Intensive Insulin Therapy Advances in MDI and CSII

1
Intensive Insulin TherapyAdvances in MDI and CSII

• Bruce W. Bode, MD, FACE
• Atlanta Diabetes Associates
• Atlanta, Georgia

2
Goals of Intensive Insulin Therapy

• Maintain near-normal glycemia
• Avoid short-term crisis
• Minimize long-term complications
• Improve the quality of life

3
The Basal/Bolus Insulin Concept

• Basal insulin
• Suppresses glucose production between meals and
  overnight
• 40 to 50 of daily needs
• Bolus insulin (mealtime)
• Limits hyperglycemia after meals
• Immediate rise and sharp peak at 1 hour
• 10 to 20 of total daily insulin requirement at
  each meal

4
Physiological Serum Insulin Secretion Profile
75
Breakfast
Lunch
Dinner
50
Plasma insulin (µU/mL)
25
400
800
1200
1600
2000
2400
400
800
Time
5
Rapid-acting Insulin Analogs Provide Ideal
Prandial Insulin Profile
Breakfast
Lunch
Dinner
Aspart Aspart Aspart
or
or
or
Lispro Lispro Lispro
Plasma insulin
400
1600
2000
2400
400
800
1200
800
Time
6
Basal/Bolus Treatment Program with Rapid-acting
and Long-acting Analogs
Breakfast
Lunch
Dinner
Aspart Aspart Aspart
or
or
or
Lispro Lispro Lispro
Plasma insulin
Glargine or Detemir
400
1600
2000
2400
400
800
1200
800
Time
7
Advancing Basal/Bolus Insulin in Type 2 Diabetes

• Indicated when FBG acceptable but
• A1C gt7 or gt6.5 and/or
• SMBG before dinner gt130 mg/dL
• Insulin options
• To basal insulin, add mealtime aspart/lispro
• To supper time 70/30, add morning 70/30
• Consider insulin pump therapy

8
Insulin Pens

• First pen launched in 1985
• Committed to developing one new insulin
  administration system per year

Photograph reproduced with permission of
manufacturer.
9
Insulin Pens
Photograph reproduced with permission of
manufacturer.
10
Prefilled Syringe with Flexible Dosing
Photograph reproduced with permission of
manufacturer.
11
Pen Preference Study

• 83 of DM Patients Preferred FlexPen

n 58
Asakura T. Diabetes 52,(Suppl 1), 2003 Abstract
437.
12
Combined Insulin Pen and Meter

• Feature
• Combined insulin doser and blood glucose monitor

Photograph reproduced with permission of
manufacturer.
13
Combined Insulin Pen and Meter

• Feature
• Remembers amount of insulin delivered and time
  since last dose
• Benefit
• Helps people inject the right amount of insulin
  at the right time

Photograph reproduced with permission of
manufacturer.
14
Combined Pen/Meter Device

• 79 of DM 1 Patients Preferred the InDuo

n 125
Bode B et al. Diabetes 52,(Suppl 1), 2003
Abstract 440.
15
Starting MDI

• Starting insulin dose is based on weight
• 0.2 x weight in lb or 0.45 x weight in kg
• Bolus dose (aspart/lispro)20 of starting dose
  at each meal
• Basal dose (glargine/NPH)40 of starting dose at
  bedtime

16
Starting MDI in 180-lb person

• Starting dose 0.2 x weight in lb
• 0.2 x 180 lb 36 U
• Bolus dose 20 of starting dose at each meal
• 20 of 36 U 7 U AC (TID)
• Basal dose 40 of starting dose at bedtime
• 40 of 36 U 14 U HS

17
Correction Bolus

• Must determine how much glucose is lowered by 1 U
  of short- or rapid-acting insulin
• This number is known as the correction factor
  (CF)
• Use the 1700 rule to estimate the CF
• CF1700 divided by the total daily dose (TDD)
  example if TDD36 U, then CF1700/36?50,
  meaning 1 U will lower the BG ?50 mg/dL

18
Correction Bolus Formula
Current BG - Ideal BG Glucose Correction Factor

• Example
• Current BG 220 mg/dL
• Ideal BG 100 mg/dL
• Glucose CF 50 mg/dL

220 - 100
2.4 U
50
19
Options to MDI

• A simpler regimen
• Insulin pump
• Premixed BID (DM 2 only)

20
Variable Basal Rate CSII Program
Breakfast
Lunch
Dinner
Bolus
Bolus
Bolus
Plasma insulin
Basal infusion
400
1600
2000
2400
400
800
1200
800
Time
21
Photograph reproduced with permission of
manufacturer.
22
Pump Infusion Sets
Photograph reproduced with permission of
manufacturer.
23
Insulin Aspart CSII vs Insulin Aspart/Glargine MDI

• Open-label, randomized, crossover, 2-arm study of
  10-week duration
• Comparison of insulin aspart CSII vs insulin
  aspart/glargine MDI
• Subjects n100, type 1 patients on CSII at
  entry, A1C lt9
• Assessments
• Efficacy A1C, fructosamine, 8-point BG profile,
  glucose exposure (CGMS)
• Safety frequency of hypoglycemia, AEs

IAsp CSII
IAsp Gar MDI
IAsp CSII
IAsp Gar MDI
Run-in (1 week) Period 1 (5 weeks) Period 2 (5
weeks)
Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract
438.
24
Characteristics of Enrolled Population
Treatment Sequence Treatment Sequence
CSII to MDI MDI to CSII All Subjects
Subjects treated 50 50 100
Age (y) 41.7 ? 11.1 44.2 ? 11.0 43.0 ? 11.1
BMI (kg/m2) 27.1 ? 4.1 26.7 ? 4.0 26.9 ? 4.0
A1C at screening () 7.5 ? 0.8 7.4 ? 0.8 7.5 ? 0.8
Duration of diabetes (y) 19.7 ? 11.3 23.9 ? 12.3 21.8 ? 11.9
Daily insulin dose 42.3 ? 17.9(n45) 41.6 ? 16.1(n50) 41.9 ? 16.9(n95)
Basal 21.1 ? 8.1 22.6 ? 10.7 21.9 ? 9.2
Bolus 22.7 ? 13.8 19.3 ? 8.7 20.9 ? 11.4
Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract
438.
25
Aspart (CSII) vs Aspart/Insulin Glargine (MDI)
8-Point Blood Glucose Profiles
200
CSII (n93)
MDI (n91)
180
160
Self-monitored BG (mg/dL)
140
120
100
BB
AB
BL
AL
BD
AD
Midnight
3 AM
Mean 2 SEM
Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract
438.
26
Aspart (CSII) vs Aspart/Insulin Glargine (MDI)
Glucose Exposure During CGMS
P0.0027
3000
2500
2000
AUCglu (mgh/dL)
n63 in each treatment
1500
1000
500
0
CSII
MDI
Measurement of AUC(glu) 80 mg/dL during the
48-hour continuous glucose monitoring period.
Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract
438.
27
Aspart (CSII) vs Aspart/Insulin Glargine (MDI)
Rate of Hypoglycemia
12
P0.0039
CSII
10
MDI
Plt0.0001
8
Episodes/subject/5 weeks
6
P0.0006
4
2
0
Total
Daytime
Nocturnal
Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract
438.
28
Aspart (CSII) vs Aspart/Insulin Glargine (MDI)
Serum Fructosamine
P0.0001
400
n97
300
means 2 SEM
200
Fructosamine (?mol/L)
100
0
CSII
MDI
Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract
438.
29
CSII vs. MDI with Glargine in Children
(Randomized, Prospective)

• 60 DM 1 patients age 8-18, duration gt1 year, A1C
  6.5-11
• Naïve to glargine and pump
• Treatment
• CSII with insulin aspart
• MDI with insulin aspart and glargine
• Primary outcome A1C

Boland, E. Diabetes 52,(Suppl 1), 2003 Abstract
192.
30
CSII vs. MDI with Glargine in Children
(Randomized, Prospective)
Boland, E. Diabetes 52,(Suppl 1), 2003 Abstract
192.
31
Metabolic Advantages with CSII

• Improved glycemic control
• Better pharmacokinetic delivery of insulin
• Less hypoglycemia
• Less insulin required
• Improved quality of life

32
CSII Factors Affecting A1C

• Monitoring
• A1C8.3 - (0.21 x BG per day)
• Recording 7.4 vs 7.8
• Diet practiced
• CHO 7.2
• Fixed 7.5
• WAG 8.0
• Insulin type (aspart)

Bode B, et al. Diabetes. 199948(suppl
1)264. Bode B, et al. Diabetes Care. 200225439.
33
Insulin Aspart vs Buffered R vs Insulin Lispro in
CSII Study
Insulin aspart
Screening
Buffered regular human insulin (Velosulin)
Insulin lispro

• 146 patients in the US 2 to 25 years with type 1
  diabetes 7 ? A1C ?9 previously treated with
  CSII for 3 months

Bode B, et al. Diabetes Care. 200225439-444.
34
Glycemic Control with CSII
Type 1 diabetes
NovoLog
8.0
Human insulin
Humalog
7.8
7.6
A1C ()
7.4
7.2
7.0
0
Baseline
Week 8
Week 12
Week 16
Bode B. Diabetes. 200150(suppl 2)A106.
35
SMBG in CSII
220
NovoLog
Buffered regular
Humalog
200
180

160
Blood glucose (mg/dL)


140
120
Type 1 diabetes
100
80
Before and90 minutes after breakfast
Before and90 minutesafter lunch
Before and90 minutesafter dinner
Bedtime
2 AM
Bode B. Diabetes. 200150(suppl 2)A106.
36
Pharmacokinetic Comparison Aspart vs Lispro
350
Aspart
300
Lispro
250
200
Free insulin (pmol/L)
150
100
50
0
7
8
9
10
11
12
13
Time (h)
Hedman CA, et al. Diabetes Care.
2001241120-1121.
37
Symptomatic or Confirmed Hypoglycemia
Plt0.05
Plt0.05
12
10
8

• Episodes/mo/patient

6
4
2
0
Insulin aspart
Human insulin
Insulin lispro
Bode B, et al. Diabetes Care. 200225439-444.
38
Long-term Heat Stability of Insulin Aspart in
Infusion Pumps

• In vitro 6-day stability study under conditions
  of simulated CSII pump use (37C with constant
  shaking)

MiniMed (506) pumps

• Antimicrobial effectiveness and particulate
  matter were within USP requirements after 6 days
• Stable pH during the 6 days
• Physicochemical integrity of insulin aspart was
  retained

Disetronic H-Tron plus V100
700
600
500
400
Concentration (nM)
300
200
100
0
Day 05C
Day 2
Day 6
Lawton S, et al. Diabetes. 52 (Suppl 1) 2003,
Abstract 450.
39
DM 1 CSII Patient Lispro to Aspart
Lispro Average140 SD118
Aspart Average118 SD73
40
Glycemic Control in Type 2 DM CSII vs MDI in
127 Patients
Baseline
End of study (24 weeks)
8.4
8.2
8.0
7.8
A1C ()
7.6
7.4
7.2
7.0
CSII
MDI
Raskin et al. Diabetes. 200150(suppl 2)A128.
41
CSII vs MDI in DM 2 Patients
MDI
CSII
Less pain
Fewer social limitations
Preference
Advocacy
Less hassle
Less life interference
General satisfaction
Flexibility
Convenience
Less burden
-5
0
5
10
15
20
25
30
35
Change in scores (raw units) from baseline to
endpoint
Raskin et al. Diabetes. 200150(suppl 2)A128.
42
Case 3 DM 2 Poorly Controlled

• A 58-year-old woman presented with a 12-year
  history of poorly controlled, insulin-treated
  diabetes
• Ht 66", Wt 174 lb, BMI 28, C-peptide 2.1
• A1C 10.4 on 165 U/d (70/30 BID)
• Added troglitazone, metformin, glimepiride to MDI
  insulin
• A1C range 7.7 to 12.6 over 3 years

43
Case 3 DM 2 Poorly Controlled

• Admitted twice for IV insulin and fasting with
  short-lived success (A1C to 7.6 but back up to
  12.6)
• Tried Weight Watchers and appetite suppressants
  no help
• Decided to try CSII

44
Case 3 DM 2 on CSII, A1C Results
A1C ()
45
Case 3 DM 2 Poorly Controlled

• Patient loves the pump
• On 110 U/d consuming 2 meals only per day (1.4
  U/kg or 0.6 U/lb)
• Also on rosiglitazone 4 mg/d

46
Normalization of Lifestyle

• Liberalization of diettiming and amount
• Increased control with exercise
• Able to work shifts and through lunch
• Less hassle with traveltime zones
• Weight control
• Less anxiety in trying to keep on schedule

47
Current Continuation Rate Continuous
Subcutaneous Insulin Infusion (CSII)
Continued 97
Discontinued 3
N165. Average duration3.6 years. Average
discontinuation lt1/y.
Bode BW, et al. Diabetes. 199847(suppl 1)392.
48
US Pump Usage Total Patients Using Insulin Pumps
49
Current Pump Therapy Indications

• Diagnosed with diabetes (even new- onset DM type
  1)
• Need to normalize blood glucose (BG)
• A1C ?7.0
• Glycemic excursions
• Hypoglycemia

50
Pump Therapy

• Basal rate
• Continuous flow of insulin
• Takes the place of NPH or glargine insulin

• Meal boluses
• Insulin needed premeal
• Premeal BG
• Carbohydrates in meal
• Activity level
• Correction bolus for high BG

6
5
Meal bolus
4
Units
3
2
1
Basal rate
12 AM
12 PM
12 AM
Time of day
51
Initial Adult Dosage Calculations

• Starting doses
• Based on prepump total daily dose (TDD), reduce
  TDD by 25 to 30 for pump TDD
• Calculated based on weight
• 0.24 x weight in lb (0.5 x weight in kg)

Bode BW, et al. Diabetes. 199948(suppl
1)84. Bell D, Ovalle F. Endocr Pract.
20006357-360. Crawford LM. Endocr Pract.
20006239-243.
52
Initial Adult Dosage Calculations

• Basal rate
• 45 to 50 of pump TDD
• Divide total basal by 24 hours to decide on
  hourly basal
• Start with only 1 basal rate
• See how it goes before adding basals

53
Estimating the Carbohydrate to Insulin Ratio (CIR)

• Individually determined
• CIR(2.8 x weight in lb)/TDD
• Anywhere from 5 g to 25 g CHO is covered by 1 U
  of insulin

54
If A1C Is Not at Goal
Must look at

• SMBG frequency and recording
• Diet practiced
• Do they know what they are eating?
• Do they bolus for all food and snacks?

• Infusion site areas
• Are they in areas of lipohypertrophy?
• Other factors
• Fear of low BG
• Overtreatment of low BG

55
If A1C Is Not at Goal and No Reason Identified

• Place on a continuous glucose monitoring system
• CGMS by Medtronic MiniMed or GlucoWatch by Cygnus
  to determine the cause

56
Summary

• Insulin remains the most powerful agent we have
  to control diabetes
• When used appropriately in a basal/bolus format,
  near-normal glycemia can be achieved
• Newer insulins and insulin delivery devices,
  along with glucose sensors, will revolutionize
  our care of diabetes

57
Billing

• Get paid for what you do
• Use your codes and negotiate for coverage
• Detailed visit 99214
• Prolonged visit with contact plus above 99354 or
  99355 (insulin start or pump start)
• Prolonged visit without contact plus above 99358
  or 99359 (faxes, phone calls, e-mails)

58
Billing (contd)

• Bill faxes as prolonged visits without contact or
  negotiate a separate charge
• Bill meter download 99091
• Bill CGMS 95250
• Bill immediate A1C 83036

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Question and Answer Session

• For a copy of these slides go towww.adaendo.com