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MANAGEMENT OF TYPE II DIABETES

MANAGEMENT OF TYPE II DIABETES. PRESENTED BY MUHAMMAD OMAR JAMIL M.D. CONTENTS. PATHOPHYSIOLGY OF DIABETES LIFESTYLE MODIFICATIONS ORAL HYPOGLYCEMICS BIGUANIDES SULFONYL UREAS MEGLITINIDES THIAZOLIDINEDIONES ALPHA GLUCOSIDASE INHIBITORS DPP IV INHIBITORS INJECTABLE HYPOGLYCEMICS

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MANAGEMENT OF TYPE II DIABETES

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  1. MANAGEMENT OF TYPE II DIABETES PRESENTED BY MUHAMMAD OMAR JAMIL M.D

  2. CONTENTS • PATHOPHYSIOLGY OF DIABETES • LIFESTYLE MODIFICATIONS • ORAL HYPOGLYCEMICS • BIGUANIDES • SULFONYL UREAS • MEGLITINIDES • THIAZOLIDINEDIONES • ALPHA GLUCOSIDASE INHIBITORS • DPP IV INHIBITORS • INJECTABLE HYPOGLYCEMICS • INSULIN • GLP ANALOGUES • AMYLIN ANALOGUES

  3. What is Diabetes? It is a metabolic state characterized by persistent hyperglycemia due to absolute or relative deficiency of insulin. • Type 1: Pancreas produces little to no insulin • Type 2: Over time, lose ability to use the insulin that the body makes Sandwich Blood sugar Blood sugar Insulin

  4. TRANSPORT ACTIVITY IRS P SECONDARY MESSENGER PATHWAYS ENZYMES CHANGES IN METABOLISM

  5. TRANSPORT ACTIVITY IRS P SECONDARY MESSENGER PATHWAYS ENZYMES CHANGES IN METABOLISM

  6. Insulin: Summary and Control Reflex Loop

  7. LIPOLYSIS GLUCOSE UPTAKE GLYCOGEN SYNTHESIS( STORAGE) GLUCONEOGENEIS(LIVER) GLYCOLYSIS (MUSCLE) AMINO ACID UPTAKE (PROTEIN SYTHESIS) K+ UPTAKE INTO CELLS CONVERSION OF CARBOHYDRATE TO FAT (LIPOGENESIS) FAT EFFECTS OF INSULIN PROTEIN CARBOHYDRATES POTASSIUM

  8. Insulin Degradation • Hydrolysis of the disulfide linkage between A&B chains. • 60% liver, 40% kidney(endogenous insulin) • 60% kidney,40% liver (exogenous insulin) • Half-Life 5-7min (endogenous insulin)

  9. PATHOPHYSIOLOGY OF TYPE II DM • Resistance to insulin • Raised levels of insulin in the body • Role of UCP 2 and Amylin

  10. Epidemiology • Type 1: • Usually diagnosed in children and young adults • About 5-10% of people with diabetes have type 1 • Type 2: • Older Adults Children, adults, and older adults!!! • About 90-95% of people with diabetes have type 2 diabetes

  11. Risk factors for type 2 diabetes • Age • Physical inactivity • Being overweight • For women: gestational diabetes • Some racial/or ethnic groups • Type 2 diabetes in the family

  12. 40% of older people are insulin resistant mostly secondary to obesity and inactivity (important in prevention and treatment) • 20% of the elderly have type 2 diabetes • 8.5% of all adults have type 2 diabetes

  13. Aims of Management • To achieve target glucose levels • Short term- to prevent symptoms of hyper & hypo • Long term- to prevent complications • Good quality of life, near normal life expectancy

  14. Targets for non-pregnant patients • HbA1c - NICE 6.5-7.5% - ADA <7% - IDF <6.5% • BP - <130/80 • LDL <70

  15. Therapeutic Lifestyle Change Monotherapy Combination Therapy - Oral Drugs Only Combination Therapy - Oral Drug with Insulin Treatment of Type 2 Diabetes Diagnosis

  16. MANAGEMENT OF DIABETES WITH LIFESTYLE MODIFICATIONS

  17. Nutrition Guidelines for Type 2 diabetes • Lose weight if overweight • Lose weight slowly and safely, 1-2 pounds weekly • Exercise to promote or maintain weight loss • 30 minutes most days of the week is recommended • Include aerobic exercise and resistance training for the best results • Start slowly and increase the duration and intensity of exercise if you are new to exercise.

  18. Nutrition Guidelines for Type 2 diabetes • Monitor carbohydrate intake to maintain blood sugar control • At least 130 grams carbohydrate should be consumed per day (do not use low-carbohydrate diets to treat diabetes) • Use sugar substitutes if desired • Carbohydrates should be obtained mainly from fruits, vegetables, whole grains, legumes, and low-fat or skim milk • These foods are the best carbohydrate sources • They are usually high in fiber and high in nutrients your body needs

  19. MANAGEMENT OF DIABETES WITH ORAL MEDICATIONS

  20. sensitize the body to insulin +/- control hepatic glucose production (sensitizers) stimulate the pancreas to make more insulin (secretagogues) slow the absorption of starches decreased degradation of GLP1 Thiazolidinediones Biguanides Sulfonylureas Meglitinides Alpha-glucosidase inhibitors DPP IV inhibitors Major Classes of Medications

  21. Biguanide • Enhance hepatic & peripheral (muscle) tissue insulin sensitivity • increases uptake of glucose in tissues • No direct effect on β cells • Decrease hepatic glucose production

  22. Biguanides Efficacy • Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L) • Reduce A1C 1.0-2.0%

  23. Pharmacokinetics

  24. Metformin ADVERSE EFFECTS • Gastrointestinal: Diarrhea (10% to 53%), nausea/vomiting (7% to 26%), flatulence (12%), Indigestion (7%), abdominal discomfort (6%), abdominal distention, abnormal stools, constipation, dyspepsia/ heartburn, taste disorder • Neuromuscular & skeletal: Weakness (9%) • Cardiovascular: Chest discomfort, flushing, palpitation • Central nervous system: Headache (6%), chills, dizziness, lightheadedness • Dermatologic: Rash • Respiratory: Dyspnea, upper respiratory tract infection • Miscellaneous: Decreased vitamin B12 levels (7%), increased diaphoresis, flu-like syndrome, nail disorder • Rare: Lactic acidosis, leukocytoclastic vasculitis, megaloblastic anemia, pneumonitis

  25. CONTRAINDICATIONS: • Hypersensitivity • Renal dysfunction • serum creatinine ≥ 1.5 mg/dL from any cause, including shock, acute myocardial infarction, or septicemia; acute or chronic metabolic acidosis with or without coma (including diabetic ketoacidosis) • Heart failure • Hepatic impairment • Stress-related states

  26. Precautions: • Ethanol use • Iodinated contrast: • Should be withheld for 48 hours after the radiologic study and restarted only after renal function has been confirmed as normal. • Surgical procedures • resume only after normal intake resumed and normal renal function is verified.

  27. Elderly: • should not be initiated in patients ≥ 80 years of age unless normal renal function is confirmed. • Pediatrics: • Safety and efficacy have not been established in children <10 years of age. • safety and efficacy for the extended release preparation have not been established in children <17 years of age.

  28. DRUG INTERACTIONS • Cephalexin: May increase the serum concentration • Cimetidine: May decrease the excretion • Corticosteroids: • May diminish the hypoglycemic effects • In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia

  29. Luteinizing Hormone-Releasing Hormone Analogs: • May diminish the therapeutic effect of Antidiabetic Agents. • Pegvisomant: • May enhance the hypoglycemic effect of Antidiabetic Agents. • Somatropin: • May diminish the hypoglycemic effect of Antidiabetic Agents.

  30. PREGNANCY IMPLICATIONS • Adverse events have not been observed in animal studies; therefore, metformin is classified as pregnancy category B. • LACTATION  • Enters breast milk/not recommended

  31. Sulfonylureas Ca Ca INS suf INS

  32. Sulfonylureas Ca Ca INS suf INS

  33. Sulfonylureas • Sulfonylureas increase endogenous insulin secretion • Efficacy • Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L) • Reduce A1C by 1.0-2.0% • No specific effect on plasma lipids or blood pressure • Generally the least expensive class of medication

  34. Sulfonylureas First generation Second generation Long acting Short acting Long acting Short acting Intermediate acting Glyburide Glibenclamide Glimepiride Chlorpropamide Glipizide Tolbutamide Acetohexamide Tolazamide

  35. FIRST GENERATION SULPHONYLUREA COMPOUNDS * Good for pts with renal impairment **Pts with renal impairment can expect long t1/2

  36. SECOND GENERATION SULPHONYLUREA COMPOUNDS

  37. Sulfonylureas

  38. Sulfonylureas

  39. ADVERSE EFFECTS OF SULPHONYLUREAS 1) Nausea, vomiting, abdominal pain, diarrhea 2) Hypoglycaemia 3) Dilutional hyponatraemia & water intoxication (Chlorpropamide) 4) Disulfiram-like reaction with alcohol (Chlorpropamide) 5) Weight gain

  40. ADVERSE EFFECTS OF SULPHONYLUREAS 6) Blood dyscrasias (not common; less than 1% of patients) - Agranulocytosis - Haemolytic anaemia - Thrombocytopenia 7) Cholestatic obstructive jaundice (uncommon) 8) Dermatitis (Mild) 9) Muscle weakness, headache, vertigo (not common) 10) Increased cardio-vascular mortality with longterm use ??

  41. CONTRAINDICATIONS OF SULPHONYLUREAS 1) Type 1 DM ( insulin dependent) 2) Parenchymal disease of the liver or kidney 3) Pregnancy, lactation 4) Major stress

  42. DRUGS THAT AUGMENT THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS WARFARIN SULFONAMIDES SALICYLATES PHENYLBUTAZONE PROPRANOLOL ALCOHOL CHLORAMPHENICOL FLUCONAZOLE

  43. DRUGS THAT ANTAGONIZE THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS DIURETICS (THIAZIDE, FUROSEMIDE) DIAZOXIDE CORTICOSTEROIDS ORAL CONTRACEPTIVES PHENYTOIN, PHENOBARB., RIFAMPIN ALCOHOL ( chronic pts )

  44. Factitious Hypoglycemia If a person uses oral sulphonylureas to induce hypoglycemia then the c peptide levels are also raised so urinary sulphonylurea level is checked to make the diagnosis • ·        Sulphonylureas have a longer half life so the patient needs to be under observation and glucose should be monitored for about 24 hours  in case of sulphonylurea toxicity

  45. All sulphonylureas have a renal clearance mechanism except for tolbutamide which is cleared by hepatic metabolism. So in renal failure tolbutamide should be used to avoid prolonged uncontrolled effect. Otherwise tolbutamide is usually not used because it needs to be used 3 or 4 times per day while most of the others have a long half life and require once daily dosage

  46. Meglitinides • Stimulate insulin secretion (rapidly and for a short duration) in the presence of glucose. • Efficacy • ↓ peak postprandial glucose • ↓ plasma glucose 3.3-3.9 mmol/L • ↓ HbA1C 1.0-2.0%

  47. Adverse Effects • Hypoglycemia (may be less than with sulfonylureas if patient has a variable eating schedule) • Weight gain • No significant effect on plasma lipid levels • Safe at higher levels of serum Cr than sulfonylureas • Medications in this Class: repaglinide , nateglinide

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