Optimalisasi Tatalaksana Diabetes

Mellitus dengan Terapi Insulin

MAT-ID-2100690-V.1(05/2021)
Outline
• Definisi dan klasifikasi diabetes mellitus
• Patomekanisme hiperglikemia pada diabetes mellitus
• Penatalaksanaan diabetes mellitus dengan terapi insulin
• Perbedaan antara Insulin Basal Gla300 dengan Gla100
• Intensifikasi Insulin Basal dengan Insulin Prandial : “Kenapa & bagaimana”
Diabetes Mellitus
Definisi :
Kelompok penyakit metabolik dengan
karakteristik hiperglikemia yang terjadi karena
kelainan sekresi insulin, kerja insulin atau
kedua-duanya.
 PATHOGENIK
MEKANISME
DIABETES MELLITUS
• Genetic and environmental risk factors
impact inflammation, autoimmunity,
and metabolic stress
• An insufficient number or functional
decline of β-cells is central to
hyperglycemia and the downstream
complications of diabetes.
Understanding the state of the β -cell is
key to defining subtypes of diabetes

Entrepreneur Slides
KLASIFIKASI DIABETES MELLITUS

DIABETES TIPE 1 DIABETES TIPE 2 DIABETES TIPE LAIN DIABETES GESTATIONAL

Kebanyakan autoimun, Resistensi insulin yang Bisa karena infeksi, Dikarenakan pengaruh
absolut insulin deficiency kemudian diikuti oleh keganasan, obat-obatan hormonal pada saat
defisiensi insulin yang mempengaruhi kerja kehamilan
pancreas menghasillkan
insulin
T2DM is a progressive disease

Lifestyle + OADs
β-cell function (%)
Basal insulin + OADs

Titrate dose to reach/maintain glycaemic targets

Initiate Basal and 1–3 injections of bolus or premix

Intensify for mealtime insulin coverage

Optimise

Intensify

Treatment optimisation and intensification

OAD, oral antidiabetic drug

Schematic diagram adapted from Kahn. Diabetologia 2003;46:3–19

Inzucchi et al. Diabetologia 2012;55:1577–96
Kendali glukosa darah yang baik
DAPAT MENURUNKAN KEJADIAN KOMPLIKASI DIABETES
Setiap penurunan HbA1c 1 % akan mengurangi komplikasi diabetes jangka panjang

43% 37% 19% 16% 14% 12%

Stroke
Infark
Heart
Miokard
Cataract failure
extraction
Microvascular
disease

Lower extremity amputation

or fatal peripheral vascular
disease
• UKPDS: Prospective observational study in 23 hospital-based clinics in
England, Scotland and Northern Ireland
• n=4,585 patients; 3,642 included in analysis
of relative risk
KONTRIBUSI FPG DAN PPG 16

Entrepreneur Slides
 Algorithm of type 2 diabetes management in Indonesia
(PERKENI, 2019)
GOAL THERAPY : HbA1c <7% (Individualized)

HEALTHY LIFESTYLE MODIFICATION

Entry HbA1c Entry HbA1c Entry HbA1c
<7.5% >7.5%-9% >9%

MONOTHERAPY SYMPTOMS
DUAL THERAPY
Metformin (combination of 2 NO YES
GLP-1 RA drugs with different
mechanism)
If not at DUAL INSULIN
DPP-4i goal in 3 GLP-1 RA TRIPLE THERAPY THERAPY ±
Metformin or other first line drug

months,
AG-i (combination of 3 drugs with Other
proceed
to DUAL
DPP-4i different mechanism) OR Agents
SGLT-2i THERAP If not at
Y TZD goal in 3 GLP-1 RA TRIPLE

Metformin or other first line drug

months, THERAPY
TZD proceed to
SGLT-2i DPP-4i
TRIPLE

Second line drugs

SU/GN THERAPY If not at
Basal (combinatio TZD goal in 3
Insulin n of 3 months,
drugs) ADD OR INTENSIFY
SGLT-2i proceed to
SU/GN ADD OR INSULIN
Basal Insulin INTENSIF
AG-i Y Insulin
Therapy
SU/GN

AG-i
Fix Fasting First –
Lowering FPG Helps Lowers PPG As Well!!

Basal
Insulins Elevated Fasting Hyperglycemia

Normal Fasting Blood Glucose

Hence ‘Fix Fasting First’

References: Hirsch IB, Bergenstal RM, Parkin CG, et al. A Real-World

Abbreviations: FPG: Fasting Plasma Glucose; PPG: Post-prandial Plasma Glucose Approach to Insulin Therapy in Primary Care Practice. 2005. Available at:
http://clinical.diabetesjournals.org/content/23/2/78/T1.
 Pertimbangan Memilih Insulin

Perspektif Klinisi :
▪ Hipoglikemia
▪ Kenaikan Berat Badan
▪ Efficacy
▪ Dosis besar – volume besar ?

Pasien :
1. Takut Jarum, Nyeri suntikan
2. SMBG/PGDM
 Aspirasi Untuk Insulin Basal

> 24-hour coverage Long duration of action

Reduced hypoglycaemic risk Flat time-action profile

Stable glucose lowering High day-to-day reproducibility

Flat time-action profile

Dosing flexibility Long duration of action
JENIS JENIS INSULIN

Published in The lancet. Diabetes & endocrinology 2015

New forms of insulin and insulin therapies for the treatment of type 2 diabetes.
A. Cahn, R. Miccoli, A. Dardano, S. Del Prato
 Perbedaan insulin Gla-300 dengan Gla-100?

Reduction of volume by 2/31

Same number
Smaller volume of
of units
injection for
Gla-300 vs Gla-1001 Gla-100 Gla-300

Smaller surface area1,2

Gla-100 Gla-300
More compact smaller
SC depot with Gla-300
vs Gla-1001,2

For illustrative purposes only2

Different absorption kinetics:

More gradual and slower release1-4 Gla-300 has a distinct PK/PD profile vs Gla-
100:
More stable, prolonged duration
of action beyond 24 hours4

• Insulin glargine metabolism is the same regardless of Gla-100 or Gla-300 administration; M1 metabolite was confirmed as
the prinicpal active moiety circulating in blood3 14
PD, pharmacodynamic; PK, pharmacokinetic; SC, subcutaneous
1. Pettus J, et al. Diabetes Metab Res Rev. 2015 Oct 28. doi: 10.1002/dmrr.2763. [Epub ahead of print]; 2. Adapted from Sutton G et al. Expert Opin Biol Ther. 2014;14:1849-60; 3. Steinstraesser A et al.
Diabetes Obes Metab. 2014;16:873-6; 4. Becker RH et al. Diabetes Care. 2015;38:637-43
 Profil Gla-300 vs Gla-100 – Euglycemic Clamp PK/PD Study

Gla-100

Mean GIR (mg/min/kg)

2

Gla-300

0 6 12 18 24 30 36

160
Blood glucose (mg/dL)

Gla-100
140

120

Gla-300
100

0 6 12 18 24 30 36

Time, h

• GIR, glucose infusion rate

Adapted from Becker RH et al. Diabetes Care. 2015;38:637-43; Bailey TS et al. Diabetes Metab. 2017 Nov 16. pii: S1262-
3636(17)30538-4. doi: 10.1016/j.diabet.2017.10.001. [Epub ahead of print]

SAGLB.TJO.15.09.0742
 Data dari Continous Glucose Monitoring
Gla300 Vs Gla100
Gla-300 vs Gla-100:
Improved glycemic control, with less fluctuation
CGM Data
Euglycemic Clamp Clinical Study

Within-day Between-day
PK/PD Profile CGM data
fluctuation variability

Gla-300 presents a Low within-day Low between-day More constant 24-

more stable and fluctuation variability hour glucose
prolonged profile profile
vs. Gla-100 with Gla-300 vs.
Gla-100

Randomized, multicenter, 16-week, open-label, parallel-group, two-period crossover study in 59 patients with T1DM
CGM, continuousOnce-daily Gla-300
glucose monitoring; or Gla-100 given
PD, pharmacodynamic; in the morning
PK, pharmacokinetic; ortype
T1DM, evening
1 diabetes
Becker RHA et al. Diabetes Care 2015;38:637−643. Becker RHA et al. Diabetes Obes Metab 2015;17:261−267; Adapted from
Bergenstal RM et al. Diabetes Care. 2017;40:554-560
Hasil Study RCT Gla300 vs Gla100 (EDITION) dan Study Gla300 vs Ideg100
(BRIGHT)

Gla-300 vs Gla-100 Gla-300 vs IDeg

EDITION studies The BRIGHT study

Comparable HbA1c reductions between Similar glycemic control with Gla-300 and IDeg for
Gla-100 and Gla-3001–7 HbA1c and FSMPG reduction in T2DM patients9

Lower risk of confirmed or severe hypoglycemia in Incidence and rates of anytime and nocturnal
T2DM with Gla-300 vs confirmed hypoglycemia comparable for Gla-300 and
Gla-1008 IDeg during full study and maintenance periods9

Lower incidence and rates of confirmed

Lower or similar hypoglycemia risk in T1DM with
hypoglycemia with Gla-300 vs IDeg at any time of
Gla-300 vs Gla-1005,7
day during the titration period9

1. Riddle MC, et al. Diabetes Care. 2014;37(10):2755–2762; 2. Yki-Järvinen H, et al. Diabetes Care. 2014;37(12):3235–3243; 3. Bolli GB, et al. Diabetes Obes
FSMPG, fasting self-monitored plasma glucose Metab. 2015;17(4):386–394; 4. Terauchi Y, et al. Diabetes Obes Metab. 2016;18(4):366–374 (main article and Supplementary Table 2); 5. Home PD, et al. Diabetes
Care. 2015;38(12):2217–2225; 6. Data on file, EDITION 4 CSR (6 months) pg 88; 7. Matsuhisa M, et al. Diabetes Obes Metab. 2016;18(4):375–383 (main article and
Supplementary Table 1); 8. Roussel R, et al. Diabetes Metab. 2018;44(5):402–409; 9. Rosenstock J, et al. Diabetes Care. 2018;41:2147–2154.

17
FOR MEDICAL and SCIENTIFIC PURPOSES ONLY – LOCAL ADAPTATION FOR EXTERNAL USE
Penyakit Progresif membutuhkan Pengobatan yang Progresif

• Insulin basal analog sering kali ditambahkan dengan obat

anti hiperglikemik (OAD)

• Seiring waktu, Insulin basal saja mungkin tidak cukup untuk

mempertahankan glikemik kontrol yang optimal & pasien
membutuhkan terapi tambahan lainnya (Contoh: insulin
lainnya) untuk mengontrol kadar glukosa postprandial

Meece J, Diabetes Ther 2018; 9:877–90

 Kapan dan bagaimana menambahkan insulin
prandial setelah optimalisasi basal ?

Pasien yang tidak memenuhi target glikemik dengan insulin

basal1-4 dan :

HbA1C masih belum GDP dengan insulin basal Peningkatan lebih

mencapai kendali HbA1c meningkat berada dalam kisaran lanjut dosis insulin
glikemik dengan 0,5 meskipun GDP normal yang ditargetkan, tetapi basal dapat
unit/kg/jam insulin basal dengan insulin basal2,3 PPG tetap berada di atas menyebabkan
harian3 sasaran3,4 hipoglikemia3

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.
Algoritma Intensifikasi Terapi Injeksi pada DM Tipe 2
(PERKENI 2019)

PERKENI. Konsensus Insulin 2019

Intensifikasi Insulin Basal:
Rekomendasi ADA & AACE/ACE
ADA Guideline, 2021

Intensifikasi pengobatan tidak boleh

ditunda pada pasien T2DM1
AACE guidelines, 2020

Intensifikasi prandial insulin harus Insulin Premixed

didasarkan pada kebutuhan pasien.
Direkomendasikan untuk menggunakan menunjukkan fleksibilitas
insulin basal-prandial secara bertahap1 dosis yang lebih rendah
dan kejadian hipoglikemia
Alternative, insulin premixed 2x sehari
yang lebih tinggi
dapat digunakan untuk intensifikasi1 dibandingkan dengan
regimen basal-prandial
Regimen basal-prandial lebih disukai untuk
atau basal-bolus2
pasien dengan pola makan yang tidak
teratur karena fleksibiltasnya yang lebih
besar1

References: 1. American Diabetes Association. Diabetes Care. 2021; 44(Suppl. 1):S111–S124. 2. American Association of Clinical
Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2020
 Insulin Glulisine :
A novel rapid-acting insulin analogue (Human Recombinant Insulin Analogue)
Insulin glulisine: Subsitusi asparagine B3 dengan lysine, dan lysine B29 dengan glutamic acid

Glu + Lys =
Glulisine

The two substitutions favour monomer formation and facilitate rapid absorption from the tissue following subcutaneous injection

Insulin Glulisine memiliki struktur molekul yang unik & formula bebas Zinc. Struktur molekul yang unik ini
memberikan absorpsi & onset kerja yang lebih cepat, serta stabilitas tanpa membutuhkan Zinc.

1.Becker RHA . Diabetes Ther & Tech 2007;9(1)109-21

 Glulisine : Mekanisme Aksi
Zn2+
‘Rapid-acting’
insulin
analogues:
Insulin lispro
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)
 Gives Effect Faster than Aspart

A multinational, randomized, double-blind, two-way crossover trial comparing the PK and PD characteristics of glulisine & aspart in insulin-naÏve,
obese subjects with type 2 diabetes, n=30 patients with T2DM

Lower blood glucose is shown faster in glulisine Glulisine insulin concentration is higher than
group rather than aspart group during the first hour aspart

Bolli GB, et al. Comparative pharmacodynamic and pharmacokinetic characteristics of subcutaneous insulin glulisine and insulin aspart
prior to a standard meal in obese subjects with type 2 diabetes. Diabetes Obes Metab 2011;13:251-257.
Fleksibilitas Penggunaan Glulisine: pemberian post prandial
vs pra pandial
multicenter, randomized, open-label trial conducted in USA, 345 patients, for a 52-week treatment period

premeal arm: insulin glulisine 3x/hari ,0–15 min sebelum 3 makan utama + insulin glargine 1x/hari ±metformin
postmeal arm: insulin glulisine 3x/day, 20 min setelah memulai makan +insulin glargine 1x/hari, ±metformin.

Insulin Glulisine mencapai kontrol glikemik yang serupa (non-inferior) baik diberikan 0-15 menit sebelum makan atau 20 menit
setelah memulai makan, begitu juga dengan kenaikan berat badan tidak ada perbedaan yang bermakna.

Ratner R, et al. Diabetes Obes Metab. 2011;13(12):1142-1148.

OPAL study: satu injeksi insulin glulisine (saat Sarapan vs Makan Utama) +
Glargine memperbaiki HbA1c secara signifikan
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
8.0 p<0.0001 p<0.0001 p<0.0001 Endpoint

7.35 7.29 7.32

7.03
HbA1c (%)

6.94 6.99
7.0
Overall HbA1c
reduction
–0.33%

6.0

0.0
1. Lankisch, M.R, et al. Introducing a simplified approach to insulin therapy in type 2 diabetes: a comparison of two single-dose

Breakfast Overall
(n=162) (n=316)
Lankisch M, et al. Diabetes Obes Metab. 2008;10:1178-85.
 Peralihan dari Aspart/Lispro/RHI ke Glulisine Menunjukkan
Manfaat yang Signifikan
Prospective, open-label, 24-week study, 59 Diabetic Patients (49 type 1 & 10 type 2); 52.9±13.3 years old, uncontrolled BG level HbA1c>6.2% with basal
insulin glargine with multiple daily pre-meal injections of bolus insulin [aspart (n=19), lispro (n=37) & RHI (n=3)] for at least 8 weeks

Significantly decreased Prevented vascular

level of HbA1c damage

Yanagisawa K, et al. Diabetes Metab Res Rev. 2014 Nov; 30(8): 693-700
 Peralihan dari Aspart/Lispro/RHI ke Glulisine Menunjukkan
Manfaat yang Signifikan
Prospective, open-label, 24-week study, 59 Diabetic Patients (49 type 1 & 10 type 2); 52.9±13.3 years old, uncontrolled BG level HbA1c>6.2% with basal
insulin glargine with multiple daily pre-meal injections of bolus insulin [aspart (n=19), lispro (n=37) & RHI (n=3)] for at least 8 weeks

DTSQ (Diabetes Treatment Satisfaction

Questionnaire (DTSQ) Score

Six items assess DTSQ: satisfaction, convenience, flexibility, understanding of treatment, patients’ willingness to continue with
treatment, likelihood that they would recommend such treatment to others. Higher scores indicating higher satisfaction

Yanagisawa K, et al. Diabetes Metab Res Rev. 2014 Nov; 30(8): 693-700
Kesimpulan
• Regimen Basal insulin cukup mudah dan efektif untuk mencapai kontrol glikemik bagi
pasien DM tipe 2 yang belum terkontrol dengan obat-obatan oral.
• Hampir semua Guideline Manajemen DM tipe 2 merekomendasikan inisiasi insulin
dengan insulin basal.
• Insulin Basal Gla300 dapat menurunkan HbA1c secara efektif dengan resiko hipoglikemia
yang lebih rendah dibandingkan dengan Insulin Gla100. Gla300 juga memiliki variabilitas
glukosa yang lebih rendah dibandingkan gla100 baik disuntikkan malam hari maupun
pagi hari.
• Jika target Glukosa puasa sudah tercapai namun nilai HbA1c belum tercapai maka
sebaiknya menambahkan insulin prandial
• Insulin Glargine and Glulisine efektif dalam mencapai kendali glukosa
• Insulin Glulisine memiliki onset kerja yang lebih cepat dan mempunyai fleksibilitas dalam
waktu pemberian
TERIMA KASIH