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

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%

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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

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9%9%8%8%7%7%

Time During Study (Years)Time During Study (Years)

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4 4

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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.

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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.

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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

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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

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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…?