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DIABETES CONTROL

DIABETES CONTROL. The Alphabet Strategy. A dvice Smoking , diet , exercise B lood pressure < 140/80 C holesterol TC ≤ 4 , LDL : HDL ≤ 2 D iabetes control HbA1c ≤ 7% E ye examination Annual examination F eet examination Annual examination G uardian drugs Aspirin, ACEI, statins &c.

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DIABETES CONTROL

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  1. DIABETES CONTROL

  2. The Alphabet Strategy • Advice Smoking , diet , exercise • Blood pressure < 140/80 • Cholesterol TC ≤ 4 , LDL : HDL ≤ 2 • Diabetes control HbA1c ≤ 7% • Eye examination Annual examination • Feet examination Annual examination • Guardian drugs Aspirin, ACEI, statins &c

  3. Effect on diabetes complications of HbA1c% reduction Reductions in HbA1c and corresponding reductions in microvascular and macrovascular complications described in major studies of persons with T1 DM and T2 DM

  4. UKPDS : HbA1c% 7.0% versus 7.9% endpoints Micro albuminuria any diabetes Retinal laser micro vasculars cataract MI 0% -5% -10% 12% 16% -15% -20% P=0.052 25% 24% -25% 29% P=0.046 P=0.0099 33% -30% P=0.0031 -35% P<0.001

  5. UKPDS : glycaemic control

  6. Type 1 diabetes - treatment options

  7. Type 1 diabetes - treatment options • Lifestyle • Diet, exercise • Insulin • Islet transplantation

  8. Type 1 diabetes Premixed Insulin Basal Bolus Regime

  9. Diagrammatic representation of physiological insulin secretion and 30/70 pre-mixed insulin time-action profile Physiological insulin Pre-mixed 30/70 regimen Blood insulin levels 24.00 06.00 18.00 06.00 12.00 Breakfast Lunch Dinner Why pre-mixed insulins don’t work

  10. Type 2 diabetes - treatment options

  11. Type 2 diabetes - treatment options • Lifestyle • Diet, exercise • Oral monotherapy • Oral combination therapy • Insulin (with or without oral agents)

  12. -glucosidase inhibitors Carbohydrate Sulphonylureas Incretin mimetics DPP-IV inhibitors Insulin acts on all tissues Biguanides Primary sites of action of hypoglycaemic agents Stomach Gut I Glucose G I Adipose tissue I G Insulin G G I G I Pancreas G I G I G I G I G Muscle I G G Thiazolidinediones Liver Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.

  13. Oral hypoglycaemic agents

  14. Oral hypoglycaemic agents • Metformin • Sulphonylureas • Acarbose • Guar gum • Postprandial glucose regulators • Thiazolidinediones • Dipeptidyl peptidase-IV inhibitors By injection • Incretin mimetics

  15. Metformin : history • French Lilac or Goat’s Rue (Galega officianalis) - a traditional remedy for diabetes - is rich in guanidine

  16. Metformin : history • Used by mediaeval monks • 1920s : guanidine derivatives introduced, then forgotten • 1957 : metformin, phenformin • 1970s : phenformin withdrawn • 1994 : metformin obtained FDA approval in USA

  17. Metformin : efficacy •  FPG 2 - 4,  HbA1c 1 - 2% • Effect depends on the presence of insulin • Hypoglycaemia unlikely with monotherapy • Weight neutral • Small improvement in lipid profile • Reduced cardiovascular events

  18. UKPDS : metformin in over- weight subjects Myocardial infarction Diabetes-related endpoints All-cause mortality Diabetes-related deaths 0 5 10 15 20 Risk reduction (%) 25 30 35 p = 0.0023 p = 0.011 40 p = 0.01 45 p = 0.017 p values in comparison to conventional treatment group United Kingdom Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 854–865.

  19. Metformin : use • First – line monotherapy in obese and non-obese • Combination with other oral agents : effects additive • Combination with insulin

  20. Metformin : contraindications

  21. Metformin : contraindications • Impaired renal function • Cardiac or respiratory insufficiency • Liver disease, alcohol abuse • History of metabolic acidosis • Severe sepsis • Use of IV contrast media

  22. Metformin : adverse effects

  23. Metformin : adverse effects • Lactic acidosis: • 0.03 cases / 1000 patient years • 50% mortality • GI symptoms • B12 malabsorption

  24. Sulphonylureas : history • 1940s : sulphonamides noted to cause hypoglycaemia. • 1950s : carbutamide, tolbutamide • 1960s : tolazamide, chlorpropamide • 1970s : ? detrimental cardiovascular effects • 1970s – 1980s : glibenclamide, glipizide, gliclazide • 1990s : glimepiride

  25. Sulphonylureas : efficacy •  FPG 2 - 4,  HbA1c 1 - 2% • Only effective if beta-cell still functioning. • Can initiate insulin release when plasma glucose < 5. • Maximum glucose lowering effect may be achieved below maximum permitted dose.

  26. Sulphonylureas : use • Not preferred in obese subjects • Monotherapy • Combination with other oral agents : effects additive • ? Combination with insulin

  27. Sulphonylureas : adverse effects

  28. Sulphonylureas : adverse effects • Hypoglycaemia • Weight gain : 1 - 4 KGm in 6 months • Sensitivity reactions

  29. Postprandial glucose regulators • Nateglinide, repaglinide • Reduce postprandial glucose spikes by restoring early phase insulin release • Reduce HbA1c% by 0.5-2.0% • Main use in combination with metformin • Meal time flexibility • ? Less weight gain than with sulphonylureas • Gastrointestinal side-effects, hypoglycaemia • No outcome data

  30. Glitazones : history • 1980s : effect first described • 1997 : troglitazone introduced – and withdrawn • 1999 : rosiglitazone (Avandia  , GSK) and pioglitazone (Actos  , Takeda) introduced. • 2005 : PROactive Study – small reduction in CV events with pioglitazone. • 2007 : does rosiglitazone increase CV events?

  31. Glitazones : efficacy •  FPG 2 - 3,  HbA1c around 1 % • Effect depends on the presence of insulin • Full expression of dose may not be apparent for 3 months • Not all patients respond

  32. Glitazones : adverse effects

  33. Glitazones : adverse effects • Fluid retention : oedema , heart failure , anaemia • Weight gain : 1 – 4 KGm in 6 months • Hypoglycaemia in combination with other oral agents • ? Unforeseen chronic effects

  34. Glitazones : contraindications

  35. Glitazones : contraindications • Heart failure • Oedema • Anaemia • ? Insulin therapy • ? Impaired liver function

  36. New agents for T2D • CB1 receptor antagonist • Rimonabant • Glucagon-like peptide-1 (GLP-1) receptor agonists (incretin mimetics) • Exenatide • Liraglutide • Dipeptidyl peptidase-4 (DPP-4) inhibitors (incretin enhancers) • Sitagliptin • Vildagliptin

  37. UKPDS : glycaemic control

  38. UKPDS : decline of -cell function over time 100 100 Start of treatment 80 80 60 60 -cell function (%) 40 40 20 0 –10 –9 –8 –7 –6 –5 –4 –3 –2 –1 1 2 3 4 5 6 Time from diagnosis (years) HOMA model, diet-treatedn = 376 Adapted from Holman RR. Diabetes Res Clin Pract 1998; 40 (Suppl.):S21–S25.

  39. Insulin : history • 1921 : Banting and Best • 1940s : protamine and zinc • 1980s : human insulin • 1990s : insulin analogues

  40. Insulin : mechanisms • Reduces : • Glycogen breakdown • Gluconeogenesis • Lipolysis • Protein breakdown Increases : • Glucose uptake by cells • Glycogen synthesis • Fatty acid synthesis • Cholesterol & LDL synthesis • Amino acid transport • Protein synthesis

  41. Insulin : use

  42. Insulin : use • Type 1 diabetes • Improved metabolic control in type 2 diabetes • Oral therapies contraindicated or not tolerated • Post-myocardial infarction (DIGAMI) • Severe intercurrent illness , surgery • Gestational diabetes not controlled by diet

  43. Insulin : adverse effects

  44. Insulin : adverse effects • Hypoglycaemia • Weight gain • Allergy • Lipohypertrophy and lipoatrophy • Transient deterioration of retinopathy • Insulin neuritis

  45. Control versus hypos : DCCT

  46. 10.0 7.5 Intensive (Insulin) 5.0 Change in weight (kg) 2.5 Conventional 0 0 3 6 9 12 15 Years from randomisation Weight gain with insulin : UKPDS

  47. Insulin preparations Short acting onset 30 mins Humulin S peak 2-4 hours Actrapid duration 8 hours Intermediate onset 1-2 hours Insulatard peak 4-12 hours Humulin I duration 16-24 hours Long acting onset 1-2 hours Human Ultratard peak 4-12 hours Humulin Zn duration 20-35 hours Analogue onset 0-15mins Humalog (Lispro) peak 1-2 hours Novorapid (Aspart) duration 4-6 hours duration 24 hours Glargine , Levemir

  48. How many do you need ?

  49. How many do you need ? • Novorapid • NPH • Glargine • Detemir • Novomix 30

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