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Metformina 13º Curso Internacional de Diabetes Mellitus.

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Presentación del tema: "Metformina 13º Curso Internacional de Diabetes Mellitus."— Transcripción de la presentación:

1 Metformina 13º Curso Internacional de Diabetes Mellitus.
¿Qué hemos aprendido en los últimos 50 años? 13º Curso Internacional de Diabetes Mellitus. Morelia, Marzo 2014 Dr. José Roberto Gómez Cruz

2 Historia del desarrollo de Metformina
1ª sintesis Metformina Werner y Bell Dublin Descubrimiento de metformina Como agente antidiabético Jean Sterne, Paris, Francia Lanzamiento Glucophage En Francia Uso de fenformina En USA y Europa Se retira Fenformin por alto riesgo de acidosis láctica, metformina en USA Se incorpora uso de biguanidas En Europa, Latinoamerica y Canada Se incorpora su uso en USA UKPDS Efectos antiaterogénicos 1ª línea de terapia Terapia de Combinación

3 Metformina, mecanismo de acción
Reduce la gluconeogénesis lipogénesis Activación AMP cinasa Activa la ON sintetasa Inhibe Neoplasia Biochemical Pharmacology 2013; 86:

4 MTF, mecanismo de acción
Glucagón Metformina Glut2 Adenilato ciclasa OCT1 Receptor Glucagón Glucosa Glucosa 6 P Fructosa 6 P Fructosa 1,6 BP Fosfoenólpiruvato Oxaloacetato Piruvato ATP AMPc NADH ATP AMP PKA AMPK Otros blancos Síntesis de lípidos y colesterol Núcleo Expresión de genes lipogénicos Expresión de genes gluconeogénicos Diabetologia. 2013; 56:

5 UKPDS Descenso de HbA1c Years from randomisation 10 9 8 7 6 3 12 15
Conventional Glibenclamide Insulin Chlorpropamide Metformin Clinical outcomes in the UKPDS Intensive glycaemic management with metformin significantly reduced the incidence of a range of clinical outcomes, including diabetes-related death and myocardial infarction, relative to conventional diet-based management.1 Although patients receiving intensive glycaemic management with a sulphonylurea or insulin benefited from the same degree of blood glucose control, significant protection from these complications was not observed in these patients. Thus, metformin may provide benefits above and beyond those arising from improved blood glucose control per se. A subgroup analysis of the UKPDS data showed that the cardioprotective effects of metformin did not differ significantly between patients on different average daily doses of metformin (<1000 mg, 1000–1699 mg, or 1700 mg).2 Patients whose optimised dose of metformin is relatively low may therefore expect to benefit from the cardioprotective properties of metformin. 1. UK Prospective Diabetes Study Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352: 2. Stratton IM, Holman RR. The cardioprotective effects of metformin may not be dose-dependent. Diabet Med 2003; 20 Suppl 2: A55. UKPDS 34. Lancet :

6 UKPDS Desenlaces clínicos
Metformina (n= 342) Cambio en el riesgo P Mortalidad general 36% 0.011 Muertes relacionadas a DM 42% 0.017 Cualquier desenlace relacionado con diabetes 32% 0.0023 Infarto al miocardio 39% 0.01 AVC 41 % 0.13 UKPDS 34. Lancet :

7 Desenlace: Mortalidad.
Mortalidad asociada a la monoterapia con sulfonilurea comparado con metformina Estudio retrospectivo. Clinical Practice Research Datalink (CPRD). 10% de pacientes del UK Pacientes: Diabéticos tipo 2, que iniciaron tratamiento del 2000 al 2012 Desenlace: Mortalidad. Diabetologia 2013; 56 (Suppl) S1-S566

8 SU vs MFT mortalidad Seguimiento de 2.9 años SU 15,687 2,172 13.8 3.32
Cohorte Pacientes Eventos Tasa de eventos RR (IC 95%) SU 15,687 2,172 13.8 3.32 MFT 76,811 3,209 4.1 ( ) 8,836 1,121 12.6 1.52 739 8.36 ( ) Seguimiento de 2.9 años Diabetologia 2013; 56 (Suppl) S1-S566

9 MFT vs SU mortalidad NNT: 23 MFT 76,811 3,209 4.1 0.30 SU 15,687 2,172
Cohorte Pacientes Eventos Tasa de eventos RR (IC 95%) MFT 76,811 3,209 4.1 0.30 SU 15,687 2,172 13.8 ( ) 8,836 739 8.36 0.66 1,121 12.6 ( ) NNT: 23 Modificado de Diabetologia 2013; 56 (Suppl) S1-S566

10 Metformina, mecanismo de acción, Activación de óxido nítrico
Activación de AMP cinasa Reduce la gluconeogénesis Aumenta la relación AMp/ATP Activa la ON sintetasa Disminuye la degradación del AMP Neoplasia Biochemical Pharmacology 2013; 86:

11 MTF y endotelio Activa la ON sintetasa favorece la vasodilatación
Inhibe la adhesión de monocitos a las células endoteliales Disminuye la adhesión, activación y agregación plaquetaria Slide 18. Recruitment of blood monocytes by endothelial cell adhesion molecules Adhesion molecules are involved in the adhesion of monocytes to endothelial cells. Monocytes come in random contact with endothelial cells, and the adhesion molecule E-selectin slows the monocyte by inducing rolling of the monocyte along the endothelial surface before firm attachment to vascular cell adhesion molecule 1 (VCAM-1) or intercellular adhesion molecule 1 (ICAM-1), which interact with integrins on the monocyte surface. Once the monocyte is tightly bound, it then migrates between endothelial cells in response to MCP-1. Reference: Charo IF. Monocyte–endothelial cell interactions. Curr Opin Lipidol 1992;3: {no PubMed link} Keywords: adhesion molecules, atherogenesis, E-selectin, ICAM-1, inflammation, MCP-1, monocytes, VCAM-1 Slide type: figure Gargiulo P et al. Diabetes Metab Res Rev, Marzo/Abril 2002;18: Kirpichnikov D et al. Ann Intern Med, Julio 2002;137:25-33 Caballero AE et al. J Clin Endocrinol Metab, Agosto 2004;89: De Jager J et al. J Intern Med, Enero 2005;257: Formoso G et al. Diabetes Metab Res Rev, Marzo/Abril 2008;24: Mamputu JC et al. Br J Diabetes Vasc Dis, Julio/Agosto 2003;3: Bruun JM et al. J Clin Endocrinol Metab, Abril 2005;90:

12 MTF y Corazón Previene el daño por reperfusión
Limita el tamaño del infarto Reduce la expresión de colágena, previene la fibrosis cardiaca. Slide 18. Recruitment of blood monocytes by endothelial cell adhesion molecules Adhesion molecules are involved in the adhesion of monocytes to endothelial cells. Monocytes come in random contact with endothelial cells, and the adhesion molecule E-selectin slows the monocyte by inducing rolling of the monocyte along the endothelial surface before firm attachment to vascular cell adhesion molecule 1 (VCAM-1) or intercellular adhesion molecule 1 (ICAM-1), which interact with integrins on the monocyte surface. Once the monocyte is tightly bound, it then migrates between endothelial cells in response to MCP-1. Reference: Charo IF. Monocyte–endothelial cell interactions. Curr Opin Lipidol 1992;3: {no PubMed link} Keywords: adhesion molecules, atherogenesis, E-selectin, ICAM-1, inflammation, MCP-1, monocytes, VCAM-1 Slide type: figure Preserva la viabilidad del miocito y posiblemente prevenga el remodelamiento y la falla cardiaca Curr Cardiol Rep 2013; 15: 327

13 MTF y Corazón MTF SICA e IAM Enfermedad Coronaria Estable
Slide 18. Recruitment of blood monocytes by endothelial cell adhesion molecules Adhesion molecules are involved in the adhesion of monocytes to endothelial cells. Monocytes come in random contact with endothelial cells, and the adhesion molecule E-selectin slows the monocyte by inducing rolling of the monocyte along the endothelial surface before firm attachment to vascular cell adhesion molecule 1 (VCAM-1) or intercellular adhesion molecule 1 (ICAM-1), which interact with integrins on the monocyte surface. Once the monocyte is tightly bound, it then migrates between endothelial cells in response to MCP-1. Reference: Charo IF. Monocyte–endothelial cell interactions. Curr Opin Lipidol 1992;3: {no PubMed link} Keywords: adhesion molecules, atherogenesis, E-selectin, ICAM-1, inflammation, MCP-1, monocytes, VCAM-1 Slide type: figure Insuficiencia cardiaca Diabetes Metab 2013; 39:

14 MTF en DM y SICA o IAM Estudios observacionales Autor Diseño
Comparador HR IC 95% Inzucchi. 2005 Cohorte retrospectiva. Cualquier agente 0.92 Jorgensen. 2010 Cohorte retrospectiva Danés Cualquier SU 0.80 Jorgensen. 2011 Base de datos Nacional Glibenclamida 0.40 Mellbin. 2011 Análisis post hoc DIGAMI 2 0.65 Inzucchi. Diabetes care 2005; 28: 1680 RESEARCH DESIGN AND METHODS— We conducted a retrospective cohort study of 24,953 Medicare beneficiaries with diabetes discharged after hospitalization with AMI between April 1998 and March 1999 or July 2000 and June The independent association between discharge prescription for metformin, TZD, or both agents and outcomes at 1 year was assessed in multivariable Cox proportional hazards models, adjusting for patient, physician, and hospital variables. The primary outcome was time to death within 1 year of discharge; secondary outcomes were time to first rehospitalization within 1 year of discharge for AMI, heart failure, and all causes. RESULTS— There were 8,872 patients discharged on an antihyperglycemic agent, of which 819 were prescribed a TZD, 1,273 metformin, and 139 both drugs. After multivariable analysis, compared with patients prescribed an antihyperglycemic regimen that included no insulin sensitizer, mortality rates were not significantly different in patients treated with either metformin (hazard ratio [HR] 0.92 [95% CI 0.81–1.06]) or a TZD (0.92 [0.80 –1.05]) but were lower in those prescribed both drugs (0.52 [0.34–0.82]). The results were similar among patients with heart failure. The prescription of a TZD was associated with a borderline higher risk of all-cause readmission (1.09[1.00 –1.20]), predominately due to a higher risk for heart failure readmission (1.17 [1.05–1.30]). Cardiovasc Diabetol Sep 16;9:54. doi: / Effects of oral glucose-lowering drugs on long term outcomes in patients with diabetes mellitus following myocardial infarction not treated with emergent percutaneous coronary intervention--a retrospective nationwide cohort study.Jørgensen CH1, Gislason GH, Andersson C, Ahlehoff O, Charlot M, Schramm TK, Vaag A, Abildstrøm SZ, Torp-Pedersen C, Hansen PR.Author informationAbstractBACKGROUND:The optimum oral pharmacological treatment of diabetes mellitus to reduce cardiovascular disease and mortality following myocardial infarction has not been established. We therefore set out to investigate the association between individual oral glucose-lowering drugs and cardiovascular outcomes following myocardial infarction in patients with diabetes mellitus not treated with emergent percutaneous coronary intervention.MATERIALS AND METHODS:All patients aged 30 years or older receiving glucose-lowering drugs (GLDs) and admitted with myocardial infarction (MI) not treated with emergent percutaneous coronary intervention in Denmark during were identified by individual-level linkage of nationwide registries of hospitalizations and drug dispensing from pharmacies. Multivariable Cox regression models adjusted for age, sex, calendar year, comorbidity, and concomitant pharmacotherapy were used to assess differences in the composite endpoint of non-fatal MI and cardiovascular mortality between individual GLDs, using metformin monotherapy as reference.RESULTS:The study comprised 9876 users of GLDs admitted with MI. The mean age was 72.3 years and 56.5% of patients were men. A total of 3649 received sulfonylureas and 711 received metformin at admission. The average length of follow-up was 2.2 (SD 2.6) years. A total of 6,171 patients experienced the composite study endpoint. The sulfonylureas glibenclamide, glimepiride, glipizide, and tolbutamide were associated with increased risk of cardiovascular mortality and/or nonfatal MI with hazard ratios [HRs] of 1.31 (95% confidence interval [CI] ), 1.19 ( ), 1.25 ( ), and 1.18 ( ), respectively, compared with metformin. Gliclazide was the only sulfonylurea not associated with increased risk compared with metformin (HR 1.03 [ ]).CONCLUSIONS:In patients with diabetes mellitus admitted with MI not treated with emergent percutaneous coronary intervention, monotherapy treatment with the sulfonylureas glibenclamide, glimepiride, glipizide, and tolbutamide was associated with increased cardiovascular risk compared with metformin monotherapy. Diabetes Metab 2013; 39:

15 MTF en DM y enfermedad coronaria estable
Estudios observacionales Mortalidad en pacientes con DMT2 e IAM en tx con MTF Autor , año (seguimiento) Diseño Comparador HR IC 95% Fisman. 1999 (5 años) Israel (n:2395) alimentación 1.42 Schramm. 2011 (9 años) Base de datos Nacional, Danés. (n:9607) Glimepirida 0.77 Pantalone Cohorte retrospectiva EUA, (n: 2721) Glibenclamida, glipizida 0.72 0.71 Cardiology. 1999;91(3): Antihyperglycemic treatment in diabetics with coronary disease: increased metformin-associated mortality over a 5-year follow-up.Fisman EZ1, Tenenbaum A, Benderly M, Goldbourt U, Behar S, Motro M.Author informationAbstractMortality rates are considerably higher in chronic ischemic heart disease (IHD) patients with non-insulin-dependent diabetes mellitus (NIDDM) than in those who are nondiabetics. The relationship between different types of antihyperglycemic pharmacological therapy and mortality rate in this NIDDM population is uncertain. We aimed to examine the survival in NIDDM patients with IHD using various types of oral antidiabetic treatments over a 5-year follow-up period. The study sample comprised 11,440 patients with a previous myocardial infarction and/or stable anginal syndrome, aged years, who were screened, but not included in the Bezafibrate Infarction Prevention study. Among them, 9,045 were nondiabetics and 2,395 diabetics. The diabetic patients were divided into four groups on the basis of their therapeutic regimen at screening: diet alone (n = 990), sulfonylureas (n = 1,041), metformin (n = 78) and a combination of a sulfonylurea and metformin (n = 266). All NIDDM groups were similar with regard to age, gender, hypertension, smoking, heart failure, angina and prior myocardial infarction. Crude mortality rate was lower in the nondiabetic group (11.21 vs. 21.8%; p < 0.001). In the diabetic group, mortality was 18.5% for patients on diet alone, 22.5% for those on sulfonylureas, 25.6% for patients on metformin, and 31.6% for the combined sulfonylurea/metformin group (p < 0.01). When analyzing age-adjusted mortality rate and actuarial survival curves, the lowest mortality was found in patients on diet alone and the highest in patients on metformin (alone or in combination with sulfonylureas). After adjustment for variables connected with long-term prognosis, the use of metformin was associated with increased relative risk (RR) for all-cause mortality of 1.42 (95% CI ), whereas the use of sulfonylureas alone was not [RR 1.11 (95% CI )]. NIDDM patients with IHD using metformin, alone or in combination with sulfonylureas, exhibited a significantly increased mortality. Until the results of problem-oriented prospective studies on oral control of NIDDM will be available, alternative therapeutic approaches should be investigated in these patients. Diabetes Metab 2013; 39:

16 MTF en DM e insuficiencia cardiaca
Objetivo: Evaluar la morbilidad y la mortalidad del empleo de MTF en pacientes diabéticos con falla cardiaca (FC). Desenlaces: Mortalidad general, hospitalización y morbilidad y mortalidad asociada a FC. Análisis en pacientes con Insuficiencia renal y FC. Estrategia de búsqueda. De ,2012. Health Star, EMBASE, AMED, CINAHL, IPA, Medline, Web of Science y Cochrane Central Registry of Controlled trialls. Circ Heart Fail 2013; 6:

17 MTF en DM e insuficiencia cardiaca
Resultados: De 12,994 referencias se incluyeron: 9 estudios observacionales. 34,504 pacientes, 19 % (6,624) recibieron MTF. Circ Heart Fail 2013; 6:

18 MTF en DM e insuficiencia cardiaca
Resultados MFT Comparador RR IC (95%) Mortalidad 23% (1497/6624) 37% (10221/27880) 0.69 Riesgo ajustado IC 95% Hospitalización 3 estudios 0.93 Hospitalización por FC 2 estudios 0.92 En pacientes con IRC y FC MTF no se asoció con incremento de la mortalidad Circ Heart Fail 2013; 6:

19 Metformina, mecanismo de acción, Activación de óxido nítrico
Activación de AMP cinasa Reduce la gluconeogénesis Aumenta la relación AMp/ATP Activa la ON sintetasa Disminuye la degradación del AMP Neoplasia Biochemical Pharmacology 2013; 86:

20 Metformina, mecanismo de acción, Neoplasia
Inhibe el crecimiento celular Activación de AMPK Inactiva TORC1 Inactiva GTP-Rheb Favorece autofagocitosis Activa el complejo TSC1/TSC2 (Actividad GTPasa) Inhibe Angiogénesis Detiene el ciclo celular dependiente de energía Biochemical Pharmacology 2013; 86:

21 MTF y riesgo de cáncer. Metaaálisis
Incluyeron estudios analíticos. Bases de datos de estudios experimentales Desenlace incidencia o mortalidad por cáncer PurposeTo assess the effect of metformin intake on cancer incidence and mortality.MethodsOriginal articles in English published until June 15, 2012 were searched for in electronic databases (MEDLINE, ISI Web of Science and EMBASE databases) and relevant reviews were examined. Meta-analysis was applied to calculate the summary relative risk (SRR) and their 95% confidence intervals (95% CI). Sensitivity analysis was conducted to assess the robustness of the pooled estimator. The risk of publication bias was assessed by the Egger regression asymmetry test.ResultsAccording to the eligibility criteria, 37 studies comprising 1,535,636 participants, were selected in terms of intervention and data of cancer incidence or mortality. Among metformin users compared with non-users, the SRR for overall-cancer incidence was 0.73 (95% CI, 0.64–0.83) and that for mortality was 0.82 (95% CI, 0.76–0.89). The risk reductions for liver, pancreatic, colorectal and breast cancer incidence were 78%, 46%, 23% and 6%, respectively. Also, metformin can reduce the mortality of liver cancer (SRR, 0.23; 95% CI, 0.09–0.60) and breast cancer (SRR, 0.63; 95% CI, 0.40–0.99). No statistically significant association between metformin and prostate cancer incidence was found.ConclusionsMetformin can reduce the incidence of overall cancer, liver cancer, pancreatic cancer, colorectal cancer and breast cancer as well as the mortality of overall cancer, liver cancer and breast cancer. No beneficial effect on prostate cancer incidence was found for meformin intake in the meta-analysis. Cancer Epidemiology 2013; 37:

22 MTF y riesgo de cáncer. Metaaálisis
Cancer Epidemiology 2013; 37:

23 MTF y riesgo de cáncer hepático. Metaaálisis
Cancer Epidemiology 2013; 37:

24 MTF y riesgo de cáncer pancreático. Metaaálisis
Cancer Epidemiology 2013; 37:

25 Mortalidad por cáncer Seguimiento 9.6 años;edad 68 años;A1c 7.5
Indice de mortalidad estandarizado(SMR) fué 1.47 (95% CI 1.22–1.76). Metformina vs Pts que no tomaban metformina el HR para cáncer fué de 0.43 (IC 95% ( ). In general, patients with type 2 diabetes are at increased risk for cancer mortality. In our group, metformin use was associated with lower cancer mortality compared with nonuse of metformin. Although the design cannot provide a conclusion about causality, our results suggest a protective effect of metformin on cancer mortality. Landman et al, Diabetes Care 33:322–326, 2010

26 MTF, mecanismo de acción
Metformina Glucagón Glut2 Adenilato ciclasa OCT1 Receptor Glucagón Glucosa Glucosa 6 P Fructosa 6 P Fructosa 1,6 BP Fosfoenólpiruvato Oxaloacetato Piruvato ATP AMPc NADH ATP AMP PKA AMPK Otros blancos Síntesis de lípidos y colesterol Núcleo Expresión de genes lipogénicos Expresión de genes gluconeogénicos Diabetologia. 2013; 56:

27 MFT y acidosis láctica

28 MFT y acidosis láctica Objetivo: Evaluar la incidencia de acidosis láctica fatal y no fatal, MTF vs otros. Evaluar los niveles de A. Láctico MTF vs otros. Estrategias de búsqueda: The Cochrane Library, MEDLINE, EMBASE, OLD MEDICINE y REACTIONS, ( ,2005) Selección de artículos: Ensayos prospectivos y cohortes prospectivas con diabéticos tipo 2, de mas de un mes de duración

29 MFT y acidosis láctica MTF: Metformina

30 MTF e insuficiencia renal
Resultados de estudios observacionales Mortalidad en pacientes que recibieron metformina comparada con otros antidiabéticos Autor TFG MTF vs comparados HR IC 95% Roussel 2010 >60 44442 vs 6326 0.89 30-60 1572 vs 3388 0.64 Ekstrom 2012 28,015 vs 31,614 0.87 45-60 4079 vs 6176 30-45 715 vs 2152 1.02 TGF: Tasa de filtrado glomerular mL/min/1.73m2 Diabetes Metab 2013; 39:

31 MTF e insuficiencia renal
Recomendaciones propuestas para el uso de MTF Filtración Glomerular (mL/min por 1.73m2) Recomendación > 60 Sin contraindicación Monitorear función renal anualmente 60-45 Continuar su uso Monitorear función renal cada 3-4 meses 45-30 Usar con precaución Y el 50% de la dosis máxima Monitorear función renal cada 3 meses < 30 Suspender el uso de MTF Diabetes Care 2011; 34:

32 MTF y daño hepático Estudio observacional, del 100 diabéticos con cirrosis por hepatitis C, 5.7 años de seguimiento Riesgo Ca Hepatocelular HR: 0.19 IC 95%: Riesgo de muerte o trasplante HR: 0.22 IC 95%: J Clin Endocrinol Metab 2011; 96: 2398

33 MTF e Hígado graso no alcohólico
Metformina puede ser utilizada No incrementa el riesgo de acidosis láctica No mejora el contenido graso del hígado Am J Gastroenterol 2005; 100: 1082 Diabetes 2004; 53: 2169 Diabetologia 2012; 55:885 Gastroenterology 2012; 142: 1592

34 La falla hepática es una contraindicación
MTF y falla hepática Debido a la falta de estudios que documenten su seguridad. La falla hepática es una contraindicación Diabetes Metab 2013; 39: 179

35 MTF en no diabéticos The Lancet Diabetes & Endocrinology, Early Online Publication, 7 November 2013doi: /S (13)

36 MTF en no diabéticos Un ensayo clínico controlado, doble ciego realizado en Glasgow Clinical Research Facility (Glasgow, UK) Pacientes: Sujetos con enfermedad coronaria, obesidad central, SIN DIABETES. Intervención: MTF 850 mg dos veces al día o placebo. Desenlaces: a 18 meses , grosor de la intima media carotidea (IntMedCa), escala de la placa carotidea (EPC), niveles de glucosa, Hba1c, HOMA, lípidos y marcadores de inflamación. Resultados: Sin diferencias en IntMedCa,EPC, lípidos y marcadores de inflamación. Menor nivel de glucosa HbA1c y HOMA. The Lancet Diabetes & Endocrinology, Early Online Publication, 7 November 2013doi: /S (13)

37 Colofón Que bueno que se descubrieron hace mas de 50 años
La Metformina Medicamento extraordinario Disminuye las complicaciones crónicas Tiene protección cardiovascular Muy bajo riesgo de acidosis láctica Estudios sugieren Disminuir riesgo de neoplasia y mejorar el pronóstico Potencial uso en pacientes con insuficiencia cardiaca cardiopatía isquemica. Seguridad de empleo en pacientes con filtrado glomerular > 30 ml/min 1.73m2 Que bueno que se descubrieron hace mas de 50 años

38 Gracias.


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