The Role Of Prandial Insulin after

Basal Optimization

SAID.GLU.20.03.0159 (03/2020)
High PPG on HbA1c in Asian People

Contribution of PPG to hyperglycaemia is more prominent in Asian

people with T2DM.

a a
80 ab 80 PPG FBG
a
Contribution (%)

Contribution (%)
60 60

40 40 b
b

20 20

0 0
<7.3 7.3-8.4 8.5-9.2 9.3-10.2 >10.2 <7.1 7.1-7.5 7.6-8.0 8.1-8.7 8.8-12.7
HbA1c quintiles (mean)1 HbA1c quintiles (mean)2
non-Asian patients Asian patients
Significant difference between fasting blood glucose (FBG) and PPG; bSignificant difference from all other quintiles.
a

1. Monnier L, et al. Diabetes Care. 2003;26(3):881-885. 2. Wang JS, et al. Diabetes Metab Res Rev. 2011;27(1):79-84.
PPG control and early mealtime insulin treatment for Asian

Low BMI

! β-cell dysfunction PPG control and early

mealtime insulin
treatment are important
Young-onset T2DM
components of T2DM
management in Asian
High PPG excursion populations

High carbohydrate diet

Chan JC, Diabetes Voice, 2014

 High PPG excursion

Asians show greater glycaemic excursion than Caucasians to the

same BG load.

Glucose beverage Cereal

4.5 4.5

Incremental BG (mmol/l)
Incremental BG (mmol/l)

Asian Asian
4.0 European 4.0
European
3.5 3.5
3.0 3.0
2.5 2.5
2.0 2.0
1.5 1.5
1.0 1.0
0.5 0.5
0 0
0 15 30 45 60 75 90 105 120 0 15 30 45 60 75 90 105 120
Time (min) Time (min)

Venn BJ, et al. Diabet Med. 2010;27(10):1205-1208.

 Glucose Tetrad Concept (have to be controlled)
Glucose fluctuations and activation of oxidative stress contribute to progression of vascular
complications
Glucose
fluctuation
Activation of
(MAGE) oxidative stress

Activation of
oxidative stress

PPG

HbA1c
(glycation)
FBG

Monnier L et al. Diabetes Metab Res Rev 2009;25:393-402

Algorithm Type 2 Diabetes Mellitus
PERKENI Guideline 2019
Algoritma Intensifikasi Terapi Injeksi pada
DM Tipe 2

PERKENI. Konsensus Insulin

Diabetes Care 2020;43(Suppl. 1):S98–S110
Con’t…..

Diabetes Care 2020;43(Suppl. 1):S98–S110

 When and how to add prandial insulin after
basal optimization

The individual is not meeting glycemic targets on basal

insulin1-4
and:

FPG with basal

HbA1C still not at HbA1c elevated Further increases
insulin is within
goal with 0.5 despite normal in basal insulin
targeted range, but
units/kg/d of daily FPG with basal result in
PPG is persistently
basal insulin3 insulin2,3 hypoglycemia3
above goal3,4

1. Skyler JS. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders. Alexandria, VA: American Diabetes Association, Inc.; 2004:207-223.
2. American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011:1-68.
3. Inzucchi S, et al. Diabetes Care. 2012;35:1364-1379.
4. Davidson MB, et al. Endocr Pract. 2011;17:395-403.
Basal/Bolus Treatment with Rapid-acting &
Long-acting Insulin Analogs

Braithwaite S. Inpatient Insulin Therapy: Benefits and Strategies for Glycemic Control: Case-Based Strategies for Optimizing Insulin in the
Hospital Setting. Available at http://www.medscape.org/viewarticle/544930_4
How to titrate prandial insulin?
Injection Time BG Check Time Dosage adjustment

Before breakfast Before lunch Next breakfast the day after

Before lunch Before dinner Next lunch the day after

Before dinner Before bed time Next dinner the day after

How much ?
Pre-meal (mg/dL) Prandial Titration Dose (U)
< 70 -1

70-130 0

> 130 +1

Pfutzner A. Int J Clin Pract. 2009

Insulin Glulisine has unique molecule structure and zinc-free formula. The unique molecular structure of
insulin Glulisine provides faster absorption and onset of action, plus stability without the need for zinc
 Glulisine : Mechanism of Action
T T
T
Zn2+
T
‘Rapid-acting’
insulin TT T T
analogues:
Insulin lispro

T
Insulin aspart Phenol

Structures R-format Hexamers T-format Dimer Monomer

No added zinc
‘Rapid-acting’
insulin analogue: Polysorbate 20 (Tween 20)
Insulin glulisine

Capillary

Action: Glulisine terikat dengan reseptor insulin pada jaringan meningkatkan

pengambilan glukosa

1.Becker RHA . Diabetes Ther & Tech 2007;9(1)109-21. 2. Hollemen F, et al. N Engl J Med 1997;337:176–83 (adapted from Brange 1988)
 Insulin Glulisine has a faster onset of action vs.
insulin aspart in healthy volunteers

• Randomized, double-blind, cross-over, euglycemic clamp study comparing the PK/PD

profile of insulin glulisine vs. insulin aspart in 12 healthy volunteers

Variable Insulin glulisine Insulin aspart P-value

Mean (SD) or
median (range) - in AUC-GIR0–30 min (mg/kg) 30 (26) 16 (18) 0.0421
case of time GIRmax-t10% (min) 9 (2-23) 17 (3-20) 0.0146
parameters -
metabolic effects INSmax-t10% (min) 3 (0-15) 12 (1-15) 0.0005

AUC-GIR0-30 min = Area under the glucose infusion rate curve from 0 to 30 min after drug administration
GIRmax-t10% (min) = Time to 10% of the maximum glucose infusion rate
INSmax-t10% (min) = Time to 10% of the maximum observed insulin concentration

Insulin glulisine had a significantly higher early metabolic effect, an earlier

onset of action and a faster absorption compared with insulin aspart

Arnolds S, et al. Exp Clin Endocrinol Diabetes 2010;118:662-4.

Lower glucose levels with glulisine vs. aspart for 1-h
after meal in obese subjects with T2DM

Mean plasma glucose concentrations over time

Randomized, double-blind, Insulin injection 2 min prior
cross-over study comparing to Start of test meal
the PK/PD profile of insulin Test meal

concentration (mg/dL) ± SEM

glulisine with insulin aspart 10

concentration (mmol/L) ± SEM

180

Mean plasma glucose

in 30 insulin-naive, obese

Mean plasma glucose

160 Insulin Glulisine 9
subjects with T2D Insulin Aspart
140 8

7
120
6
100
5
80
0 40 80 120 160 200 240 280 320 360

SEM=standard error of mean Time (min)

Adapted from Bolli GB, et al. Diabetes Obese Metab 2011;13:251-7.

Peak insulin concentration was significantly higher
for glulisine than for aspart

Bolli GB, et al. Diabetes Obese Metab 2011;13:251-7

 Flexibility Usage of Glulisine : postprandial vs
prepandial administration
multicenter, randomized, open-label trial conducted in USA, 345 patients, for a 52-week treatment period

premeal arm: insulin glulisine 3x/day ,0–15 min before 3 main meals + insulin glargine once daily ±metformin
postmeal arm: insulin glulisine 3x/day, 20 min after the start of ameal +insulin glargine once daily, ±metformin.

Postprandial glulisine administration provided similar glycaemic control and was non-inferior to preprandial
administration showing dosing flexibility and the feasibility of such approach when clinically indicated.
Ratner R, et al. Diabetes Obes Metab. 2011;13(12):1142-1148.
OPAL study: Glargine + glulisine improves glycemic control irrespective
of whether glulisine is given with breakfast or the main meal

multicentre, randomized, open-label, parallel-group study of 393 patients with type 2 diabetes, suboptimally
controlled (HbA1c >6.5–9.0%, FBG 6.7 mmol/l) on their previous glargine and OAD regimen. A single injection of
glulisine was added, either at breakfast or at main mealtime, to their existing therapy.

Baseline

End-point

1. Lankisch, M.R, et al. Introducing a simplified approach to insulin therapy in type 2 diabetes: a comparison of two single-dose

Lankisch M, et al. Diabetes Obes Metab. 2008;10:1178-85.

 Glulisine membantu memperbaiki glikemik variable
yang lebih baik

Perbandingan Insulin analog aksi cepat dalam intensifikasi dengan Glargine U300: Triple Crossover
Study, n = 30 pasien T2DM secara acak dialokasikan ke dalam 3 kelompok

Takeishi S et al., Diabetes 2018 Jul; 67 (Supplement 1)

MAT-ID-2000062-V 1.0 (06/2020)
 Glulisine membantu memperbaiki
glikemik variable yang lebih baik

Takeishi S et al., Diabetes 2018 Jul; 67 (Supplement 1)

MAT-ID-2000062-V 1.0 (06/2020)
Basal Plus (Gla-Glu) give control of FPG better than
BID premix, and giving similar improving A1c as BID
Premix

• Premix BID
■ Basal Plus (G+1)
▲ Basl Bolus (G+3)

Riddle, et al. Diabetes, Obesity and Metabolism. 2014; 16: 396–402

Weight gain & Hypoglycemia in basal plus
(Gla-Glu) and Basal Bolus is lower than
premix
• Premix BID
■ Basal Plus (G+1)
▲ Basl Bolus (G+3)

Riddle, et al. Diabetes, Obesity and Metabolism. 2014; 16: 396–402

 GINGER Study: An intensified basal-bolus using
glargine/glulisine results in a significantly superior
glycaemic control vs. premix

Fritsche A, Larbig M, Owens D, et al. Diabetes Obesity and Metabolism. 2010;12:115-123.

Conclusions
• PPG control and early mealtime insulin treatment are important
components of T2DM management in Asian populations
• The Basal Plus strategy, i.e. glargine once daily with glulisine once daily
given with breakfast or the main meal, demonstrated combined
efficacy with an acceptable safety profile.
• The Basal Bolus strategy is an optimized approach for patients with
advanced type 2 diabetes
• Findings from a ‘real life’ prospective study confirm the results of
randomized controlled clinical trials in terms of the superior efficacy of
Basal-Bolus vs. premixed insulins
• Glulisine has the following features: faster onset of action & meal time
flexibility