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75
(% of normal by HOMA)
DIAGNOSIS
undiagnosed
Beta-cell function
50
Pancreatic function
= 50% of normal
25 IGT Postprandial
Hyperglycemia
0
–10 -2 0 2 6 10 14
Years from Diagnosis
HOMA, homeostasis model assessment
Adapted from Holman1 1. Holman RR. Diabetes Res Clin Pract 1998;40(Suppl 1):S21–5
Lebovitz H. Diabetes Review 1999;7:139-53 (modified) 2. UKPDS Group. Diabetologia 1991; 34:877–90
T2DM is a progressive condition
350 DIAGNOSIS
300 Post-meal
250 glucose Fasting
Glucose glucose
200
(mg/dl)
150
100
50
Clinical
features Risk for diabetes complications
Years −10 −5 0 5 10 15 20 25 30
• Primary prevention
Plasma creatinine
>120mol/l: 3%
Abnormal ECG : 18%
Intermittent
Claudicasio: 3% Early diagnosis is important !
Erectal Dysfuntion : 20% Early intervention is important !
Treatment target
HOW LOW SHOULD WE GO ?
Others
PPG
< 180
mg/dL
Konsensus Perkeni 2015
MANAGEMENT of TYPE 2 DM :Early Intervention
Physiologic Insulin Secretion: 24-hour Profile
Prandial insulin
50
Insulin
(µU/mL) 25
Basal Insulin
0
Breakfast Lunch Dinner
Time of day
FIX FASTING FIRST:
Rationale for Basal Insulinization
Contribution of fasting hyperglycaemia to overall
glycaemia increases with worsening diabetes
• 290 patients with T2DM treated with diet or OHAs
• Baseline (normal) PG defined as 6.1 mmol/l (110 mg/dl) ― threshold defined by ADA as the upper limit of
normal PG at fasting or preprandial times
100
Relative contribution (%)
100
5
Normal
Meal Meal Meal
Comparison of 24-hour glucose levels in control subjects vs 0 0
patients with diabetes (p<0.001). 6 10 14 18 22 2 6
Adapted from Polonsky K, et al. N Engl J Med 1988;318:1231―9.
Time of day (hours)
A stepwise approach for the treatment of
patients with type 2 diabetes
24 hours
Long Acting Insulin Analog
Insulin Glargine
• Peakless
• Clear solution
• Basal Insulin
• Could be given 1 – 2
times a day
• Not for intravenous
use
The simple way to add basal insulin
Initiate insulin with a single injection of a basal insulin
• Bedtime or morning long-acting insulin OR
INITIATE • Bedtime intermediate-acting insulin
• Daily dose: 10 units or 0.2 units/kg
FBG, fasting blood glucose Adapted from Nathan DM, et al. Diabetologia 2006;49:1711–21
Matching treatment to disease progression using a
stepwise approach
Basal Plus
Add prandial insulin at main meal
Basal
Add basal insulin and titrate
*As the disease progresses, a second daily injection of glulisine may be added
Adapted from Raccah D, et al. Diabetes Metab Res Rev 2007;23:257–64
The Basal Plus strategy using once-daily
glargine + once-daily glulisine
1Nathan DM, et al. Diabetes Care 2008;31:1–11; 2Del Prato S, et al. Diabetologia 2008;51 Suppl.
1:S452;
3Sanofi-aventis data on file. Glargine titration optimization: Using algorithms employed by clinical
studies for patients with type 2 diabetes, the target FPG should be ≤100 mg/dL (5.5 mmol/l)
Straight to three bolus doses Sequential addition of bolus doses
Fix the FPG first using basal insulin (dose optimisation) Fix the FPG first using basal insulin (dose optimisation)
Goal: FPG 70-130 mg/dl Goal: FPG 70-130 mg/dl
Consider adding bolus insulin when: Consider adding bolus insulin when:
A1C >7% and FPG at goal or basal insulin dose >0.5 U/kg2 A1C >7% and FPG at goal or basal insulin dose >0.5 U/kg2
If A1C >7% after 3 months despite titrating bolus dose, or bolus If A1C >7% after 3 months despite titrating bolus dose, or bolus
doses are more than 30 U per meal: dose is more than 30 U per meal:
Resume titration of basal insulin and/or consider performing a 7 Add 2nd bolus of 4U at 2nd largets meal and titrate as befor.
point profile Repeat for 3rd dose at final meal of the day
A. Pfu¨ tzner, T. ForstInt. J Clin Pract, October 2009, 63 (Suppl. 164), 11–14
Insulin glulisine:
A novel rapid-acting insulin analogue
The two substitutions favour monomer formation and facilitate rapid
absorption from the tissue following subcutaneous injection
Human Rekombinan insulin analog Glu+ Lys=
Insulin glulisine:
Substitution of asparagine B3
Gluisine
with lysine, and of lysine B29
A chain with glutamic acid =substitution
Gly
S
1 S 20
Glu
B chain Gln Cys
Ala
Lys 5 Thr
Phe Gln Lys
Ile S Pro 30
1 Asn
S
10 15
His S S Phe
5 25
Gly
His
10 Leu 20
15
Qualitative composition
150 4
100
2
50
0 0
0 120 240 360 480 600 0 120 240 360 480 600
Time (minutes) Time (minutes)
10
2 2
0 0
All <25 25–30 30–35 ≥35 All <25 25–30 30–35 ≥35
BMI groups (kg/m2) BMI groups (kg/m2)
7.5
Insulin glulisine
7.4 RHI
HbA1c (%)
7.3
N=876 withT2DM;
BMI=34.6 kg/m2 and
7.2 34.51kg/m2 in the insulin
glulisine and RHI groups
7.1 respectively; NPH=basal
* insulin
7.0
*p<0.05
6.9
*
Baseline 12 weeks 26 weeks
p=0.0499
30
8
HbA1c (%)
POC 8.0
20 7.8 7.8
22.4 7.5
7
10
8.8
0 6
Control Glargine Control Glargine
group + glulisine group + glulisine
p=0.028 p=NS
60 9
% achieving HbA1c <7.0
p<0.0001 p<0.0001
52.2
40 8
HbA1c (%)
OPAL
36.5
Baseline
20 7 7.35 7.29
7.03 Endpoint
6.94
0 6
Breakfast Main meal Breakfast Main meal
group group group group
The main meal group also included subjects whose main meal was breakfast Sanofi-aventis data on file. Basal Plus (POC) study
Lankisch M, et al. Diabetes Obes Metab 2008;10:1178–8
POC study: the Basal Plus approach is safe and
associated with only minor weight gain
0.6 10 0.3
p=NS p=NS p=NS
(event/patient-year)
(event/patient-year)
8
Symptomatic hypo
from baseline (kg)
0.5 8.19
0.4 7.68 0.2
6 0.2
4
0.2 0.1
0.2
2
0.0
0.0 0 0.0
Control Glargine Control Glargine Control Glargine
group + glulisine group + glulisine group + glulisine
1.0 3.69
(event/patient-year)
(event/patient-year)
0.04
from baseline (kg)
Confirmed hypo
1.0 0.04
Severe hypo
0.8 0.9
2.72 0.03
0.6 2
0.02
0.4
1
0.2 0.01
0.01
0.0 0 0.00
Breakfast Main Breakfast Main Breakfast Main
group meal group meal group meal
Basal Plus
Add prandial insulin at main meal
Basal
Add basal insulin and titrate
100 8.5
8.16 Simple algorithm
% achieving HbA1c <7.0
p=NS
CHO counting
80 8.0
8.16
73
HbA1c (%)
60 69 7.5
40 7.0
ADA/EASD target 6.70
20 6.5
6.54
p=NS
0 6.0
Simple CHO Baseline 2 6 12 18 Endpoint
algorithm counting
Weeks
8.0
(event/patient-year)
(event/patient-year)
3.6 0.89
from baseline (kg)
0.8
3 6
Severe hypo
0.6 0.67
2 2.4 4 4.9
0.4
1 2
0.2
0 0 0.0
Simple CHO Simple CHO Simple CHO
algorithm counting algorithm counting algorithm counting
Randomization 52 weeks
p=0.0004
50 9.0
8.6
% achieving HbA1c <7.0
47
40
8.5 p=0.0001
8.0
HbA1c (%)
30 7.7
28
20 7.3
7.0
10 Premixed insulin
Glargine + glulisine
0 6.0
Glargine Premixed 0 3 6 9 12
+ glulisine insulin Months
(event/patient-year)
(event/patient-year)
Symptomatic hypo
3.6 13.4 0.20
from baseline (kg)
3 0.2
Severe hypo
10
0.15
9.9
2
2.2
0.10
5 0.1
1
0.05
0 0 0.00
Glargine Premixed Glargine Premixed Glargine Premixed
+ glulisine insulin + glulisine insulin + glulisine insulin
Randomization 9 months
42 9 0.3
9.2 9.25
5 0.3
30 8
HbA1c (%)
30 0.2 0.24
8
20
7.52
7 0.1
10
6.93
0 6 0.0
Glargine Premixed Glargine Premixed Glargine + Premixed
+ glulisine insulin + glulisine insulin glulisine insulin