1. www.diabetesclinic.ca BEDTIME INSULIN IN TYPE 2 DIABETES J. Robin Conway M.D. Diabetes Clinic, Smiths Falls,ON www.diabetesclinic.ca

2. Objectives Optimize type 2 diabetes management Assist you in initiating insulin in your office –When to start insulin therapy? –Insulins, doses, delivery options –Patient training

3. www.diabetesclinic.ca Challenges in Initiating Insulin? Patient attitudes 1. Patient attitudes –Fear of needles –Insulin viewed as a threat by patient & physician –Hypoglycemia Physician Attitudes 2. Physician Attitudes –Discomfort with insulin Lack of knowledge and experience –Fear of needles

4. www.diabetesclinic.ca Insulin in Type 2 Diabetes 87% of Type 2 Diabetes is treated by Primary Care Providers 10% of Type 1 Diabetes is treated by Primary Care Providers 23.5% of visits to GP offices involve Diabetics Diabetics have multiple comorbidities

5. www.diabetesclinic.ca Diabetes in Canada Affects 5 - 10 % of population Diagnosed: 2.0 million Undiagnosed: ???

6. www.diabetesclinic.ca Diabetes: mortality Diabetes in Canada, National Statistics and Opportunities for Improved Surveillance, Prevention, and Control. Minister of Public Works and Government Services Canada, 1999. Number of deaths Year MaleMale projected FemaleFemale projected 8000 7000 6000 5000 4000 3000 2000 1000 0 1950 1958 1966 1974 1982 1990 1998 2006 2014

7. www.diabetesclinic.ca MacrovascularMicrovascular Stroke Heart disease and hypertension Foot problems Diabetic eye disease (retinopathy and cataracts) Renal disease Neuropathy Foot problems Diabetes: complications Peripheral vascular disease

8. www.diabetesclinic.ca Pathophysiology of Type 2 Diabetes Insulin resistance Insulin production Glucose level Time Non- diabetes Pre- diabetes Type 2 diabetes Opara JU, Levine JH, South Med J. 1997;90:1162-1168.

9. www.diabetesclinic.ca UKPDS: long-term glucose control 0 6 7 8 9 03691215 HbA 1c ( % ) Years of treatment Conventional Intensive ULN = 6.2 % UKPDS Study Group, Lancet, 1998;352:837-853.

10. www.diabetesclinic.ca Beta cell function in the UKPDS Years from diagnosis Beta cell function (%) 100 90 80 70 60 50 40 30 20 10 0 –12–10–8–6–4–20246 Holman RR et al. Diabetes Res Clin Pract 1998;40(suppl):S21–S25

11. www.diabetesclinic.ca Type 2 Diabetes: Double Impairment Impaired ß cell function: –  insulin secretion Impaired insulin action: –  insulin resistance Results in unacceptable blood glucose control

12. www.diabetesclinic.ca Insulin resistance: progressive ß-cell failure Insulin resistance Hyperinsulinemia Increasing insulin resistance ß-cell failure Insulin deficiency Impaired glucose tolerance Hyperglycemia / Type 2 DIABETES

13. www.diabetesclinic.ca

14. Diabetes Control and Complications Trial (DCCT) Research Group. N Engl J Med. 1993;329:977-986. Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103-117. UK Prospective Diabetes Study Group (UKPDS) 33: Lancet. 1998;352:837-853. Findings from Clinical Trials Intensive therapy to reduce glycemia reduces the risk of microvascular and neurologic complications. Insulin therapy does not increase the risk of complications. Type 2 diabetes is a progressive disease. Managing postprandial glucose is critical to effective diabetes management. 14

15. www.diabetesclinic.ca HbA 1c Retinopathy Nephropathy Neuropathy Macrovascular disease DCCT 9  7% 63% 54% 60% 41%* Kumamoto 9  7% 69% 70% – UKPDS 8  7% 17-21% 24-33% – 16%* * not statistically significant Good Glycemic Control Reduces Incidence of Complications15 Diabetes Control and Complications Trial (DCCT) Research Group. N Engl J Med. 1993;329:977-986. Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103-117. UK Prospective Diabetes Study Group (UKPDS) 33: Lancet. 1998;352:837-853.

16. www.diabetesclinic.ca Type 2 Diabetes: Key Concepts Minimizing the complications of diabetes requires: –Early diagnosis and treatment of diabetes –Maintaining HbA 1C level < 7% Achieving HbA 1C < 7% requires control of post-prandial and fasting hyperglycemia

17. www.diabetesclinic.ca CDA Guidelines (for glycemic control) NormalOptimal A 1C level (0.04-0.06) (< 0.07) Preprandial glycemia (mmol/L) 3.5-6.14-7 Postprandial glycemia (mmol/L) 4.4-7.87-11 Haars s et al., CMAJ 2003; 159 (Suppl.): S1-29. Gerstein, H.C. et al. CDA views on the UKPDS and revision of the guidelines affected by the results of this study.

18. www.diabetesclinic.ca When oral agents are insufficent to achieve target HbA1c 1. Add bedtime insulin to oral agents Why combine insulin and oral agents rather than just switching to insulin? Better glycemic control with smaller insulin dose + fewer injections. Less weight gain. Why just switch, rather than combining? Cost, simplicity

19. www.diabetesclinic.ca Next steps 2. OPTIMIZE INSULIN THERAPY Increase insulin dose as needed. 3.IF BEDTIME INSULIN THERAPY FAILS TO ACHIEVE SATISFACTORY CONTROL 4.Add daytime insulin according to needs.Consider adding rosiglitazone, metformin or acarbose to insulin regimens to attempt further improvements in glucose control. 5.Once full insulin support is given there is no point in continuing secretagogues

20. www.diabetesclinic.ca Indications for Starting Insulin 1. Sub-optimal glycemic control despite maximal doses of oral hypoglycemics HbA 1C > 7% (NEW CPG SUGGEST 7%) AC glycemia > 10 mmol PC glycemia > 14 mmol 2. Complications

21. www.diabetesclinic.ca Type 2 Diabetes: Double Impairment Impaired ß cell function: –  insulin secretion Impaired insulin action: –  insulin resistance Results in unacceptable blood glucose control

22. www.diabetesclinic.ca Insulin: Advantages Controls ANY patient Can be used to overcome glucose toxicity Flexibility of dose and lifestyle Ease of use with new insulin delivery technology

23. www.diabetesclinic.ca Insulin: Disadvantages Hypoglycemia Weight gain Injections

24. www.diabetesclinic.ca Plasma Glucose, mmol/L 6 AM10 AM2 PM6 PM10 PM2 AM6 AM Time of Day 22.016.511.05.50 Diabetic Control B L D Plasma Glucose Normally Maintained in Narrow Range Data from Polonsky KS, et al. N Engl J Med. 1988;318:1231-1239. 24

25. www.diabetesclinic.ca American Diabetes Association. Diabetes Care. 1999; 22(supp 1): S32-S41. Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders, 3rd ed. ADA Clinical Education Series, 1998. Alexandria, VA: ADA, Inc. Targets for Glycemic Control HbA 1c < 7% Fasting/preprandial glucose4-7 mmol/L Postprandial glucose5-8 mmol/L Bedtime glucose 5-8 mmol/L 25

26. www.diabetesclinic.ca BEDTIME INSULIN NPH Insulin at Bedtime Signalling to liver to decrease hepatic glu Decreases Gluconeogenesis Dose usually small Risk of Hypoglycemia Small Patient can adjust dose

27. www.diabetesclinic.ca Novolin ® ge NPH Time-Action Profile Intermediate-acting insulin Onset: 1.5 hour Maximum effect: 4-12 hours Duration: 24 hours

28. www.diabetesclinic.ca Bedtime Insulin Advantages Safe, unlikely to cause Hypoglycemia Small doses of Insulin, no weight gain One injection a day Good starting point Learn Insulin adjustment Easy to Teach, no mixing, use Pen

29. www.diabetesclinic.ca Advancing Insulin Therapy Through Device Innovation

30. www.diabetesclinic.ca Bedtime Insulin-Pt Selection No longer responding to oral agents Relative Insulin deficiency Pt must have ability & be motivated Physically capable of injecting Must be self monitoring Helps with glucose toxicity

31. www.diabetesclinic.ca Bedtime Insulin Start at low dose, give the patient time to get used to injections Give first injection in the office Review in a Month Then start insulin adjustment

32. www.diabetesclinic.ca Bedtime Insulin-Adjustment Start with 10u (or.1-.3 u/kg) Target Fasting Glucose <7 mmol/L If FBS >7 for 3 days in a row, increase Give ceiling dose (+/- 30u) Review in a month After 3 mo do A1c (goal <7%)

33. www.diabetesclinic.ca Bedtime Insulin-Goals FBS <7 mmol/L A1c <7% If Goals not reached look at next highest glucose and treat this If Glu >8 in evening, consider Novomix 30/70 or Humalog Mix 25 at supper, or Novolin 30/70, Humulin 30/70

34. www.diabetesclinic.ca SUMMARY If A1c <7% cannot be achieved on OHA, add bedtime insulin Use NPH, start with low dose until patient is comfortable Titrate up until Fasting Glucose <7 If daytime glucose remains elevated go to full insulin support