4 (Deacon C, 2010) Química Metabolización EliminaciónSitagliptina Derivado de β-amino acido No metabolizado Renal (~80% inmodificado)Vildagliptina Cianopirrolidina Hidrolizado a metabolito inactivo (P450 Renal (22% como molécula madre, independent) 55% como metabolito) Metabolizado en hígado – Metabolito activo Renal (12-29% como madre, 21-52%Saxagliptina Cianopirrolidina (via P450 3A4/5) como metabolito)Alogliptina Pirimidinediona modificada No metabolizado Renal (>70% inmodificado)Linagliptina Derivado xantinico No metabolizado Biliar (inmodificado); <6% via renal
  • Selectivity for DPP-4 vs other enzymesC. Deacon Diabetes, Obesity and Metabolism 13: 7–18, 2011
  • DPP-4 Inhibitors Differ in Molecular Structures and Pharmacologic Properties Chemical β-Phenethylamines1 Cyanopyrrolidines Aminopiperidine8 Xanthine Class Generic Sitagliptin2,3 Vildagliptin2,4,5 Saxagliptin2,6,7 Alogliptin9,10 Linagliptin11,12 Name O F FNH2O H O CN Molecular H NH2 N N N N N H3C N N N Structure F N N H N N N N N N NC O O N O CF3 HO NC O NH2 HO NH2 DPP-4 Inhibitory 9.96 ± 1.03 nM 5.28 ± 1.04 nM 3.37 ± 0.90 nM 6.9 ± 1.5 nM ~1 nM Activity (IC50) 2.5 h (parent) Half-life 12.4 h ~2–3 h 12.4–21.4 h 113–131 h 3.1 h (metabolite)DPP-4=dipeptidyl peptidase-4. IC50 =half maximal inhibitory concentration1. Kim D et al. J Med Chem. 2005;48:141–151. 2. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76:98–107. 3. JANUVIA EU-SPC 2010.4. Villhauer EB et al. J Med Chem. 2003;46:2774–2789. 5. Galvus EU-SPC 2010. 6. Augeri DJ et al. J Med Chem. 2005;48:5025–5037. 7. OnglyzaEU-SPC 2010. 8. Feng J et al. J Med Chem. 2007;50:2297–2300. 9. Lee B et al. Eur J Pharmacol. 2008;589:306–14. 10. Christopher R et al. ClinTher. 2008;30:513–527. 11. Thomas L et al. J Pharmacol Exp Ther. 2008;325:175–182. 12. Heise T et al. Diabetes Obes Metab. 2009;11:786–794.
  • Características de los inhibidores DPP-4 (Deacon C, 2010) Química Metabolización EliminaciónSitagliptina Derivado de β-amino acido No metabolizado Renal (~80% inmodificado)Vildagliptina Cianopirrolidina Hidrolizado a metabolito inactivo (P450 Renal (22% como molécula madre, independent) 55% como metabolito) Metabolizado en hígado – Metabolito activo Renal (12-29% como madre, 21-52%Saxagliptina Cianopirrolidina (via P450 3A4/5) como metabolito)Alogliptina Pirimidinediona modificada No metabolizado Renal (>70% inmodificado)Linagliptina Derivado xantinico No metabolizado Biliar (inmodificado); <6% via renal
  • 44 Sitagliptin: Dose reduction is based on PK data 28 <2-fold AUC increase Dose-Adjusted (to 50 mg) AUC, μM/h with mild renal insufficiency 24 vs normal renal function 20 Dose adjustments CrCl <30 mL/min: ¼ dose 16 CrCl 30–50 mL/min: ½ dose CrCl >50 mL/min: full dose 12 2× GM of 8 healthy subjects 4 GM of healthy subjects 0 10 30 50 70 90 110 130 150 170 190 210 230 Creatinine Clearance, mL/minAUC=area under the curve; CrCl=creatinine clearance; GM=geometric mean.1. Data on file, MSD.
  • Sitagliptin vs Glipizide in Patients With Type 2 Diabetes Mellitus and Chronic Renal Insufficiency: Change From Baseline in Estimated GFR1 APaT, Excluding Data After Initiation of Glycemic Rescue Therapy GFR Estimation MDRD (mL/min/1.73m2) Change From Baseline (Mean ± SE) 1 0 -1 -2 -3 -4 -5 0 6 12 18 30 42 54 Week Sitagliptin GlipizideaAPaT=All Patients as Treated ; GFR=glomerular filtration rate; SE=standard error.a Mean dose of glipizide was 7.7 mg per day.1. Data on file, MSD.
  • Selectivity for DPP-4 vs other enzymesC. Deacon Diabetes, Obesity and Metabolism 13: 7–18, 2011
  • FDA requirement
  • 24-hour Weighted Mean Glucose Change From Baseline at Day 28 Sitagliptin, Linagliptin compared to placebo Change from Baseline at Week 24 (Primary End Point) Baseline-HbA1c 7.17 ± 0.44 7.32 7.47 ± 0.53 ± 0.59 5,0 n=38 0,0 24 h- Weighted Mean Glucose 0.1 ± 3.0 –5,0 n=40 n=39 n=40 n=39 [units: mg/dL] Mean ± SD –1 0,0 –1 5,0 –20,0 * P < 0,001 vs placebo –25,0 –30,0 -26.1 ± 2.8 -19.8 ± 2.9* Sitagliptin Linagliptin PlaceboRef.: clinicaltrials.gov 100 mg/day 5 mg/day
  • Fasting Plasma Glucose Change From Baseline at Day 28 Sitagliptin, Linagliptin compared to placebo Change from Baseline at Week 24 (Primary End Point) Baseline-HbA1c 7.17 ± 0.44 7.32 7.47 ± 0.53 ± 0.59 5,0 n=38 0,0 [units: mg/dL] n=41 n=40 n=39 n=39 Mean ± SD –5,0 -0.1 ± 3.6 FPG –1 0,0 * P = 0.0283 –1 5,0 vs placebo –20,0 -15.6 ± 3.1 -10.9 ± 3.5 * Sitagliptin Linagliptin PlaceboRef.: clinicaltrials.gov 100 mg/day 5 mg/day
  • Head to Head StudyLinagliptin versus glimepride, both on top ofmetformin Full Analysis Set 0,00% - 0.16% -0,10% - 0.36% -0,20% - 0.60% - 0.38% -0,30% Glim Lina -0,40% not c ude c 1 Ab H -0,50% 0,22% 0,20% Non-inferiority margin: -0,60% 0.35% r 52 weeks 104 weeks Per protocol analysis (more robust) i Differences: 0.26% 0.28%EMA/ European public assessment report Linagliptin
  • Linagliptin PK interacionsEfects of coadministered drugs on linagliptinUS- PI 2011
  • EMA Scientific discussionEMA webside
  • Linagliptin Phase III Meta-analysis:Cardiovascular Endpoints Favors Linagliptin Secondary Endpoints: Hazard Rate Estimates Favors Comparators CV death, MI, or stroke 0.17 0.36 0.78 All CV events* 0.33 0.55 0.94 FDA-custom MACE† 0.15 0.34 0.75 0.125 0.25 0.5 1 2 4 Ratio (95% CI) of linagliptin to control *All major CV events include CV death, MI, stroke, transient ischemic attack, UAP, and stable angina pectoris. † FDA-custom MACE includes 34 unadjudicated MedRA preferred terms for MI and stroke. ADA 2011 Poster 30-LB
  • Linagliptin Product information Canada
  • G. Schernthaner et al. Diabetes, Obesity and Metabolism 2012
  • Lina CV safety G. Schernthaner et al. Diabetes, Obesity and Metabolism 2012
  • FDA requirement
  • Conclusion Linagliptin Only limited clinical experience Less indications No RCTs in patients with moderate/severe renal failure and dialysis Xanthin based molecule: HR increase, proarrythmic? No CV benefit over Placebo in pooled safety analysis Why inhibit FAP? Glucose lowering efficacy? (Lina/Sita 24h WMG study)
  • Vildagliptin Main points to note: – Need to check hepatic enzymes – BID dosing – No CV outcome trial – Poorer in vitro selectivity than other DPP4 inhibitors – Pre-clinical tox issues - maybe due to DPP8 and DPP9 inhibitory activity
  • The Marfella issue• Repeat nonsense* until it is believed• * retrospective analysis of as much data as possible until you find a difference that probably occured by chance• The only way to compare compounds is with appropriately powered, prospective randomised clinical trials
  • Cross-Sectional Study: Sitagliptin vs Vildagliptin in Patients With Type 2 Diabetes Uncontrolled on MetforminJournal of Diabetes and Its Complications, Marfella R, Barbieri M, Grella R, et al., Effect so vildagliptintwice daily vs. sitagliptin once daily on 24-hour acute glucose fluctuations, Vol. 24(2),79-83 (2010),
  • Effects of vildagliptin twice daily vs sitagliptin once daily on24-hour acute glucose fluctuationsMarfella R et al. Method: Not a prospective, randomized, blinded clinical trial Sitagliptin (100 mg qd; n=20) Vildagliptin (50 mg bid; n=18)Plasma glucagon (mg/dL) Inadequate glycaemic control while 80 on max metformin (3000 mg/d) ** * * * FPG PPG MPG MAGE 60 * * ** Glucose changes (mg/dL) * -60 } } } } * * * 40 -40 * 20 -20 Intact GLP-1 (pmol/L) 30 0 20 * * * 10 * * * * * MAGE = mean amplitude of glycaemic * excursion, determined from arithmetic 0 0 180 300 0 180 300 0 180 300 min mean of differences between Breakfast Lunch Dinner consecutive glycaemic peaks and (+5 h) (+ 10 h) nadirs Marfella et al J Diabetes Complication 2009
  • Why don’t we like this analysis Small study Not sufficiently powered Retrospective analysis SD is a more typical measure of variability We have no problems convincing SLs about the weakneses of this study – but primary health care physicians??
  • Once-Daily Dosing of JANUVIA Delivers Maximal DPP-4 Inhibition Over 24 Hours Percent Plasma DPP-4 Inhibition* 100 Mean Percent Inhibition of DPP-4 90 80 70 Sitagliptin 100 mg QD Activity (±SE) 60 Saxagliptin 5 mg QD 50 Vildagliptin 50 mg QD ** 40 Vildagliptin 50 mg BID ** 30 Placebo 20 10 0 0 5 10 15 20 25 Hours* Single day dosing** Vildagliptin is not approved in the US 65
  • OPTIMA : Optimized Glycemic Control With Vildagliptin vs. Sitagliptin - Study Design1 CGM for 3 days Inclusion Criteria: CGM for Vildagliptin + Metformin (N=19) •Age > 18 yrs 3 days •HbA1c between 6.5 and 8.0% CGM for •BMI between 22 and R 3 days 45 kg/m2 2-4 Weeks •Currently on stable, maximum tolerated metformin dose Sitagliptin + Metformin (N=19) 8 WeeksCGM=continuous glucose monitoring.1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.
  • 67 OPTIMA : Optimized Glycemic Control With Vildagliptin vs. Sitagliptin - Study Objectives1  Primary Objective: – Change in mean amplitude of glycemic excursions (MAGE) after 8 weeks of treatment  Secondary Objectives: – Time spent in the optimal glycemic range, ≥ 70 and ≤ 140 mg/dL – Time spent in hyperglycemic range, ≥140 and ≥180 mg/dL – Time spent in hypoglycemic range, < 70 mg/dL1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.
  • 68 OPTIMA : Optimized Glycemic Control With Vildagliptin vs. Sitagliptin - Patient Characteristics1 Sitagliptin 100 mg QD Vildagliptin 50 mg BID (N=19) (N=19) Mean age, yrs 53.5 59.1 Males, n (%) 11 (57.9) 10 (52.6) Body Weight, kg 87.6 86.1 BMI, kg/m2 30.9 31.2 Mean HbA1c, % 7.09 7.16 Mean metformin dose, mg/day 2113 2115 Duration of disease, yrs 6.3 7.6BID=twice daily; QD=once daily.1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.
  • 69 OPTIMA : Glycemic Variability Results Were Similar Between Sitagliptin and Vildagliptin Treated Groups 1 P=0.83 At baseline At 8 weeks Variable, mg/dL P=0.61 P=0.89 MAGE SD of 24-h MODD Mean GlycemiaBID=twice daily; MAGE=mean amplitude of glycemic excursions; MODD=mean of daily differences; QD=once daily; SD=standard deviation.1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.
  • 2 abstracts/posters published in 1Q/2012 Poster at ATTD meeting – Barcelona, Spain. February 2012 Poster at SFD congress in France March 2012 (arguably the most important national diabetes congress in France)
  • Methods A multicentre, prospective, randomised, open label study with blinded endpoint. Type 2 patients who were treated with either vilda or sita as an add-on to metformin in patients with starting HbA1c levels in rage 6.5-8.0. NB Starting HbA1c is 7.1 – compared to Marfella study (8.3- 8.4 Blood glucose was continuously monitored over two 72- hour periods: – First Observation – pts on metformin alone
  • Results Primary Endpoint – Glycaemic Variability (eg MAGE) – Both vilda and sita significantly improved MAGE, SD and MODD – No differences between vilda and sita Secondary Endpoints – Effect on HbA1c was similar with both compounds: Sita: decrease of 0.34 from a baseline of 7.12, Vilda decrease of 0.49 from a baseline of 7.14 – Time spent in the optimal glycaemic range (70-140 mg/dL) increased significantly by vilda, although no difference between the 2 inhibitors is evident – Time spent at hyperglycaemic levels (AUC Total: AUC>/=100 mg/dl over the full 24- hour period; • Reduced by 37% by vildagliptin Sig (level?) • Reduced by 9% on sitagliptin, NS • Again, no difference was observed between the 2 inhibitors – Time spent at hyperglycaemic levels (>/= 140 mg/dL) • Poster: Only patients in the vildagliptin group had a significant decrease in time spent above 140 mg/dL. Decrease observed with sitagliptin was not sinificant • Again, the between-group difference did not achieve statistical significance.
  • 73 Glycemic Variability Results Were Similar Between Sitagliptin and Vildagliptin Treated Groups1 P=0.83 At baseline At 8 weeks Variable, mg/dL P=0.61 P=0.89 MAGE SD of 24-h MODD Mean GlycemiaBID=twice daily; MAGE=mean amplitude of glycemic excursions; MODD=mean of daily differences; QD=once daily; SD=standard deviation.1. Guerci B et al. Poster.
  • 74 Sitagliptin and Vildagliptin Increased the Time Patients Spent in the Ideal Glycemic Range at 8 Weeks1 P=0.11 At baseline At 8 weeks Time, minutes P=0.09 Glucose levels 70 – 140 mg/dL Glucose levels >140 mg/dLBID=twice daily; QD=once daily.1. Guerci B et al. Poster.
  • 75 Sitagliptin Reduced HbA1c Levels at a Similar Rate From Baseline Compared With Vildagliptin1 Mean Baseline HbA1c 7.12 7.14 N=16 N=14 -0.34a -0.49b P=0.42a P=0.09 .b P<0.001.1. Guerci B et al. Poster.
  • Other Notes/Questions Publication of full paper: Within one year (Valensi – personal communication to Elisabeth Eymard) Some (secondary?) endpoints quoted on posters do not appear to have been pre-specified – ie retrospective data analysis No incretin or pancreatic endocrine data presented – it is unclear whether the protocol includes measurement of these hormones. One imagines an attempt will be made to link this data to differences in binding of the two inhibitors (although we have commented publically on the limitations of this linkage) Study was small – statistical power calculation?
  • Saxagliptin Was Noninferior to Sitagliptin in Reducing HbA 1c at 18 Weeks Primary End Point (Per-Protocol Population; on background of metformin therapy) Mean baseline HbA1c, % 7.69 7.68 Sitagliptin 100 mg + metformin 0.00 n=343 n=334 Saxagliptin 5 mg + metformin Adjusted Mean HbA1c (SE), % –0.15 Change From Baseline in In the FAS population, –0.30 numerically greater HbA1c reductions from –0.45 baseline were observed for sitagliptin 100 mg –0.60 –0.52 compared with saxagliptin (95% CI: –0.60, –0.45) 5 mg. Difference between –0.62 groups: 0.17% (95% CI: –0.75 (95% CI: –0.69, –0.54) 0.06, 0.28) 0.09 (95% CI: –0.01, 0.20)a (Prespecified noninferiority margin=0.30%)CI=confidence interval; FAS=full-analysis-set; SE=standard error.a Difference in adjusted change from baseline vs sitagliptin + metformin.Scheen AJ et al. Diabetes Metab Res Rev. 2010;26(7):540–549.
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