Abbas orabi.translating evidence

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  • 1. Translating evidence into patients benefitsBy: Abbas Oraby

2. Drugs in this classSulfonylureas were the first widely used oral anti-hyperglycaemicmedications. Many types of these pills have been marketed but not allremain available. Acetohexamide Glipizide Chlorpropamide Gliclazide Glibenclamide (glyburide) Tolbutamide Gliquidone Tolazamide Glyclopyramide 3. MECHANISMS OF ACTION OF SUs 4. Insulin releaseIt involves 3 main steps : 1. Translocation of insulin granules. 2. Docking of insulin granules. 3. Fusion of insulin granules. 8 5. Microtubules form a network radiating from theperinuclear region outwords. The framework provides the mechanical pathway along which secretory granules move toward the exocytic sites close to the plasma membrane.It gives the way but not the force 10 6. Ca+ is essential for almost all stepsinvolved in insulin release, thus factorsincreasing intracellular Ca+ will augmentinsulin release.Mechanisms involved inincreasing intra-cytoplasmic Ca+ : Ca-influx from outside. Inhibition of Ca-reuptake by Ca++ Storeintracellulas stores. x Increased Ca-sensitivity.12 7. Increased intracellular Ca+ is essential for granules translocation and fusion hence release of insulin. ATP-sensitive Voltage-gate CaGlucoseK+ channel channel6 GLUT2 XFusionK retention 4 Glucose3 DepolarizationCa+ 2Glucokinase15G-6-PATPTranslocation Each B-cell contains up to 500 Ca channels13 8. Mechanisms of action cont. The rise in intracellular calcium leads toincreased fusion of insulin granules with thecell membrane, and therefore increasedsecretion of (pro)insulin. There is some evidence that sulfonylureasalso sensitize -cells to glucose, that theylimit glucose production in the liver, that theydecrease lipolysis and decrease clearance ofinsulin by the liver. 9. Insulin Secretion (Glimepiride)Glimepiride binds to the 65 kDa subunit of the sulfonylureareceptor; glibenclamide binds to the 140 kDa subunit 10. Therapeutic actions PancreasSulfonylurea + Impairedglimepiride Insulin secretionInsulin resistance Increased Decreased glucose glucose productionHyperglycaemiauptakeLiverMuscleMetformin 16 11. Attributes of sulfonylureas How they work Enhance insulin secretion Expected HbA1c 1 to 2% reduction Adverse eventsHypoglycemia*(but severe episodes are infrequent) Weight effects~ 2 kg weight gain common when therapy initiated CV effectsNone substantiated by UKPDS or ADVANCE study* Substantially greater risk of hypoglycemia with chlorpropamide and glibenclamide (glyburide) than othersecond- generation sulfonylureas (gliclazide, glimepiride, glipizide)17Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203. 12. IDF Global Guideline for Type 2 Diabetes DiagnosisLifestyle intervention then metforminHbA1c 6.5 % Add sulfonylureaHbA1c 6.5 %HbA1c 6.5 %*Alternatively, startAdd thiazolidinedione* Add insulinthiazolidinedione beforesulfonylurea,and sulfonylurea later.HbA1c 7.5 % HbA1c 7.0 % Start insulin intensify insulin Meal-time + basal insulin + metformin thiazolidinedione IDF. Global Guideline for Type 2 Diabetes. 2005 13. ADA and EASD algorithm for the managementof type 2 diabetesTier 1: Well validated therapies Lifestyle andAt Lifestyle and met + intensive diagnosis:met + basal insulinLifestyleinsulin + metforminLifestyle andmet + SUaStep 1 Step 2Step 3Tier 2: Less well validated therapiesLifestyle andmet + pio Lifestyle and met No hypoglycaemia Oedema/CHF+ pio + SUa Bone lossLifestyle and met+ GLP-1 agonistb Lifestyle and No hypoglycaemia Weight loss met + basal insulin Nausea/vomitingReinforce lifestyle interventions every visit and check HbA1C every3 months until HbA1C is