1. University of Washington, Seattle
Maximizing MDI
Irl B. Hirsch, M.D.
University of Washington, Seattle

2. First, Why is Mealtime Insulin So Important?
Raise your hand if you or your child take 1 shot daily
Raise your hand if you or your child take 2 shots daily
Raise your hand if you or your child take 3 shots daily
Raise your hand if you or your child take 4 or more shots daily
Raise your hand if you or your child wear an insulin pump

3. Why do so many physicians frown when they meet patients with type 1 diabetes on one or two daily injections?

4. Risk for Retinopathy in Conventional and Intensive Treatment: Thinking Out of the Box
Risk for Retinopathy in Subgroups of the DCCT 24 20 16 12 8 4
11%
10% 9%
Mean HbA1c
Conventional
Rate Per Patient Year 8% 7%
Time During Study (Years)
Intensive
Rate Per Patient Year 9% 8% 7%
Time During Study (Years) 24 20 16 12 8 4
Mean HbA1c
Adapted from Diabetes 44: , 1995

5. What We Now Know
The more up AND down the more damage to cells through a mechanism called “oxidative stress”
Most of this is based on very basic science data, but clinical studies now supporting this finding
New goal of therapy: improve A1c AND reduce glucose variability

6. Does Intensive Therapy (Reduced GV) Preserve Beta Cell Function?
1.0
0.9
Could some of this preservation also be related to improvement in glucose variability?
0.8
0.7
Patient
probability
of maintaining C-peptide > 2.0
0.6
0.5
0.4
0.3
Intensive therapy
0.2
0.1
Conventional
therapy
0.0 1 2 3 4 5 6
Years Post Enrollment
Number of evaluated patients in each treatment group
Intensive
108
131 80 53 32 8 2
Conventional
165
150 63 32 22 3
Adapted from: DCCT Study Group: Ann Intern Med. 1998;128:

7. Trends in Average # Injections/Day, 2001-2005
U=678
W=3995
GfK Market Measures

8. Implications? Postprandial hyperglycemia and glycemic variability
Ability to proceed to more sophisticated diabetes regimens
What are the main barriers why so many receiving insulin do so poorly?

9. Basics of MDI: What to Consider

10. Who Does Best With MDI (or CSII!?)
POINT 1
Who Does Best With MDI (or CSII!?)
Minimum of 4-6 SMBG/day
Carb counting or similar system for estimation of prandial insulin dosing
Frequent SMBG can make up for poor carb estimation!
Understanding basics of insulin therapy, knowing how to correct ac and pc hyperglycemia

11. The Physiological Insulin Profile
POINT 2
The Physiological Insulin Profile
Short-lived, rapidly generated prandial insulin peaks 70
Normal free insulin levels from genuine data (mean) 60 50
Insulin (mU/l) 40
Low, steady, basal insulin profile 30 20 10
0600
0900
1200
1500
1800
2100
2400
0300
0600
Breakfast
Lunch
Dinner
Adapted from Polonsky, et al

12. Definitions for Flexible Diabetes Management
Standardization of Terminology
Definitions for Flexible Diabetes Management
Basal insulin replacement
that insulin required to suppress hepatic glucose production over night and between meals
Bolus (prandial or mealtime) insulin replacement
that insulin required to dispose of glucose in muscle after eating

13. Definitions for Flexible Diabetes Management
Standardization of Terminology
Definitions for Flexible Diabetes Management
Correction dose (also called a supplement)
additional insulin for premeal hyperglycemia
can also be between-meal hyperglycemia
this insulin can only be regular, lispro, aspart or glulisine (Humulin R, Novolin R, Humalog, Novalog, Apidra)

14. Glulisine Glulisine Glulisine
Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs
Breakfast
Lunch
Dinner
Aspart, Aspart, Aspart,
Lispro Lispro Lispro or or or
Glulisine Glulisine Glulisine
Plasma insulin
Glargine or
Detemir
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time

15. Does Basal Insulin Really Look Like a Flat Line?

16. Klein et al: 325-OR, ADA, 2006

17. POINT 3
In general, 40-50% of insulin should be basal insulin glargine (Lantus), insulin detemir (Levemir), or delivery from a pump and the rest should be mealtime (bolus) insulin

18. Pearls with MDI Basal Insulin
Basal insulin approximately 40-50% total daily insulin dose (TDD)
Basal insulin best assessed by fasting glucose levels and glycemic curves with missed meals
Lower doses often require twice daily injections of basal insulin
With MDI, most patients prefer pens for prandial insulin; however, less likely to make an error in insulin if basal insulin used is vial (or at least pens are different brands)

19. Pearls with MDI: Prandial Insulin
LAG times
The amount of time between giving the prandial insulin and eating the meal
Due to the timing of insulin absorption compared to carbohydrate absorption, insulin usually needs to be injected a minimum of 10 min prior to eating, even if glucose levels are within target.
Longer lag times are required for pre-meal hyperglycemia

20. Humalog with Different Lag Times
270
230
180
200
160
Diabetes Care 22:133, 1999

21. Pearls with MDI: Prandial Insulin
Insulin-on-Board (IOB)

22. Key Concepts Pharmacokinetics Pharmacodynamics
Measurement of insulin levels after subcutaneous injection
Pharmacodynamics
Measurement of insulin action in a glucose clamp study

23. Key Concepts INSULIN-ON-BOARD (IOB, insulin remaining)
The amount of insulin from the last prandial dose which has not yet been absorbed based on insulin action (not insulin blood levels)
INSULIN STACKING
Using correction dose insulin to treat before-meal or between-meal hyperglycemia in a situation when there is still significant IOB

24. Insulin lispro (Humalog) and insulin aspart (NovoLog) “insulin action” disappearance curves
100 80 60
% insulin remaining 40 20

25. Correction Dose (insulin sensitivity factor)
The amount of glucose reduction (in mg/dL) to expect from 1 unit of insulin
Numerous formulas published but in general most type 1’s start with an ISF of about 50

26. Example
TIME BG DOSE
7 PM U
8 PM
9 PM
9:30 PM 180
With a target of 120 mg% and an ISF of 30, how much insulin should be provided at 9:30 pm?

27. NOW what should be done with the insulin?
Example
TIME BG DOSE
7 PM U
IOB
8 PM
7.2 U
9 PM
5.0 U
9:30 PM 180
4.0 U
10:00 PM U
NOW what should be done with the insulin?

28. So how much insulin should be given?
Example
210 – 120 = 90 mg/dL over target
Correction dose = 90/30 = 3 units
3.2 units on board – 3 units for correction dose
So how much insulin should be given?

29. Glycemic trend trumps IOB! One can only know GT by frequent SMBG
TAKE HOME POINT
Glycemic trend trumps IOB!
One can only know GT by frequent SMBG

30. Pearls for Success Frequent SMBG (until CGM available)
Knowledge of how to best use lag times
General knowledge of insulin requirements for food, but with frequent SMBG not required
Keeping track of IOB
Keeping track of glycemic trend

31. Some Concerning Facts
¼-1/3 of those with T1DM are still taking 1 or 2 shots daily-shown ineffective in 1993
< 20% of T1DM in US with A1c < 7%
Insulin therapy is not taught in medical schools or residency
The average primary care resident doesn’t know what 1 unit of insulin is.

32. Conclusion (1)
After 84 years we are finally starting to understand a little about how to use insulin

33. Conclusion (2)
Although it is a lot of work, rewards later on are huge. Frequencies of PDR, ESRD, LEA are declining rapidly

34. Conclusion (3)
The number 1 barrier to type 1 diabetes therapy (especially in adults) in 2006 is…?