Dapagliflozina

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  • The current therapies for type 2 diabetes mellitus target the following organs and tissues in the body:
    Pancreas,
    Liver,
    Skeletal tissue,
    Fatty tissue,
    Intestinal tract.
    With the exception of α-glucosidase inhibitors, insulin is a major mediator of the different antidiabetic treatments used so far, having an insulin-dependent mechanism of action.
    Reference:
    Tahrani AA, et al. Management of type 2 diabetes: new and future developments in treatment. Lancet 2011;378:182-97.
  • De los 450 gramos almacenados en el organismo, 250 gramos se renuevan cada día (aporte y consumo).
    En condiciones normales:
    Aporte de glucosa: aproximadamente 180 g por la dieta y unos 70 g mediante la gluconeogénesis hepática y renal.
    Gasto de glucosa: 125g a nivel cerebral y los otros 125 g por el resto del organismo.
    Importante: los riñones reabsorben la práctica totalidad de la glucosa ingerida (≈180 g), que se filtran en el glomérulo. La reabsorción se lleva a cabo gracias a la existencia de co-transportadores de sodio-glucosa en el túbulo contorneado proximal renal de la nefrona
    Bibliografía:
    Wright EM, et al. J Int Med 2007;261:32–43.
  • En la diabetes se produce un aumento del aporte de glucosa por el aumento de la gluconeogénesis.
    Hasta un cierto punto, el organismo establece sistemas de compensación, como un aumento de la reabsorción en el tubo contorneado proximal.
    Sin embargo, a partir de una concentración de glucosa ≈200 mg/dl, se satura el sistema y la glucosa se elimina por la orina (glucosuria).
    En la siguiente diapositiva se muestra cómo ocurre.
    Bibliografía:
    Wright EM, et al. J Int Med 2007;261:32–43
  • In both healthy individuals and in patients with type 2 diabetes, the majority of glucose entering the kidneys is returned to the circulation.1,2
    The high plasma glucose levels that are characteristic of uncontrolled type 2 diabetes exceed the maximum threshold of glucose reabsorption, saturating the SGLT receptors and resulting in an increased excretion of glucose in the urine.
    Nevertheless, even in the presence of hyperglycaemia, renal SGLT2 continues to reabsorb glucose and its associated calories through an insulin-independent pathway, contributing to elevated plasma glucose levels.1,2
    Renal tubular reabsorption is known to undergo adaptations in patients with uncontrolled diabetes through up-regulation of SGLT2; this is an important adaptation in diabetes permitting maintenance of renal tubular glucose reabsorption. Saturation and excretion thresholds are shifted in diabetic patients, probably due to an increased expression of SGLT2 cotransporters in diabetes.3,4
    References:
    Chao EC, et al. SGLT2 inhibition - a novel strategy for diabetes treatment. Nat Rev Drug Discov 2010;9:551-559.
    Marsenic O. Glucose control by the kidney: an emerging target in diabetes. Am J Kidney Dis 2009;53:875-883.
    Nairs S, et al. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab 2010;95:34-42.
    Rahmoune H et al. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005;54:3427-34.
  • Altered SGLT2 is associated with familial renal glucosuria; the majority of patients with this condition do not develop significant clinical problems over time.
    Altered GLUT2 is associated with Fanconi–Bickel syndrome, the numerous symptoms characteristic of this condition including enlarged liver, abdominal bloating and vitamin D-resistant rickets.
    Altered SGLT1 is associated with glucose–galactose malabsorption syndrome, the principal symptom of this condition being severe diarrhoea.
    Altered GLUT1 is associated with De Vito disease, patients presenting with numerous symptoms including microcephaly and mental and motor developmental delays.
    Reference:
    Pichler, International Diabetes Federation, 2009.
  • More precisely, this slide shows the mechanism of glucose transport through the proximal tubule. Glucose is actively co-transported with sodium by SGLT2 from the tubular lumen and is released into the circulation via GLUT2, one of the major facilitated glucose transporters, which is also expressed in the kidneys.1,2
    References:
    Lee YJ, et al. Regulatory mechanisms of Na(+)/glucose cotransporters in renal proximal tubule cells. Kidney Int Suppl 2007;106:S27–35.
    Wright EM. Renal Na(+)-glucose cotransporters. Am J Physiol 2001;280:F10-8.
    Wright EM. Surprising versatility of Na+-glucose cotransporters: SLC5. Physiology 2004;19:370-6.
  • A nivel del túbulo contorneado proximal se produce la reabsorción de la glucosa, mediada por dos transportadores: SGLT1 y SGLT2.
    El SGLT2 es el responsable del 90% de la reabsorción (a nivel de los segmentos S1 y S2 del túbulo) y el SGLT1 (segmento S3) del 10% restante.
    A continuación se presenta el mecanismo de acción de la reabsorción.
    Bibliografía:
    Bailey CJ. Trends in Pharmacological Sciences 2011;32 (2):63-71
  • Explicar la inhibición del SGLT2 en el túbulo contorneado proximal y cómo ello tiene como consecuencia la excreción de la glucosa no reabsorbida a través de la orina.
    Bibliografía:
    Ficha técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
    Bailey CJ, et al. Lancet 2010;375:2223–33
    Ferrannini E, et al. Diabetes Care. 2010; 2010;33:2217–2224
    Strojek K et al. Diabetes Obes Metab 2011; 13:928-938
    Nauck MA, et al. Diabetes Care 2011;34:2015–22; 2
    Wilding J.P.H et al Ann Intern Med. 2012;156:405-415
  • The main features of phlorizin are as follows:
    Bitter white glycoside,
    Identified by French chemists in the early nineteenth century,
    Initially used to treat malaria and infectious diseases,
    Glycosuria observed at high doses,
    Widely used in physiology research,
    Found to be an effective inhibitor of SGLT1 and SGLT2, accounting for the majority of glucose reuptake in the kidney.
    Reference:
    Ehrenkranz JRL, et al. Phlorizin: a review. Diabetes Metab Rev 2005;21:31-8.
  • The natural product phlorizin, an O-glucoside found in the root and bark of certain fruit trees, is a non-selective SGLT inhibitor.
    The potential therapeutic value of phlorozin was described by Émile Achard, professor of internal medicine at the University of Paris, who identified its potential as a treatment for diabetes at the end of the nineteenth century.
    However, phlorizin was not suitable for development as a drug candidate because of its low oral bioavailability and rapid clearance via the gut, liver and kidneys.
    The finding that a defective SGLT1 transporter in the gut was responsible for glucose and galactose malabsorption disorders in humans suggested that the pursuit of specific SGLT2 inhibitors was preferable.
  • An overview of the most important pharmacokinetic characteristics of dapagliflozin is presented below. In the next few slides, we will examine these in more detail.
    SGLT2 selectivity1:
    Cell-based assays measuring glucose analogue uptake were used to assess dapagliflozin's ability to inhibit sodium-dependent and facilitative glucose transport activity. Dapagliflozin potently and selectively inhibited human SGLT2 versus human SGLT1, the major cotransporter of glucose in the gut, and did not significantly inhibit facilitate glucose transport in human adipocytes.
    Dapagliflozin exhibits a mean EC50 against hSGLT2 of 1.12 nmol/L, compared with 35.6 nmol/L for phlorizin. Against hSGLT1, dapagliflozin and phlorizin displayed mean EC50 values of 1,391 and 330 nmol/L, respectively, indicating that dapagliflozin has high (1,200-fold) selectivity for hSGLT2 vs. hSGLT1.
    Reference:
    Han S, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 2008;57:1723-9.
  • This slide and the next slide present the extensive dapagliflozin clinical development programme. Phase 3 trials assessed dapagliflozin in patients with early and advanced disease, as monotherapy and as an add-on to other antidiabetic medications. Investigations included special populations (renal insufficiency, high cardiovascular risk).
    In a 24-week, double-blind, randomised, parallel-group, placebo-controlled phase 3 trial (85 sites: US, Canada, Mexico, Russia), dapagliflozin monotherapy was evaluated in treatment-naïve patients with newly diagnosed type 2 diabetes and inadequate glycaemic control by diet and exercise.1 Patients with an HbA1c 7.0-10% (n=485) were randomly assigned to one of seven treatment arms: once-daily placebo or dapagliflozin 2.5, 5 or 10 mg once-daily in the morning (main cohort) or evening (exploratory cohort). Patients with an HbA1c 10.1-12% (high-HbA1c exploratory cohort; n=73) were randomly assigned 1:1 to receive blinded treatment with a morning dose of dapagliflozin 5 or 10 mg/day. Dapagliflozin lowered hyperglycaemia with a near absence of hypoglycaemia.
    In a 24-week double-blind, randomised parallel-group, placebo-controlled, phase 3 trial (80 sites in the US, Canada, Argentina, Mexico, Brazil), dapagliflozin was tested as add-on to metformin in type 2 diabetic patients achieving inadequate glycaemic control with metformin alone.2 Patients (n=546) were randomised to placebo or dapagliflozin 2.5 mg, 5 mg or 10 mg once daily on top of their stable pre-study metformin regimen. Addition of dapagliflozin to metformin achieved greater glycaemic control than placebo, the incidence of hypoglycaemia being similar to that seen with placebo
    In an 52-week, double-blind, randomised, active-controlled, multicentre, non-inferiority trial, dapagliflozin was compared to glipizide as add-on therapy in type 2 diabetic patients achieving inadequate glycaemic control with metformin alone.3 Patients (baseline mean HbA1c 7.7%) receiving metformin monotherapy were randomised to add-on dapagliflozin (n=406) or glipizide (n=408) up-titrated over 18 weeks, based on glycaemic response and tolerability, to ≤10 or ≤20 mg/day, respectively. While achieving similar 52-week glycaemic efficacy, dapagliflozin reduced weight and produced less hypoglycaemia than glipizide.
    References:
    1. Ferrannini E, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217-24.
    2. Bailey CJ, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.
    3. Nauck MA, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011; 34:2015-22.
    4. Dapagliflozin Is Effective as Add-on Therapy to Sitagliptin With or Without Metformin: A 24-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. Diabetes Care October 21, 2013
  • Steady and clinically relevant decreases from baseline HbA1c values with dapagliflozin 10 mg were observed across all studies, regardless of therapy combination, decreases in HbA1c from baseline ranging from 0.52-1.0%, or even up to -1.98% in combination with metformin extended release. All decreases were statistically significantly different from those seen with placebo.
    References:
    1. Ferrannini E, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217-24.
    2. Bailey CJ, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.
    3. Strojek K, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 2011;13:928-38.
    4. Rosenstock J, et al. Dapagliflozin added-on to pioglitazone reduces HbA1c and mitigates weight gain with low incidence of hypoglycemia in type 2 diabetes. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 0986-P].
    5. Wilding JPH, et al. Dapagliflozin in patients with type 2 diabetes poorly controlled on insulin therapy - efficacy of a novel insulin-independent treatment. Diabetes 2010;59(Suppl 1):A21-A22 [Abstract 0078-OR].
    6. Henry RR, et al. Dapagliflozin, metformin-XR, or both together as initial therapy for T2DM. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR.
  • The results illustrated in this slide, obtained in four of the six phase 3 trials described in the previous slides, were calculated according to the Last Observation Carried Forward principle and exclude data obtained after recourse to rescue medication.
    A dose-dependent decrease in FPG was seen across all studies, regardless of the therapeutic regimen (monotherapy or combination) assessed. With regard to dapagliflozin 10 mg, the adjusted mean decrease from baseline in FPG at 24 weeks ranged from 21.7 to 30.0 mg/dL. FPG was a secondary endpoint in these studies.
    The references for the four studies illustrated are provided below.
    References:
    1. Ferrannini E, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217-24.
    2. Bailey CJ, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.
    3. Wilding JPH, et al. Dapagliflozin in patients with type 2 diabetes poorly controlled on insulin therapy - efficacy of a novel insulin-independent treatment. Diabetes 2010;59(Suppl 1):A21-A22 [Abstract # 0078-OR].
    4. Rosenstock J, et al. Dapagliflozin added-on to pioglitazone reduces HbA1c and mitigates weight gain with low incidence of hypoglycemia in type 2 diabetes. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract # 0986-P].
  • Plasma glucose: mg/dL=0.0555 mmol/L.
    This slide illustrates the reduction in postprandial glucose (PPG) achieved by dapagliflozin as monotherapy, as an add-on to pioglitazone and as an add-on to glimepiride. Significant reductions in mean baseline PPG ranged from -39.3 to -67.5 mg/dL with dapagliflozin 5-10 mg over 24 weeks in three placebo-controlled Phase 3 studies. PPG was a secondary endpoint, where change in A1c was usually the primary endpoint in these studies.
    Monotherapy (12 weeks)
    Mean 2-hour PPG levels were numerically reduced in all dapagliflozin groups compared with placebo when dapagliflozin was administered as monotherapy for 12 weeks. In this study, the statistical significance of the mean change in 2-hour PPG levels was not evaluated. Both HbA1c and FPG levels were significantly reduced at all doses of dapagliflozin.
    Add-on to glimepiride (24 and 48 weeks)
    Statistically significant reductions in mean 2-hour PPG levels were observed with dapagliflozin (≥5 mg) following 24 weeks of treatment as an add-on to glimepiride compared with placebo. These reductions in PPG observed with dapagliflozin at 24 weeks were sustained for up to 48 weeks.
    Add-on to pioglitazone (24 and 48 weeks)
    Mean PPG levels were significantly reduced across all dapagliflozin groups when dapagliflozin was administered for 24 weeks to patients with type 2 diabetes inadequately controlled with pioglitazone alone. These reductions were statistically significant compared with placebo. The reductions in mean PPG levels observed with dapagliflozin as an add-on to pioglitazone at 24 weeks were sustained for up to 48 weeks.
    Reference:
    Salsali A, et al. Reduction in postprandial glucose with dapagliflozin in type 2 diabetes. 71st ADA Scientific Sessions, San Diego, 24–28 June, 2011 [Poster 1104-P].
  • This slide illustrates the sustained efficacy of dapagliflozin as an add-on to metformin up to 102 weeks in patients with type 2 diabetes inadequately controlled with metformin alone1 (results excluding data obtained after administration of rescue medication). This is the longest dapagliflozin treatment duration reported to date, comprising the initial 24-week treatment period of this phase 3 trial2 and the subsequent 78-week extension period.
    The mean baseline HbA1c of the patients enrolled in this study was 8.13 in the placebo + metformin group, 7.99 in the dapagliflozin 2.5 mg + metformin group, 8.16 in the 5 mg dapagliflozin + metformin group and 7.95 in the 10 mg dapagliflozin + metformin group.
    Dapagliflozin added to metformin achieved durable glycaemic control and reduced body weight over the entire 102-week treatment period without increasing the risk of hypoglycaemia.
    During the additional 78-week extension period, the completion rate was lower in the placebo group (63.5%) than in the DAPA groups (68.3–79.8%). More patients in the placebo group (23.5%) withdrew during the extension period due to lack of efficacy compared to the dapagliflozin groups (13.3, 13.9 and 7.6% in the dapagliflozin 2.5, 5 and 10 mg groups, respectively).
    The proportion of patients (%) having required rescue medication or having been withdrawn because of failure to achieve glycaemic targets was higher in the placebo group (83/137 [60.6%]) than in the dapagliflozin 2.5 mg (71/137 [51.8%]), 5 mg (63/137 [46.0%]), and 10 mg (57/135 [42.2%]) groups at week 102.
    References:
    1. Bailey CJ, et al. Long-term efficacy of dapagliflozin as add-on to metformin (MET) in T2DM inadequately controlled with MET alone. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 988-P].
    2. Bailey CJ, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.
  • This slide illustrates the sustained efficacy of dapagliflozin as an add-on to metformin up to 102 weeks (initial 24-week treatment period1 plus the 78-week extension period2) in patients with type 2 diabetes inadequately controlled by metformin alone.
    A dose-dependent increase in the percentage of patients achieving the target HbA1c (<7.0%, adjusted according to the baseline value) was observed with dapagliflozin + metformin compared to placebo + metformin throughout the 102-week treatment period (results excluding data obtained after administration of rescue therapy).
    References:
    1. Bailey CJ, et al. Long-term efficacy of dapagliflozin as add-on to metformin (MET) in T2DM inadequately controlled with MET alone. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 988-P].
    2. Bailey CJ, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.
  • Early weight loss might be partly due to a mild osmotic diuresis caused by dapagliflozin. However, the gradual progressive reduction in body weight thereafter, seen in all studies,1-7 accompanied by a decrease in waist circumference as shown in the study evaluating dapagliflozin as an add-on to metformin,2 is consistent with a reduction of fat mass. This reduction is potentially attributable to the loss of excess energy through glucose excretion in the urine, an effect clearly evident at week 24, as shown by the increased urinary glucose/creatinine ratio in patients randomised to dapagliflozin.
    References:
    1. Ferrannini E, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217-24.
    2. Bailey CJ, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.
    3. Nauck MA, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011; 34:2015-22.
    4. Strojek K, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 2011;13:928-38.
    5. Wilding JPH, et al. Dapagliflozin in patients with type 2 diabetes poorly controlled on insulin therapy - efficacy of a novel insulin-independent treatment. Diabetes 2010;59(Suppl 1):A21-A22 [Abstract # 0078-OR].
    6. Rosenstock J, et al. Dapagliflozin added-on to pioglitazone reduces HbA1c and mitigates weight gain with low incidence of hypoglycemia in type 2 diabetes. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract # 0986-P].
    6. Henry RR, et al. Dapagliflozin, metformin-XR, or both together as initial therapy for T2DM. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR.
  • The mean changes in body weight shown in this slide were calculated on the basis of the number of subjects (N) in the full analysis set. At baseline, N corresponds to the number of subjects in the full analysis set with a non-missing baseline value and at least one post-baseline value.
    Difference dapagliflozin + metformin vs. glipizide + metformin: -5.06 (95%CI: -5.73, -4.4)
    This was a randomised, double-blind, parallel-group, active-controlled study. In addition to metformin, patients could be receiving one further oral antidiabetic drug at enrollment (but only up to half the maximum dose available). Eligible patients discontinued other oral antidiabetic drugs and were stabilised on ≥1500 mg of metformin daily, after which no further changes in metformin dose were allowed.
    After a 2-week single-blind lead-in period, patients were randomised 1:1 to receive dapagliflozin or glipizide treatment. Patients commenced at dapagliflozin 2.5 mg or glipizide 5 mg and were then up-titrated over 18 weeks, on the basis of tolerability and glycaemic response, to a maximum dose of 10 mg and 20 mg, respectively. Treatment was subsequently maintained without further up-titration up to the primary analysis point at 52 weeks, although down-titration was allowed in the event of recurrent hypoglycaemia.
    Patients then entered the long-term extension period 1 for a further 52 weeks of double-blind treatment, during which a single up-titration, if HbA1c was >7.0% (only until the subject reached the maximum dose), and down-titration, if medically indicated, was allowed. Patients with inadequate glycaemic control at maximum dose were withdrawn from the study on the basis of progressively stricter criteria (during the long-term extension period 1 if FPG was >200 mg/dL and HbA1c was ≥8%).
    References:
    Nauck M, et al. Long-term efficacy and safety of add-on dapagliflozin vs add-on glipizide in patients with T2DM inadequately controlled with metformin: 2-year results. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 40-LB].
  • The results presented include data obtained after the administration of rescue medication and were calculated according to the last observation carried forward (LOCF) principle.
    Data are adjusted mean changes from baseline using ANCOVA, including data after rescue (LOCF).
  • En este estudio de no inferioridad frente a glipizida, FORXIGA® (dapagliflozina) reduce la presión arterial y esta reducción se mantiene a largo plazo.
    Bibliografía:
    Nauck MA, et al. Diabetes Care 2011;34:2015–22 (supplementary data)
  • En este estudio de no inferioridad frente a glipizida, FORXIGA® (dapagliflozina) reduce la presión arterial y esta reducción se mantiene a largo plazo.
    Bibliografía:
    Nauck MA, et al. Diabetes Care 2011;34:2015–22 (supplementary data)
  • a.- [aplica a titulo de la gráfica] La tabla muestra los datos de 24 semanas (corto plazo) independientemente del tratamiento de rescate glucémico.
    b.- [aplica a vulvovaginitis, balanitis e infecciones genitales relacionada, infecciones del tracto urinario, Depleción del volumen]. (Para más información consulte Ficha Técnica de Forxiga)
    c.- [aplica a Vulvovaginitis, balanitis e infecciones genitales relacionadas] Vulvovaginitis, balanitis e infecciones genitales relacionadas incluyen, por ejemplo, los términos preferentes predefinidos: infección micótica vulvovaginal, infección vaginal, balanitis, infección fúngica genital, candidiasis vulvovaginal, vulvovaginitis, balanitis por Candida, candidiasis genital, infección genital, infección genital masculina, infección del pene, vulvitis, vaginitis bacteriana y absceso vulvar.c
     
    d.- [aplica a poliuria] La poliuria incluye los siguientes términos preferentes: polaquiuria, poliuria, aumento de la diuresis.
    e.- [aplica a la depleción del volumen] La depleción del volumen incluye, por ejemplo, los términos preferentes predefinidos: deshidratación, hipovolemia, hipotensión.
     
    f.- [aplica a dislipidemia] El porcentaje medio de cambio desde el valor inicial para dapagliflozina 10 mg frente a placebo, respectivamente, fue de: colesterol total 1,4% frente a -0,4%; colesterol HDL 5,5% frente a 3,8%; colesterol LDL 2,7% frente a -1,9%; triglicéridos -5,4% frente a -0,7%.
     
    g.- [aplica a aumento del hematocrito] La variación media del hematocrito respecto del valor inicial fue del 2,15% con dapagliflozina 10 mg frente al -0,40% con placebo.
     
    * [aplica a reacciones adversas frecuentes] Notificadas en ≥ 2% de los sujetos tratados con dapagliflozina 10 mg y con una frecuencia ≥ 1% mayor que en los sujetos tratados con placebo.
    ** [aplica a reacciones adversas poco frecuentes] Notificadas en ≥ 0,2% de los sujetos y un ≥ 0,1% más veces y en al menos 3 sujetos más tratados con dapagliflozina
    Bibliografía:
    Ficha Técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
  • Asumir que este tratamiento puede no ser adecuado en algunos tipos de paciente, como aquellos que sufran infecciones urinarias de repetición.
    Bibliografía:
    Ficha Técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
  • A diferencia de otros tratamientos para la diabetes, FORXIGA® (dapagliflozina) se asocia a un bajo riesgo de episodios de hipoglucemia.
    Criterios de hipoglucemia:
    Hipoglucemia mayor definida como un episodio sintomático que necesitó de asistencia externa debido a una afectación grave de la consciencia o comportamiento, con una concentración capilar o plasmática inferior a 54 mg/dl (3 mmol/l) y una rápida recuperación después de la administración de glucosa o glucagón.
    Hipoglucemia menor definida como un episodio sintomático con una concentración capilar o plasmática inferior a 63 mg/dl (3,5 mmol/l), con independencia de la necesidad de asistencia externa, o un episodio asintomático con una concentración capilar o plasmática de 63 mg/dl (3,5 mmol/l) no clasificada como hipoglucemia grave.
    Otras hipoglucemias se definieron como un episodio con síntomas indicativos de hipoglucemia pero sin una medida que lo confirme.
    Bibliografía:
    Nauck MA, et al. Diabetes Care 2011;34:2015–22
  • Analysis of pooled study date showed higher rates of genital infections in all dapagliflozin groups than in the placebo group, particularly in women. All these events were mild or moderate in intensity and in general responded well to treatment. Most patients who experienced such an event had no recurrence during the102-week observation period (74.6% dapagliflozin vs. 77.8% placebo).
    The table below presents the actual numbers of these events overall, according to sex and, in the case of women, in patients with a prior history of genital infections.
    Reference:
    List J, et al. Characterization of genital infections in the setting of pharmacologically induced glucosuria. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Poster 985-P].
  • Analysis of pooled study data showed higher rates of urinary tract infections in all dapagliflozin groups than in the placebo group, particularly in women. All events were mild or moderate in intensity and in general responded well to treatment. Most patients who experienced such an event had no recurrrence during the 102-week observation period (74.6% dapagliflozin vs. 86.4% placebo).
    The table below presents the actual numbers of these events overall, according to sex and in patients with a prior history of urinary tract infections.
  • Indicación: en monoterapia tanto en combinación con otros antidiabéticos orales e insulina cuando no existe un control glucémico adecuado.
    Bibliografía:
    Ficha técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
  • Dapagliflozina

    1. 1. ELIMINACIÓN DE LA GLUCOSA COMO TRATAMIENTO PARA LA DM TIPO 2: Un cambio en el paradigma 1
    2. 2. Metformina Glitazonas Sulfonilureas Glinidas IDPPIV Insulina Análogos GLP1 Glucosúricos Acarbosa
    3. 3. Potencia HbA1C Estilo de vida Metformina Insulina Sulfonilurea (glicazidaglimepirida) Repaglinida Problemas Ventajas Insuficiencia renal. Hipoxemia crónica. Tolerancia gastrointestinal. Para todos. Vence resistencia insulínica. Pierde peso. 1-2% 1-2% 1,5-3,5% 1-2% 0,5-1,5% Monitorización frecuente. Más pinchazos. Ganancia peso. Hipoglucemia. Lo más rápido. No límite de dosis. No problemas con insuficiencias de órganos. Mejora lípidos. Hipoglucemia. Ganancia de peso. Interacciones I.renal Acción rápida. Pierde utilidad con el tiempo. Ganancia de peso. Múltiples tomas. Hipoglucemia. Acción rápida. Glucemias postprandiales Ideal en Insuficiencia renal y hepática.
    4. 4. TZD GLP-1agonista (Exenatide Liraglutide) DPP-4 inhibidor (Sitagliptina Vildagliptina Saxagliptina Linagliptina) Inhib alfa glucosidasa Inhibidores GLT2: DAPAGLIFLOZI NA 0,5-1,4% 0,5-1% Ganancia de peso. Retención de líquidos.ICC. Fracturas óseas. Inyectables. Efectos Gastrointestinales. Poca experiencia. 0,5-0,8% Efectos gastrointestinales. Aumento infecciones. Reacciones cutáneas severas. Poca experiencia???. 0,5-0,8% Efectos gastrointestinales. Múltiples dosis al día. De elección en resistencia insulínica. Mejora perfil lipídico. Se puede en Insuficiencia renal. Pierde peso. Mejora glucemias postprandiales. Pierde peso. Mejora glucemias postprandiales. Se puede coformular con metformina/TZD/SU. No afecta peso. Controla.
    5. 5. Most current therapies for type 2 diabetes have an insulin-dependent mechanism of action Sulphonylureas Incretins DPP4 inhibitors Incretins Slow gastric emptying Stimulate insulin secretion ↑ insulin secretion ↓ glucagon secretion Metformin Thiazolidinediones ↑ glucose metabolism Thiazolidinediones ↑ glucose intake ↓ FFA release Metformin Thiazolidinediones Suppress glucose production DPP4 = Dipeptidyl peptidase 4; FFA = free fatty acids; Adapted from Tahrani AA, et al. Lancet 2011;378182-97. All Disease Education materials must be reviewed in accordance with local review requirements 6
    6. 6. El riñón, protagonista de la homeostasis de la glucosa Balance ~0 g/día Disponibilidad de glucosa ~250 g/día  Ingesta por la dieta ~180 g/día  Producción glucosa ~70 g/día  Gluconeogénesis  Glucogenolisis Consumo de glucosa ~250 g/día Cerebro ~125 g/día Resto del organismo ~125 g/día − + El riñón filtra la glucosa circulante Glucosa filtrada El riñón reabsorbe y Glucosa reabsorbida ~ 1 8 0 7 Wright, E. M, et al. J Intern Med 2007; 261: 32–43 g
    7. 7. La diabetes altera la homeostasis de la glucosa Balance ~0 g/día Disponibilidad de glucosa >280 g/día Ingesta por la dieta >180 g/día Producción de glucosa ~100 g/día  Gluconeogénesis*  Glucogenolisis + 8 Consumo de glucosa >250 g/día Cerebro ~125 g/día Resto del organismo >125 g/día − Aumento de la reabsorción C o n c e Por encima del umbral renal n t Glucosa filtrada r a c i *La elevación en la producción de glucosa en pacientes con diabetes tipo 2 se atribuye a la gluconeogénesis hepática y renal ó Wright, E. M, et al. J Intern Med 2007; 261: 32–43
    8. 8. Continued glucose reabsorption even at high glucose levels induces sustained hyperglycaemia in diabetics1,2 Paradoxically, SGLT2 reabsorbs glucose through an insulin-independent pathway, even in the presence of hyperglycaemia Filtered glucose Rate of glucose filtration / reabsorption / excretion (mmol/min) No excretion Excretion threshold 3 Excreted glucose Reabsorbed glucose (diabetes) 2 Reabsorbed glucose (normal) Saturation threshold 1 0 0 8.3 13.3 25 mmol/L 0 149.6 239.6 450.5 Plasma glucose mg/dL Adapted from Chao EC, et al. Nat Rev Drug Discov 2010;9:551-559; Marsenic O. Am J Kidney Dis 2009;53:875-883; Nairs S, et al. J Clin Endocrinol Metab 2010;95:34-42. All Disease Education materials must be reviewed in accordance with local review requirements 9
    9. 9. All Disease Education materials must be reviewed in accordance with local review requirements 10
    10. 10. Other conditions associated with altered glucose transport Transporter SGLT2 GLUT2 SGLT1 GLUT1 Condition leading to defective glucose transport Symptoms of condition Familial renal glucosuria Most patients do not develop significant clinical problems over time Fanconi–Bickel syndrome Numerous symptoms, including enlarged liver, abdominal bloating and vitamin D-resistant rickets Glucose–galactose malabsorption syndrome De Vito disease Severe diarrhoea Numerous symptoms, including microcephaly and delayed mental and motor development Adapted from Bays H. Curr Med Res Opin 2009;25:671– 681. All Disease Education materials must be reviewed in accordance with local review requirements 11
    11. 11. SGLT2 and GLUT2 mechanism of transport Basolateral membrane Tubular lumen Interstitial space SGLT2 GLUT2 Na+ Glucose Glucose Glucose Na+ Na+ K+ K+ Na+/K+ pump Tight junction Lateral intercellular space Adapted from Wright EM, et al. Physiology 2004;19:370–376; All Disease Education materials must be reviewed in accordance with local review requirements 12
    12. 12. El 90% de la glucosa se reabsorbe en el túbulo proximal mediante los cotransportadores SGLT2 180 g glucosa filtrada cada día Glomérulo Túbulo proximal S1 Túbulo colector S2 Filtración de glucosa SGLT2 90% Túbulo distal SGLT1 10% S3 Reabsorción de glucosa Hasta un ~90% de la Hasta un ~90% de la glucosa glucosa se reabsorbe se reabsorbe en los segmentos S1/S2 en los segmentos S1/S2 ~10% de la glucosa ~10% de la glucosa se reabsorbe se reabsorbe en el segmento S3 en el segmento S3 Asa de Henle SGLT1: Cotransportador sodio-glucosa tipo 1; SGLT2: Cotransportador sodio-glucosa tipo 2 13 Bailey CJ. Trends in Pharmacological Sciences 2011;32 (2):63-71 Mínima excreción de glucosa
    13. 13. FORXIGA® (dapagliflozina) reduce la reabsorción renal de glucosa y produce su excreción por la orina1 Disminución de la reabsorción de la glucosa FORXIGA SGLT2 ® Túbulo proximal FORXIG A® SGLT2 Excreción urinaria del exceso de glucosa (≈ 70 g/día equivalentes a 280 kcal/día*) 1 Filtración Glucosa de la glucosa Dapagliflozina actúa mediante un mecanismo independiente de la insulina 2  Actúa con independencia de la funcionalidad de las células β 2-6  Complementa los mecanismos de acción basados en la insulina 2-6 *Los incrementos del volumen de orina observados en sujetos con diabetes mellitus tipo 2 tratados con dapagliflozina 10 mg se mantuvieron a las 12 semanas y ascendieron a aproximadamente 375 ml/día. SGLT2: Cotransportador sodio-glucosa tipo 2 14 1. Ficha técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013 2.Bailey CJ, et al. Lancet. 2010;375:2223–2233. 3.Ferrannini E, et al. Diabetes Care. 2010; 2010;33:2217–2224. 4.Strojek K et al. Diabetes Obes Metab 2011; 13:928-938. 5. Nauck MA, et al. Diabetes Care 2011;34:2015–22; 2. 6.Wilding J.P.H et al Ann Intern Med. 2012;156:405-415.
    14. 14. Development of SGLT2 inhibitors The search for a potent, selective SGLT2 inhibitor….from apple trees to candidate drugs All Disease Education materials must be reviewed in accordance with local review requirements 15
    15. 15. Discovery of phlorizin by French chemists in the early 1800s Isolated from apple tree bark (1835) Glycosuric effect revealed (1865) Renal effects identified in rat (1903) and man (1933) Antidiabetic effect discovered (1987) Found to inhibit SGLT1 and SGLT2 Ehrenkranz JRL, et al. Diabetes Metab Rev 2005;21:31–38. All Disease Education materials must be reviewed in accordance with local review requirements 16
    16. 16. In the 1880s-1890s, phlorizin was shown to induce glycosuria In 1886, Von Mering observed that dogs receiving doses of phlorizin above 1.0 g developed glycosuria “In a diabetic with 2.857 g of glucose per litre of blood, the injection of 50 mg of phlorizin was also followed by a slight decrease, to 2.706 g, while glycosuria increased by 115 to 140 g…” (Émile) Charles Achard, 1899 Cited in Joel RL, et al. Diabetes Metab Res Rev 2005;21:31–38. All Disease Education materials must be reviewed in accordance with local review requirements 17
    17. 17. Dapagliflozin - a potent and selective SGLT2 inhibitor in vitro and in vivo pharmacokinetic characteristics 1 Good oral bioavailability independent of food intake 1 2 Half-life consistent with once-daily dosing1 3 Low risk of drug-drug interactions1-5 4 1200-fold selectivity for SGLT2 vs. SGLT16 Komoroski BJ, et al. Clin Pharmacol Ther 2009;85:520–526. 2Obermeier M, et al. Drug Metab Dispos 2010;38:405–414; 3Kasichayanula S, et al. Diabetes Obes Metab 2011;13:47–54; 4Kasichayanula S, et al. AAPS 2010, Diabetes Obes Metab 2011;13:770-773; 5Wilcox, et al. ASN 2010, Denver, CO [Poster 4509]; 6Han S, et al. Diabetes 2008;57:1723–1729 1 All Disease Education materials must be reviewed in accordance with local review requirements 18
    18. 18. Dapagliflozin – An extensive clinical program 14 Phase 3 double-blind, randomised, controlled clinical trials >5000 randomised patients Studies up to 4 years in duration >30% of patients originating from Europe Early disease Advanced Disease Treatment-naive patients Add-on after initial treatment failure to: Monotherapy versus placebo Combination with metformin as initial therapy Special at-risk populations Versus placebo - added • Metformin • Sulphonylurea (SU) • Insulin • TZD • DPP4 inhibitor (SITAGLIPT) Versus SU - added to: • Metformin Safety and efficacy versus placebo: • Patients with moderate renal insufficiency • Patients at increased risk of CV events All Disease Education materials must be reviewed in accordance with local review requirements 19
    19. 19. Efficacy comparisons across Phase 3 dapagliflozin studies All Disease Education materials must be reviewed in accordance with local review requirements 20
    20. 20. Descenso mantenido de HbA1c en TODOS los estudios, semana 24 Monotherapy1 Add-on to Met2 Add-on to Glim3 Add-on to Pio4 Add-on to Ins5 Dapa + Met XR6 7.92 8.06 8.11 8.37 8.53 9.05 Baseline HbA1c Primary endpoint for 24-week adjusted ∆ from baseline HbA1c (%) 10 m g o eb ac Pl 10 m g o eb ac Pl 10 m g o eb ac Pl 10 m g o eb ac Pl 10 m g o eb ac Pl 10 m g o eb ac Pl -0.13 -0.23 -0.3 -0.3 -0.42 -0.89 * -0.84 * -0.82 * -0.97 * -0.9 * -1.44 -1.98 *p <0.001 compared with placebo * Ferrannini E, et al. Diabetes Care 2010;33:2217-24. 2Bailey CJ, et al. Lancet 2010;375:2223-33. 3Strojek K, et al. Diabetes Obes Metab 2011;13:928-38. 4 Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 0986-P. 5Wilding J, et al. Diabetes. 2010;59 (Suppl 1):A21-A22. Abstract 0078-OR. 6Henry R, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR. 1 All Disease Education materials must be reviewed in accordance with local review requirements 21
    21. 21. Descenso mantenido de glucemia en Ayunas, semana 24 (21-30 mg/dL) Monotherapy1 mmol/L mg/dL 10 m g o eb c la P Add-on to Met2 10 g m o eb c la P Add-on to Ins3 10 g m o eb c la P 10 m g o eb c la P 3.3 0.28 FPG adjusted mean change from baseline Add-on to Pio4 0.00 0.28 -4.1 -5.94 0.56 -6 0.83 1.11 1.39 1.67 -23.4 -21.7 -28.8 -30 1.94 Ferrannini E, et al. Diabetes Care 2010;33:2217–2224; 2Bailey CJ, et al. Lancet 2010;375:2223–2233; 3Wilding J, et al. Diabetes 2010;59 (Suppl 1):A21–A22 [Abstract 0078-OR]; 6Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, 24–28 June, 2011 [Abstract 0986-P]; 1 All Disease Education materials must be reviewed in accordance with local review requirements 22
    22. 22. Descenso de Glucemia Postprandial dapagliflozin (39-67mg/dL) Mean change in PPG levels (24 weeks) Time (min) Mean change in PPG levels (12 weeks) Time (min) 30 60 90 120 150 Placebo 2.5 mg/d 5 mg/d 10 mg/d 60 90 120 150 -40 -60 -20 180 Placebo 5 mg/d 10 mg/d -40 -60 -90 Monotherapy (12 weeks) (Phase 2) Add-on to pioglitazone (24 and 48 weeks) Dapagliflozin mg/d Dapagliflozin mg/d Placebo 2.5 5 10 Placebo 0 5 10 0 -10 2.5 -10 -20 Adjust ed mean chang e in 2-h PPG levels (mg/d L) Adjusted mean change in 2-h PPG levels (mg/dL) 30 0 -20 -90 0 180 Mean change PPG levels (mg/dL) Mean change in PPG levels (mg/dL) 0 0 -20 -30 -30 -40 -50 -40 24 weeks -50 48 weeks Add-on to glimepiride (24 and 48 weeks) Salsali A, et al. 71st ADA Scientific Sessions, San Diego, 24–28 June [Poster 1104-P]. All Disease Education materials must be reviewed in accordance with local review requirements 23
    23. 23. Sustained long-term efficacy of dapagliflozin as add-on to metformin (1) Mean change from baseline in HbA1c (102 weeks) Week 24 Week 50 Week 102 0.0 Adjusted mean change from baseline in HbA1c (%) 0.2 Adjusted mean change from baseline at week 102 (95% CI) 0.02 (-0.20,0.23) -0.2 -0.4 -0.48 (-0.68, -0.29) -0.6 -0.58 (-0.77, -0.39) -0.8 -0.78 (-0.97, -0.60) -1.0 Placebo 2.5 mg/d -1.2 0 16 32 48 64 Time (weeks) 80 96 11 2 Bailey CJ, et al. Lancet 2010;375:2223–2233. Bailey CJ et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 988-P]. All Disease Education materials must be reviewed in accordance with local review requirements 5 mg/d 10 mg/d 24
    24. 24. Eficacia a largo plazo en Dapa+Metformina (102 semanas) Percentage of patients with HbA1c <7.0%* PBO + MET (n = 137) DAPA 2.5 mg + MET (n = 137) DAPA 5 mg + MET (n = 137) 45 DAPA 10 mg + MET (n = 135) 40 35 30 25 20 15 10 5 0 Week 24 Week 50 Week 76 Week 102 * Excluding data after rescue Bailey CJ, et al. Lancet 2010;375:2223–2233. Bailey CJ et al. 71st ADA Scientific Sessions, San Diego, 24–28 June, 2011 [Abstract # 988-P]. All Disease Education materials must be reviewed in accordance with local review requirements 25
    25. 25. Weight loss comparisons across phase 3 dapagliflozin studies All Disease Education materials must be reviewed in accordance with local review requirements 26
    26. 26. Consistent reductions in body weight with dapagliflozin 24-wk Monotherapy Baseline 24-wk add-on to Met2 52-wk add-on to Met3 24-wk add-on to Glim4 24 wk-add-on to Ins5 24-wk add-on to Pio6 24-wk Dapa + Met XR7 90.2kg 88kg 85.9kg 81.1kg 93.8kg 86.3kg 81.1kg Weight m 24- and 52-week adjusted ∆ from baseline weight (kg) 10 g Pl bo ce a 10 m g o eb c la P a ap D et m + lip G et m + 10 m g o eb ac Pl 10 m g Pl o eb ac 10 m g Pl o eb ac 10 m 1.64 1.44 g o eb ac Pl 0.02 -0.14 * -0.72 -0.89 -1.36 -1.67 -2.19 -2.26 -2.86 -3.16 NS * -3.22 * * * *p <0.001 vs. comparator NS: not significant -3.33 * Ferrannini E, et al. Diabetes Care 2010;33:2217–2224; 2Bailey CJ, et al. Lancet 2010;375:2223–2233; 3Nauck MA, et al. Diabetes Care 2011;34:2015-2022; 4 Strojek K, et al. Diabetes Obes Metab 2011;13:928-938 5Wilding J, et al. Diabetes 2010;59 (Suppl 1):A21–A22 [Abstract 0078-OR]; 6Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, 24–28 June, 2011 [Abstract 0986-P]; 7Henry R, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR. 1 All Disease Education materials must be reviewed in accordance with local review requirements 27
    27. 27. Sustained body weight reduction of add-on dapagliflozin vs. add-on glipizide in patients on metformin Baseline weight DAPA + MET : 88.4 kg GLIP + MET : 87.6 kg Change in total body weight (kg) 3.0 Week 104 weight 2.0 +1.36 kg (0.88, 1.84) 1.0 -0.0 GLI + MET (n = 401) -1.0 Between-group difference: −5.06 kg (95% CI; −5.73, −4.4) DAPA + MET (n = 400) -2.0 -3.0 -3.70kg (-4.16, -3.24) -4.0 -5.0 0 6 12 18 26 34 42 52 65 78 91 104 Nauck M, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 40-LB]. All Disease Education materials must be reviewed in accordance with local review requirements 28
    28. 28. Dapagliflozin reduces total body weight and fat mass at week 24 DXA: dual X-ray absorptiometry Langkilde A.M, Study D1690C00012. Internal Presentation January, 2011. All Disease Education materials must be reviewed in accordance with local review requirements 29
    29. 29. Effects on Blood Pressure Comparisons across Phase 3 Dapagliflozin Studies All Disease Education materials must be reviewed in accordance with local review requirements 30
    30. 30. FORXIGA® (dapagliflozina) ofrece el beneficio adicional de una reducción de la presión arterial sistólica FORXIGA® (dapagliflozina) consigue una reducción significativa de la presión arterial sistólica a las 52 semanas de tratamiento Diferencia PAS 5,1 mmHg Diferencia PAD 1,2 31 *Diferencia vs glipizida+metformina -5,0 mmHg (IC 95% -6,7; -3,4); ** Diferencia vs glipizida+metformina -1,2 mmHg (IC 95% 2,3; -0,2) PAS: Presión arterial sistólica; PAD: Presión arterial diastólica Nauck MA, et al. Diabetes Care 2011;34:2015–22 (supplementary data) mmHg
    31. 31. FORXIGA® (dapagliflozina) ofrece el beneficio adicional de una reducción de la presión arterial sistólica FORXIGA® (dapagliflozina) consigue una reducción significativa de la presión arterial sistólica a las 52 semanas de tratamiento Diferencia PAS 5,1 mmHg Diferencia PAD 1,2 32 *Diferencia vs glipizida+metformina -5,0 mmHg (IC 95% -6,7; -3,4); ** Diferencia vs glipizida+metformina -1,2 mmHg (IC 95% 2,3; -0,2) PAS: Presión arterial sistólica; PAD: Presión arterial diastólica Nauck MA, et al. Diabetes Care 2011;34:2015–22 (supplementary data) mmHg
    32. 32. Safety Comparisons across Phase 3 Dapagliflozin Studies All Disease Education materials must be reviewed in accordance with local review requirements 33
    33. 33. FORXIGA® (dapagliflozina): Resultados de seguridad en 1.193 pacientes en 12 estudios controlados con placebo *Notificadas en ≥ 2% de los sujetos tratados con dapagliflozina 10 mg y con una frecuencia ≥ 1% mayor que en los sujetos tratados con placebo. **Notificadas en ≥ 0,2% de los sujetos y un ≥ 0,1% más veces y en al menos 3 sujetos más tratados con dapagliflozina 10 mg independientemente del tratamiento de rescate glucémico en comparación con placebo. 34 Ficha Técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
    34. 34. La mayoría de las infecciones fueron leves o moderadas y se resolvieron con un único ciclo de tratamiento estándar La mayoría de las infecciones genitales e infecciones del tracto urinario fueron de tipo leve a moderado, raramente llevaron a una interrupción del tratamiento y generalmente se resolvieron con un único ciclo de tratamiento estándar Infecciones del tracto urinario (24 semanas) Placebo 3,7% FORXIGA® 10 mg 4,3% Infecciones genitales (24 semanas)* Placebo 0,9% 35 FORXIGA® 10 mg 4,8% Análisis conjunto de 12 ensayos controlados con placebo * Las infecciones genitales incluyen los siguientes términos de preferencia, que aparecen listados por orden de frecuencia de aparición: infección vulvovaginal micótica, infección vaginal, balanitis, infección genital por hongos, candidiasis vulvovaginal, vulvovaginitis, balanitis por cándida, candidiasis genital, infección genital, infección genital masculina, infección peneana, vulvitis, vaginitis bacteriana, absceso vulvar Ficha Técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
    35. 35. FORXIGA® (dapagliflozina) disminuye en más de 10 veces los episodios de hipoglucemia en comparación con una SU Pacientes con ≥1 episodio hipoglucémico a 1 año (criterio de valoración secundario) *Diferencia vs. GLIP + MET, -37,2% (IC 95% de la diferencia -42,3 a -21,2; p< 0,0001) SU: Sulfonilurea; GLIP: Glipizida; MET: Metformina 36 Nauck MA, et al. Diabetes Care 2011;34:2015–22
    36. 36. Genital infections summary of pooled data up to 24 weeks The rate of clinically diagnosed vaginitis and other related genital infection was higher in the 10 mg dapagliflozin group than with placebo 10 Placebo DAPA 10 mg 8 6.9 Events were more frequently 6 4.8 Perce ntage of subje cts with clinic al diagn osis of genit al infect ion experienced by women than by men All events were mild to moderate in intensity 4 2.7 Most events did not recur with time Most events responded to the initial 2 1.5 0.9 0.3 course of standard therapy 0 Tota l Women Men List J, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Poster # 985-P]. All Disease Education materials must be reviewed in accordance with local review requirements 37
    37. 37. Urinary tract infections summary of pooled data up to 24 weeks The rates of clinically diagnosed UTI were in intensity Most events did not recur with time Placebo DAPA 10 mg 10 clinical diagnosis of UTI All events were mild to moderate Percentage of subjects with slightly higher in the dapagliflozin 10 mg group than with placebo and these events were more frequent in women than men 12 7.7 8 6 4.3 Most events responded to the initial course of standard therapy 6.6 3.7 4 Upper UTI was rare and balanced between groups 1.0 2 0.8 0 Tota l Women Men Parikh SJ, et al. 71st ADA Scientific Sessions, San Diego, June 24-28, 2011 [abstract 984-P]. All Disease Education materials must be reviewed in accordance with local review requirements 38
    38. 38. RESULTADOS: Control de DM tipo 2: naïve o en asociación con otro antiDM (excepto análogos de GLP1) • Descenso de HbA1C. • Descenso de Glucosa en ayunas y postprandial • Útil en pacientes con HbA1C mayor del 9%: descenso de un 2,04% en la semana 24 (solo Dapa) y de 1,32% Dapa+Met Pérdida de peso, incluso en combinacion con Insulina: -2 a -5kg (dependiendo de la combinación de fármacos). Descenso de grasa visceral (medido por DEXA). Descenso de TA sistolica y diastolica:-4,4mmHg y -2,1mmHg Perfil lipídico… All Disease Education materials must be reviewed in accordance with local review requirements 39
    39. 39. Resultados No existe aumento del riesgo cardiovascular. Pero: aumenta colesterol (frente a placebo,sem 24): • Total: +1,4% vs -0,4% • HDL: +5,5% vs 3,8% • LDL:+2,7 vs -1,9% Útil en pacientes con HbA1C mayor del 9%: desenso de un 2,04% en la semana 24 (solo Dapa) y de 1,32% Dapa+Met Renal: menos efecto en Insuf Renal moderada. Descenso de HbA1C: -0,44%. All Disease Education materials must be reviewed in accordance with local review requirements 40
    40. 40. Efectos secundarios Tumores: NO Infecciones de mucosa genital: más frecuente (4% más) Infecciones urinarias: más frecuente (0,6% más) Aumento de Hematocrito (2,15%) Aumento de creatinina inicial-meseta-normalización. Aumento de PTH no asociado a pérdida ósea. Descenso ácido úrico. All Disease Education materials must be reviewed in accordance with local review requirements 41
    41. 41. Situaciones especiales: Insuficiencia renal moderada –grave CrCL: menor 60ml/min).: EVITAR • Función renal al principio y una vez al año. Insuficiencia hepática: Sí, incluso en estadios avanzados (5mg) Infecciones urinarias o genitales previas: EVITAR Situaciones de depleción de volumen: EVITAR • Uso con diuréticos de asa. • Atención a IECAS ARA2. • Situaciones aguda de depleción de volumen: GEA • Ancianos. (No en mayores de 75 años) All Disease Education materials must be reviewed in accordance with local review requirements 42
    42. 42. Situaciones especiales: NO en embarazo , lactancia ni edad pediátrica. Estudios de combinación con antiDM, excepto análogos de GLP1 No interacciona con CIT p450 ni CYP No existe problemas de interacciones farmacológicas (digoxina, sintrom, rifampicina, fenitoinas…) Pioglitazona: tumores vejiga…mejor evitar combinación. Bajar dosis de insulina, secretagogos cuando se añada Dapa NO DM tipo 1…(¿) All Disease Education materials must be reviewed in accordance with local review requirements 43
    43. 43. Situaciones especiales: Sobredosis: • • • • • NO toxicidad en ingestas únicas de 500 mg (50 veces más). NO alteraciones hidroelectroliticas. No hipotensión arterial. No alteraciones QTc. No hipoglucemia. All Disease Education materials must be reviewed in accordance with local review requirements 44
    44. 44. RESUMEN:           FORXIGA 10 MG AL DIA: 1 comprimido. 55,95 euros. Independiente de hora y alimentos Perdida de 70 gramos de glucosa /día en orina mantenido Aumento de diuresis de 375mL al día Pérdida de 280kcal al día. Control de HbA1C con potencia intermedia (menos de 1,5%) Efectos secundarios “clínicos”: infecciones genitourinarias Efectos secundarios laboratorio: poco importantes. No interacciones medicamentosas Puede combinarse con CUALQUIER Antidiabético.  Ojo dosis Insulina y Sulfonilureas. No estudios con análogos GLP1. 45
    45. 45. FORXIGA® (dapagliflozina) – 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 la intolerancia Tratamiento adicional en combinación  En combinación con metformina, iDPP4, sulfonilureas e insulina, cuando estos, junto con dieta y ejercicio, no logren un control glucémico adecuado iDDP4: Inhibidores de la dipeptidil peptidasa tipo 4 Ficha técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
    46. 46. “Forxiga está indicado en adultos de 18 años de edad o mayores con DM tipo 2 para mejorar el control glucémico en terapia doble con metformina cuando esta solo con dieta y ejercicio no alcanza el control glucémico adecuado y en lugar de la asociación metformina con sulfonilurea cuando esta última no se tolera o está contraindicada”.

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