Insulins And Insulin Delivery

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  • 1. Insulins and Insulin Delivery Rob Dyer 6 February 2009
  • 2. Case 1
    • 37 year old man referred by GP.
    • Type 1 diabetes for 18 years. HbA1c consistently 9.0 – 10.5%
    • Was on bd H Mixtard until 2002. Transferred to Actrapid 20, 20, 20 and H Insulatard 20 when in hospital in 2002.
    • ‘ Would he be a good candidate for Glargine?’
  • 3. Miss RL – HbA1c Normal range Target Age 10 Age 17
  • 4. Glycaemic excursion and Premixed insulin
  • 5. DCCT Effect of intensive therapy on complications and hypoglycaemia
  • 6. Intensive education, the German experience.
    • 1983 Muhlhauser et al (Michael Berger). 5 day intensive educational programme for patients with Type 1 diabetes
    • 636 patients
    • 6 years of follow up
    • Sustained improvement in HbA1c to 7.6%
    • Reduced risk of hypoglycaemia
    • Refs Mulhauser I et al, Diabetologia 25;470-6, 1983
    • Bott S et al, Diabetologia 40:926-32, 1997
  • 7. Food Comparisons How much carbohydrate?
  • 8.  
  • 9. SALAD MEAL 15g Lettuce minimal Cucumber " Tomatoes " Radish " Red Pepper " Cold chicken " Mayonnaise " Crisps 15g
  • 10. Italian Meal Garlic Bread Whole Pizza Ice Cream ???g
  • 11. Italian Meal Garlic Bread 70g Whole Pizza 100g Ice Cream 30g 200g
  • 12. Mrs BS (3 months after course)
    • Running marathons
    • 1 unit insulin: 12g CHO when inactive
    • 1 unit insulin: 20g CHO when active
    • No nocturnal hypos
    • HbA1c 7.9% (9.5% before course)
  • 13. Mrs BS (4)
    • Insulin dose before course
    • Lispro 8, 8, 8
    • Humulin I 8 32
    • Insulin dose after course
    • Lispro 9 approx
    • Humulin I 5 14
  • 14. Case 1 (contin)
    • Has completed CHO counting course.
    • HbA1c 8.9%
    • On Novorapid variable doses with meals
    • H Insulatard at bedtime 22 units
    • Prone to hypos if increases H Insulatard.
    • What are the options?
  • 15. Short acting analogues
    • Are more convenient to take than standard soluble insulin
    • Give better post-prandial glycaemic control
    • Probably do not result in better HbA1c
    • May reduce hypoglycaemia
  • 16. 1530 Levemir® vs. NPH in treat-to-target trial: Hypoglycaemia Hypoglycaemia Hermansen K, et al., Diabetologia 2004;47(Supplement 1):A273
  • 17.  
  • 18. Within-patient variability with NPH insulin Selected clamp profiles on 4 identical study days for 8 out of 17 subjects on NPH who completed the study The CV for all 17 patients on NPH who completed the study was 68% Heise, T. et al., Diabetes, 2004; Vol. 53: 1614-1620 Data on file: InsDet 09 2004
  • 19. Within-patient variability with Levemir ® Selected clamp profiles on 4 identical study days for 8 out of 18 subjects on Levemir ® who completed the study The CV for all 18 patients on Levemir ® who completed the study was 27% Heise, T. et al., Diabetes, 2004; Vol. 53: 1614-1620 Data on file: InsDet 09 2004
  • 20. HbA1c (%) Post- Baseline Post-CSII Post-TIFA Changes in HbA1c during transfer to Pump therapy (CSII) Individual patients
  • 21. Torbay CSII First 11 patients
  • 22. Other benefits of CSII
    • Reduction in hypoglycaemia
    • Reduction of post-prandial glucose excursion
    • Reduction in Hba1c (in the majority)
    • Easier to manage illness
    • Management of ‘dawn phenomenon’
    • Less swings in blood glucose levels
    • Improved QOL.
    • Feeling in control
    • ‘ Patient power’
  • 23. Primary Care Insulin Initiation
    • A practice is just starting out on insulin initiation in Type 2 diabetes.
    • The staff find it confusing that there are so many insulins.
    • They ask you to advise them on a limited range to make life simpler as they are starting out.
    • What would you advise?
  • 24. 4T Baseline Characteristics
    • Biphasic Prandial Basal N=235 N=239 N=234
    • Age (years) 61.7 ±8.9 61.6 ±10.5 61.9±10.0
    • Diabetes duration (years)* 9 (6-2) 9 (6-4) 9 (6-12)
    • Body weight (kg) 86.9 ±16.8 84.9 ±14.4 85.5 ±16.3
    • Body mass index (kg/m 2 ) 30.2 ±4.8 29.6 ±4.5 29.7 ±4.6
    • HbA 1c (%) 8.6 ±0.8 8.6 ±0.8 8.4 ±0.8
    • Fasting plasma glucose (mmol/l) 9.7 ±2.8 9.6 ±2.7 9.5 ±2.6
    • LDL cholesterol (mmol/l) 2.5 ±0.7 2.4 ±0.7 2.3 ±0.7
    • HDL cholesterol (mmol/l) 1.0 ±0.3 1.0 ±0.2 1.0 ±0.3
    • Triglycerides (mmol/l) * 1.6 (1.2-2.1) 1.5 (1.2-2.3) 1.5 (1.1-2.2)
    • No significant differences between groups *interquartile range
    N Engl J Med 2007; 357: 1716-30
  • 25. Randomisation N Engl J Med 2007; 357: 1716-30 * Intensify to a combination insulin regimen in year one if unacceptable hyperglycaemia 708 T2DM on dual OAD Add biphasic insulin twice a day Add prandial insulin three times a day R Year 1 Comparison of three single insulin regimens, added to OADs* Add basal insulin once (or twice) daily Add prandial insulin at midday Add basal insulin before bed Years 2 and 3 If HbA 1c >6.5%, stop sulfonylurea and add a second insulin formulation Add prandial insulin three times a day
  • 26. Insulin Dose Adjustments
    • Morning injection of basal insulin
      • 34% (n=79) of patients randomised to pre-bedtime basal insulin required, per protocol, an additional morning injection by one year
    • Adherence to dose adjustment suggestions (±10%)
      • Biphasic 89.7%
      • Prandial 80.4%
      • Basal 90.2%
    N Engl J Med 2007; 357: 1716-30
  • 27. Primary Outcome: HbA 1c at One Year N Engl J Med 2007; 357: 1716-30 — Biphasic — Prandial — Basal Mean ±SD at 1 year (%) 7.3±0.9 Baseline to 1 year (%) -1.3±1.1 7.2±0.9, p=0.08 vs. biphasic 7.6±1.0, p<0.001 vs. biphasic or prandial -0.8±1.0 -1.4±1.0 Months since randomisation Glycated haemoglobin (%) P<0.001
  • 28. Glucose Profiles Before & After Starting Insulin — Biphasic — Prandial — Basal Change in FPG (mmol/l)) -2.5±3.1 Change in PPG (mmol/l) -3.8±3.5 - 1.3±2.7 -3.3±2.9 -2.6 ±3.0 -4.6±3.0 p<0.001 vs. biphasic p<0.001 vs. biphasic or prandial 0 — At baseline
  • 29. Hypoglycaemia (≥ Grade 2) at One Year N Engl J Med 2007; 357: 1716-30 Months since randomisation Proportion with events (%) P=0.001 — Biphasic — Prandial — Basal Mean at 1 year (events/patient/year) 5.7 12.0, p<0.002 vs. biphasic 2.3, p=0.01 vs. biphasic, p<0.001 vs.prandial
  • 30. Biphasic analogue insulins vs standard biphasic insulin
    • Are more convenient to take
    • May give better post-prandial control
    • Probably don’t result in better HbA1c
    • Probably cause less hypoglycaemia than standard biphasic insulins
    • ‘ Convenience insulins’
    • Good devices
  • 31.
    • Conclusions –
    • In 518 patients with type 2 diabetes, once daily bedtime insulin glargine is as effective as once or twice daily NPH in improving and maintaining glycemic control.
  • 32.
    • Conclusions –
    • In 518 patients with type 2 diabetes, once daily bedtime insulin glargine is as effective as once or twice daily NPH in improving and maintaining glycemic control.
    • But
    • All patients were taking multiple injection therapy
  • 33. Raskin P, Rojas P, Hu P et al. Comparison of twice-daily biphasic insulin aspart 70/30 (NovoLog Mix® 70/30) with once-daily insulin glargine in patients with type 2 DM on oral antidiabetic agents. Diabetes Care 2005; 28; 260-5.
  • 34. 1530 Levemir® vs. NPH insulin Treat-to-target trial: Weight p<0.001 Hermansen K, et al., Diabetologia 2004;47(Supplement 1):A273
  • 35. Baseline BMI 35 36 34 39 55 37 42 50 69 76 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 -0.5 Mean weight change (kg)  25 >25-27 >27-29 >29-31 >31 Insulin detemir NPH insulin 1530 Hermansen: Change in weight by baseline BMI K. Hermansen et al. EASD 2005
  • 36. Type 1 effect of improved HbA1c
  • 37. HbA 1c cross-sectional, median values
  • 38. Any diabetes related endpoint M v I p=0.0034 overweight patients M v C p=0.0023