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Diabetes mellitus: An update

Diabetes mellitus: An update. D. Hunt March 2010. Significance of diabetes mellitus. 5% of the population has diagnosed diabetes prevalence increases with age: 20 - 44: 1% 45 - 65: 5% > 65: 10%

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Diabetes mellitus: An update

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  1. Diabetes mellitus: An update D. Hunt March 2010

  2. Significance of diabetes mellitus • 5% of the population has diagnosed diabetes • prevalence increases with age: 20 - 44: 1% 45 - 65: 5% > 65: 10% • the true prevalence of diabetes is estimated to be twice the prevalence of diagnosed diabetes

  3. Significance of diabetes mellitus Frequency of diagnosed and undiagnosed diabetes and IGT, by age (U.S. data - Harris) Harris. Diabetes Care 1993;16:642-52.

  4. Eye Disease Type 1: 25% after 15 years Type 2: 4% - 12% after 15 years Diabetes is the leading cause of adult-onset blindness

  5. Kidney Disease Type 1: 30% after 15 years Type 2: 20% after 15 years Diabetes is the leading cause of end-stage renal disease

  6. Foot complications Loss of foot sensation > foot ulcers and infections > foot amputations Amputation rate: 2 - 30/1000 patient-years Diabetes is the leading cause of non-traumatic amputation

  7. Cardiovascular Disease Risk is Increased 2 to 4 Times Framingham study: diabetes and CAD mortality at 20-year follow-up Haffner Am J Cardiol 1999;84:11J-4J.

  8. UK Prospective Diabetes Study Blood glucose control reduces the risk of diabetic complications, especially microvascular complications

  9. UK Prospective Diabetes Study • 20-year Interventional Trial from 1977 to 1997: • 5,102 patients with newly-diagnosed DM2 • Median follow-up 10.0 years, range 6 to 20 years • Results presented in 1998

  10. Microvascular Endpoints renal failure or death, vitreous haemorrhage or photocoagulation 346 of 3867 patients (9%)

  11. Myocardial Infarction fatal or non fatal myocardial infarction, sudden death 573 of 3867 patients (15%)

  12. UK Prospective Diabetes Study • 20-year Interventional Trial from 1977 to 1997 • 5,102 patients with newly-diagnosed DM2 • Median follow-up 10.0 years, range 6 to 20 years • Results presented in 1998 • 10-year Post-Trial Monitoring from 1997 to 2007 • Annual follow-up of the survivor cohort • Clinic-based for first five years • Questionnaire-based for last five years • Median overall follow-up 17.0 years, range 16 to 30 years

  13. UKPDS resultspresented Post-Trial Changes in HbA1c

  14. (photocoagulation, vitreous haemorrhage, renal failure) Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI) Microvascular Disease

  15. (fatal or non-fatal myocardial infarction or sudden death) Intensive (SU/Ins) vs. Conventional glucose control Myocardial Infarction

  16. Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI) All-cause Mortality

  17. After median 8.5 years post-trial follow-up Aggregate Endpoint19972007 Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040 Microvascular disease RRR: 25% 24% P:0.0099 0.001 Myocardial infarction RRR: 16% 15% P:0.052 0.014 All-cause mortality RRR: 6% 13% P:0.44 0.007 RRR = Relative Risk Reduction, P = Log Rank Legacy Effect of Earlier Glucose Control

  18. After median 8.8 years post-trial follow-up Aggregate Endpoint19972007 Any diabetes related endpoint RRR: 32% 21% P: 0.0023 0.013 Microvascular disease RRR: 29% 16% P:0.19 0.31 Myocardial infarction RRR: 39% 33% P:0.010 0.005 All-cause mortality RRR: 36% 27% P:0.011 0.002 RRR = Relative Risk Reduction, P = Log Rank Legacy Effect of Earlier Metformin Therapy

  19. UKPDS Conclusions • Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for MI and death were observed during 10 years of post-trial follow-up

  20. Pharmacologic Management of Type 2 Diabetes • If glycemic targets are not achieved within 2 to 3 months of lifestyle management, pharmacotherapy should be initiated. • Timely adjustments should be made to attain target A1C within 6 to 12 months. • In patients with marked hyperglycemia (A1C ≥ 9.0%), pharmacotherapy should be initiated concomitantly with lifestyle management, and consideration be given to either combination therapy or insulin.

  21. Management of hyperglycemia in type 2 diabetes Clinical Assessment Lifestyle intervention (initiation of nutrition therapy and physical activity) If not at target A1C <9.0% A1C >9.0% Symptomatic with metabolic decompensation • Initiate pharmacotherapy immediately without waiting for effect from lifestyle interventions: • Consider initiating metformin concurrently with another agent from a different class or • Initiate insulin Initiate metformin Initiate insulin± metformin L I F E S T Y L E

  22. ↓ = < 1.0% decrease in A1C ↓ ↓ = 1.0–2.0% decrease in A1C ↓ ↓ ↓ = >2.0% decrease in A1C Oral agents beyond metformin

  23. If not at target • Add another drug from a different class; or • Add bedtime basal insulin to other agent(s); or • Intensify insulin regimen Timely adjustment to and/or addition of antihyperglycemic agents should be made to attain target A1C within 6 to 12 months Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada; Canadian Journal of Diabetes: 2008 Vol:32 Supplement

  24. Natural History of Type 2 Diabetes Henry. Am J Med 1998;105(1A):20S-6S.

  25. Natural deterioration of -cell function  cell function in type 2 diabetic patients -cell function Years after diagnosis

  26. Insulin

  27. Insulin regimens – Type 2 DM Many different potential regimens! • Oral + hs insulin (basal) • Oral + AM insulin (basal) • Pre-mixed insulin with breakfast and supper • Short-acting with meals + bedtime basal

  28. Holman RR. NEJM 2009;361:1736-47

  29. Aims First Phase • One-year head-to-head comparison of the efficacy of three different types of analogue insulins, when given in addition to dual oral antidiabetic therapy: • Biphasic insulin • Prandial insulin • Basal insulin

  30. Patient Disposition 235Assigned to biphasic insulin(biphasic aspart) 239Assigned to prandial insulin(aspart) 234Assigned to basal insulin(detemir) 34 Discontinued 51Discontinued 45 Discontinued 201 (86%)Completedthree years 188 (79%)Completedthree years 189 (81%)Completedthree years • Overall, 18.4% of patients did not complete three years • No difference in proportions between groups (p=0.15) • No difference in baseline characteristics between those who completed or did not complete three years follow up

  31. Transition to a Complex Insulin Regimen From one year onwards, if HbA1c levels were >6.5%, sulfonylurea therapy was stopped and a second type of insulin was added First Phase Second Phase Add biphasic insulin*twice a day Add prandial insulinat midday 708 T2DMon dual oral agents Add prandial insulin*three times a day Add basal insulinbefore bed R Add basal insulin*once (or twice) daily Add prandial insulin three times a day * Intensify to a complex insulin regimen in year one if unacceptable hyperglycaemia

  32. Demographic Characteristics *interquartile range No significant differences between groups

  33. Glycaemic targets and Insulin Injections Fasting and pre-meal: 4.0-5.5 mmol/l (72-99 mg/dl)‏ Two-hours post meal: 5.0-7.0 mmol/l (90-126 mg/dl)‏ Biphasic Prandial * Basal * Twice a day if required

  34. Complex Insulin Regimens Proportion eligible for a second type of insulin per protocol Proportion taking two types of insulin

  35. Insulin Doses Over 3 Years Median±95% confidence interval Biphasic±prandial Prandial±basal Basal±prandial

  36. Total Daily Insulin Doses at 3 Years Median±95% confidence interval

  37. HbA1c Values Over 3 Years Median±95% confidence interval Overall6.9% (6.8 to 7.1) Biphasic±prandial Prandial±basal Basal±prandial

  38. Primary Outcome: HbA1c at 3 Years Median±95% confidence interval

  39. Body Weight over 3 Years Median±95% confidence interval Biphasic±prandial Prandial±basal Basal±prandial

  40. Increase in Body Weight Over 3 Years Mean±1SD

  41. Hypoglycaemia Categorised as • Grade 1- Symptoms only with glucose (if measured) ≥3.1 mmol/l (≥56 mg/dl) • Grade 2- Symptoms plus glucose <3.1 mmol/l (<56 mg/dl) • Grade 3- Third party assistance required

  42. Grade 2 or 3 Hypoglycaemia Over 3 Years Biphasic±prandial Prandial±basal Basal±prandial

  43. Grade 2 or 3 Hypoglycaemia Over 3 Years Allpatients Patients withHbA1c ≤6.5%

  44. Overview of Main Results

  45. 4T trial Three quarters of patients added a second insulin Those commencing therapy with a basal or prandial insulin more often achieved glycaemic targets than patients commencing with a biphasic insulin Patients commencing therapy with basal insulin had fewer hypoglycaemic episodes and less weight gain These findings provide clear evidence in people with type 2 diabetes to support starting insulin therapy with a once a day basal insulin, and then adding a mealtime insulin if glycaemic targets are not met

  46. Beyond Glycemic Control Blood pressure control Lipid therapy Microvascular complication screening and management

  47. UK Prospective Diabetes Study Blood Pressure Control Study

  48. Randomisation

  49. Blood Pressure : Tight vs Less Tight Control cohort, median values Less tight control Tight control

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