Optimal diabetes control in adults.

1. Optimal diabetes control in adults. Dr H Oosthuizen

2. Management principals • Preserve Beta cell function. • Early aggressive treatment. • Reduce glucose toxicity. • Treat to target. • Information and education.

3. Three corner stones of therapy. • Diet • Exercise • Medication

4. Additional metabolic targets. • BP: 130/80 mmHg (with no proteinuria). • BP: 125/75 mmHg (with proteiuria). • Total cholesterol < 5mmol/L • LDL cholesterol < 3mmol/L (diabetes only) < 2.6mmol/L(additional riskfactors) • HDL cholesterol > 1mmol/L • Trigliserides < 1.7mmol/L • BMI = 20-24 kg/m2 • Waist circumfence = 102 cm (f), 88cm (m).

5. Medication for Type 2 diabetic patient. 6 classes of drugs: • Sulphonylurea • Biguanide • Acarbose • Meglitinides • Thiazolidinediones • Insulin

6. PHARMACOLOGICAL MANAGEMENT. SITES OF ACTION OF CURRENT ORAL ANTIDIABETIC AGENTS • Liver: glucose production - biguanides - thiazolidinediones • Pancreas: insulin secretion - sulphonylureas - meglitinides insulin replacement - insulin

7. PHARMACOLOGICAL MANAGEMENT. SITES OF ACTION OF CURRENT ORAL ANTIDIABETIC AGENTS • Adipose tissue: peripheral glucose uptake and and muscle utilization - thiazolidinediones - biguanides • Intestine: glucose absorption - alpha-glucosidase inhibitors

9. / TZD

10. Biguanides :metformin(glucophage) Mechanism of action • Inhibits hepatic glucose prodution (gluconeogenesis). • Increases the sensitivity of peripheral tissue to insulin. • Increases peripheral glucose uptake. • Decreases glucose absorption from the intestine. • Does not stimulate insulin secretion.

11. Metformin Contra-indications • Impaired renal function. • Impaired hepatic function. • Alcoholism. • Conditions which promote tissue hypoxia: coronary heart disease, cardiac failure, peripheral vascular disease, obstructive airways disease • Pregnancy. • Major surgery. • Type 1 Diabetes • Ketoacidosis

12. Metformin Side effects • Diarrhea • Abdominal discomfort • Nausea • Metallic taste • Anorexia • Lactic acidosis • Impaired intestinal Vit B12 & Folate absorption • Megaloblastic anemia (B12 malabsorption)

13. Metformin ADVANTAGES • Reduces insulin resistance. • High initial response rate. • Long record of relative safety. • No weight gain or modest weight loss.

14. Thiazolidinedionespioglitazone (actos), rosiglitazone (avandia)troglitazone (rezulin) TZD/pioglitazone: Mechanism of action • Primary effects on adipocytes are secodarily transmitted to muscle and liver via other mediators (TNF, leptin and FFA). • TZD induce lipoprotein lipase: trigliseride uptake into fat and circulating FFA. • Reduced insulin resistance at liver and muscle. • Enhances GLUT4 gene expression, thus improved insulin action at target tissue.

15. TZD/pioglitazone: Mechanism of action • Pioglitazone increases glucose uptake in skeletal muscle and adipose tissue – increasing glycolysis + synthesis of glycogen in skeletal muscle. • Increase oxidation and lipogenesis in adipose tissue – increase peripheral glucose sensitivity and utilization. • Reduces gluconeogenesis.(by liver) • Reduce insulin resistance.

16. Thiazolidinediones Contra-indications/precautions • Impaired hepatic function or active liver disease. • Cardiac failure. • Type 1 diabetes. • Diabetic ketoacidosis. • Pregnancy. • Lactation.

17. Thiazolidinediones Side effects • Upper Respiratory Tract infection. • Weight gain. • Anemia - Hb and Hematocrit. • Haemodulation and Oedema. • Plasma volume expansion and cardiac hypertrophy. • Ovulation and possible pregnancy. • Unknown long term safety profile.

18. Thiazolidinediones ADVANTAGES • Corrects a primary pathophysiologic impairment: insulin resistance. • Once daily dosing. • Lowers serum triglycerides. • Increases HDL cholesterol. • Can be used in renal insufficiency.

19. Insulin secretagogues • Repaglinide • Nateglinide • Sulphonylureas

20. Sulphonylureas • Chlorpropamide (diabinese) • Gliclazide (diamicron, glucomed) • Glipmepiride (amaryl) • Glipizide (minidiab) • Glybenclamide (daonil, glyben, glycomin) • Tolbutamide (rastinon)

21. Sulphonylureas Contra-indications • Impaired renal and hepatic function. • Pregnancy • Type 1 diabetes • Thyroid and adrenal dysfunction.

22. Sulphonylureas DISADVANTAGES • Hypoglycaemia – may be prolonged or severe. • Weight gain. • Drug interactions, especially 1st generation. • Hyponatraemia with Chlorpropamide. • Cannot use if allergic to SU compounds. • Direct Exocytosis of Beta cells: ? Beta cell life span?

23. Type 2 Hyperglycaemia • 3rd generation sulphonylureas. Amaryl • Once daily. • Insulin release action. • Stimulation of glucose transport. • Stimulation of non-oxidative glucose metabolism in fat and muscle cells

24. Meglitinide analogues • Repaglinide • Nateglinide

25. Nateglinide/Repaglinide • Meglitinide group of drugs • Stimulate insulin secretion from beta cells (glucose dependent) • Minimal excretion via kidneys

26. Repaglinide/Nateglinidemechanism of action • Pharmacologically distinct binding site on potassium channel. • No direct exocytosis of insulin from beta cell. • Beta cell sparing? • Overcome metabolic stress on cells.

27. Repaglinide/Nateglinide ADVANTAGES • Improve primary pathophysiologic impairment: insulin secretion. • Physiologic route of insulin delivery. • Permits flexibility in lifestyle: Dose coupled to meals –no need for snacking-promote weight loss. • High initial response rate. • No lag period before response. • Can be used in various degrees of renal impairment. • Low incidence of severe hypoglycaemic episodes.

28. Alpha-Glucosidase Inhibitors Acarbose (glucobay)

29. Alpha-Glucosidase InhibitorsMechanism of action • Acts by competitive inhibition of alpha-glucosidase enzymes. • Reduces the rate of monosaccharide generation and absorption. • Delays glucose absorption in the intestine. • Modulates peaks in post-prandial glucose. • Taken with meals.

30. Alpha-Glucosidase InhibitorsAcarbose Indications • Obese and non-obese Type 2 patients inadequately controlled by diet and exercise therapy. • May be used in combination with Repaglinide, SU’s, Metformin or Insulin.

31. Alpha-Glucosidase InhibitorsAcarbose Side effects • Dose related absorption. • Flatulence • Abdominal bloating/upset. • Skin reactions.

32. Alpha-Glucosidase InhibitorsAcarbose ADVANTAGES • Good safety profile. • No weight gain. • Dose coupled to meals. • Unique mechanism.

33. Rationale for COMBINATION THERAPY • Improving metabolic effect by combining drugs with different mechanisms of action. • Reducing side effects by sub-maximal dosage. • Starting combination therapy according to metabolic guidelines. • Prescribing drugs according to individual patient need.

34. Management of patients prsenting with very high Blood Glucose levels. • Level higher than~20mmol/L-admission into hospital, depending on symptoms. • If type of diabetes is uncertain - C-peptide test needed. Check for blood/urine ketones. Initiation of insulin may be necessary: • Use supplementation/adjustment scale. • Work insulin dosage out according to Body weight. • Adjust insulin dosage according to blood glucose readings.

35. Pre-meal reading <3mmol/L 3-5mmol/L 5-7mmol/L 7-10mmol/L 10-13mmol/L 13-17mmol/L 17-22mmol/L Change insulin Decrease 1-3 units Decrease 0-1 units Increase 0-1 units Increase 1-2 units Increase 2-3 units Increase 3-4 units Increase 4-6 units Insulin adjustment scale Eg. Of patients on basal-bolus regimen

36. When and how to start insulin treatment in type 2 diabetes. Insulin therapy in Type 2 patients on OAD’s can be started in two ways: • Supplemental therapy • Substitution therapy

37. Insulin initiation-suplemental therapy • Continue OAA treatment. • Add 02iu/kg NPH at breakfast or at bedtime. • Dose increase by 2-4iu every 3-4 days, if necessary. • If more than 36iu insulin needed to obtain control – stop OAA treatment and continue insulin alone. • Divide dose into 2 daily injections – 2/3 mane, 1/3 nocte-(30/70 premix).

38. Protophane dosage 60kg patient = 12u 70kg patient = 16u 80kg patient = 20u 90kg patient = 24u >100 kg = 28u patient

39. Insulin initiation-Substitution therapy • Stop OAA treatment. • Start 2 injections – 0.2iu/kg NPH or premixed insulin (30/70); 2/3 TDD before breakfast, 1/3 TDD before supper. • Increase dose 2-4iu every 3-4 days if necessary. • If PP BG is too high, prmixed insulin better than NPH.

40. Drug interactions Substances that may enhance the hypoglycaemic effects of oral medication • Monoamine oxidase inhibitors (MOAI’s) • Beta blocking agents • Angiotensin converting enzyme inhibitors (ACE-inhibitors). • Non-steroidal anti-inflammatory agents (NSAIDS) • Salicilates • Alcohol • Octreotide and anabolic steroids

41. Drug interactions Substances that may reduce the hypoglycaemic effects of oral medication. • Oral contraceptives • Thiazides • Corticosteroids • Danazol • Thyroid hormones • Sympathomimetics

42. Drug interactions Beta Blocking Agents • May mask the symptoms of hypoglycaemia. • May mask the body’s response to hypoglycaemia. Alcohol • May intensify and prolong the hypoglycaemic effect of oral hypoglycaemic medication.

43. Drug interactions Agents that may delay the metabolism of certain oral hypoglycaemic agents • Interactions with antifungal agents e.g. ketoconazole. • Interactions with antibacterial agents e.g. erythromycin.

44. Drug interactions Compounds that induce or inhibit the cytochrome-P450 (CYP3A4 or CYP2C9) enzyme system • May either delay or increase the metabolism of certain oral hypoglycaemic agents e.g. • Ketoconazole is a CYP3A4 inhibitor • Rifampicin is a CYP3A4 inducer

45. Advantages Frequent measurements. Availability. Treatment adaptable. Testing at appropriate times. Disadvantages Inaccuracy due to wrong technique. Not all readings are reported. Cost Home glucose monitoring.

46. Advantages Laboratory measurement. Done 3-6 monthly. Gold standard. Disadvantages Average reading Hypoglycaemic episodes not picked up. Expensive Different methods in different labs. False security. Monitoring via HbA1c

47. Home glucose monitoring. • New trends in diabetes management. • New Glucometers – Optium Plus Accutrend sensor Lifescan Glucometer Elite Freestyle • Computer assisted systems.

48. Type 2 Diabetes • Treat the patient not the glucometer. • Control other risk factors: • Obesity – life style modification drug therapy • Dislipidaemia • Hypertension – drug side effects combination therapy • Smoking

49. Conclusion • Elevated postprandial blood glucose = risk factor for Cardiovascular disease and mortality, independent of Fasting blood glucose levels and HbA1C. • Early and aggressive treatment of Type 2 diabetes, to improve glycaemic control, decreases the risk of long term complications. • Insulin treatment initiated when near normalization of BG cannt be achieved with OAA’s alone.

50. Conclusion • Better BG control – reduces/avoids atherosclerosis – BP management. • Education on dislipidemia. • Quality of Life factors affect control and management.