Inisiasi dan

adjusting dosis
insulin di layanan
primer
Iin Novita Nurhidayati Mahmuda
 PUSDATIN
KEMENKES
 Timely insulin initiation crucial to reduce huge
burden of diabetes complications

52% people with diabetes have

Low insulin Delayed
use3,4 complications at diagnosis1 insulin use5

2 of 3 patients on treatment don’t achieve

glycaemic control2

Insulin initiation is urgent and simple

1. Pengobatan Diabetes Habiskan 33 Persen Biaya Kesehatan dari BPJS
https://lifestyle.kompas.com/read/2016/04/09/150000023/Pengobatan.Diabetes.Habiskan.33.Persen.Biaya.Kesehatan.dari.BPJS (Date accessed: 9 May 2019)
2. Soewondo et al. The DiabCare Asia 2008 study – Outcomes on control and complications of type 2 diabetic patients in Indonesia. The DiabCare Asia 2008 study.
2010. 19(4);235-244
3. IMS Q1 2018 MAT MU
4. IDF Diabetes Atlas 8th Edition.
5. Khunti et al. Diabetes Obes Metab 2012;14:654–61
 Diabetes is a global heath challenge1,2
Diabetes is expected to grow 73% by 2045

736 MILLION2
PATIENTS Only ONE in TWO adults with diabetes know that
they have diabetes.1
73%
425 MILLION2 INCREASE

PATIENTS
Many patients have poor glycaemic control – and
poor control can lead to costly, life-threatening
177 MILLION1 complications2-4:
PATIENTS
AMPUTATIONS BLINDNESS

HEART DISEASE KIDNEY FAILURE

2000 2015 2045

References: 1. International Diabetes Federation. IDF Diabetes Atlas, 2 ed. Brussels, Belgium: International Diabetes Federation, 2003. 2. International Diabetes Federation. IDF Diabetes Atlas,
8ed. Brussels, Belgium: International Diabetes Federation, 2017. 3. Harris S et al., Glycemic control and morbidity in the Canadian primary care setting (results of the diabetes in Canada evaluation
study). Diabetes Research and Clinical Practice 2005; 70:90–97. 4. UK Prospective Diabetes Study (UKPDS) Groups. Lancet 1998: 352 (9131):837-53. 5. The Diabetes Control and Complications Trial
Research Group. N Engl J Med 1993;329(14):977-86.
 Almost 70% patient in Indonesia not achieve target DM therapy
Diabcare 2008 Diabcare 2012

80 170

69.2

164
67.8
70

60 160

MEAN FPG (MG/DL)

50
% OF PATIENTS

150
40

144.1
30

140
20

10
130
0
HBA1C (ADA ≥ 7%)

1. Soewondo, P, et al. The DiabCare Asia 2008 Study – Outcomes on control and complications of type 2 Diabetets patients in Indonesia. Med J Indones 2010; 19:235-44).
2. Cholil AR, et al. DiabCare Asia 2012: diabetes management, control, and complications in patients with type 2 diabetes in Indonesia. Medical Journal of Indonesia. 2019 5
May 8;28(1):47-56
T2D is a major and independent risk factor for both microvascular and macrovascular
complications

Macrovascular

Microvascular

World Health Organization. http://www.who.int/diabetes/action_online/basics/en/index3.html

22/06/2021 6
Improving control reduces the risks of long-term complications1

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

Stroke
Myocardial infarction
Heart failure
Cataract extraction

Microvascular disease

Lower extremity
amputation or fatal
peripheral vascular
disease

Every 1% drop in HbA1c can reduce long-term diabetes complications

References: 1. Stratton IM et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405-412.
Risk of complications increases as HbA1c
increases
80
1000 patient-years
Incidence per

60

40
Myocardial infarction
20

0
5 6 7 8 9 10 11
Updated mean HbA1c (%)

Stratton et al. BMJ 2000;321:405–12

22/06/2021 8
Early insulin therapy improves beta-cell function and
glycaemic control

CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injection; OHA, oral hypoglycaemic agent
Weng et al. Lancet 2008;371:1753–60
Inisiasi Insulin
 PowerPoint Presentation Date 11

Kasus A
• Ny. ABN - 62 thn, seorang IRT, terdiagnosis DM sejak 8 tahun yll.
• Datang untuk kontrol rutin ke FKTP, Keluhan masih sering BAK, terutama
malam hari, mudah lelah
• Vital sign dan pemeriksaan fisik DBN.
• Hasil Lab : GDP 281 mg/dL; GDPP 322 mg/dL; HbA1c (bulan lalu) 9.7%
• Terapi DM selama ini:
• Glibenclamide 3x5mg
• Metformine 3x500mg
 Stepwise management of type 2 diabetes

More complex
insulin strategies
Oral agent(s)
+ insulin + +
Combination oral
agent/ incretin
therapy + +

+
Oral agent
Diet and
exercise

Adapted from Williams. Lancet 1994;343:95–100

 Insulin remains the most efficacious glucose lowering agent

Decrease in HbA1c: Potency of monotherapy

HbA1c %

CHOOSING INSULIN EARLIER

FOR BETTER EFFICACY

Nathan et al., Diabetes Care 2009;32:193-203.

Blood glucose control is individualistic

15
ADA. Standards of Medical Care In Diabetes - 2018
Insulin therapy strategy

Lifestyle + OADs
β-cell function (%)

Basal / Premix insulin + OADs

Titrate dose to reach/maintain glycaemic targets

Initiate Basal and 1–3 injections of bolus or premix

Intensify for mealtime insulin coverage

Optimize

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
Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0
Strategic of Insulin Therapy
Start with Insulin Therapy
INITIATION (Basal insulin)

OPTIMALIZE Titrate Dosage to ensure patients to get

benefit from treatment

Modify Insulin Regime

e.g: add bolus insulin
INTENSIFY Or switch to premix insulin to achieve glycemic control

17
How to start basal insulin

Start with basal insulin 10 U

Or
0,1-0,2 U per Kg BB

Once daily injection, anytime injection but in same time per each day

Consensus Perkeni 2011, American Diabetes Association. Diabetes Care 2015.

How to titrate basal insulin
Dose Titration Guidelines:
Basal Insulin

3-0-3 Algorithm

Simple Dose titration

Mean 3-day FPG
(mg/dL)
Start with 10 U or 0,1-0,2 U per Kg BB
FPG>110 mg/dL +3U
80-110 mg/dL 0

FPG <80 mg/dL -3U

Patients who experienced hypoglycemia reduced their daily dose by 3 units

Blonde L et al. Diabetes Obes Metab. 2009; 11(6):623-631.

 PowerPoint Presentation Date 20

Kasus B
• Ny. ABN - 62 thn, seorang IRT, terdiagnosis DM sejak 8 tahun yll.
• Datang untuk kontrol rutin ke FKTP, Keluhan mudah lelah, kaki kesemutan
• GDP 178 mg/dL; GDPP 267 mg/dL; HbA1c ( 3 bulan lalu) 9.7%
• Terapi metformin 2x500 mg dan Levemir 16 unit malam

• Jika perlu, apa yang akan Dokter sarankan untuk terapi lanjutan pasien
ini?
 PERKENI Consensus on Insulin Management
Insulin basal
Jml injeksi Biasanya dengan metformin +/- non-insulin lainnya Kompleksitas

1 Awal: 10 U/hari atau 0,1-0,2 U/kgBB/hari

Rendah
• Penyesuaian: 10-15% atau 2-4 U, 1-2 kali/minggu sampai tercapai sasaran GD
puasa
• Hipoglikemia: tentukan dan atasi penyebab, turunkan dosis 4 U atau 10-20%

Jika setelah GD puasa

tercapai, tapi GD pp masih
tinggi (atau jika dosis >0,5
U/kgBB/hari),
atasi GD pp dengan insulin
waktu makan (pertimbangkan
untuk memberikan GLP-1-RA)

Tambahkan 1 injeksi insulin cepat Ganti dengan insulin

sebelum makan terbesar premixed 2x/hari
21
 • Awal: 4 U, 0,1 U/kgBB, • Awal: bagi dosis basal
atau 10% dosis basal. Jika menjadi 2/3 siang, 1/3
Jml injeksi A1C<8% pertimbangkan malam atau ½ siang, ½ Kompleksitas
untuk menurunkan basal malam
2 dalam jumlah yang sama • Penyesuaian: naikkan Sedang
• Penyesuaian: naikkan dosis 1-2 U atau 10-15%,
dosis 1-2 U atau 10-15%, 1- 1-2 kali/minggu sampai
2 kali/minggu sampai sasaran SMBG tercapai
sasaran SMBG tercapai • Hipoglikemia: tentukan
• Hipoglikemia: tentukan dan atasi
dan atasi penyebab, Penyebab, turunkan dosis
turunkan dosis 2-4 U atau 2-4 U atau 10-20%
10-20%

Jika tidak Tambahkan ≥ Jika tidak

terkendali, 2 injeksi terkendali,
pertimbang insulin rapid pertimbang
sebelum
kan basal
makan (basal
kan basal
bolus bolus) bolus

22
3+
 Diabetes Care, Diabetologia. 19 April 2012
T2DM Antihyperglycemic Therapy: General Recommendations [Epub ahead of print]
 Diabetes Care, Diabetologia. 19 April 2012
T2DM Antihyperglycemic Therapy: General Recommendations [Epub ahead of print]
 Diabetes Care, Diabetologia. 19 April 2012
T2DM Antihyperglycemic Therapy: General Recommendations [Epub ahead of print]
 Diabetes Care, Diabetologia.
19 April 2012 [Epub ahead of print]
 PowerPoint Presentation Date 27

Kasus B
• Ny. ABN - 62 thn, seorang IRT, terdiagnosis DM sejak 8 tahun yll.
• Datang untuk kontrol rutin ke FKTP, Keluhan masih sering BAK, terutama
malam hari, mudah lelah
• GDP 178 mg/dL; GDPP 267 mg/dL; HbA1c ( 3 bulan lalu) 9.7%
• Terapi metformin 2x500 mg dan Levemir 16 unit malam

• Tambahkan Insulin Rapid Acting (Novorapid/Apidra 4 unit sebelum makan

terbanyak ), edukasi untuk penyesuaikan dosis.
• Apabila dengan tambahan 3x4 unit GDP 112, pertahankan dosis atau
switch ke pre mix  16 + 12 = 28, dibagi dua dosis 14 – 0- 14 – 0
2 of 3 patients on treatment don’t achieve
glycaemic control

❂ Patients uncontrolled on triple therapy

❂ Patients with long-standing diabetes that is poorly controlled
❂ Any patient not at HbA1c target despite intensive treatment

Soewondo et al. The DiabCare Asia 2008 study – Outcomes on control and complications of type 2 diabetic patients in Indonesia. The
DiabCare Asia 2008 study. 2010. 19(4);235-244
 29

Aim of insulin therapy

Short-lived, rapidly
generated meal-related
70 insulin peaks (prandial)
• To recreate the normal
60
blood insulin profile
Insulin (µU/mL)

50

40 Sustained
insulin profile (basal)
30

20

10

0
6:00 10:00 14:00 18:00 22:00 2:00 6:00
Time of day
Breakfast Lunch Dinner

Polonsky et al. J Clin Invest 1988;81:442–48

Injection 10 U IDet OD bed time. Titrate the dose (+3 or -3) every 3 days until
reaches the FPG target 80-130 mg/dl (PERKENI 2015)
Basal – Bolus concept with IDet - IAsp
400
Plasma glucose (mg/dl)

300 T2DM
15 T2DM
Profile
200
Hyperglycaemia due to an increase in fasting glucose

100

Normal
0 Meal Meal Meal

06.00 10.00 14.00 18.00 22.00 02.00 06.00

Time of day (hours)
Adding IAsp (4 U) to control BG, reaches the PPG target <180 mg/dL (PERKENI
30
2015)
Clinical inertia: patient and physician barriers

Lack of appropriate Complex regimens

education

“Head in the sand” Hypoglycaemia

“I can do it with Barriers Excess weight gain

lifestyle”

Patient perceptions of
worsening disease Health service delivery

Patient perceptions of
insulin treatment and
outcomes Resource issues Financial restrictions

Peyrot et al. Diabetes Care 2005;28:2673–9; Elgrably et al. Diabet Med 1991;8:773–7; Wallace & Matthews. QJM 2000;93:369–74; Kunt
& Snoek. Int J Clin Pract 2009;63(Suppl. 164):6–10
 PowerPoint Presentation Date 32

Kasus C

• Tn. CTJ - 49 thn, dirujuk balik dari PPK 2 dengan diagnosis DM, HT satu bulan yang lalu.
• BB 66 Kg; TB 165 cm
• GDP 124 mg/dL; GDPP pagi 221 mg/dL; GDPP siang 253 mg/dL; HbA1c 8.4% (sudah turun)
• Terapi DM selama ini:
• Insulin Detemir 24U malam hari
• Metformine 3x500mg
• Acarbose 1x50 mg saat makan siang

• Jika perlu, apa yang akan Dokter sarankan untuk pasien ini ?
a) Tambahkan acarbose sampai 3x50 mg
b) Atau insulin rapid acting, atau swicth ke pre mix
 Strategies for dose intensification
Complete Basal Bolus Stepwise

Add bolus 2U at each meal

Add bolus 4U at largest meal
Titrate to next pre-prandial goals ( and bedtime)
Titrate to next pre-prandial (or bedtime) goal daily
daily
If subsequent pre-meal sugars are:
If subsequent pre-meal sugars are:
<70mg/dl -1U
<70mg/dl -1U
70-130mg/dl 0
70-130mg/dl 0
>130mg/dl +1U
>130mg/dl +1U
Discontinue SU on addition of bolus insulin
Discontinue SU on addition of bolus insulin
Patients may need monitor up to 4x per day
Patients need to monitor up to 4x per day

If A1C>7% after 3 months despite titrating

If A1C>7% after 3 months despite titrating
bolus dose, or bolus dose is more than 30 U per
bolus dose, or bolus doses are more than 30 U
meal:
per meal:
Add 2nd bolus of 4U at 2nd largest meal and
Resume titration of basal insulin and/or
titrate as before.
consider performing a blood glucose 7 point
Repeat for 3rd bolus dose at final meal of the
profile
day
Pfutzner A, Forst T. Intensification with prandial insulin. Int J Clin Pract 2009; 63 (Suppl. 164): 11–14
Date 33
 PowerPoint Presentation Date 34

Kasus D
• Tn. DN - 52 thn.
• Dibawa keluarganya ke IGD dengan penurunan kesadaran. Pasien mengalami mual,
muntah dan demam 4 hari, Riwayat DMT2 sejak 7 tahun terakhir dengan pengobatan tidak teratur
• TD 90/55 mmHg, nadi 130x/mnt, RR 22x/menit
• Hasil Lab:
• Gula darah 610 mg/dl,
• Na+ 127 mEq/L,
• K+ 4.2 mEq/L,
• HCO3- 19 mEq/L;
• pH 7.40,
• keton urin (+)

• Bagaimana rencana terapi saat emergency, monitoring dan terapi selanjutnya yang akan
Dokter berikan?
 Diagnostic Criteria for DKA and
HHS

Abbas E. Kitabchi et al. DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009
 Protocol for management of adult patients with DKA or HHS.

DKA diagnostic criteria: blood glucose 250 mg/dl, arterial pH 7.3, bicarbonate 15 mEq/l, and moderate ketonuria or ketonemia. HHS diagnostic criteria:
serum glucose 600 mg/dl, arterial pH 7.3, serum bicarbonate 15 mEq/l, and minimal ketonuria and ketonemia. †15–20 ml/kg/h; ‡serum Na should be
corrected for hyperglycemia (for each 100 mg/dl glucose 100 mg/dl, add 1.6 mEq to sodium value for corrected serum value). (Adapted from ref. 13.)
Bwt, body weight; IV, intravenous; SC, subcutaneous.
Abbas E. Kitabchi et al. DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009
 Intravenous insulin aspart in a hospital setting: results from
an observational study examining patient outcomes and
physician preferences
Udwadia et al. Diabetes Management 2012;2:103–10

• Background
• Hyperglycaemia is common in critically ill individuals, even those with no history of
diabetes
• IV insulin administration allows rapid dosing adjustments in hospital setting
• Objective
• To evaluate the safety and efficacy of intravenous insulin aspart in hospitalised
patients

IV, intravenous
 Change in blood glucose
30 540 Baseline
* * End of treatment
25 450
Mean BG (mmol/L)

Mean BG (mg/dL)
20.7
20 17.7 360

15 270

10 8.4 8.9 180

5 90

0 0
ICU Non-ICU
*p=0.0001
BG, blood glucose; ICU, intensive care unit
Udwadia et al. Diabetes Management 2012;2:103–10
 Hypoglycaemia
ICU Non-ICU Overall
(n=2010) (n=976) (n=3024)

Major hypoglycaemia†,
14 (0.7) 3 (0.3) 17 (0.6)
n (%)

Minor hypoglycaemia‡,
61 (3.0) 24 (2.4) 85 (2.8)
n (%)

Overall, n (%) 75 (3.7) 27 (2.8) 102 (3.4)

†Major: symptoms of hypoglycaemia that the patient is unable to treat themselves and either BG <2.2 mmol/L (<40 mg/dL), or
reversal of symptoms after either carbohydrate intake, glucagon or IV glucose
‡Minor: symptoms of hypoglycaemia with confirmation by blood glucose 2.2–3.8 mmol/L (40–69 mg/dL) and that are handled by the

patient themselves, or any asymptomatic BG 2.2–3.8 mmol/L (40–69 mg/dL)

BG, blood glucose; ICU, intensive care unit; IV, intravenous
Udwadia et al. Diabetes Management 2012;2:103–10
 Adverse events
ICU
(n=2010)

SAEs, n (%) 6 (0.2)

Fatal SAEs (death due to septicaemia and shock) 3

Death due to MI 2

Death due to bleeding peptic ulcer 1

All deemed unlikely related to treatment

ICU, intensive care unit; MI, myocardial infarction; SAE, serious adverse event
Udwadia et al. Diabetes Management 2012;2:103–10
 Conclusions
• IV insulin aspart effectively reduced mean BG levels in both ICU and non-
ICU settings
• IV insulin aspart appears to be an effective and well-tolerated option for
managing inpatient hyperglycaemia in ICU and non-ICU settings

BG, blood glucose; ICU, intensive care unit; IV, intravenous

Udwadia et al. Diabetes Management 2012;2:103–10
 Summary
• T2D is a progressive disease which will lead to the need of insulin therapy

• Early glycaemic control reduces complications; conversely, poor glycaemic control is

an important driver for diabetes complications

• There are benefits associated with early insulin initiation

• Insulin initiation is urgent and simple

• We should consider for prandial insulin when basal insulin with any oral combination
could not reach the target
 Always Start with a small doses and adjust the doses once or twice a week
42
TERIMA KASIH
Slide deck RTD MI 2019 -9ii 44
Insulin Action Profiles

Rapid (lispro, aspart, glulisine)

Insulin Level
Short (regular)

Intermediate (NPH)
Long (detemir)
Long (glargine)

0 2 4 6 8 10 12 14 16 18 20 22 24
Hours After Injection
 Type of Insulin Onset Peak Duration Presentation
of Action of Action of Action

Insulin prandial (meal-related)

Insulin short-acting

Insulin in Indonesia
Regular (Actrapid®, Humulin® R) 30-60 min 30-90 min 3-5 hours Vial, pen/cartridge

Insulin analog rapid-acting

Insulin lispro (Humalog®) 5-15 min 30-90 min 3-5 hours Pen/cartridge

Insulin glulisine (Apidra®) 5-15 min 30-90 min 3-5 hours Pen

Insulin aspart (NovoRapid®) 5-15 min 30-90 min 3-5 hours Pen, vial

Insulin intermediate-acting

NPH (Insulatard®, Humulin® N) 2-4 hours 4-10 hours 10-16 hours Vial, pen/cartridge

Insulin long-acting

Insulin glargine (Lantus®) 2-4 hours No peak 18-26 hours Pen

Insulin detemir (Levemir®) 2-4 hours No peak 22-24 hours Pen

Insulin Campuran

70% NPH; 30% regular 30-60 min Dual 10-16 hours Pen/cartridge
(Mixtard®, Humulin® 30/70)

70% insulin aspart protamine 10-20 min Dual 15-18 hours Pen
30% insulin aspart (NovoMix® 30)

75% insulin lispro protamine 5-15 min Dual 16-18 hours Pen/cartridge
30% insulin lispro (Humalog Mix® 25)

PERKENI Consensus Guidelines 2011.

Target gula darah
Sliding Scale
Pathogenesis of DKA and HHS:
stress, infection, or insufficient insulin. FFA, free fatty acid

Abbas E. Kitabchi et al. DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009