INSULIN TREATMENT FOR TYPE 2 DIABETES MANAGEMENT
APIRADEE SRIWIJITKAMOL
DIVISION OF ENDOCRINOLOGY AND METABOLISM
DEPARTMENT OF MEDICINE
FACULTY OF MEDICINE SIRIRAJ HOSPITOL
QUESTION 1
1. ทา่นเคยเป็นแพทยค์นแรกทีเ่ริม่ใหอ้นิสลุนิรักษาในผู ้เป็นเบาหวานทีม่าตรวจที ่OPD หรอืไม ่
A. YES
B. NO
Breakfast Lunch Dinner
S L E E P
Insulin
Level
“Prandial” Insulin
“Basal” Insulin
Normal Secretory Pattern of Insulin
Total daily insulin requirement = 0.5-1 unit/kg/D
The 50/50 Rule
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 HbA1C 9%, FPG 220 mg/dl
A. Lifestyle modification
B. Add TZD
C. Add AGI
D. Add DPP-IV inhibitor
E. Add insulin therapy
QUESTION 2 ทา่นจะใหก้ารรักษาผูป่้วยรายนี้อยา่งไร?
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
a day
Her last HbA1C 9%,
FPG 220 mg/dl
A. Continue OHA + NPH 6 u
B. Continue OHA + NPH 10 u
C. Off SU, Cont MET + NPH 10 u
D. Continue OHA + Glargine 10 u
E. Off OHA + Mix insulin 15 u bid
QUESTION 3 ถา้ทา่นเลอืกจะใหอ้นิสลุนิในผูป่้วยรายนี ้ทา่นจะเริม่ใหอ้ยา่งไร?
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
a day
Her last HbA1C 9%,
FPG 220 mg/dl
Oral Hypoglycemic agents failure
Add basal insulin
STUDY METHOD
700 T2DM
on OAD Add twice daily
biphasic insulin*
Add once (or twice)
daily basal insulin*
Add thrice daily
prandial insulin*
Randomisation
visit
One
year
* progress to more intensive insulin regimen only if clinically necessary † stop sulphonylurea if taken
Glycemic target: A1C ≤ 6.5%
R Add midday prandial insulin
if glycaemic target not met†
Add prandial insulin
if glycaemic target not met†
Add basal insulin
if glycaemic target not met†
Two
years
Three
years
Basal group
Biphasic group
Prandial group
4T Trial
Holman RR.N Engl J Med 2009;361:1736
0
20
40
60
80
HbA1C < 6.5% HbA1C < 7.0%
% Attainment of Target HbA1c
Basal group Biphasic group Prandial group
EFFICACY
4T Trial
0
2
4
6
8
Biphasic Prandial Basal
Body weigh gain (kg)
0
10
20
30
40
50
Biphasic Prandial Basal
%Hypoglycemia (mod to severe)
Basal group Biphasic group Prandial group
ADVERSE EFFECTS
4T Trial
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
6-37
BASAL INSULIN
•Which type?
• How to start?
• How to adjust?
Hours
Long (Glargine)
Intermediate (NPH)
Long (Detemir)
Insulin
Level
0 2 4 6 8 10 12 14 16 18 20 22 24
NPH insulin
Onset: 1 1/ 2 hr Peak: 4-12 hr Duration: 24 hr
Long-acting analogue insulin
Onset: 2-3 hr Peak: none Duration: 24 hr
TYPE OF BASAL INSULIN
TREAT-TO-TARGET TRIALS
Insulin glargine once-daily (evening)
NPH once-daily (evening)
Insulin continually titrated to target:
Fasting PG ≤100 mg/dl
n = 367
n = 389
Insulin detemir twice-daily
NPH twice-daily
Insulin continually titrated to target: Fasting and pre-dinner PG ≤ 108
mg/dl
n = 237
n = 238
Riddle et al 2003
Hermansen et al 2006
8.5
9.0
8.0
7.5
7.0
6.5
0 4 8 12 16 20 24
Hb
A1
c
(%
)
NPH + OAD
Glargine + OAD
Weeks
0
2
4
6
8
10
12
14
16
18
21% risk reduction p <0.02
42% risk reduction p <0.01
Overall Nocturnal Hypoglycaemia
Even
ts p
er p
ati
en
t p
er y
ear
-2 0 12 24
8.5
9.0
8.0
7.5
7.0
6.5
Weeks
NPH + OAD
Detemir + OAD
TREAT TO TARGET
Hermansen et al. Diabetes Care 2006;29: 1269
Riddle et al Diabetes Care 2003;26:3080-6.
Even
ts p
er p
ati
en
t p
er y
ear
0
2
4
6
8
10
12
14
16
18
Overall Nocturnal Hypoglycaemia
47% risk reduction
p < 0.001
55% risk reduction p < 0.001
Basal insulin
•Which type?
• How to start?
• How to adjust?
TREAT-TO-TARGET TRIALS
Insulin glargine once-daily (evening)
NPH once-daily (evening)
Insulin continually titrated to target:
Fasting PG ≤100 mg/dl
n = 367
n = 389
Insulin detemir twice-daily
NPH twice-daily
Insulin continually titrated to target: Fasting and pre-dinner PG ≤ 108
mg/dl
n = 237
n = 238
Riddle et al 2003
Hermansen et al 2006
The starting dose of both insulins was 10 IU
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?
785 Insulin naive type 2 diabetes (A1C ≥8.0%)
Receiving 2 or 3 OHAs for ≥3 months
1.2.3 STUDY:
BASAL INSULIN
PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN
Davidson M et al. Endocr Pract 2011;17:395.
RUN-IN PHASE
Add Insulin glargine OD
14 weeks
A1C ≥7.0%
RANDOMIZATION
Basal insulin +
Prandial insulin 1 shot
Basal insulin +
Prandial insulin 2 shot
Basal insulin +
Prandial insulin 3 shot
ADD BASAL INSULIN
• Start BASAL INSULIN 10 unit
10.2
7.9
6.5
7.5
8.5
9.5
10.5
Baseline 14-wk run-in
HbA1c (%)
At 14-wk run-in 288/785 (37%) A1C < 7%
Maximum dose of Basal insulin
Increase insulin dose is associated with weight gain
Insulin dose <0.5 u/kg/D
decrease HbA1c 0.5% for each increment in insulin dose equal to 0.1 u/kg/D
Insulin dose >0.5 u/kg/D decrease HbA1c 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)
A. Lifestyle modification
B. Add TZD
C. Add AGI
D. Add DPP-IV inhibitor
E. Add insulin therapy
QUESTION 2 ทา่นจะใหก้ารรักษาผูป่้วยรายนี้อยา่งไร?
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
a day
Her last HbA1C 9%,
FPG 220 mg/dl
Efficacy of different OHAs
Class of
medicine
Expected decrease
in HbA1C
Biguanide 1.0 - 2.0%
Sulfonylureas 1.0 - 2.0%
Glinides* 0.5-1.5%
TZDs 0.5-1.4%
-glucosidase
inhibitors
0.5-0.8%
GLP-1 agonists 0.5-1.0%
DPP4 inhibitors 0.5-0.8%
A. Lifestyle modification
B. Add TZD
C. Add AGI
D. Add DPP-IV inhibitor
E. Add insulin therapy
QUESTION 2 ทา่นจะใหก้ารรักษาผูป่้วยรายนี้อยา่งไร?
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
a day
Her last HbA1C 9%,
FPG 220 mg/dl
A. Continue OHA + NPH 6 u
B. Continue OHA + NPH 10 u
C. Off SU, Cont MET + NPH 10 u
D. Continue OHA + Glargine 10 u
E. Off OHA + Mix insulin 15 u bid
QUESTION 3 ถา้ทา่นเลอืกจะใหอ้นิสลุนิในผูป่้วยรายนี ้ทา่นจะเริม่ใหอ้ยา่งไร?
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
a day
Her last HbA1C 9%,
FPG 220 mg/dl
Mrs B
Currently on
Glipizide 20 mg a day
Metformin 2000 mg a day
NPH 26 unit per day
Her last HbA1C 7.8%, FPG 100 mg/dl
A. Lifestyle modification
B. Check insulin technique
C. Add TZD
D. Add DPP-IV inhibitor
E. Switch to Glargine 20 u
QUESTION 4 ทา่นจะใหก้ารรักษาผูป่้วยรายนี้อยา่งไร?
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 NPH 26 unit per
day Her last HbA1C 7.8%, FPG 100 mg/dl
A. Add TZD
B. Add DPP-IV inhibitor
C. Switch to Glargine 20 u
D. Add RI 4 u at big meal
E. Switch to Mix insulin 14 u bid
QUESTION 5 ทา่นจะใหก้ารรักษาผูป่้วยรายนี้อยา่งไร?
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 NPH 26 unit per
day Her last HbA1C 7.8%, FPG 100 mg/dl
WHEN TO INTRODUCE MORE COMPLEX INSULIN REGIMENS?
• FPG is acceptable, but HbA1c is still high or post
prandial higher than goal
• When aggressive titration is limited by hypoglycemia
• In insulin deficiency end of type 2 diabetes spectrum maximum dose of basal insulin
Oral Hypoglycemic agents failure
Add basal insulin
Switch to Premixed Insulin
Add Prandial Insulin
ALL TO TARGET
STUDY DESIGN
3 m
B+P x3
+ met/TZD
A1C > 7
Premix x 2 + met and/or TZD
1 m
B+P x1
+ met/TZD
BASAL INSULIN
+ 2 OADs
3m
3 m
3 m
A1C > 7
A1C > 7
Current
OADs
B+P x2
+ met/TZD
BASAL + 1 PRANDIAL+ met and/or TZD
BASALINSULIN
+ 2 OADs
572 T2DM
2-3 OADs
A1C >7.5% @
screening
A1C >7% @
randomization
N=192
N=189
N=191
TTT • FPG and pre prandial BG < 100 mg/dl
• A1C <6.5%
Riddle MC and Rosenstock J et al. ADA 2011, San Diego.
60-week study
ALL TO TARGET
EFFICACY
A1C (%)
6.5
7.5
8.5
9.5
Premixed Basal +
1 shot
Basal +
0-3 shot
* *
* P < 0.05 vs. Premixed
39
49 45
14
0
20
40
60 *
24 *
*
24 *
Premixed Basal +
1 shot
Basal +
0-3 shot
% Patients with A1C <7%
Baseline <7% without hypo 60 weeks
ALL TO TARGET
SYMPTOMATIC HYPOGLYCEMIA
Event-rates per person-yr
Premixed Basal +
1 shot
Basal +
0-3 shot
* P < 0.05 vs. Premixed
0
5
10
15
*
*
*
*
BG < 70 mg/dl BG < 50 mg/dl
Basal + prandial Insulin had better efficacy and less hypoglycemia compare to Premixed
Oral Hypoglycemic agents failure
Add basal insulin
Switch to Premixed Insulin
Add Prandial Insulin
PRANDIAL INSULIN
0 2 4 6 8 10 12 14 16 18 20 22 24
Insulin
Level
Rapid (Lispro, Aspart, Glulisine)
Rapid-acting analogue insulin
Onset: <1/2 hr Peak: 1 hr Duration: 3-4 hr
Hours
Short (Regular)
Regular insulin Onset: 1/2 hr Peak: 1-3 hr Duration: 6-8 hr
785 Insulin naive type 2 diabetes (A1C ≥8.0%)
Receiving 2 or 3 OHAs for ≥3 months
1.2.3 STUDY:
BASAL INSULIN
PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN
Davidson M et al. Endocr Pract 2011;17:395.
RUN-IN PHASE
Add Insulin glargine OD
14 weeks
A1C ≥7.0%
RANDOMIZATION
Basal insulin +
Prandial insulin 1 shot
Basal insulin +
Prandial insulin 2 shot
Basal insulin +
Prandial insulin 3 shot
1.2.3 STUDY:
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
A1C in all subjects (n=785) = 9.8 at run-in and 7.3 at randomization
Evolution of A1C in the randomized
Run in Randomization Wk 8 Wk 16 Wk 24
7.40
7.0
A1
Cc (%
)
10.19 10.19
10.16
7.44
7.29
8.0
9.0
10.0
PRANDIAL 1x
PRANDIAL 2x
PRANDIAL 3x
BASAL
(alone)
BASAL plus PRANDIAL
(patients with A1C >7%)
1.2.3 STUDY:
BASAL INSULIN PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN
p=NS for all other pairwise comparisons
x1 x2 x3 0
1
2
3
4
5
Mean b
ody w
eig
ht
change
from
baselin
e (
kg)
3.7 3.8 3.9
PRANDIAL
0
5
10
15
20
x1 x2 x3 PRANDIAL
Confirm
ed s
ym
pto
matic h
ypo
(event/
patient-
year)
12.2
12.9
17.1
p=0.043
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
Severe
or
serious h
ypo
(event/
patient-
year)
x1 x2 x3 PRANDIAL
0.10
0.30
0.26
1.2.3 STUDY:
BASAL INSULIN PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN
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 u
dose, 10-20 u
dose, >20 u
add 1 unit
add 2 unit
add 3 unit
A. Add TZD
B. Add DPP-IV inhibitor
C. Switch to Glargine 20 u
D. Add RI 4 u at big meal
E. Switch to Mix insulin 14 u bid
QUESTION 5 ทา่นจะใหก้ารรักษาผูป่้วยรายนี้อยา่งไร?
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 NPH 26 unit per
day Her last HbA1C 7.8%, FPG 100 mg/dl
Mrs B
Currently on
Metformin 2000 mg a day
NPH 30 unit per day
RI 10 unit at lunch time
Her last HbA1C 8.1%, FPG 130 mg/dl
A. Add RI 4 u at dinner
B. Switch to Mix insulin 15 u
bid
C. Switch to Mix insulin 20 u
at breakfast and 10 u at
dinner
QUESTION 6 ทา่นจะใหก้ารรักษาผูป่้วยรายนี้อยา่งไร?
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 RI 10 unit at lunch time
Her last HbA1C 8.1%, FPG 130 mg/dl
Oral Hypoglycemic agents failure
Add basal insulin
Switch to Premixed Insulin
Add Prandial Insulin
Premixed Insulin
• Human insulin 70/30
• Insulin analog 75/25
• Insulin analog 70/30
Mixtures of Pre-meal Insulin
Regular/NPH
Combined effect
B S L HS B
Insu
lin
Eff
ect
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 a 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 SU, should we stop?
• The only consistent advantage of continue SU 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 Titration
Blood Glucose Adjust Insulin*
Prebreakfast <70 mg/dL Decrease PM 1-2 U
140-250 mg/dL Increase PM 1-2 U
>250 mg/dL Increase PM 2-4 U
Presupper <70 mg/dL Decrease AM 1-2 U
140-250 mg/dL Increase AM 1-2 U
> 250 mg/dL Increase AM 2-4 U
Person J. Diabet Educat 2006;32:195
A. Add RI 4 u at dinner
B. Switch to Mix insulin 15 u
bid
C. Switch to Mix insulin 20 u
at breakfast and 10 u at
dinner
QUESTION 6 ทา่นจะใหก้ารรักษาผูป่้วยรายนี้อยา่งไร?
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 RI 10 unit at lunch time
Her last HbA1C 8.1%, FPG 130 mg/dl
THANK YOU