Irl B. Hirsch, M.D. University of Washington, Seattle Maximizing MDI
Mar 26, 2015
Irl B. Hirsch, M.D.
University of Washington, Seattle
Maximizing MDIMaximizing MDI
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
Why do so many physicians frown when they meet
patients with type 1 diabetes on one
or two daily injections?
0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9
24 24
20 20
16 16
12 12
8 8
4 4
00
Risk for Retinopathy in Conventional and Intensive
Treatment: Thinking Out of the Box
Conventional
Adapted from Diabetes 44:968-983, 1995
11%11%
Ra
t e P
er
Pa
tie
nt
Ye
ar
Ra
te P
er
Pa
tie
nt
Ye
ar 10%10%
9%9%
8%8%
7%7%
Time During Study (Years)Time During Study (Years)
Mean HbA1cMean HbA1c
Risk for Retinopathy in Subgroups of the DCCT
0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9
Intensive
Ra
t e P
er
Pa
tie
nt
Ye
ar
Ra
te P
er
Pa
tie
nt
Ye
ar
9%9%8%8%7%7%
Time During Study (Years)Time During Study (Years)
24 24
20 20
16 16
12 12
8 8
4 4
00
Mean HbA1cMean HbA1c
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
Does Intensive Therapy (Reduced GV) Preserve Beta Cell Function?
Adapted from: DCCT Study Group: Ann Intern Med. 1998;128:517-523.
0 1 2 3 4 5 6
0.00.10.20.30.40.50.60.70.80.9
1.0
Years Post Enrollment
Number of evaluated patients in each treatment group
IntensiveConventional
0
131 80 53 32 8 2108150 63 32 22 3 0165
Conventionaltherapy
Intensive therapy
Patient probability
of maintaining C-peptide > 2.0
Could some of this preservation also be related to improvement in glucose variability?
Trends in Average # Injections/Day, 2001-2005
1
1.5
2
2.5
3
3.5
2001 2002 2003 2004 2005
T1DM
T2DM
TOTAL
GfK Market Measures
U=678
W=3995
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?
Basics of MDI: What to Consider
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
POINT 1
The Physiological Insulin Profile
Adapted from Polonsky, et al. 1988.
10
20
30
Insulin(mU/l)
0
40
50
60
70Short-lived, rapidly generated
prandial insulin peaks
Low, steady, basalinsulin profile
Normal free insulin levelsfrom genuine data (mean)
0600 0900 1200 1500 1800 2100 2400 0300 0600
Breakfast Lunch Dinner
POINT 2
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
Standardization of Terminology
Definitions for Flexible Diabetes Management
Correction dose (also called a supplement)additional insulin for premeal hyperglycemiacan also be between-meal hyperglycemia this insulin can only be regular, lispro,
aspart or glulisine (Humulin R, Novolin R, Humalog, Novalog, Apidra)
Standardization of Terminology
4:00 16:00 20:00 24:00 4:00
Breakfast Lunch Dinner
8:0012:008:00
Time
Glargineor
Detemir
Lispro Lispro LisproAspart, Aspart, Aspart,
or oror
Pla
sma
insu
lin
Basal/Bolus Treatment Program withRapid-acting and Long-acting Analogs
Glulisine Glulisine Glulisine
Does Basal Insulin Really Look Like a
Flat Line?
Klein et al: 325-OR, ADA, 2006
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
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)
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
270
160
200
230
Humalog with Different Lag Times
Diabetes Care 22:133, 1999
180
Pearls with MDI: Prandial Insulin
♦ Insulin-on-Board (IOB)
Key Concepts
♦ Pharmacokinetics♦ Measurement of insulin levels after
subcutaneous injection
♦ Pharmacodynamics♦ Measurement of insulin action in a glucose
clamp study
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
0 1 2 3 4 5 6 7 8
% i
nsu
lin
re
mai
nin
g
20
40
60
80
100
0
Insulin lispro (Humalog) and insulin aspart (NovoLog) “insulin action” disappearance curves
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
Example
TIME BG DOSE
7 PM 95 8 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?
Example
TIME BG DOSE
7 PM 95 8 U
8 PM
9 PM
9:30 PM 180
IOB
7.2 U
5.0 U
4.0 U
10:00 PM 210 3.2 U
NOW what should be done with the insulin?
Example
210 – 120 = 90 mg/dL over target
3.2 units on board – 3 units for correction dose
Correction dose = 90/30 = 3 units
So how much insulin should be given?
TAKE HOME POINT
Glycemic trend trumps IOB!
One can only know GT by frequent SMBG
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
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.
Conclusion (1)
After 84 years we are finally starting to understand a little
about how to use insulin
Conclusion (2)
Although it is a lot of work, rewards later on are huge. Frequencies of
PDR, ESRD, LEA are declining rapidly
Conclusion (3)
The number 1 barrier to type 1 diabetes therapy (especially in
adults) in 2006 is…?