Diabetes Mellitus


Published on

Detailed info about Diabetes

Published in: Health & Medicine
  • Fioricet is often prescribed for tension headaches caused by contractions of the muscles in the neck and shoulder area. Buy now from http://www.fioricetsupply.com and make a deal for you.
    Are you sure you want to  Yes  No
    Your message goes here
  • can u download this presentation??
    Are you sure you want to  Yes  No
    Your message goes here
  • new idea for presentation
    Are you sure you want to  Yes  No
    Your message goes here
No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide
  • Diabetes Mellitus

    1. 1. Management of Diabetes
    2. 2. MANAGEMENT OF DIABETES MELLITUS <ul><li>The aims of treatment are to alleviate and prevent both the symptoms and complications of diabetes.   </li></ul><ul><li>Methods of Management </li></ul><ul><ul><li>Non-Pharmacological : </li></ul></ul><ul><ul><ul><li>Diet and weight control </li></ul></ul></ul><ul><ul><ul><li>Exercise </li></ul></ul></ul><ul><ul><li>Pharmacological: </li></ul></ul><ul><ul><ul><li>Sulfonylureas/Meglitinides </li></ul></ul></ul><ul><ul><ul><li>Biguanides </li></ul></ul></ul><ul><ul><ul><li>Alpha glycosidase inhibitors </li></ul></ul></ul><ul><ul><ul><li>Thiazolidinediones </li></ul></ul></ul><ul><ul><ul><li>Incretins </li></ul></ul></ul>
    3. 3. Goals of Treatment in Type 2 DM <ul><li>Glucose control </li></ul><ul><li>Preserve B-cell function </li></ul><ul><li>Maintenance of weight to as near normal as possible </li></ul><ul><li>Blood pressure control </li></ul>
    4. 4. Goals of Treatment in Type 2 DM <ul><li>Lipid control </li></ul><ul><li>Decrease micro/macrovascular complications </li></ul><ul><li>Decrease mortality/morbidity </li></ul>
    5. 5. Basic Steps in Glycemic Control for Type 2 Diabetes + + Lifestyle: diet & exercise oral monotherapy oral combination oral plus insulin insulin +
    6. 6. Stepped Care: Type 2 Diabetes Step 1: Nutrition Therapy, exercise, lifestyle changes; training in self-management and self monitoring of blood glucose Step 2: Add oral agents - monotherapy - combination therapy Step 3: Add or change to insulin Step 4: Intensify insulin therapy Consensus Statement. Diabetes Care. 1995;18:1510-1518
    7. 8. Classification of Drug Treatment for Diabetes
    8. 10. SULPHONYLUREAS <ul><li>Introduction </li></ul><ul><li>In 1955, Sulphonylureas became widely available for the treatment of NIDDM. </li></ul><ul><li>Mechanism of Action </li></ul><ul><li>At least 3 mechanisms of sulphonylureas action have been proposed: </li></ul><ul><ul><li>Release of insulin from Beta cells </li></ul></ul><ul><ul><li>Reduction of serum Glucagon levels </li></ul></ul><ul><ul><li>Extra pancreatic effects to potentiate the action of insulin on its target tissues </li></ul></ul>
    9. 11. MECHANISM OF ACTION Basic Structure Classification R 1 SO 2 – NH – CO – NH- R 2 1 ST GENERATION (Chlorpropamide) Tolbutamide 2 nd GENERATION Gliclazide Glibenclamide Glipizide Glimepiride
    10. 12. <ul><li>Insulin Release from Pancreatic Beta Cell </li></ul><ul><ul><li>Sulphonylureas bind to a specific receptor that is associated with a potassium channel in the beta cell membrane. Binding of a sulphonylurea inhibits the channel and results in depolarization. Depolarization in turn opens a voltage gated calcium channel and results in calcium influx and the release of preformed insulin. </li></ul></ul><ul><li>  Reduction of Serum Glucagon Concentrations </li></ul><ul><ul><li>It is now established that chronic administration of sulphonylureas to NIDDM diabetics reduces serum glucagon levels. The mechanism of this suppressive effect is unclear but to enhanced release of insulin from Beta cells which in enbits Alpha cells secretions </li></ul></ul>SULPHONYLUREAS
    11. 13. Main Site of Action of Sulfonylureas and Meglitinides Adipose tissue Carbohydrate Blood Glucose Digestive enzymes Gut Pancreas Muscle Liver Insulin Sulfonylureas and meglitinides stimulate pancreas to release more insulin
    12. 14. Sulfonylureas <ul><li>Tolbutamide </li></ul><ul><li>Chlorpropamide </li></ul><ul><li>Glibenclamide </li></ul><ul><li>Glipizide </li></ul><ul><li>Gliclazide </li></ul><ul><li>Glimeperide </li></ul>
    13. 15. Meglitinides <ul><li>Also stimulates insulin secretion by the pancreas </li></ul><ul><li>Shorter acting than sulfonylureas </li></ul><ul><li>Targets the postprandial elevation of blood sugar </li></ul>
    14. 16. Meglitinides <ul><li>Repaglinide </li></ul><ul><li>Nateglinide </li></ul>
    15. 17. Sulfonylureas Action Insulin secretagogue Insulin sensitivity No effect ? Hepatic glucose output No effect Serum insulin Increased Hypoglycaemia Yes Lipids No effect Onset of action Fast Weight Increased Effectiveness over time Reduced Safety Hypoglycemia Drug interactions Weight gain
    16. 18. Biguanides (Metformin) <ul><li>Suppresses hepatic glucose output </li></ul><ul><li>An insulin sensitizer </li></ul><ul><li>May cause Lactic acidosis </li></ul><ul><li>Contraindicated in patients with hepatic and renal insufficiency and in patients with hypoxemia </li></ul>
    17. 19. Main Site of Action of Metformin Metformin suppresses hepatic glucose production Carbohydrate Adipose tissue Blood Glucose Digestive enzymes Gut Pancreas Muscle Liver Insulin
    18. 20. <ul><li>Contraindications of Metformin </li></ul><ul><ul><li>Type 1 diabetes </li></ul></ul><ul><ul><li>Pregnancy </li></ul></ul><ul><ul><li>Breast Feeding </li></ul></ul><ul><ul><li>Diabetic pre- coma and coma </li></ul></ul><ul><ul><li>Known hypersensitivity to metformin </li></ul></ul><ul><ul><li>Hepatic failure limits the ability to clear lactic acid </li></ul></ul><ul><ul><li>Renal failure and concomitant diseases affecting renal function (dehydration, infection, hypoxia) </li></ul></ul><ul><ul><li>Cardio – respiratory failure and acute myocardial infarction </li></ul></ul>BIGUANIDES
    19. 21. <ul><li>Precautions </li></ul><ul><ul><li>Patient > 65 years old </li></ul></ul><ul><ul><li>Use of contrasting agents </li></ul></ul><ul><ul><li>During surgery </li></ul></ul><ul><li>Conclusion </li></ul><ul><ul><li>Metformin is the only biguanide in clinical practice </li></ul></ul><ul><ul><li>Numerous side –effects </li></ul></ul><ul><ul><li>GI side – effects might be associated with weight loss </li></ul></ul><ul><ul><li>Can induce lactic acidosis, which is a life-threatening emergency </li></ul></ul>BIGUANIDES
    20. 22. Metformin Action Reduce liver glucose production Insulin sensitivity Yes (liver predominantly) Hepatic glucose output Reduced Serum insulin No effect Hypoglycaemia No Lipids Reduced Onset of action Moderate Weight Neutral or reduced Effectiveness over time Reduced Safety GI effects Drug interactions Renal insufficiency (Lactic acidosis)
    21. 23. Metformin: Added Benefits and New Controversy <ul><li>Compared with “conventional treatment”, metformin in overweight patients resulted in: 42% risk reduction in DM related deaths ( p=0.017 ) </li></ul><ul><li>When added to sulphonylureas, metformin appeared to increase DM related deaths ( p=0.039 ) </li></ul><ul><li>HOWEVER, caution required due to very small number of deaths (26 SU vs 14 Met + SU) </li></ul>ukpds Adapted from
    22. 25.  -Glucosidase Inhibitors  -Glucosidase inhibitors delay digestion and absorption of carbohydrates in GI tract Carbohydrate Adipose tissue Blood Glucose Digestive enzymes Gut Pancreas Muscle Liver Insulin
    23. 26. Acarbose Action Reduced glucose absorption Insulin sensitivity No effect Hepatic glucose output No effect Serum insulin No effect Hypoglycaemia No effect Lipids No effect Onset of action Moderate Weight Neutral or reduced Effectiveness over time Uncertain (at 3 years) Safety GI effects Hepatic (LFT elevation) Drug interactions (few
    24. 27. Thiazolidinediones <ul><li>Insulin sensitizers </li></ul><ul><li>Acts by activation of PPAR </li></ul><ul><li>Must monitor liver enzymes </li></ul><ul><li>Side effects include fluid retention, edema, anemia </li></ul>
    25. 28. Main Site of Action of Thiazolidinediones Thiazolidinediones Reduce Insulin Resistance Decreases hepatic glucose production Increases glucose entry into adipose and muscle tissue Glucose (G) Carbohydrate Glucose DIGESTIVE ENZYMES Insulin (I) I I I I I I I I G G G G G G G G I G G G
    26. 29. Thiazolidinediones <ul><li>Troglitazone </li></ul><ul><li>Rosiglitazone </li></ul><ul><li>Pioglitazone </li></ul>
    27. 30. Thiazolidinediones Hepatic (Inc LFT in Troglitazone) Drug interactions (few) Weight gain ? Edema ? Safety Durable Effectiveness over time Increased Weight Moderate to late Onset of action Generally positive Lipids No effect Hypoglycaemia Decreased Serum insulin Slight decrease Hepatic glucose output Increased Insulin sensitivity Insulin sensitizer Action
    28. 31. Activation of PPAR  alters expression of specific genes PPRE (DR-1) coding sequences AGGTCA X AGGTCA retinoic RSG RXR lipoprotein lipase, PEPCK, aP 2 PPAR 
    29. 32. <ul><li>Improvements in insulin sensitivity induced by TZDs require several days of treatment </li></ul><ul><ul><li>transcriptional modifications are involved </li></ul></ul><ul><ul><li>as much as 4-8 weeks are needed to bring blood glucose down </li></ul></ul><ul><ul><li>can be given once a day </li></ul></ul>Thiazolidinedione: Mechanism of Action
    30. 33. Incretins <ul><li>Peptides released from the gastrointestinal tract in response to nutrient ingestion that enhance glucose-dependent insulin secretion from the pancreas and aid in the overall maintenance of glucose homeostasis </li></ul><ul><li>The 2 principal incretin hormones are glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) </li></ul><ul><li>Rapidly stimulate the release of insulin only when blood glucose levels are elevated, thereby enhancing the glucose-sensing and insulin secretory capacity of the endocrine pancreas during postprandial hyperglycemia </li></ul><ul><li>Also exert significant cytoprotective and proliferative effects on the islets of Langerhans </li></ul><ul><li>Elicit their actions through direct activation of distinct G-protein-coupled receptors expressed on islet beta cells </li></ul>
    31. 35. Incretins <ul><li>Native GLP-1 and GIP are rapidly inactivated by the ubiquitously expressed proteolytic enzyme dipeptidyl peptidase (DPP)-IV, which cleaves 2 N-terminal amino acids from both peptides to produce inactive metabolites </li></ul><ul><li>More focus has been put on the use of GLP-1 to treat type 2 diabetes because diabetes is often associated with a blunted or absent response to GIP </li></ul>
    32. 36. Exenatide <ul><li>GLP-1 receptor agonist </li></ul><ul><li>Mimics the biological actions of native GLP-1, but exenatide is resistant to cleavage by DPP-IV </li></ul><ul><li>Improved glucose tolerance, reduced levels of glycosylated hemoglobin (A1C), and reduced weight in diabetic patients when given alone or during concurrent administration with either sulfonylureas or metformin </li></ul><ul><li>GLP-1, but not GIP, inhibits glucagon secretion indirectly via effects on endogenous somatostatin </li></ul><ul><li>GLP-1 can modulate the differentiation of ductal precursor cells into insulin-secreting beta cells </li></ul><ul><li>also produced clinically significant improvements in lipid levels and reduced blood pressure </li></ul><ul><li>most common side effects were gastrointestinal </li></ul>
    33. 37. DPP-IV Inhibitors <ul><li>Sitagliptin </li></ul><ul><li>well tolerated, reduced A1C levels, and decreased fasting glucose in humans </li></ul>
    34. 38. Indications for Insulin in Type 2 Diabetes <ul><li>Hyperglycemia despite maximum doses of oral agents </li></ul><ul><li>Decompensation due to intercurrent events e.g., infection, acute injury, or other stress </li></ul><ul><li>Development of severe hyperglycemia with ketonemia and/or ketonuria </li></ul><ul><li>Uncontrolled weight loss </li></ul>
    35. 39. Indications for Insulin in Type 2 Diabetes <ul><li>Perioperative in patients undergoing surgery </li></ul><ul><li>Pregnancy </li></ul><ul><li>Renal or hepatic disease </li></ul><ul><li>Allergy or other serious reaction to oral agents </li></ul>
    36. 40. INSULIN <ul><li>Characteristics of Available Insulin </li></ul><ul><ul><li>Commercial Insulin Preparations </li></ul></ul><ul><ul><ul><li>Different in a number of ways including </li></ul></ul></ul><ul><ul><ul><ul><li>Differences in the animal species </li></ul></ul></ul></ul><ul><ul><ul><li>From which they are obtained </li></ul></ul></ul><ul><ul><ul><ul><li>Their purity </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Concentration & </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Solubility </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Time of onset and durations of biologic action </li></ul></ul></ul></ul><ul><ul><li>In the past 12 years, a number of human insulin preparations have been added to the list of available insulins and some animal preparations have been removed </li></ul></ul>
    37. 41. <ul><li>Principal types and duration of Action of Insulin Preparations </li></ul><ul><ul><li>Short acting, with rapid onset of action </li></ul></ul><ul><ul><li>Intermediate acting </li></ul></ul><ul><ul><li>Long acting with slow onset of action </li></ul></ul><ul><li>Short Acting Insulin </li></ul><ul><li>Regular insulin is a short acting soluble crystalline give insulin whose effect appear within 15 minutes of subcutaneous injection and generally last 5-7 hours </li></ul><ul><li>Short acting soluble insulin is the only type of insulin that can be administered intravenously or by infusion pumps </li></ul>INSULIN
    38. 42. INSULIN <ul><li>Lente & Ultra Lente Insulin </li></ul><ul><ul><li>Lente insulin is a mixture of 30% Semi-lente (an amorphous precipitate of insulin with zinc, ions in acetate buffer that was a relatively rapid onset of Action) with 70% ultra lente. </li></ul></ul><ul><ul><li>Insulin (a poorly soluble crystal of zinc insulin that has a delayed onset and prolonged duration of action </li></ul></ul><ul><ul><li>NPH Insulin: NPH insulin is an intermediate acting insulin wherein the onset of action is delayed by combining protamine. </li></ul></ul>
    39. 43. INSULIN TYPES <ul><li>Type Of Insulin Onset of Peak of Duration of Action Action Action </li></ul><ul><li>(mins) (hours) (hours)   </li></ul><ul><li>Short acting </li></ul><ul><li>Insulin lispro* 10-15 0.5 – 1 4 </li></ul><ul><li>Actrapid (Novo Nordisk) 15 1.5 – 4 6 </li></ul><ul><li>Velosuline (Novo Nordisk) 30 1-3 8 </li></ul><ul><li>Humulin (Eli –Lilly) 15 1-3 6 - 8 </li></ul><ul><li>Humology </li></ul><ul><li>Novorapid / Norolog </li></ul><ul><li>  </li></ul><ul><li>Intermediate acting </li></ul><ul><li>Semi ((Novo Nordisk) 60 2.5 – 7 10 – 12 </li></ul><ul><li>Rapitard (Novo Nordisk) 20 3 – 9 16 – 12 </li></ul><ul><li>Isophane (NPH ***) (Eli Lilly) 45 2 – 9 16 - 26 </li></ul><ul><li>  </li></ul><ul><li>Long acting </li></ul><ul><li>Lente ((Novo Nordisk) 90 4 – 13 24 – 36 </li></ul><ul><li>Ultralente (Novo Nordisk) 120 5 – 22 >30 </li></ul>
    40. 44. <ul><li>  Side effects </li></ul><ul><ul><li>Allergies to insulin </li></ul></ul><ul><ul><li>Skin changes </li></ul></ul><ul><ul><li>Erythema </li></ul></ul><ul><ul><li>Lipo dystrophy </li></ul></ul><ul><ul><li>Weight gain </li></ul></ul><ul><ul><li>Atheroma </li></ul></ul><ul><ul><li>Hypoglycemia </li></ul></ul>INSULIN
    41. 45. <ul><li>Hypoglycemia </li></ul><ul><li>It is a treatment complication </li></ul><ul><ul><li>Insulin treated diabetic </li></ul></ul><ul><ul><li>From an absolute over dosage </li></ul></ul><ul><ul><li>Error of dosing due to misunderstanding, no checking of dose. </li></ul></ul><ul><ul><li>Error of injection timing </li></ul></ul><ul><ul><li>Poor technique </li></ul></ul><ul><ul><li>From a relative over dosage </li></ul></ul><ul><ul><li>Carbohydrates intake, abnormal dietary intake </li></ul></ul><ul><ul><li>Digestive problems </li></ul></ul><ul><ul><li>Sudden physical exercise </li></ul></ul>INSULIN TYPES
    42. 46. <ul><li>Clinical symptoms and signs of hypoglycemia </li></ul><ul><li>General </li></ul><ul><ul><li>Sudden and severe tiredness, cramps, headache, vertigo </li></ul></ul><ul><li>Neuro vegetative </li></ul><ul><ul><li>Major signs: cold sweats </li></ul></ul><ul><ul><li>Pallor, trembling </li></ul></ul><ul><li>Cardiovascular </li></ul><ul><ul><li>Tachycardia, palpitations, << pins and needles>> </li></ul></ul><ul><li>Digestive </li></ul><ul><ul><li>Confusion, agitation, aggression, convulsions, abnormal behavior </li></ul></ul><ul><li>Neuro psychiatric </li></ul><ul><ul><li>Confusion, agitation, aggression, convulsions, abnormal behavior 3 </li></ul></ul>Hypoglycemia
    43. 47. <ul><li>Treatment of Hypoglycemia </li></ul><ul><li>  As soon as signs appear </li></ul><ul><ul><li>Stop all currents activity (sports, driving) </li></ul></ul><ul><ul><li>Take sugar (sugary drink, sugar lump) </li></ul></ul><ul><ul><li>If no action taken and hypoglycemia progress severe </li></ul></ul><ul><ul><li>Hospitalization </li></ul></ul><ul><ul><li>Intravenous glucose – 10% or 30% </li></ul></ul><ul><ul><li>Glucagon injection </li></ul></ul>Hypoglycemia
    44. 49. Combination Therapy Diabetes Care 1998 <ul><li>Agents which lower PPG > FPG </li></ul><ul><li>Alpha glucosidase inhibitors; monomeric insulin; </li></ul><ul><li>Meglitinides </li></ul><ul><li>Agents which lower PPG = FPG </li></ul><ul><li>Thiazolidinediones </li></ul><ul><li>Agents which lower FPG > PPG </li></ul><ul><li>Sulfonylureas, biguanides; insulin </li></ul>
    45. 50. Combination Therapy in Type 2 Diabetes Acarbose Reduces absorption Sulphonylurea Repaglinide Stimulates pancreas Metformin Reduces hepatic glucose output (??muscle/fat effects) Glucose (G) Carbohydrate Glucose DIGESTIVE ENZYMES Insulin (I) I I I I I I I I G G G G G G G G I G G G Thiazolidinediones Reduce Insulin Resistance - + -
    46. 52. Drawbacks of therapies limit patient compliance Scheen and Lefebevre Drug Safety 1995; 12:32-45; Repaglinide Package Insert. 1998. Scheen and Lefebevre Drugs 1998; 55:225-236. Kobayashi Diabetes, Obesity and Metabolism 1999; 1 (Supplement 1): S32. Lydick, Gaskin and Bakst Diabetes 1998; 47 (Supplement 1):A387 (Abstract 1490). SU Metfor min  GIs Megli tinide Increased risk of hypoglycemia Drug interactions GI side effects  Risk of  cell exhaustion Lactic acidosis Caution with elderly Poor patient compliance
    47. 53. K ATP CHANNELS <ul><li>Octameric (4+4) structure of the K + ATP channel </li></ul><ul><li>2 types of subunits: </li></ul><ul><ul><li>A pore forming subunit Kir 6.2 </li></ul></ul><ul><ul><li>Regulatory subunit SUR (sulphonylurea receptor) </li></ul></ul><ul><li>  The physiological role of SUR is to mediate regulation of channel activity. </li></ul><ul><li>  The SUR units exists in different isoforms (SUR1, SUR2A, SUR2B) that are structurally different from each other </li></ul>SUR: Sulphoonylurea Receptor Kir: Potassium Inward Rectifying Channel
    48. 54. <ul><li>K ATP channels in different tissues </li></ul><ul><li>Pancreatic  -cells </li></ul><ul><li>Heart </li></ul><ul><li>Vascular Smooth Muscle </li></ul>K ATP CHANNELS
    49. 55. <ul><li>K ATP Channels in Pancreatic  -Cells (Kir 6.2 / SUR 1) </li></ul><ul><ul><li>Role of pancreatic K ATP channels is regulation of insulin secretion </li></ul></ul>K ATP CHANNELS In the unstimulated  -cell, K ATP channels are open and the outward movement of K + ions holds the membrane potential at a negative level Insulin Pro-insulin  -cell K + Ca 2+ Glu t-2
    50. 56. Insulin release in non-diabetic Glucose Glucose Glucose Glucose ATP Insulin release Metabolism Glucokinase Glut 2 Opening of Ca 2+ channel Arrest of K + release Ca 2+ ATP Ca 2+ K + K + K +
    51. 57. Insulin release in diabetic Less Glucose ATP Glucose K + K + K + K + Partial Arrest of K + release ATP Ca 2+ channel Ca 2+ Glucokinase Metabolism Glucose Glucose Glut 2 Insulin release
    52. 58. Insulin release with existing SUs 140 kDa 65 kDa Glucose ATP Augmentation of K + blockage Glucokinase Metabolism Ca 2+ channel Ca 2+ Ca 2+ ATP K + K + K + Glucose Glucose Glucose Glut 2 Insulin release
    53. 59. <ul><li>SU - K ATP interactions </li></ul><ul><ul><li>3 parameters to characterize the interactions of SU with K ATP channels in different tissues: </li></ul></ul><ul><ul><ul><li>Affinity </li></ul></ul></ul><ul><ul><ul><li>Selectivity </li></ul></ul></ul><ul><ul><ul><li>Reversibility </li></ul></ul></ul>K ATP CHANNELS
    54. 60. Glimepiride interacts with a subunit of the K + channel at the  - cell, which seems to be absent at the K + channels in the cardiovascular system Lesser Cardiovascular Complications glibenclamide glimepiride K + 140 kDa 65 kDa  - cell membrane Sulfonylurea receptor K + K ATP channel Different binding site at  - cell
    55. 61. Ischemic Preconditioning (IP) <ul><li>IP is a powerful, endogenous mechanism by which the heart protects itself from lethal ischemic insult </li></ul><ul><li>IP occurs when cardiac KATP channels open automatically during brief episodes of mild myocardial ischemia </li></ul><ul><li>Drugs that inhibit cardiac KATP channel opening may be harmful to the ischemic myocardium by blunting the KATP channel-dependent component of the ischemic preconditioning response </li></ul>Brady et al. J Am Coll Cardiol 1998;31(5):950.
    56. 62. Ischemic Preconditioning Glyburide and tolbutamide inhibit ischemic preconditioning resulting in a large infarct size
    57. 63. <ul><li>Patients underwent 3 coronary artery dilations by balloon inflation: </li></ul><ul><ul><li>Dilation 1: to determine patient eligibility </li></ul></ul><ul><ul><li>Dilation 2: baseline (before drug administration) </li></ul></ul><ul><ul><li>Dilation 3: to determine effects of glimepiride, glyburide/glibenclamide, and placebo on preconditioning </li></ul></ul><ul><li>Drug Dosing: </li></ul><ul><ul><li>Glimepiride: 1 mg IV followed by 18  g/min for 9 min (  4 mg oral) </li></ul></ul><ul><ul><li>Glyburide/Glibenclamide : 2 mg IV followed by 60  g/min for 9 minutes (  10 mg oral) </li></ul></ul><ul><ul><li>Placebo (saline): 3 min bolus followed 9 min </li></ul></ul><ul><ul><li>infusion </li></ul></ul>Sulfonylureas and Ischemic Preconditioning Klepzig et al. Eur Heart J 1999;20:439.
    58. 64. Mean ST Segment Depression Klepzig et al. Eur Heart J 1999;20:439. Glimepiride reduced the mean ST segment depression during balloon occlusion by 34% (placebo 35%) suggesting no detrimental effect on ischemic preconditioning,whereas the effect of glyburide was negligible % Change Mean ST Shift 0 50 100 150 Placebo Glimepiride Glyburide/ Glibenclamide Dilation 2 (Baseline) Dilation 3 (After treatment) P = .01 P = NS P = .049
    59. 65. <ul><li>Glyburide/Glibenclamide abolishes the cardioprotective effect of ischemic preconditioning by inhibiting opening of mitochondrial K ATP channels in cardiomyocytes </li></ul><ul><li>Glimepiride binds to a different receptor specific to the pancreas and does not blunt ischemic preconditioning </li></ul>Cardiovascular Profile Klepzig et al. Eur Heart J 1999;20:439. Mocanu et al. Circulation 2000;102(suppl 1):288 .
    60. 66. HYPERGLYCEMIA GLUCOSE AUTO-OXIDATION LDL Oxidation Protein Glycation Endoneural blood flow NCV Heparan sulphate Polyol pathway NO dependent Vasodilatation VSMC proliferation Microangiopathy UKPDS 1998 Haemorrheological disturbance Coagulation activation RETINOPATHY NEUROPATHY NEPHROPATHY HYPERGLYCAEMIC “PEAKS” AND “COMPLICATIONS”
    61. 67. Glimepiride inhibited the oxidative modification of LDL in a dose-dependent manner (IC50 = 8.8 x 10-7 M) without cytotoxicity; glibenclamide and gliclazide did not. Effect of glimepiride on HCAEC-modified LDL oxidation *Inhibition % of vehiccle control Data are mean + SD of 3 experiments performed in triplicate Control level (1% EtOH-0.1% DMSO) Glimepiride Glibenclamide Gliclazide 50 mM Indomethacin 20 mM BHT Blank level Test compunds (- log M) 10 8 6 4 2 0 8 7 6 5 4 TBARS (nmol/mL)
    62. 68. The addition of glimepiride to the 1% CHOL diet resulted in a significant reduction in the observed percentage of oil red-positive atherosclerotic lesions in studies one and two (p <0.01). Examples of typical oil red-positive atherogenic lesions observed in thoracic aorta in rabbits treated with a diet containing 1% CHOL with or without glimepiride, glibenclamide or gliclazide Effect of glimepiride on atherosclerotic lesions in thoracic aorta in rabbits treated with 1% CHOL-diet with or without glimepiride, glibenclamide or gliclazide for 10 weeks. 100 80 60 40 20 0 Control Glimepiride 0.1 mg/kg Glibenclamide 0.25 mg/kg Gliclazide 0.4 mg/kg Control (n=14) Glimepiride 0.1 mg/kg (n=15) 100 80 60 40 20 0 Atherosclerotic lesions (%) Mean + SE (n=8) *p < 0.05 ** p < 0.01) ** * Mean + SE (n=8) ***p < 0.001 Study one Study two *** NORMAL CONTROL GLIMEP GLIBEN GLICLA
    63. 69. Glimepiride treatment upregulates adiponectin and downregulates TNF  levels in the plasma and ameliorates insulin resistance Baseline 8 weeks Data are means ± SD * P < 0.05 ( Diabetes Care 2003; 26:285–289) 5 10 0 25 50 0 * TNF-  PAI-1 * 0 10 20 Adiponectin  g/ml 5 10 0 * Glucose disposal rate mg  kg -1  min -1 pg/ml ng/ml
    64. 70. MAPK Raf RAS Grb 2 IRS PI-3K Glut 4 Translocation p Caveolae Growth and Gene Expression Target cell Insulin G G G G PDK-1 PKC
    65. 71. MAPK Raf RAS Grb 2 IRS PI-3K Glut 4 Translocation p Caveolae Growth and Gene Expression Target cell Insulin G G G G PDK-1 PKC
    66. 72. MAPK Raf RAS Grb 2 IRS PI-3K Akt Glycogen Synthesis Glut 4 Translocation Lipid Synthesis p Caveolin Caveolae p Growth and Gene Expression Target cell Protein Synthesis Insulin Action Insulin glimepiride PDK-2 PDK-1 PKC
    67. 73. Weight Profile Weight Change (kg) Large - scale (>22,000 patients) Postmarketing Surveillance Study (Germa ny):  Change in body weight (kg) after 2 months of glimepiride treatment Body Mass Index Herrmann et al. Diabetes Res Clin Pract 2000;15(suppl 1). 0.2 -0.4 -1.4 -2.2 -1.4 -3 -2 -1 0 1 < 20 20 < 25 25 - 30 > 30 All patients
    68. 74. Large - scale Surveillance Study (Germany): Change of body weight - individual data no change body weight gain (kg) body weight loss (kg) Number of Patients Weight Profile Data on file, submitted for publication. 0 1000 2000 3000 4000 5000 6000 -15 -12 -9 -6 -3 0 3 6 9 12 15 18 21 24
    69. 75. Severe Hypoglycemia Per 1000 Person-Years 0.43 episodes/1000 person-years vs 5.8 episodes/1000 person-years <ul><li>Result/Conclusion: </li></ul><ul><li>In everyday practice, glimepiride leads to considerably fewer episodes of severe* hypoglycemia than glibenclamide </li></ul>N = 21,607 patients Holstein et al. Diabetologia 2000;43:A40. * Defined as requiring IV glucose or glucagon 0.43 5.8 0 2 4 6 # Episodes/1000 person-years Glimepiride Glyburide
    70. 76. Shorter - Lasting Interaction with the  - cell Glimepiride associates to the receptor 2.5 - 3 times faster glibenclamide. Glimepiride dissociates from its binding protein 8 - 9 times more rapidly than glibenclamide. Glimepiride Glibenclamide min min SU association SU dissociation W. Kramer Half-life & Hypos
    71. 77. Sulfonylurea Prescriptions + Prevalence of Severe* Hypoglycemia (Germany ) * Defined as impaired consciousness, requiring IV glucose or glucagon injection and confirmed by blood glucose measurement 1997 1998 1999 Periods - Quarters Number of Prescriptions (Patients) 0 500 1000 1500 2000 2500 3000 I II III IV I II III IV I II III IV 0 2 4 6 8 10 Glibenclamide hypoglycemia Glimepiride hypoglycemia Glibenclamide Glimepiride Cases of Severe* Hypoglycemia Favorable Hypoglycemia Profile Holstein et al. Diabetologia 2000;43:A40.
    72. 78. Thank You