Insulin Therapy & Oral Hypoglycaemics

1. Applied Sciences Lecture Course Insulin Therapy & Oral Hypoglycaemics Dr Cathy Armstrong SpR In Anaesthesia & Clinical Fellow in Undergraduate Medical Education Manchester Royal Infirmary March 2011

2. Aims & Objectives • Discuss insulin therapy • Classify oral hypoglycaemics into groups • Describe mechanisms of action • Describe relevant pharmacokinetic aspects • Discuss common clinical uses • Diabetes Mellitus

3. Diabetes Mellitus • Metabolic disorder of multiple aetiology characterised by chronic hyperglycaemia with disturbances of carbohydrate, protein & fat metabolism resulting from defects in insulin secretion, insulin action or both. • Clinical symptoms • Polyuria, polydipsia, unexplained weight loss, slow healing • 2.8 million people diagnosed in Uk • Estimated 850,000 undiagnosed cases

4. Which of the values below is indicative of Diabetes mellitus • Random glucose of > 7.0 mmol/l • Fasting blood glucose > 7.0 mmol/l • HBA1c < 5.0%

5. WHO Diagnostic criteria Fasting blood glucose > 7.0mmol/l Venous plasma glucose > 11.1 2 hours after a 75g oral glucose load (OGTT)

6. Insulin

7. Insulin • Clinical Uses • Diabetes Mellitus • Hyperkalaemia • Side effects • Hypoglycaemia • Weight gain

8. Insulin preparations • Human or analogue of human sequence • Produced using recombinant DNA technology • Ineffective orally • Given S/C or IV

9. Insulin Preparations • Rapid-acting analogues • Onset 15 min • Duration of action 2-5 hours • Short-acting • Onset 30 – 60 min • Duration of action up to 8 hours • Intermediate-acting • Onset of action 1 – 2 hours • Duration of action 16 – 35 hours • Long-acting • Onset of action 1 – 2 hours • Duration of action > 24 hours

10. Rapid-acting insulin analogues • Faster onset and shorter duration of onset than soluble insulin • Easier to time with meals • Slightly less incidence of hypoglycaemia • E.g • Insulin Aspart • Novorapid • Insulin Lispro • Humalog

11. Short – acting insulin • Soluble insulin • E.g. Actrapid, Humulin S • SC administration • Onset 30 – 60 min • Peak effect 2-4 hours • Duration of action up to 8 hours • IV administration • Half life 5 min • Duration of action up to 30 min • Recommended for sliding scale & emergency management

12. Intermediate-acting • Isophane insulin • Insulin suspended with protamine • E.g. Insulatard, Humulin I • Useful in combination with short-acting insulin for BD regimens • Biphasic pre-mixed preparations • Novomix 30 • Mixtard 30

13. Long - acting • Once daily preparations • Human insulin analogues with prolonged duration of action • Insulin glargine • Lantus • Insulin detemir • Levemir

14. Examples of regimens • MDI (multiple daily injection) • Rapid or short-acting insulin before each meal with intermediate or long acting insulin once or twice daily • Rapid or short acting insulin – pre-mixed or self-mixed with intermediate acting insulin, once or twice daily before meals • Insulin pump therapy

15. Hypoglycaemia • Reduced conscious level • 150 – 160ml 10% dextrose • OR 75-80ml 20% dextrose • OR Glucagon 1mg IV/IM Repeat after 10min until BM > 4.0 (50ml 50% dextrose on arrest trolley - irritant to veins) • Conscious & co-operative • Sugary drink • food

16. Diabetic Ketoacidosis • Type 1 diabetes only • Precipitants • Infection/ concurrent infecton • Non-compliance / wrong insulin dose • Diagnosis requires hyperglycaemia, ketosis & acidosis • pH < 7.3

17. Diabetic Ketoacidosis management • Insulin • Iv bolus (4-8iu) • Sliding scale • Fluid replacement • Potassium replacement

18. Sliding Scale • 2 components • Soluble insulin 50IU in 50ml N saline • E.g. actrapid • Rate will depend on BM • IV fluids via controlled pump • Fluid type will depend on BM

19. Sliding Scale Example 50 iu soluble insulin (actrapid) in 50ml N saline BM > 16 infuse with N saline approx 50ml/hr BM < 16 infuse with 5% dextrose approx 50ml/hr

20. If the insulin preparation is 100 iu/ml - what volume would contain 50 iu? • 0.5 ml • 1 ml • 5ml • 10ml • 50ml

21. 1000 units

22. Oral Hypoglycaemics

23. Oral Hypoglycaemics Reduce absorption of glucose from GI tract Enhance insulin release from pancreas Enhance glucose uptake & utilisation by the peripheral tissues

24. Oral hypoglycaemics • Biguanides • Metformin • Sulphonylureas • Tolbutamide • Glibenclamide • Glicazide • Thiazolidinediones • Rosiglitazone • α-Glucosidase inhibitors • Acarbose • GLP-1 analogues • exenatide

25. Biguanides • Metformin • Inhibits AMP-activated protein kinase (AMPK) • Liver enzyme • Increase glucose uptake and utilisation by skeletal muscle (↑ insulin sensitivity) • Reduces gluconeogenesis in liver & glucose uptake by the gut • Suppresses appetite • First line in obese diabetic pts • Does not cause hypoglycaemia

26. Oral Hypoglycaemics Reduce absorption of glucose from GI tract Enhance insulin release from pancreas Enhance glucose uptake & utilisation by the peripheral tissues

27. Metformin • other effects • GI • Diarrhoea • Lowers cholesterol • Vit B 12 deficiency • Lactic acidosis • Esp in alcohol abuse, renal impairment, shock & sepsis • Excreted unchanged in urine • Renal impairment prolongs action

28. Sulphonylureas • Stimulate secretion of insulin from the β cells in the pancreas • Bind to ATP-dependent K+ channels in β cell membrane • ultimately causing increased Ca levels and secretion of insulin • 1st generation • Tolbutamide • 2nd generation • Glicazide (short-acting) • Glibenclamide, Glipizide (long – acting)

29. Oral Hypoglycaemics Reduce absorption of glucose from GI tract Enhance insulin release from pancreas Enhance glucose uptake & utilisation by the peripheral tissues

30. Sulphonylureas • Side effects • Can cause hypoglycaemia • Stimulate appetite, cause weight gain • Cross placenta • Cause hypoglycaemia of the newborn • Potentially teratogenic

31. Thiazolidinediones • Increase lipogenesis & enhances uptake of fatty acids & glucose • Bind to nuclear receptors – peroxisome proliferator-activated receptors (PPARγ) found in adipose tissue skeletal muscle & liver • E.g. • Rosiglitazone • pioglitazone

32. Oral Hypoglycaemics Reduce absorption of glucose from GI tract Enhance insulin release from pancreas Enhance glucose uptake & utilisation by the peripheral tissues

33. Thiazolidinediones • Side effects • Weight gain • Fluid retention / oedema • ?? Increased cardiovascular risk

34. α-Glucosidase inhibitors • Acarbose • Inhibit gastrointestinal α-glucosidase which delays carbohydrate absorption • Useful in obese patients • Side effects • Flatulence, diarrhoea, abdo pain

35. Oral Hypoglycaemics Reduce absorption of glucose from GI tract Enhance insulin release from pancreas Enhance glucose uptake & utilisation by the peripheral tissues

36. GLP-1 analogues • New drug • exenatide • Glucagon-like peptide 1 (GLP-1) stimulates insulin release, β-cell growth & ↓ glucagon secretion • Expensive • Present in NICE guidelines but judicious use at present

37. Oral Hypoglycaemics Reduce absorption of glucose from GI tract Enhance insulin release from pancreas Enhance glucose uptake & utilisation by the peripheral tissues

38. Type 2 Diabetes – NICE guidance

39. A 75 year old man, known to have type 2 diabetes presents with a reduced conscious level & blood glucose of 55mmol/lWhat is the most likely diagnosis? • HONK • DKA • Opiate overdose

40. HONK coma • Hyperosmolar hyperglycaemic Non-ketotic coma • BM often > 35 • Plasma osmolality raised • Precipitants • Intercurrent illness / dehydration • Hyperglycaemia causes an osmotic diuresis causing cellular dehydration

41. Summary • Discussed insulin therapy • Classified oral hypoglycaemics into groups • Discussion of common clinical uses • Management of Type 1 & 2 diabetes • DKA / HONK • Hypoglycaemia

42. ?