INSULIN TREATMENT FOR TYPE 2 DIABETES MANAGEMENT

INSULIN TREATMENT FOR TYPE 2 DIABETES MANAGEMENT

แผ่นแปะเท้า

QUESTION 1
1. ท่านเคยเป็นแพทย์คนแรกที่เริ่มให้อินสุลินรักษาในผู้ เป็นเบาหวานที่มาตรวจที่ OPD หรือไม่
A. YES B NO

ML Normal Secretory Pattern of Insulin
ระ^ท^
Total daily insulin requirement = 0.5-1 unit/kg/D
“Prandial” Insulin
Insulin
Level
The 50/50 Rule
I
I
I
SLEEP
Breakfast Lunch Dinner

Mrs B
60 years old Thai female Type 2 DM Diagnosed 10 years ago Co-morbid diseases: HT, Dyslipidemia BW 60 kg.
Currently on ❖Glipizide 20 mg a day
❖Metformin 2000 mg a day (used to on 2500 mg a day, but had diarrhea)
Her last HbAlC 9%, FPG 220 mg/dl

<*60 years old Thai female
❖Type 2 DM Diagnosed 10 years ago ❖Co-morbid diseases: HT, Dyslipidemia ♦>Bพ 60 kg ❖Currently on
❖ Glipizide 20 mg a day
❖ Metformin 2000 mg a day (used to on 2500 mg a day, but had diarrhea)
❖ Pioglitazone 30 mg
❖Her last HbAlC 9%,
FPG 220 mg/dl

QUESTION 2
ท่านจะให้การรักษาผู้ป่วยรายนี้ อย่างไร?
A. Lifestyle modification
B. Add TZD c. Add AGI
อ. Add DPP-IV inhibitor

❖60 years old Thai female
❖Type 2 DM Diagnosed 10 years ago ❖Co-morbid diseases: HT, Dyslipidemia ❖BW 60 kg ❖Currently on
❖ Glipizide 20 mg a day
❖ Metformin 2000 mg a day (used to on 2500 mg a day, but had diarrhea)
❖ Pioglitazone 30 mg
❖Her last HbAlC 9%,
FPG 220 mg/dl
QUESTION 3
ถ้าท่านเลือกจะให้อินสุลินในผู้ป่วย รายนี้ ท่านจะเริ่มให้อย่างไร?
A. Continue OHA + NPH 6 น
B. Continue OHA + NPH 10 น
c. Off รบ, Cont MET + NPH 10 น อ. Continue OHA + Glargine 10 น
£ Off OHA + Mix Insulin 15 น
Oral Hypoglycemic agents failure
Add basal insulin
4T Trial
STUDY METHOD
Basal group

700 T2DM 1/
Biphasic group
N

Glycemic target: A1C ร 6.5%
Add once (or twice) daily basal insulin*
Add twice daily biphasic insulin*
Add thrice daily prandial insulin*
Add prandial insulin if glycaemic target not ทาett
Add midday prandial insulin if glycaemic target not ทาett
Add basal insulin if glycaemic target not met-!-
Randomisation ^H One Two Three
visit ร’’,’ : ‘ * year jilljl years years
* progress to more intensive insulin regimen only if clinically necessary
1 stop sulphonylurea if taken Holman RR.N Engl J Med 2009;361:1736
4T Trial
EFFICACY
% Attainment of Target HbAlc
80
60
40
20
0
HbAlC < 6.5% HbAlC < 7.0%
Biphasic group
Prandial group Basal group
4T Trial
ADVERSE EFFECTS
Body weigh gain (kg)
%Hypoglycemia (mod to severe)
8
6
4
2
0

50
40
30
20
10
0
Biphasic Prandial Basal
Biphasic Prandial Basal
Biphasic group
Prandial group Basal group

STARTING WITH BASAL INSULIN ADVANTAGES
1 injection with no mixing Insulin pens for increased acceptance Slow, safe, and simple titration Low dosage
Effective improvement in glycemic control Limited weight gain

BASAL INSULIN
# Which type?
# How to start?
# How to adjust?

TYPE OF BASAL INSULIN
NPH insulin
Onset: 1 1/ 2 hr Peak: 4-12 hr Duration: 24 hr
Insulin
Level
Long-acting analogue insulin
Onset: 2-3 hr Peak: none Duration: 24 hr
Intermediate (NPH)
Long (Glargine)
ongjDetemir)
0 2 4 6 8 10 12 14 16 18 20 22 24
Hours
TREAT-TO-TARGET TRIALS
Insulin continually titrated to ta rget:
Fasting PG <100 mg/dl
Insulin glargine once-daily (evening) ท = 367
NPH once-daily (evening)
ท = 389
Insulin detemir twice-daily
ท = 237
NPH twice-daily
ท = 238
Riddle et ลเ2003
Hermansen et ลเ 2006
Insulin continually titrated to target: Fasting and pre-dinner PG < 108
mg/dl

TREAT TO TARGET

1
ro 1_
Q. (บิ
ะ «
<บ >■ p IU
18
16
14
12
10
8
6
4
2
0

-2 0
12
Weeks
24
I
% 1_ Q. re
ะ ร
QJ >■ £
IU
18
16
14
12
10
8
6
4
2
0

21% risk reduction p <0.02
Overall Nocturnal
Hypoglycaemia

Riddle et al Diabetes Care 2003;26:3080-6.
47% risk reduction
p < 0.001
55% risk reduction p < 0.001
I
Overall Nocturnal
Hypoglycaemia
Hermansen et al. Diabetes Care 2006;29:1269

Basal insulin
Which type? How to start? How to adjust?
TREAT-TO-TARGET TRIALS
The starting dose of both insulins was 10 IU
Insulin glargine once-daily (evening)
ท = 367
NPH once-daily (evening)
ท = 389
Riddle et ลเ2003
Insulin detemir twice-daily
ท = 237
MRU
Hermansen et ลเ 2006
starting doses were 10 units/IU.
If initial premeal PG <126 mg/dl or BMI was <26.0 kg/m2, starting doses were reduced to 6 units/IU.

Basal insulin
Which type? How to start? How to adjust?

1.2.3 STUDY:
BASAL INSULIN
PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN
785 Insulin naive type 2 diabetes (A1C >8.0%) Receiving 2 or 3 OHAs for >3 months
RUN-IN PHASE Add Insulin glargine OD 14 weeks
A1 c >7.0%
Davidson M et al. Endocr Pract 2011 ;17:395.

ADD BASAL INSULIN
Start BASAL INSULIN 10 unit
Mean fasting 2-day SMBG, mg/dL
Insulin glargine adjustments every 2 days
>250
110-250
100-109
70-99
<70
HbAlc (%)
10.5
9.5
8.5 –
7.5 –
Increase the dose at investigator discretion Increase 2 บ
Increase 0-2 บ at investigator discretion3 No change
Decrease the dose 2-4 บ at investigator discretion
10.2
At 14-wk run-in 288/785 (37%) A1C < 7%
7.9
6.5 H ‘ ‘
Baseline 14-wk run-in

Maximum dose of Basal insulin
Increase insulin dose is associated with weight gain
Insulin dose <0.5 u/kg/D -> decrease HbAlc 0.5% for each increment in insulin dose equal to 0.1 u/kg/D
Insulin dose >0.5 u/kg/D -> decrease HbAlc 0.5% for each increment in insulin dose equal to 0.2 u/kg/D
Monnier L. Daibetes Metan 2006;32:7

TIP:
BEDTIME INSULIN DAYTIME SULFONYLUREA
* Start NPH or non peak insulin 10 unit or 0.1-0.2 unit/kg at bedtime
# Continue Oral hypoglycemic agent
* Titrate
– If FPG >110 mg/dl X 2D 2 unit
• Keep FPG 90-110 mg/dl
# Basal dose ~0.5-0.6 unit/kg/D (~50% of Total daily dose)

<*60 years old Thai female
❖Type 2 DM Diagnosed 10 years ago ❖Co-morbid diseases: HT, Dyslipidemia ♦>Bพ 60 kg ❖Currently on
❖ Glipizide 20 mg a day
❖ Metformin 2000 mg a day (used to on 2500 mg a day, but had diarrhea)
❖ Pioglitazone 30 mg
❖Her last HbAlC 9%,
FPG 220 mg/dl

QUESTION 2
ท่านจะให้การรักษาผู้ป่วยรายนี้ อย่างไร?
A. Lifestyle modification
B. Add TZD c. Add AGI
อ. Add DPP-IV inhibitor
Efficacy of different OHAs
Class of medicine Expected decrease in HbA)C
Biguanide 1.0 – 2.0%
Sulfonylureas 1.0 – 2.0%
Glinides* 0.5-1.5%
TZDs 0.5-1.4%
a-glucosidase 0.5-0.8%
inhibitors
GLP-1 agonists 0.5-1.0%
DPP4 inhibitors
0.5-0.8%

❖60 years old Thai female
❖Type 2 DM Diagnosed 10 years ago ❖Co-morbid diseases: HT, Dyslipidemia ❖BW 60 kg ❖Currently on
❖ Glipizide 20 mg a day
❖ Metformin 2000 mg a day (used to on 2500 mg a day, but had diarrhea)
❖ Pioglitazone 30 mg
❖Her last HbAlC 9%,
FPG 220 mg/dl

QUESTION 2
ท่านจะให้การรักษาผู้ป่วยรายนี้ อย่างไร?
A. Lifestyle modification
B. Add TZD c. Add AGI
อ. Add DPP-IV inhibitor

<*60 years old Thai female
❖Type 2 DM Diagnosed 10 years ago ❖Co-morbid diseases: HT, Dyslipidemia ♦>Bพ 60 kg ❖Currently on
❖ Glipizide 20 mg a day
❖ Metformin 2000 mg a day (used to on 2500 mg a day, but had diarrhea)
❖ Pioglitazone 30 mg
❖Her last HbAlC 9%,
FPG 220 mg/dl
QUESTION 3
ถ้าท่านเลือกจะให้อินสุลินในผู้ป่วย รายนี้ ท่านจะเริ่มให้อย่างไร?
A. Continue OHA + NPH 6 น
B. Continue OHA + NPH 10 น
c. Off su# Cont MET + NPH 10 น อ. Continue OHA + Glargine 10 น
E Off OHA + Mix Insulin 15 น

Mrs B
Currently on ❖Glipizide 20 mg a day ❖Metformin 2000 mg a day ❖NPH 26 unit per day Her last HbAlC 7 8%, FPG 100 mg/dl

❖60 years old Thai female
❖Type 2 DM Diagnosed 10 years ago ❖Co-morbid diseases: HT, Dyslipidemia ❖BW 60 kg ❖Currently on
❖ Glipizide 20 mg a day
❖ Metformin 2000 mg
❖ NPH 26 unit per
❖Her last HbAlC 7.8%, FPG 100 mg/dl

QUESTION 4
ท่านจะให้การรักษาผู้ป่วยรายนี้ อย่างไร?
A. Lifestyle modification
B. Check insulin technique c. Add TZD
D, Add DPP-IV inhibitor
E. Switch to Glargine 20 น

❖60 years old Thai female
❖Type 2 DM Diagnosed 10 years ago ❖Co-morbid diseases: HT, Dyslipidemia ❖BW 60 kg ❖Currently on
❖ Glipizide 20 mg a day
❖ Metformin 2000 mg
❖ NPH 26 unit per
❖Her last HbAlC 7.8%, FPG 100 mg/dl
QUESTION 5
ท่านจะให้กาฬกษาผู้ป่วยรายนี้ อย่างไร?
A. Add TZD Dj Add DPP-IV inhibitor c. Switch to Glargine 20 น
D. Add RI4 น at big meal
E. Switch to Mix insulin 14 น bid

HI WHEN TO INTRODUCE ^ MORE COMPLEX INSULIN REGIMENS?
* FPG is acceptable, but HbAlc is still high or post prandial higher than goal
* When aggressive titration is limited by hypoglycemia
* เท insulin deficiency end of type 2 diabetes spectrum -> maximum dose of basal insulin
Oral Hypoglycemic agents failure
Add basal insulin

Switch to Premixed Add Prandial
Insulin Insulin

ALL TO TARGET STUDY DESIGN
572 T2DM 2-3 OADs 1 A1C >7.5% @ screening A1C >7% @ randomization
Current . OADs
1 m
60-week study
Premix X 2 + met and/or TZD
-MM=192
BASALINSULIN + 2 OADs
BASAL INSULIN + 2 OADs
BASAL + 1 PRANDIAL+ met and/or TZD
N=189
3m
I
B+P x1
+ met/TZD B+P x2
+ met/TZD
3 m
A1C > 7
I 3 m A1C > 7
I
B+P x3
+ met/TZD
*N=191
3 m
TTT
FPG and pre prandial BG <100 mg/dl
• A1C <6.5%
A1C > 7
Riddle MC and Rosenstock J et al. ADA 20111 San Diego.

ALL TO TARGET EFFICACY
A1C (%)
9.5
8.5
7.5
6.5
Premixed
Basal +
1 shot
* p < 0.05 vs. Premixed

0/ PofiontQ
with A1C <7%
60
40
20
39
14
*
49
*
45
24 24

Premixed Basal + Basal +
1 shot 0-3 shot
Baseline
60 weeks m <7% without hypo

ALL TO TARGET SYMPTOMATIC HYPOGLYCEMIA
15
Event-rates per person-yr
10
5
0
– * *
– * *

Premixed
Basal + 1 shot
Basal + 0-3 shot
*
p
Basal + prandial Insulin had better efficacy and less hypoglycemia compare to Premixed
Oral Hypoglycemic agents failure
Add basal insulin

Switch to Premixed Add Prandial
Insulin Insulin

Insulin
Level
PRANDIAL INSULIN
apid (Lispro, Aspart, Glulisine)
Rapid-acting analogue insulin
Onset: <1/2 hr Peak: 1 hr Duration: 3-4 hr
Regular insulin
Onset: 1/2 hr Peak: 1-3 hr Duration: 6-8 hr
hort (Regular)
0 2 4 6 8 10 12 14 16 18 20 22 24
Hours

1.2.3 STUDY:
BASAL INSULIN
PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN
785 Insulin naive type 2 diabetes (A1C >8.0%) Receiving 2 or 3 OHAs for >3 months
RUN-IN PHASE Add Insulin glargine OD 14 weeks
A1 c >7.0%
RANDOMIZATION

1
Basal insulin + Basal insulin + Basal insulin +
Prandial insulin 1 shot Prandial insulin 2 shot Prandial insulin 3 shot
Davidson M et al. Endocr Pract 2011 ;17:395.

h 1.2.3 STUDY:
พ BASAL INSULIN
PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN
* Definition of Main meal
• Start: 1/10 of total daily dose of BASAL INSULIN
# Titration
– Preprandial SMBG during the preceeding 7 calendar days
– Weekly titration
Mealtime dose, บ
Pattern of low preprandial blood glucose values (>2 values <70 mg/dL)
Pattern of high preprandial blood glucose values (>4 values above target)
<10 บ 11-20 บ >20 บ
Decrease by 1 บ Decrease by 2 บ Decrease by 3 บ
Increase by 1 บ Increase by 2 บ Increase by 3 บ

A 1.2.3 STUDY:
BASAL INSULIN
PLUS 1. 2 OR 3 DOSES OF PRANDIAL INSULIN
Evolution of A1C in the randomized
BASAL BASAL plus PRANDIAL
(alone) (patients with A1C >7%)

A1C in all subjects (ท=785) = 9.8 at run-in and 7.3 at randomization

1.2.3 STUDY:
BASAL INSULIN
PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN
5
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CD
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Basal + 1, 2 or 3 prandial Insulin had similar efficacy stepwise approach
Oral Hypoglycemic agents failure
Add basal insulin
Add Prandial insulin at main meal OR breakfast
TIPS:
ADDING SINGLE PRANDIAL INSULIN INJECTION
Add with the main meal Starting dose
– 10% of total daily dose, not less than 4 unit/meal
– Monitor pre-prandial glucose of next meal
– Target SMBG pre-prandial < 70-110 mg/dl, bedtime 70-120 mg/dl
Titration
dose , <10 น add 1 unit
dose, 10-20 น add 2 unit
dose, >20 น add 3 unit

❖60 years old Thai female
❖Type 2 DM Diagnosed 10 years ago ❖Co-morbid diseases: HT, Dyslipidemia ❖BW 60 kg ❖Currently on
❖ Glipizide 20 mg a day
❖ Metformin 2000 mg
❖ NPH 26 unit per
❖Her last HbAlC 7.8%, FPG 100 mg/dl
QUESTION 5
ท่านจะให้กาฬกษาผู้ป่วยรายนี้ อย่างไร?
A. Add TZD Dj Add DPP-IV inhibitor c. Switch to Glargine 20 น
D. Add RI4 น at big meal
E. Switch to Mix insulin 14 น bid

Mrs B
Currently on
❖Metformin 2000 mg a day ❖NPH 30 unit per day ❖RI 10 unit at lunch time Her last HbAlC 8.1%, FPG 130 mg/dl

❖60 years old Thai female
❖Type 2 DM Diagnosed 10 years ago ❖Co-morbid diseases:
HT, Dyslipidemia ❖BW 60 kg ❖Currently on
❖Metformin 2000 mg a day
❖NPH 30 unit per day ❖RI10 unit at lunch time
❖Her last HbAlC 8.1%, FPG 130 mg/dl

QUESTION 6
ท่านจะให้กาฬกษาผู้ป่วยรายนี้
อย่างไร?
A. Add RI 4 น at dinner
B. Switch to Mix insulin 15 น bid
c. Switch to Mix insulin 20 น at breakfast and 10 น at dinner
Oral Hypoglycemic agents failure
Add basal insulin

Switch to Premixed Add Prandial
Insulin Insulin

Premixed Insulin
Human insulin 70/30
Insulin analog 75/25 Insulin analog 70/30

Mixtures of Pre-meal Insulin

5

I
1

Regular/NPH Combined effect
L

แร
B

starting dose?
* Usually conventional initial approach to dosing premixed insulins in general practice is to prescribe
– a ratio of 2/3 of the total daily insulin dose in the morning before breakfast
– and 1/3 in the evening before dinner.

PREMIXED INSULIN DOSING IN ACTUAL PRACTICE: 2/3 IN AM, 1/3 IN PM, OR 50-50?
retrospective, observational, descriptive study
was designed to examine the use of premixed
insulins in ล community-based endocrinology practice
to analyze the ratio, for morning and evening doses of premixed insulin.
the premixed insulin dosing ratio of evening dose to TDD significantly differs from the standard value of 0.33 and is on average close to 0.5 or 50%

How about the รบ, should we stop?
The only consistent advantage of continue รบ is:
– Reduced insulin dose requirements, which may result in less daily injections
– Easier dose titration
– Improved compliance
These potential benefits must be balanced against the side effects

Dose
Blood Glucose
Adjust Insulin’
Prebreakfast <70 mg/dL Decrease PM 1 -2 บ
140-250 mg/dL Increase PM 1-2 บ
>250 mg/dL Increase PM 2-4 บ
Presupper <70 mg/dL Decrease AM 1 -2 บ
140-250 mg/dL Increase AM 1-2 บ
> 250 mg/dL Increase AM 2-4 บ
Person J. Diabet Educat 2006;32:195

❖60 years old Thai female
❖Type 2 DM Diagnosed 10 years ago ❖Co-morbid diseases:
HT, Dyslipidemia ❖BW 60 kg ❖Currently on
❖Metformin 2000 mg a day
❖NPH 30 unit per day ❖RI10 unit at lunch time
❖Her last HbAlC 8.1%, FPG 130 mg/dl

QUESTION 6
ท่านจะให้กาฬกษาผู้ป่วยรายนี้
อย่างไร?
A. Add RI 4 น at dinner
B. Switch to Mix insulin 15 น bid
c. Switch to Mix insulin 20 น at breakfast and 10 น at dinner
Foot Patch มีอย.ต้อง Mamae

 

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