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

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
The objective of this presentation is to assist you in optimizing the management of type 2 diabetes by initiating insulin treatment in your office.
The goal is to help you identify those patients that are candidates for insulin treatment as well as help you get them started. Specifically, when to start insulin, what insulin to prescribe and at what dose, the various insulin delivery options and patient training.
Why is this important? Because of the sheer number of patients relative to the number of Endocrinologists.

3. Challenges in Initiating Insulin?
1. Patient attitudes
Fear of needles
Insulin viewed as a threat by patient & physician
Hypoglycemia
2. Physician Attitudes
Discomfort with insulin
Lack of knowledge and experience
There are a few challenges when initiating insulin. First of all, we have to change the patient mind set. There is the basic fear of needles and the idea that injections are painful.
Also, insulin has been used as a threat for years creating dread and fear in the minds of patients. Insulin should not be viewed as a threat. In counselling patients it is better to explain that the pancreas has ceased to be able to do its job properly and therefore insulin needs to be added to assist in achieving glycemic control. The use of guilt and blame only complicate the treatment of diabetes and play no role in positive outcomes.
We also need to change the mindset of you as GPs so that you don’t view insulin as difficult. If so, your own fears get in the way of using a great therapy. Insulin is another tool to use for blood glucose control and should not be viewed as a last resort when all else fails.

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

6. Diabetes: mortality Male Male projected Female Female projected
8000
7000
6000
5000
4000
3000
2000
1000
Number of deaths
Year
Male Male projected Female Female projected
Diabetes in Canada, National Statistics and Opportunities for Improved Surveillance, Prevention, and Control. Minister of Public Works and Government Services Canada, 1999.

7. Diabetes: complications
Macrovascular
Microvascular
Stroke
Diabetic eye disease
(retinopathy and cataracts)
Heart disease and hypertension
Renal disease
Peripheral vascular disease
Neuropathy
Foot problems
Foot problems

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

9. UKPDS: long-term glucose control9
Conventional 8
HbA1c (%)
Intensive 7
ULN = 6.2% 6 3 6 9 12 15
Years of treatment
UKPDS Study Group, Lancet, 1998;352:

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

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

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

14. 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.
Studies have shown the following:
Intensive therapy to reduce glycemia reduces risk of complications.
Insulin therapy does not increase the risk of cardiovascular complications, contrary to what many physicians have believed.
Type 2 diabetes is a progressive disease with relentless deterioration of beta cell function.
As diabetes progresses, increased monitoring and more intense management of glucose, including postprandial glucose levels, become necessary.
Diabetes Control and Complications Trial (DCCT) Research Group. N Engl J Med. 1993;329:
Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:
UK Prospective Diabetes Study Group (UKPDS) 33: Lancet. 1998;352: 14

15. Good Glycemic Control Reduces Incidence of Complications
DCCT
9  7%
63%
54%
60%
41%*
Kumamoto
9  7%
69%
70% –
UKPDS
8  7%
17-21%
24-33% –
16%*
HbA1c
Retinopathy
Nephropathy
Neuropathy
Macrovascular disease
Three independent studies: DCCT (type 1), Kumamoto (type 2-lean), UKPDS (type 2-typical) showed significant benefits of similar magnitude.
In the DCCT, when all major cardiovascular and peripheral vascular events were combined, intensive therapy reduced the risk of cardiovascular disease by 41%, although this reduction was not statistically significant. The relative youth of the patient cohort made the detection of a difference between treatments unlikely.
The 16% reduced risk incidence of coronary heart disease in the UKPDS had a P value of 0.052, not quite statistically significant.
* not statistically significant
Diabetes Control and Complications Trial (DCCT) Research Group. N Engl J Med. 1993;329:
Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:
UK Prospective Diabetes Study Group (UKPDS) 33: Lancet. 1998;352: 15

16. Type 2 Diabetes: Key Concepts
Minimizing the complications of diabetes requires:
Early diagnosis and treatment of diabetes
Maintaining HbA1C level < 7%
Achieving HbA1C < 7% requires control of post-prandial and fasting hyperglycemia
They key concepts in type 2 diabetes are (1) minimize diabetes complications with early diagnosis and treatment with maintenance of HbA1C below 7% and (2) achieving this control by reducing both post-prandial and fasting hyperglycemia.
New treatment guidelines are expected in December 2003 which stress the need for tighter glycemic control. The recommendations will be for fewer steps and more aggressive treatment earlier on in order to reach glucose target levels.

17. CDA Guidelines (for glycemic control)
Normal
Optimal
A1C level
( )
(< 0.07)
Preprandial
glycemia
4-7
(mmol/L)
Postprandial
glycemia
7-11 (
mmol/L)
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. 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. Next steps 2. OPTIMIZE INSULIN THERAPY
Increase insulin dose as needed.
IF BEDTIME INSULIN THERAPY FAILS TO ACHIEVE SATISFACTORY CONTROL
Add daytime insulin according to needs.Consider adding rosiglitazone, metformin or acarbose to insulin regimens to attempt further improvements in glucose control.
Once full insulin support is given there is no point in continuing secretagogues

20. Indications for Starting Insulin
1. Sub-optimal glycemic control despite maximal doses of oral hypoglycemics
HbA1C > 7% (NEW CPG SUGGEST 7%)
AC glycemia > 10 mmol
PC glycemia > 14 mmol
2. Complications
New guidelines will be even tighter and suggest a target blood glucose value of 7% for all patients.

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

22. 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. Insulin: Disadvantages
Hypoglycemia
Weight gain
Injections

24. Plasma Glucose Normally Maintained in Narrow Range
22.0
16.5
11.0
5.5
Diabetic
Control
Plasma
Glucose,
mmol/L
This slide illustrates that in healthy individuals, changes in glucose after meals are modest and kept within a very narrow range. Therefore, the natural defense against hyperglycemia is very aggressive.
In patients with type 2 diabetes who have established fasting hyperglycemia, increases in postprandial glucose levels are further exaggerated. B L D
6 AM 10 AM 2 PM 6 PM 10 PM 2 AM 6 AM
Time of Day
Data from Polonsky KS, et al. N Engl J Med. 1988;318: 24

25. Targets for Glycemic Control
HbA1c < 7%
Fasting/preprandial glucose 4-7 mmol/L
Postprandial glucose 5-8 mmol/L
Bedtime glucose 5-8 mmol/L
In healthy individuals, the postprandial glucose level increases less than mg/dL above the preprandial glucose value.
In patients with diabetes, the postprandial glucose has a recommended target of 100 to 180 mg/dL.
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, Alexandria, VA: ADA, Inc. 25

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

28. 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. Advancing Insulin Therapy Through Device Innovation
Pens, for example Novolin-Pen® 3, is the most commonly used insulin delivery device.
Innovo® is the first ‘ doser ’ on the market. It has a memory feature that tells patients if and when they took their last dose and the number of units of their last dose. It has a number of other helpful features.
InDuo® is the newest insulin delivery system that has integrated both the insulin delivery device and the glucose meter.
Note to speaker:
Speak to your Novo Nordisk representative about the opportunity for the attending physicians to inject themselves, using Novo-Pen® 1.5 and NovoFine® needles. This may be useful in having them overcome their own fears.

30. 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. 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. Bedtime Insulin-Adjustment
Start with 10u (or 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. 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. 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