Glimemetfor14
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1) La terapia combinada es importante en el manejo de la diabetes mellitus tipo 2 para controlar los defectos metabólicos subyacentes como la hiperglucemia, resistencia a la insulina y deficiencia de secreción de insulina. 2) Las sulfonilureas como la glimepirida y la metformina tienen efectos sinérgicos al mejorar la secreción de insulina y sensibilidad a la insulina respectivamente. 3) La elección del régimen de tratamiento debería considerar factores como la eficacia glucémica, el
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- 1. TERAPIA COMBINADA EN EL MANEJO DE LA DIABETES MELLITUS 2 HUGO CESAR ARBAÑIL HUAMAN Jefe de servicio de endocrinología “FAUSTO GARMENDIA LORENA” Hospital nacional dos de mayo
- 2. DEFECTOS METABÓLICOS EN LA DM TIPO 2 SSEECCRREECCIIÓÓNN DDEEFFIICCIIEENNTTEE PPÁÁNNCCRREEAASS HHÍÍGGAADDOO Adaptado de De FFrroonnzzoo.. DDiiaabbeetteess 11998888 HHIIPPEERRGGLLUUCCEEMMIIAA CCAAPPTTAACCIIÓÓNN DDEE GGLLUUCCOOSSAA DDIISSMMIINNUUIIDDAA RREESSIISSTTEENNCCIIAA AA LLAA IINNSSUULLIINNAA DDEE IINNSSUULLIINNAA PPRROODDUUCCCCIIÓÓNN HHEEPPÁÁTTIICCAA DDEE GGLLUUCCOOSSAA AAUUMMEENNTTAADDAA TTEEJJIIDDOO AADDIIPPOOSSOO YY MMUUSSCCUULLAARR
- 3. PATOGÉNESIS DE LA DM2 PAPEL DE LA TOXICIDAD DE LA GLUCOSA Tolerancia disminuida a la glucosa DeFronzo RA. Diabetes 37:667,1988 – Idem Diabetes Reviews 5(3):1,1997 Toxicidad de la glucosa Secreción de insulina disminuida Resistencia a la insulina Tolerancia disminuida a la glucosa Hiperglucemia de la DM2 Toxicidad de la glucosa
- 4. LLAASS GGEENNEERRAACCIIOONNEESS DDEE SSUULLFFOONNIILLUURREEAASS GENERACIÓN PRINCIPIO ACTIVO NOMBRE COMERCIAL PRIMERA GENERACIÓN Clorpropamida Diabinese® Acetohexamida Dymelor ® Tolazamida Tolinase ® Tolbutamida Rastinon ® SEGUNDA GENERACIÓN Glibenclamida (Gliburida) Daonil ® Glipizida Minodiab ®, Glucotrol ® Gliclazida Diamicron ® ÚLTIMA GENERACIÓN* Glimepirida GLYPRIDE ® *Goldberg et al. (Diabetes Care 19:849-56,1996)
- 5. SU – MECANISMO DE SSEECCRREECCIIÓÓNN DDEE IINNSSUULLIINNAA SSUULLFFOONNIILLUURREEAASS ddeessppoollaarriizzaacciióónn GGLLUUCCOOSSAA AAMMIINNOOÁÁCCIIDDOOSS cciieerrrraa ((AATTPP)) ((AADDPP)) CCaa++++ ((CCaa++++ )) PPRROOIINNSSUULLIINNAA MMEETTAABBOOLLIISSMMOO KK++ KK++ IINNSSUULLIINNAA && PPEEPPTTIIDDOO -- CC Ref. Lebovitz,HE: Oral Antidiabetic Agents. In Joslin’s Diabetes Mellitus. 13th ed. Kahn CR, Weir GC, Eds. Lea & Febiger, 1994, p.508-529, Feinglos MN, Bethel MA. Med Clin North Am 82:757-90,1998.
- 6. Perfil Favorable de Hipoglicemia Estudio Prospectivo de tres años, basado en la población con >21,000 pacientes (Alemania). Prevalencia de Hipoglicemia Severa* I II III IV I II III IV I II III IV 1997 1998 1999 Período - Trimestres 10 8 6 4 2 0 Casos de Hipoglicemia Severa (Acumulativo) Gliburida hipoglicemia Glimepirida hipoglicemia * Definido como la cantidad de glucagon y glucosa IV requerido en caso de alteración de la conciencia y confirmado por la determinación de glucosa en sangre. Holstein et al. Diabetologia 2000;43:A40.
- 7. Cambio de peso con Terapia Antidiabética en UKPDS* Cohorte 10 0 Cambio promedio de peso (kg) Años desde la Randomización Insulina Clorpropamida Gliburida Convencional Metformina UKPDS 5 0 -5 2 4 6 8 10 *Pacientes con sobrepeso
- 8. Meta-análisis* de Datos de Estudios Clínicos Esenciales: Cambio promedio de peso entre la Línea basal y 12 meses Glimepirida Datos clínicos Fase III demuestran una tendencia hacia la 0.2 0.1 0.02 0 Glimepirida n=1,444 Control n=1,002 Gliburida n=207 Glipizida neutralidad del peso Cambio promedio de peso (kg) P =.05 P = .81 Bugos et al. Diabetes Res *Meta-análisis de datos de 4 estudios Clin Pract 2000;50(suppl 1).
- 9. Secreción Fisiológica de Insulina Depende de la Concentración de Glucosa Objetivo: • Evaluar la liberación de insulina por los islotes humanos después de una exposición aguda a glimepiride Métodos: • Los islotes pancreáticos humanos fueron expuestos a varias concentraciones de glimepirida y glucosa • Se midieron los niveles de secreción de insulina resultantes Del Guerra et al. Acta Diabetol 2000;37:139.
- 10. Secreción Fisiológica de Insulina Dependiente de la Concentración de Glucosa Resultados: 3 2.5 2 1.5 1 0.5 0 100 10 1 0 2.5 5 10 20 Concentración de Glimepirida (mmol/L) Glucosa (mmol/L) Secreción de Insulina * (mU/islot/45min) Del Guerra *Islotes pancreáticos humanos aislados et al. Acta Diabetol 2000;37:139.
- 11. Efecto de la exposición crónica a Sulfonilúreas sobre celulas de islotes b humanos Diseño: • Incubación de los islotes humanos exp. Cronic. A SU en 24 h con diferentes glucemias • Estímulo de Glucosa por 45min. 3.3mM de glucosa (sombraoscura) y 16.7mM (sombra clara) 6 5 4 3 2 1 0 Control Gp 1μM Gp 10μM Gb 1μM Gb 10μM Chl 200μM Chl 600μM Secreción de Insulina (% de contenido celular) * * P < .01 † P < .05 † * Del Guerra et al. en prensa ns Gp = Glimepirida; Gb = glibenclamida; Chl = Clorpropamida
- 12. Precondicionamiento Isquémico Una oclusión prolongada de una arteria epicárdica conduce a infarto del miocardio Las oclusiones repetidas y breves de los mismos vasos condicionan el miocardio de forma tal que las subsecuentes oclusiones prolongadas conducen a infartos mas pequeños (precondicionamiento isquémico)
- 13. Precondicionamiento Isquémico (IP) • IP es un poderoso mecanismo endógeno por el cual se autoprotege el corazón de lesiones isquémicas letales • IP ocurre cuando los canales de KATP cardíacos se abren automáticamente durante breves episodios de isquemia miocárdica leve • Las drogas que inhiben la apertura de los canales KATP cardíacos pueden ser dañinas para el miocardio isquémico por supresión de los componentes dependientes del canal KATP de la respuesta de precondicionamiento isquémico Brady et al. J Am Coll Cardiol 1998;31(5):950.
- 14. Complejo del Canal KATP SFU SUR2A Algunas sulfonilúreas no son selectivas para los canales de KATP del corazón o páncreas Kir6.2 Responsable para el flujo K+ Kir6.2 SFU SUR1 68% homólogo Los canales KATP , un complejo de receptor de sulfonilúrea (SUR2A, SUR1) y los canales de potasio (Kir6.2) es la clave de la liberación de insulina mediada por glucosa de las células b pancreáticas
- 15. Sulfonilurea y Preacondicionamiento Isquémico Objetivo: • Evaluar el efecto de glimepirida vs glibenclamida en el precondicionamiento isquémico Diseño del estudio: • N = 45 pacientes con enfermedad coronaria estable – Glimepirida (n = 15) – Glibenclamida (n = 15) – Placebo (n = 15) • Estudio controlado con placebo, doble-ciego, randomizado, • Inflado del Balón durante PTCA con registro intracoronario de ECG para marcar el desarrollo de isquemia miocárdica Klepzig et al. Eur Heart J 1999;20:439.
- 16. Sulfonilureas y Precondicionamiento Isquémico • Pacientes sometidos a dilatación de 3 arterias coronarias por inflado del balón: – Dilatación 1: Para determinar la eligibilidad de los pacientes – Dilatación 2: nivel basal (antes de la administración de la droga) – Dilatación 3: Para determinar el efecto de la glimepirida, glibenclamida, y placebo en el precondicionamiento • Dosificación de la Droga: – Glimepirida: 1 mg IV seguido de 18 mg/min por 9 min (» 4 mg oral) – Glibenclamida: 2 mg IV seguido de 60 mg/min por 9 minutos (» 10 mg oral) – Placebo (salina): 3 min bolus seguido de infusión por 9 min Klepzig et al. Eur Heart J 1999;20:439.
- 17. Promedio de Depresión del Segmento ST Glimepirida redujo el promedio de depresión del segmento ST por el balón de oclusión en 34% (placebo 35%) sugiriendo un efecto NO perjudicial en el precondicionamiento isquémico, mientras que el efecto de gliburide fué Klepzig et al. Eur Heart J 1999;20:439. insignificante promedio de ST % Cambio 150 100 50 0 Placebo Glimepirida Gliburida Dilatación 2 (Línea basal) Dilatación 3 (Después de tratamiento) P = .01 P = NS P = .049
- 18. No todas las Sulfonilúreas Bloquean KATP del Músculo Flujo sanguíneo del antebrazo en respuesta al diazóxido: la glibenclamida pero no la glimepirida bloquea la vasodilatación en respuesta al efecto de apertura del 900 700 500 300 100 % Cambio de la relación del Flujo sanguíneo en el antebrazo *P < .01 canal de KATP por diazóxido Placebo Glimepirida Placebo Glibenclamida Bijlstra et al. Diabetologia 1996;39:1083. *P = NS * Valor de P comparado con placebo
- 19. Perfil Cardiovascular • Glibenclamida suprime el efecto cardioprotector del precondicionamiento isquémico por inhibición de la apertura de los canales KATP mitocondriales en los cardiomiocitos • Glimepirida se une a diferentes receptores específicos del páncreas y no entorpece el precondicionamiento isquémico Klepzig et al. Eur Heart J 1999;20:439. Mocanu et al. Circulation 103, 2001; 3111-3116.
- 20. Nuevos datos de los Estudios Controlados de Glimepirida y los de Vigilancia de Post-Mercadeo Glimepirida : • Menos hipoglicemia que glibenclamida • Perfil de variación de peso apropiado • Potenciales efectos insulinomiméticos • Secreción fisiológica de insulina (Ej, dependiente de la concentración de glucosa) • Perfil cardiovascular favorable • Efectos pleiotropicos: PPAR g • Cambios en adiponectina
- 21. Dose-relationship of antihyperglycaemic actions of metformin †p<0.001 vs. placebo Garber AJ et al. Am J Med 1997;102:491-7 0,0 -0,5 -1,0 -1,5 -2,0 -2,5 500 mg 1000 mg 1500 mg 2000 mg 2500 mg Change in HbA1C vs. placebo (%) † † † † † Metformin dose
- 22. Antihyperglycaemic efficacy and insulin-sparing action of metformin 10 8 6 4 2 0 p<0.05 p<0.01 HbA 120 100 80 60 40 20 0 1C Fasting insulin % units pmol/L Baseline 3 months of metformin DeFronzo RA et al. Clin Endocrinol Metab 1991;73:1294-301
- 23. Comparative efficacy of metformin: meta-analysis of 11 studies HbA1C Fasting glucose Postprandial glucose Baseline Final 10 9 8 7 Metformin (n=148) SU (n=159) 10 9 8 7 Metformin (n=148) SU (n=159) 20 15 10 5 Metformin (n=214) SU (n=213) -12.5% -12.5% -14% -19% -44.5% -44.5% mmol/L % mmol/L Campbell IW et al. Diabetes Metab Rev 1995;11 Suppl 1:S57-62 SU: sulfonylurea
- 24. Choice of agents in current use Sulfonylureas Acarbose Miglitol Voglibose Glipizide Gliclazide Glimepiride Glibenclamide TZDs Metformin a-glucosidase Meglitinides inhibitors Rosiglitazone Pioglitazone Repaglinide Nateglinide
- 25. Effects of Metformin Added to a Sulfonylurea Glucose and Insulin Profiles Glipizide alone 300 200 100 Meal Meal Meal Meal Jeppesen J et al. Diabetes Care. 1994;17:1093-1099 Glipizide + metformin Insulin pmol/L 400 300 200 100 0 0800 1200 1800 2400 500 Glucose Time of day mg/dL 0 0800 1200 1800 2400
- 26. Eficacia de Tx combinado basado en metformina HbA1C (%) Base Mean change Metformin + glibenclamide1 8.8 –1.7 Metformin + glimepiride2 6.5 -0.7 Metformin + repaglinide3 8.5 -1.4 Metformin + pioglitazone4 9.8 -0.6 Metformin + rosiglitazone5 8.8 -0.8 Metformin + acarbose6 8.3 -0.6 1DeFronzo RA et al. N Engl J Med 1995;333:541-9; 2Charpentier G et al. Diabet Med 2001;16: 828-34 3Moses R et al. Diabetes Care 1999;22:119-24; 4Einhorn D et al. Clin Ther 2000;22:1395-409 5Fonseca V et al. JAMA 2000;283:1695-702; 6Rosenstock J et al. Diabetes Care 1998;21:2050-5
- 27. Outcomes associated with metformin or sulfonylurea treatment in a UK population SU monotherapy Metformin then add SU SU then add metformin Initial treatment with SU + metformin 0 1 2 3 4 5 Relative risk (95% CI) All-cause mortality Cardiovascular mortality Cardiovascular hospitalisation Evans JM et al. Diabetologia 2006;49:930-6
- 28. Little influence of weight on the antihyperglycaemic efficacy of metformin HbA1C (%, 95% CI) 0.0 Non-obese Obese in -0.4 –1.46 –1.34 change (1.34 to 1.57) (1.25 to 1.42) -0.8 Mean -1.2 -1.6 p=0.11 A reduction in BMI of 5 kg/m2 increased the HbAresponse to metformin by 0.08% 1C Obese = body mass index >30 kg/m2 Donnelly LA et al. Diabet Med 2006;23:128-33
- 29. 5 When to consider sulfonylurea as an alternative to metformin • Consider sulfonylurea here if: • not overweight (tailor the assessment of body-weight- associated risk according to ethnic group, see the diet pathway for more information) • metformin is not tolerated or is contraindicated, or • A rapid therapeutic response is required because of hyperglycaemic symptoms. • Offer once-daily sulfonylurea if adherence is a problem.
- 30. After Metformin, Are Newer Drugs Better for Type 2 Diabetes? Miriam E. Tucker,,March 17, 2014 • Diabetes Care published ahead of print February 26, 2014 1935-5548 • Diabetes Care published ahead of print February 26, 2014 1935-5548
- 31. 5 When to consider sulfonylurea as an alternative to metformin • Prescribe a sulfonylurea with a low acquisition cost (not glibenclamide) when an insulin • secretagogue is indicated. • Educate the person about the risk of hypoglycaemia, particularly if he or she has renal • impairment. NICE Pathways Diabetes pathway Copyright c NICE 2014. Pathway last updated: 17 July 2014 www.nice.org.uk nice@nice.org.uk
- 32. Parecidos PERO NO IGUALES ¡¡¡¡¡¡¡
- 33. MUCHAS GRACIAS POR SU ATENCION
Notas del editor
- Esta figura ilustra los principales defectos metabólicos de la DM tipo 2. La hiperglucemia, por un lado, es el resultado de la secreción deficiente de insulina por las células-beta pancreáticas, y por otro lado, de la resistencia a la acción insulínica en el hígado, en el tejido adiposo y en el muscular. En el hígado, la resistencia a la insulina determina el aumento en la producción hepática de la glucosa (génesis glucósica); la mayor captación de glucosa en el tejido adiposo y muscular también contribuye para la hiperglucemia.
- La expresión de la diabetes mellitus tipo 2 es mediada por DOS defectos principales: la secreción de insulina y la insulino-resistencia. El ambiente hiperglucémico de la diabetes acentúa aún más estos dos defectos empeorando la insulino-resistencia y la alteración de la secreción de insulina, lo que a su vez perpetúa el estado diabético. De esta manera la hiperglucemia, debe ser considerada como un factor patogénico que altera la secreción de insulina y es responsable de la perpetuación del estado diabético. Diversas observaciones señalan que cuando se alcanza un mejor control glucémico (con dieta, fármacos orales o insulina), esto lleva a un mejoramiento en la secreción de insulina.
- Las sulfonilureas en general están clasificadas en generaciones distintas, conforme las características farmacodinámicas de los principios activos. El perfil terapéutico más adecuado es el de las sulfonilureas de última generación, la glimepirida, principalmente en función de los beneficios terapéuticos ofrecidos, conforme parámetros resumidos en el slide siguiente. De acuerdo con Goldberg et al. (Diabetes Care 19:849-56,1996), glimepirida presenta ventajas terapéuticas sobre los agentes de segunda generación y por lo tanto es ahora clasificada como sulfonilúrea de última generación.
- La estimulación de la secreción de insulina provocada con la administración de SU se inicia con la unión de estos fármacos a sus receptores, los cuales se encuentran en la membrana de la célula beta de los islotes pancreáticos (SUR1). En estado basal, el canal de K+-ATP dependiente permanece abierto y mantiene la polarización de la membrana plasmática, en tanto que el canal de Ca++ voltaje dependiente permanece cerrado. El metabolismo de la glucosa y otros nutrientes incrementa la producción de ATP, lo cual aumenta la relación ATP/ADP cerrando los canales de K+. El incremento de K+ intracelular facilita la despolarización de la membrana plasmática, lo que abre los canales de Ca++ voltaje dependiente permitiento el ingreso de Ca++ a la célula. El aumento en el calcio intracelular estimula la secreción de insulina. Cuando las SU se unen a su receptor específico sobre el canal de K+, este se cierra, la membrana plasmática se despolariza, se abren los canales de Ca++ voltaje dependiente, aumenta el calcio intracelular, lo que causa la contracción de los microtúbulos que mueven los gránulos de insulina a la superficie celular por emiocitosis. La unión al receptor de SU es específica. Glibenclamida se une a proteína 140 kD del canal de potasio ATP dependiente, en tanto que glimepirida se une a la proteína 65 kD y tiene una alta tasa de intercambio con su receptor. Además de las células , se han descrito receptores para SU en otros tejidos: SUR 2A en musculo cardiaco y SUR 2B en músculo liso. La interacción de las diferentes SU con estos receptores parece ser diferente. Así, por ejemplo, glibenclamida a diferencia de glimepirida, parece tener una mayor interacción con los receptores SUR 2A del músculo cardiaco. Aunque estas diferencias estan relacionadas con fenómenos como el preacondicionamiento isquémico del miocardio, aún se desconoce la importancia clínica de estos hallazgos.
- Severe Hypoglycemia with Glimepiride vs Glyburide Over the 3-year observation period, there was a trend for increased incidence of severe hypoglycemic episodes associated with glyburide treatment. As the previous slide illustrates, the increase is not due to increased use of the drug in the region from which the patient data were gathered. Holstein et al. Diabetologia 2000;43:A40.
- Weight Gain in the UKPDS Insulin and/or insulin secretagogue use is often associated with weight gain. In the UKPDS, all patients with type 2 diabetes gained weight over a 10-year period. This slide shows weight gain in overweight patients. Even patients on “conventional” therapy (ie, diet and exercise) and those taking metformin gained weight over the 10-year period .
- Glimepiride Weight Profile A meta-analysis of the effects of glimepiride and placebo on weight change in patients with type 2 diabetes was performed using data from four large Phase III pivotal trials of glimepiride. Patients taking glimepiride did not experience significant weight gain after 12 months of treatment compared with baseline (P=.81), nor did they gain as much weight as patients in the control group (1002 patients receiving glyburide and 207 patients receiving glipizide). Though the difference in weight changes between the two groups were not statistically significant, the data suggested a positive trend in the weight profile of glimepiride. Bugos et al. Diabetes Res Clin Pract 2000;50(suppl 1).
- Glimepiride-Induced Insulin Release from Human Pancreatic Islets Del Guerra et al studied the effect of glimepiride on human pancreatic islet cells. Prepared pancreatic islets were challenged with varying concentrations of glimepiride and glucose. For each given glucose concentration, the effect of 0, 1, 10, and 100 mol/L glimepiride was assessed to evaluate insulin secretion in response to the varying concentrations of glucose and glimepiride. Medido en concentraciones diferentes de glucosa .Un pico de Amaryl no tiene el mismo pico de Insulina. Amaryl no es un secretagogo . Del Guerra et al. Acta Diabetol 2000,37:139.
- Glimepiride-Induced Insulin Release from Human Pancreatic Islets Increasing levels of glimepiride and glucose led to significant increases (2- to 3-fold augmentation) in insulin output. Additionally, increasing levels of glimepiride caused an increase of insulin secretion that was statistically significant at 2.5, 5, and 10 mmol/L glucose. The authors speculated, “The glucose level-dependent insulinotropic action of glimepiride may explain …why glimepiride causes a lower incidence of hypoglycemia than other Sulfonilúreas.” La secresión de Insulina dependiente de los niveles de glucosa , y no de la dosis de amaryl. No se habla de eficacia . Otras sulfonilúreas no muestran este efecto. La secresión de insulina no sigue la curva de concrentración del fármaco ,sinop la concerntración de glicemia. La glucosa estimula la secresión de insulina , con amaryl es mayor, se potencia. Por lo tanto menos hipoglicemia , Si no hay glucosa en ayunas , menos hipoglicemia en presencia de amaryl . Porque una dosis : enlace proteico de 90% Del Guerra et al. Acta Diabetol 2000;37:139.
- Effect of Chronic Exposure of Isolated Human Islet Cells to Sulfonilúreas The effect of chronic exposure of isolated human islets to different Sulfonilúreas was examined by Del Guerra and colleagues. This study assessed glucose-stimulated insulin release in human islets cultured in the presence of 1.0 and 10 M glimepiride, 1.0 and 10 M glibenclamide, and 200 and 600 M chlorpropamide. Significantly more insulin was released in response to higher glucose levels in the glimepiride-incubated (1.0 and 10 M) cells. Islet cells incubated in chlorpropamide 200 M, but not 600 M, also released more insulin at the higher glucose level. In contrast, glibenclamide-treated (both concentrations) islet cells did not release more insulin in response to increased glucose challenge. Overall, minimal disturbances of human islet function occurred after prolonged culture with glimepiride, compared with alterations observed following culture with chlorpropamide, and more markedly, glibenclamide. These in vitro data suggest glimepiride may have fewer adverse effects on pancreatic islet cells during treatment of patients with type 2 diabetes than the other Sulfonilúreas. Del Guerra et al. Submitted to 2001 EASD Annual Meeting.
- Ischemic Preconditioning Ischemic preconditioning can minimize damage (ie, infarct size) due to myocardial ischemia.
- Ischemic Preconditioning Ischemic preconditioning (IP) is a powerful autonomic mechanism by which the heart protects itself from lethal ischemic insult. IP occurs when cardiac KATP channels open during brief episodes of mild myocardial ischemia. Drugs that inhibit cardiac KATP channels may be harmful to the ischemic myocardium by blunting the KATP channel-dependent component of the ischemic preconditioning response.
- Sulfonilúreas Affect KATP channels Some Sulfonilúreas are more selective for pancreatic KATP channels than others. The KATP channel, a complex of a sulfonylurea receptor (SUR2A and SUR1) and the potassium channel (Kir6.2), plays a key role in glucose-mediated insulin release from pancreatic -cells. Glimepiride does not block the beneficial effects of mitochondrial KATP channel opening in cardiac tissue, whereas glyburide is not as selective and blunts KATP channel response in cardiac tissue. This finding may have implications for the treatment of type 2 diabetic patients at risk of myocardial infarction.
- Cardiovascular Advantages of Glimepiride Glimepiride has been shown to have less effect than glibenclamide on extrapancreatic ATP-dependent K+ channels. Klepzig and colleagues conducted a double-blind, placebo-controlled study during the period of total coronary occlusion in balloon angioplasty procedures to determine the effect of glimepiride and glibenclamide on ischemic preconditioning. Klepzig et al. Eur Heart J 1999;20:439.
- Cardiovascular Advantages of Glimepiride Quantification of myocardial ischemia was achieved by recording the intracoronary ECG and the time to the occurrence of angina during vessel occlusion. Fifteen patients underwent 3 dilatations: one to determine the severity of the vessel occlusion, one to establish baseline values, and one 10 minutes after the administration of placebo, glimepiride, or glibenclamide. Klepzig et al. Eur Heart J 1999;20:439.
- Cardiovascular Advantages of Glimepiride In the Klepzig study, mean ST segment shifts that occurred during total vessel occlusion in the placebo group decreased by 35% and a similar reduction occurred in the glimepiride group (34%), suggesting ischemic preconditioning was not affected. There was almost no effect on mean ST segment shifts during occlusion in the glyburide group. The researchers concluded that glimepiride maintains myocardial preconditioning while glyburide may actually prevent it. Klepzig et al. Eur Heart J 1999;20:439.
- Affect of Sulfonylurea Drugs on Muscle KATP Bijlstra and colleagues investigated the ability of sulfonylurea drugs, glimepiride and glibenclamide to block vascular KATP channels in humans compared with placebo. They measured the forearm vasodilator responses to administration of the specific KATP-channel-opener diazoxide to the brachial artery of healthy male volunteers. Responses were recorded by venous occlusion plethysmography. Glibenclamide significantly inhibited the diazoxide-induced increase in forearm blood-flow ratio (P&lt;.01) compared with placebo. Neither glimepiride nor placebo attenuated diazoxide-induced vasodilation. These researchers concluded that therapeutic concentrations of glibenclamide result in significant blockade of vascular KATP channels in humans. In contrast, glimepiride does not. Bijlstra et al. Diabetologia 1999;39:1083.
- Glimepiride May Offer Cardiovascular Advantages Compared With Other Sulfonylurea Drugs The onset of ischemia causes the opening of the cardiovascular ATP-sensitive potassium (KATP) channels, a mechanism that plays a role in protecting the myocardium; this process is called ischemic preconditioning. Glibenclamide abolishes the cardioprotective responses of the KATP channel opening, presumably by inhibiting mitochondrial KATP channel opening in cardiac myocytes. Unlike glibenclamide, data from animal and human studies show glimepiride does not block the beneficial effects of mitochondrial KATP channel opening in cardiac tissue.
- Glimepiride (Amaryl®) Glimepiride (Amaryl®) became available in the United States in 1995 and in many other parts of the world soon after. Since its introduction, millions of patients with type 2 diabetes worldwide have taken glimepiride to control their blood glucose levels. The wide usage of glimepiride has provided the opportunity to evaluate the long-term effects of glimepiride use by large numbers of patients, in “real world” settings. Postmarketing surveillance and phase IV controlled studies have shown glimepiride offers several advantages compared with other members of its class, sulfonylurea drugs, and compared with other oral hypoglycemic drugs. Notably, glimepiride is associated with less hypoglycemia and a more favorable cardiovascular profile than glibenclamide, the most commonly used sulfonylurea in the world. Moreover, glimepiride does not appear to be associated with the weight gain often ascribed to insulin secretagogues. In addition to its ability to stimulate insulin secretion from pancreatic -cells, studies in animals and humans suggest glimepiride exerts significant insulin-mimetic effects; ie, it appears to stimulate glucose uptake in the tissue through extrapancreatic mechanisms. Finally, though glimepiride is taken only once a day, it stimulates insulin secretion in relation to blood glucose levels, thereby improving postprandial glucose control, yet fasting insulin and C-peptide levels are typically elevated minimally and have been shown to be significantly lower than those induced after treatment with other secretagogues.
- Dose-relationship of antihyperglycaemic actions of metformin A double-blind, randomised, placebo-controlled, parallel-group study in a total of 451 patients evaluated the relationships between the dose of metformin and its antihyperglycaemic efficacy. Both fasting plasma glucose and HbA1C were reduced in a dose-dependent manner at metformin dosages between 500 mg/day and 2000 mg/day. A daily dose of metformin 2000 mg therefore appears to represent the optimum dose for control of blood glucose. Some patients, however, benefit from higher doses and this reinforces the need for dose titration for individual subjects. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med 1997;103:491-7
- Antihyperglycaemic efficacy and insulin-sparing action of metformin The data on this slide, from a double-blind, randomised, parallel-group study in type 2 diabetic patients, illustrate typical therapeutic effects of metformin that have been observed in clinical studies. The magnitude of effect of metformin on blood glucose is equivalent to that of other classes of oral antidiabetic agents. Metformin does not induce hyperinsulinaemia; in contrast, fasting plasma insulin is often reduced, consistent with improved insulin sensitivity. DeFronzo RA, Barzilai N, Simonson DC. Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. Clin Endocrinol Metab 1991;73:1294-301
- Comparative efficacy of metformin: meta-analysis of 11 studies A meta-analysis of 11 studies showed that the blood glucose-lowering efficacy of metformin, as shown by effects on HbA1C, fasting plasma glucose and postprandial plasma glucose, was comparable to that of a sulfonylurea. Campbell IW, Howlett HC. Worldwide experience of metformin as an effective glucose-lowering agent: a meta-analysis. Diabetes Metab Rev 1995;11 Suppl 1:S57-62
- Choice of agents in current use Sulfonylureas, -glucosidase inhibitors, thiazolidinediones and meglitinides, and of course metformin, are all available for use in type 2 diabetes. Metformin is located in the pivotal position given its role in reducing hyperglycaemia and excess risk of morbidity from life-threatening complications. The choice of single-agent therapy has never been so broad with at least a dozen candidate agents to select from. As a result there are a large number of potential combinations of oral antidiabetic agents to choose from.
- Efficacy of co-administered combinations based on metformin Metformin is suitable for combination with any other oral antidiabetic agent. Clinical studies have shown that metformin reduced blood glucose effectively when combined with a sulfonylurea, a meglitinide, a thiazolidinedione, or an -glucosidase inhibitor. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin dependent diabetes mellitus. N Engl J Med 1995;333:541-9 Charpentier G, Fleury F, Kabir M et al. Improved glycaemic control by addition of glimepiride to metformin monotherapy in type 2 diabetic patients. Diabet Med 2001;16:828-34 Moses R, Carter J, Slobodniuk R et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 1999;22:119-24 Einhorn D, Rendell M, Rosenzweig J et al. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: A randomized, placebo-controlled study. Clin Ther 2000;22:1395-409 Fonseca V, Rosenstock J, Patwardhan R et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus. JAMA 2000;283:1695-702 Rosenstock J, Nadeau D, Brown A et al. Efficacy and safety of acarbose in metformin-treated patients with type 2 diabetes. Diabetes Care 1998;21:2050-55
- Outcomes associated with metformin or sulfonylurea treatment in a UK population This was a prospective observational study (up to 8 years of follow-up) of 5730 patients in Tayside, Scotland who received oral antidiabetic agent(s) between 1994 and 2001: • 2286 patients were prescribed metformin and 985 later received a sulfonylurea • 3331 patients were prescribed a sulfonylurea and 1252 later received metformin • 113 patients received both drugs initially The outcome measures were all-cause mortality, cardiovascular mortality, or admission to hospital for a cardiovascular event or disease. The risk of death from any cause or cardiovascular death was lower in the metformin monotherapy group than for patients receiving sulfonylurea monotherapy. Addition of sulfonylurea to metformin, or addition of metformin to sulfonylurea, resulted in higher risks of mortality compared with metformin alone. Simultaneous prescription of metformin and sulfonylurea was not apparently associated with increased risk, but numbers of patients were small. There were no differences between groups for hospitalisation for cardiovascular causes. Evans JM, Ogston SA, Emslie-Smith A, Morris AD. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 2006;49:930-6
- Little influence of weight on the antihyperglycaemic efficacy of metformin Metformin is often considered to be especially appropriate for overweight or obese patients, due to its weight-sparing actions and the fact that metformin was evaluated in this population in the UK Prospective Diabetes Study. This prospective, observational study analysed the influence of body weight on the early antihyperglycaemic response to metformin and sulfonylureas. All patients in Tayside, Scotland, who were prescribed metformin or a sulfonylurea between 1993 and 2002 (n=3856) were included in the analysis. Increasing body mass index was associated with a higher likelihood of receiving metformin, while the reverse was true for sulfonylureas. However, mean changes in HbA1C in obese and non-obese patients did not differ significantly following prescription of metformin. Although regression analysis showed that the HbA1C response was slightly greater with decreasing body weight (p&lt;0.02), the effect was small. A reduction in BMI of 5 kg/m2 increased the HbA1C response to metformin by only 0.08%. Donnelly LA, Doney AS, Hattersley AT et al. The effect of obesity on glycaemic response to metformin or sulphonylureas in Type 2 diabetes. Diabet Med 2006;23:128-33