UNA NUEVA CLASE TERAPÉUTICA PARA EL TRATAMIENTO DE LA DM2: Dr Manuel Pérez Maraver S. Endocrinologia i Nutrició Hospital de Bellvitge-IDIBELL

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1 UNA NUEVA CLASE TERAPÉUTICA PARA EL TRATAMIENTO DE LA DM2: DEL GLUCOCENTRISMO AL ADIPOCENTRISMO Dr Manuel Pérez Maraver S. Endocrinologia i Nutrició Hospital de Bellvitge-IDIBELL

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3 Controlling multiple parameters is essential for effective treatment of patients with Type 2 diabetes HbA 1c Weight Blood pressure Reductions in glycaemic control (HbA 1c ) and other parameters that are sustained over time can benefit the health of patients with Type 2 diabetes 1 5 Lipids 3 1. Stratton IM, et al. BMJ 2000;321:405 12; 2. Pi-Sunyer FX. Postgrad Med 2009;121:94 107; 3. Williamson DF, et al. Diabetes Care 2000;23: ; 4. Patel A, ADVANCE Collaborative Group. Lancet 2007;370:829 40; 5. Pyǒrälä K, et al. Diabetes Care 1997;20: Confidential. Contains unpublished data. For training purpose only. Not to be distributed.

4 Weight gain and hypoglycaemia influence patient adherence Weight gain and hypoglycaemia are important factors in patient adherence and quality of life Risk (or perceived risk) of hypoglycaemia Weight gain (or fear of weight gain) Poor adherence to therapy 4 Khunti K, et al. Diabetes Obes Metab 2010;12: Confidential. Contains unpublished data. For training purpose only. Not to be distributed.

5 Budnitz et al. N Engl J Med 2011; 365:

6 Budnitz et al. N Engl J Med 2011; 365:

7 Depiction of the elements of decision making used to determine appropriate efforts to achieve glycemic targets. Inzucchi S E et al. Dia Care 2012;35: Copyright 2011 American Diabetes Association, Inc.

8 Depiction of the elements of decision making used to determine appropriate efforts to achieve glycemic targets. Riddle et al. Diabetes Care 2010; 33:

9 Vinagre et al. Diabetes Care 2012; 35:774-9

10 10 Confidential. Contains unpublished data. For training purpose only. Not to be distributed.

11 cerebro musculo corazón En DM2, la hiperglucemia aumenta el filtrado. GLUCOSA 1200 g/d 180 g/d g/d Si la reabsorcion de glucosa no varíase, el exceso se eliminaría Pero la reabsorción va aumentado progresivamente Adaptado de Gerich JE, Diabet Med, 2010; 27:

12 Valores normalizados Trasporte de AMG* (CPM) Aumento de expresión del trasportador SGLT2 y estímulo del trasporte de glucosa en la DM2: Estudios sobre células proximales viables recuperadas de la orina de pacientes sanos y con DM 2 Expresión de la proteína SGLT2 Transporte de glucosa Na dependiente Sanos (n=4) DM tipo 2 (n=4) P< P< X X SGLT2 0 *Uptake of alpha-methyl-glucose (AMG) is Na + dependent and is a measure of transport by SGLTs rather than GLUTs Adaptado Rahmoune de H, Rahmoune et al. Diabetes. H, et 2005;54: al. Diabetes. 2005;54:

13 Hiperglucemia Un Circulo Vicioso Diabetes tipo 2 La hiperglucemia en un circulo vicioso que va aumentando si no se frena La reabsorción continua de glucosa por el riñón perpetúa y acelera este círculo Reabsorción continua de glucosa Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain 13

14 Phlorizin Isolated from apple tree bark (1835) Glycosuric effect (1886) Renal actions identified in rats (1903) and man (1933) Antidiabetic effect discovered (1987) 14 Ehrenkranz JRL, et al. Diabetes Metab Rev 2005;21:31 8. Confidential. Contains unpublished data. For training purpose only. Not to be distributed.

15 Dapagliflozin: A potent and selective SGLT2 inhibitor in vitro Dapagliflozin is a potent, reversible and highly selective of SGLT2 versus SGLT1 (3000-fold selectivity according to the K i value 1 ) Good oral bioavailability independent of food intake 2,3 Once-daily administration 2 Low risk of pharmacokinetic drug drug interactions Bellamine A, et al. Diabetes 2009;60(Suppl. 1): Abstract 987-P; 2. Komoroski BJ, et al. Clin Pharmacol Ther 2009;85:520 6; 3. Obermeier M, et al. Drug Metab Dispos 2010:38:405 14; 4. Kasichayanula S, et al. Diabetes Obes Metab 2011;13: Confidential. Contains unpublished data. For training purpose only. Not to be distributed.

16 SGLT2 is a new target that can help lower blood glucose levels by acting on the kidney 1 3 Reduced glucose reabsorption SGLT2 Proximal tubule SGLT2 inhibitor SGLT2 Glucose Glucose filtration Increased urinary excretion of excess glucose (~70 g/day, corresponding to 280 kcal/day*) *Increases urinary volume by only ~1 additional void/day (~375 ml/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes Wright EM. Am J Physiol Renal Physiol 2001;280:F10 18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14 21; 4. Dapagliflozin. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, Confidential. Contains unpublished data. For training purpose only. Not to be distributed.

17 The benefits of dapagliflozin s novel mechanism of action Dapagliflozin s inhibition of SGLT2 results in daily urinary glucose excretion of ~70 g, providing: 1 Significant HbA 1c reductions 2-8 Additional secondary benefit of weight loss 2-8 Dapagliflozin acts independently of insulin mechanisms 2 Works regardless of β-cell function Complements insulin-dependent mechanisms Low intrinsic propensity for hypoglycaemia 1. List JF, et al. 17 Diabetes Care 2009;32:650 7; 2. Bailey CJ, et al. Lancet 2010;375: ; 3. Bailey CJ, et al. Diabetes 2011;60(Suppl. 1):988-P. 4. Bailey CJ, et al. BMC medicine 2013; 11:43 4. Ferrannini E, et al. Diabetes Care. 2010; 2010;33: Strojek K et al. Diabetes Obes Metab 2011; 13: Nauck MA, et al. Diabetes Care 2011;34: ;2. 7. Wilding J.P.H et al Ann Intern Med. 2012;156: Bailey CJ et al. Poster 721 presentado en 48th EASD Meeting, Berlin, Germany;1 5 octubre Confidential. Contains unpublished data. For training purpose only. Not to be distributed.

18 Cambio en la HbA1c % 95% IC Change in HbA 1c, % 95% CI) Reducción de la HbA 1c a la semana 24 0,0 Monoterapia 1 Añadido a metformina 2 Añadido a SU 3 N=70 N=75 N=135 N=137 N=151 N=145 Añadido a insulin 4 N=189 N=189-0,2-0,4-0, ,8-1,0 0.84* 0.82* 0.90* -1,2 0.89* HbA 1c al inicio: 7.92% 8.06% 8.11% 8.53% Dapagliflozina 10 mg Placebo The above are not head to head studies and direct comparisons should not be made. *Statistically significant versus placebo using Dunnett s correction; adjusted mean change from baseline using ANCOVA, excluding data after rescue (LOCF). ANCOVA, analysis of covariance; LOCF, last observation carried forward. 1. Ferrannini E, et al. Diabetes Care 2010;33: ; 2. Bailey CJ, et al. Lancet 2010;375: ; 3. Strojek K, et al. Diabetes Obes Metab 2011;13:928 38; 4. Wilding J, et al. Diabetes 2010;59(Suppl 1):0078-OR. Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

19 Change in weight, kg (95% CI) Reducción significativa de peso a la semana Monoterapia 1 Añadido a metformina 2 Añadido a SU 3 Añadido a insulina * * 2.3* Peso al inicio (kg): Dapagliflozina 10 mg Placebo The above are not head to head studies and direct comparisons should not be made. *Statistically significant vs placebo by hierarchical testing rule (p<0.001, except monotherapy trials); adjusted mean change from baseline using ANCOVA, excluding data after rescue (LOCF). 1. Ferrannini E, et al. Diabetes Care 2010;33: ; 2. Bailey CJ, et al. Lancet 2010;375: ; 3. Strojek K, et al. Diabetes Obes Metab 2011;13:928 38; 4. Wilding JPH, et al. Ann Intern Med 2012;156: Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

20 Fármacos hipoglucemiantes y efecto sobre el peso Rango de cambio en el peso (kg) en respuesta a los medicamentos antidiabéticos Sulfonilureas Glinidas Tiazolidinedionas Insulina Inhibidores de la DPP-4 (sitagliptina) Metformina Agonistas del GLP-1 ) Rango de cambio en el peso (kg) Mitri J, Hamdy O. Expert Opin Drug Saf. 2009;8: Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

21 Weight (kg) with 95% CI Reducción de peso y grasa corporal a la semana 24 Estudio de composición corporal con DXA Dapa 10 + MET (N=89) Pbo + MET (N=91) Peso al inicio: kg 0,5 0,0-0,5-1, , kg** -2,0 Masa Grasa y Masa Magra (kg) a la semana 24 con DXA (SE) Placebo Dapa kg + MET + MET N=79 N=82 0,0-0,5-1,0-1,5-0,74-0,6-2,5-3,0-3,5-4,0 1 BL Study Week ** Estadisticamente significativo vs placebo (p<0.0001) DXA = dual X-ray absorptiometry. Adjusted mean change from baseline using ANCOVA, including data after rescue (LOCF) -2,0-2,5-3,0-3,5 Fat Lean mass -2,22** -1,1 ** Estadisticamente significativo vs placebo por el método Hochberg (p<0.001) Bolinder et al. J Clin Endocrinol Metab 2012 ; 97: Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

22 Change in urine glucose (mmol/l) Change in fasting spot urine glucose over 102 weeks Placebo + metformin Baseline: 1.25 mmol/l Dapagliflozin 10 mg + metformin Baseline: 1.72 mmol/l Study week Change in urine glucose (mg/dl) N at each week Dapagliflozin 10 mg + metformin Placebo + metformin *Data are unadjusted mean change from baseline ± 95% CI for spot urine glucose measurements taken in the fasting state and include data after rescue therapy. Bolinder J, et al. EASD 2012; Poster 751. Confidential. Contains unpublished data. For training purpose only. Not to be distributed.

23 Cambio medio ajustado de la HbA 1c (%) desde el inicio Reducción de HbA1c a las 102 semanas (añadido a metformina) (n=133) (n=132) Primer endpoint 24 semanas Placebo + metformina (Al inicio HbA 1c 8.13%) +0.02% (95% Cl, 0.20%, 0.23%; n=28) 0.80% difference Dapagliflozina 10 mg + metformina (Al inicio HbA 1c 7.95%) 0.78% (95% Cl, 0.97%, 0.60%; n=57) Semanas N at each week Dapagliflozin 10 mg Placebo Data are mean change from baseline after adjustment for baseline value. Data after rescue are excluded. Analyses were obtained by longitudinal repeated measures analyses. Bailey CJ et al. BMC Medicine 2013, 11:43. Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

24 Durabilidad del efecto de reducción de HbA1c a la semana 208 (Dapa + Met vs SU + Met) Corte Temporal: Diferencia Dapa vs Glip (52 wks ): 0.0% (95% CI to 0.11) (104 wks ): 0.18% (95% CI; 0.33, 0.03) *Data are adjusted mean change from baseline ±95% CI derived from a longitudinal repeated-measures mixed model 1. Del Prato S. Durability of Dapagliflozin vs Glipizide as Add-on Therapies in T2DM Inadequately Controlled on Metformin: 4-year Data. 73rd ADA Meeting, Chicago, June 21 25, LB Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

25 Dapagliflozina consigue una reducción de peso sostenida en el tiempo A las 102 semanas, la diferencia de peso entre dapagliflozina y placebo fue de -3,1 kg Los datos son medias (IC 95%) obtenidas a partir del análisis longitudinal de medidas repetidas. Los datos referidos al peso incluyen pacientes que recibieron terapia de rescate (pioglitazona), lo que demuestra la capacidad de dapagliflozina para atenuar el aumento de peso ganado por este medicamento antidiabético. 1. Bailey CJ, et al. BMC Medicine 2013; 11:43 Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

26 Durabilidad del efecto de reducción de peso a la semana 208 (Dapa + Met vs SU + Met) Corte temporal: Diferencia Dapa vs Glip 52 wk: kg (95% CI to -4.17) 104 wks 5.06 kg (95% CI; 5.73, 4.4) *Data are adjusted mean change from baseline ±95% CI derived from a longitudinal repeated-measures mixed model 1. Del Prato S. Durability of Dapagliflozin vs Glipizide as Add-on Therapies in T2DM Inadequately Controlled on Metformin: 4-year Data. 73rd ADA Meeting, Chicago, June 21 25, LB Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

27 Cambio en la media HbA 1c (%) Reducción sostenida* de HbA1c a las 104 semanas (añadido a insulina) Dapagliflozina 10 mg vs placebo las diferencias a las 104 sem. fueron: 0.35% (95% CI: 0.56, 0.15) 0,0-0,1-0,2-0,3-0,4-0,5-0,6-0,7-0,8-0,9-1,0-1,1-1,2-1,3 Semana Placebo + insulina (Al inicio HbA 1c = 8.47%) ST period LT period 1 LT period 2 Dapagliflozina 10 mg + insulina (Al inicio HbA 1c = 8.57%) N at each week Dapagliflozin 10 mg + insulin Placebo + insulin *Sustained versus baseline; Data are adjusted mean change from baseline ± 95% CI derived from a mixed model and include data after insulin up-titration. OADs, oral antidiabetic agents; LT, long-term; ST, short-term. Wilding J, et al. Diabetes, Obesity and Metabolism 16: , Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

28 Reducción del peso corporal a la semana 104 (añadido a insulina) Dapagliflozina 10 mg vs placebo diferencias a las 104 semanas: 3.19 kg (95% CI: 4.24, 2.14) -2,04 kg -2,43 kg -3,19 kg *Data are adjusted mean change from baseline ± 95% CI derived from a mixed model and include data after insulin up-titration. DAPA, dapagliflozin; INS, insulin; PBO, placebo; ST, short-term; LT, long-term. Wilding J, et al. Diabetes, Obesity and Metabolism 16: , Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

29 Cambio en la dosis media diaria de insulina (U)* Dapagliflozina disminuye la necesidad de aumentar la dosis de insulina (104 semanas) Dapagliflozina 10 mg vs placebo diferencias a las 104 semanas: 19.2 U/día (95% CI: 25.5, 12.9) ST period LT period 1 LT period 2 Placebo + insulina (Dosis de insulina al inicio: 73.7 U/día) Dapagliflozina 10 mg + insulina (Dosis de insulina al inicio: 78.0 U/día) -19,2 U/día Semanas N at each week Dapagliflozin 10 mg + insulin Placebo + insulin *Data are adjusted mean change from baseline ± 95% CI derived from a mixed model and include data after insulin up-titration. Wilding J, et al. Diabetes, Obesity and Metabolism 16: , Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

30 Patients with hypoglycaemia (%) Poca propensión a causar hipoglucemia 45 Placebo-cont rolled pool Monotherapy pool Add-on to metformin Add-on to SU Add-on to insulin Dapagliflozin 10 mg (n=1193) Placebo (n=1393) The above are not head to head studies and direct comparisons should not be made. Food & Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee: Dapagliflozin BMS Available at: Last accessed February Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

31 Descenso de la tensión arterial sistólica a la semana 208 (Dapa + Met vs SU + Met) Del Prato S, et al. Presented at the 73rd ADA Scientific Sessions, Chicago, USA; June 2013: Abstract 62-LB. Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

32 Patients (%) Patients (%) Infecciones del tracto urinario. Resumen de los datos acumulados weeks weeks Dapa 10mg Placebo Dapa 10mg Placebo 7.7 WOMEN (24 weeks) 6.6 Dapa 10mg Placebo Dapa 10mg Placebo 7.7 MEN (24 weeks) Todas de Intensidad leve/moderada La mayoría respondieron a un ciclo de tratamiento estándar Raramente llevaron a discontinuación (0.3%) La mayoría de pacientes solo 1 episodio a las 102 semanas (74.6% de dapa vs 86.4% placebo) Infecciones urinarias de tracto superior muy raras y balanceadas entre ambos grupos Parikh S et al. American Diabetes Association, San Diego, P Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

33 Patients (%) Patients (%) Infecciones genitales. Resumen de los datos acumulados weeks 102 weeks Dapa 10mg Placebo Dapa 10mg Placebo 6.9 WOMEN (24 weeks) MEN (24 weeks) Dapa 10mg Placebo Dapa 10mg Placebo Todas de Intensidad leve/moderada La mayoría respondieron a un ciclo de tratamiento estándar Raramente llevaron a discontinuación (0.2%) La mayoría de pacientes solo 1 episodio a las 102 semanas (74.6% dapa vs 77.8% placebo) List JF et al. American Diabetes Association, San Diego, P Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

34 Objetivo del metaanálisis cardiovascular Objetivo Primario Analizar la proporción de riesgo relativo en el endpoint primario compuesto: Muerte CV, Infarto de Miocardio (IM), ictus, hospitalización por angina inestable Endpoints adicionales compuestos Secundario: Muerte CV, IM, ictus, hospitalización por angina inestable, revascularización coronaria no planeada y hospitalización por insuficiencia cardiaca Eventos adversos CV mayores Ad hoc : Muerte CV, IM e Ictus Food & Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee: Dapagliflozin BMS Available at: Last accessed February Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

35 Proporción de pacientes (%) Resumen de eventos que contribuyen al endpoint CV primario 4 3 Dapagliflozina vs control Hazard ratio (95% CI, to 1.152) Event rates 1.64% vs 1.99% 2 1 Comparador Dapagliflozina Days Number of subjects at risk Days Dapagliflozin Comparator Johnsson K, et al. EASD Poster 743. Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

36 Considerations for dapagliflozin dosage and administration (2) Dapagliflozin is not recommended in: Patients aged 75 years or <18 years Patients treated concomitantly with pioglitazone Patients receiving loop diuretics Dapagliflozin is also not recommended for initiation of therapy in patients who are volume depleted Temporary interruption of dapagliflozin is recommended for patients who develop volume depletion until the depletion is corrected Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk and in patients with elevated haematocrit A lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with dapagliflozin 36 Dapagliflozin. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, Confidential. Contains unpublished data. For training purpose only. Not to be distributed.

37 Subgroup analysis: Change in HbA 1c at Week 24 No differential efficacy detected with gender, race, ethnicity, region, baseline BMI or duration of Type 2 diabetes Interactions were detected with three subgroup variables in overall population * *Dapagliflozin should not be used in patients with moderate to severe renal impairment (patients with CrCl <60 ml/min or egfr <60 ml/min/1.73 m 2 ). Monitoring of renal function is recommended as follows: Prior to initiation, and at least yearly thereafter; prior to initiation of concomitant medicinal products that may reduce renal function and periodically thereafter; for renal function approaching moderate renal impairment, at least 2 4 times per year. If renal function falls below CrCl <60 ml/min or egfr <60 ml/min/1.73 m 2, dapagliflozin treatment should be discontinued. Pooled data from nine Phase III studies. 37 Dapa, dapagliflozin. Food & Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee: Dapagliflozin BMS Available at: Last accessed October Confidential. Contains unpublished data. For training purpose only. Not to be distributed.

38 Posología: Dapagliflozina se ha comercializado en Europa con el nombre de Forxiga y su posología es de 1 Comprimido de 10 mg 1 vez al día Indicaciones terapéuticas: Forxiga está indicado en adultos de 18 años de edad o mayores con diabetes mellitus tipo 2 para mejorar el control glucémico en: Monoterapia Cuando la dieta y el ejercicio por sí solos no logran un control glucémico adecuado en pacientes en los que no se considere adecuado el uso de la metformina debido a intolerancia Tratamiento adicional en combinación En combinación con otros medicamentos hipoglucemiantes incluyendo insulina, cuando estos, junto con dieta y ejercicio, no logren un control glucémico adecuado Condiciones de reembolso (Visado de inspección): Forxiga está indicado en adultos de 18 años de edad o mayores con diabetes mellitus tipo 2 para mejorar el control glucémico en terapia doble con metformina cuando ésta solo con dieta y ejercicio no alcanza el control glucémico adecuado y en lugar de la asociación de metformina con sulfonilurea cuando esta última no se tolera o está contraindicada. 38 Ficha técnica de Forxiga (dapagliflozina) Disponible en la página web Acceso: Febrero 2014 Uso exclusivo de Medical & Regulatory Affairs Dpt /AZ Spain

39 Depiction of the elements of decision making used to determine appropriate efforts to achieve glycemic targets. J Clin Invest 2014 (press)

42 Dapa add-on to sitagliptin +/- metformin Diabetes Care 2014 Mar;37(3): Confidential. Contains unpublished data. For training purpose only. Not to be distributed.

43 HbA1c (%) Adjusted mean change from baseline HbA1c (%) Adjusted mean change from baseline HbA1c (%) at Week 24 by Strata: Adjusted Mean Change from Baseline FAS: excludes data after rescue Add-on to sitagliptin monotherapy 0,4 0,3 0,4 0,3 Add-on to sitagliptin + metformin 0,2 BL=8.07 BL=7.99 0,2 0,1 0,1 BL=7.87 BL= ,1-0,2 Placebo + Sitagliptin Dapa 10mg + Sitagliptin -0,1-0,2 Placebo + Sitagliptin Dapa 10mg + Sitagliptin -0,3-0,3-0,4-0,4-0,5-0,6 * -0,5-0,6 * * p < Diabetes Care 2014 Mar;37(3): Confidential. Contains unpublished data. For training purpose only. Not to be distributed.

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