How to Initiate and

Optimize Insulin Therapy

for Outpatient Setting?
dr. Budi Enoch, SpPD
1920
Banting/Best
Insulin
isolated from dogs
 Learning Objectives

 Dokter umum
 Mengetahui batasan pengobatan yg dapat diberikan di rawat jalan
 Mengetahui pengobatan sistem rujukan
 Melanjutkan pengobatan sistem rujuk balik
 Mengetahui wewenang manajemen diabetes dokter praktek di PPK1
 Melakukan penyesuaian dosis obat sesuai dengan evaluasi

 Internist
 Mengelola kasus rujukan dari PPK1
 Mengetahui indikasi dan melakukan rujuk balik ke PPK1
 Mengetahui wewenang manajemen diabetes dokter praktek di PPK2
farmakokinetik

 Ditemukan 1922 oleh Frederick Banting

 Ekstrak pankreas sapi dan babi
 1980 : teknologi rekayasa genetik
 1990 : analog
 Macam insulin sekarang
- insulin analog (cepat atau panjang)
- insulin manusia (cepat atau menengah)
- insulin campuran (premixed)
- insulin basal (panjang)
 Outlines

• Fix the fasting with basal insulin analogue

• Simple intensification option with biphasic insulin
analogue
• Understand the basal bolus regimen
• Conclusions
“Fix the Fasting First

Start with Basal Insulin

 ADA Position Statement 2015
Healthy eating, weight control, increased physical activity
Initial METFORMIN
monotherapy

Two-drug + SU + TZD + SGLT-2i + DPP-4i + GLP-1 RA

+ INSULIN
combinations (Usually BASAL)

+TZD +SU
+SU +SU Or +TZD
Or + DPP-4i or +DPP-4i + SU
Three-drug Or +TZD Or +TZD Or +DPP-4i
combinations or +SGLT-2i Or +SGLT-2i Or +TZD
Or +DPP-4i Or +SGLT-2i Or +SGLT-2i
Or +GLP-1 RA Or +GLP-1 RA Or +INSULIN
or +INSULIN or +INSULIN Or +GLP-1 RA
or +INSULIN or +INSULIN

More complex
strategies BASAL INSULIN + MEALTIME insulin OR GLP-1 RA

DPP-4i, dipeptidyl peptidase-4 inhibitor (vildagliptin, galvus); GLP-1 RA, glucagon-like peptide-1
ADA, Diabetes Care, 2015: S43 receptor agonist; SU, sulphonylurea; TZD, thiazolidinedione; SGLT-2i, SGLT-2 inhbitor
“Standard care should begin with metformin
unless there is evidence of contraindications”
Insulin Can Be Initiated at Any Time

• Traditionally, insulin has been reserved as the last line of

therapy…

Inadequate
+ 1 OAD + 2 OAD + 3 OAD
lifestyle

INITIATE INSULIN

•…However, considering the benefits of normal glycemic status,

insulin can be initiated earlier and as soon as possible
Challenge for Physiological Insulin Replacement

 Subcutaneous insulin injection drain into the

peripheral, not portal circulation
 Insulin preparation are a poor match for the finely
tuned  cell
 Subcutaneous insulin absorbtion is highly variable
(intra-individual and inter-individual)

Bolli,2003
Events after subcutaneous injection of soluble regular insulin : concentration of
hexameric insulin are lowered by diffusion in the interstisial space allowing
dissociation into dimers and monomers which pass more readily through the
capillary membrane (Lee and Zinman,1998)
 Vascular and cellular organization of pancreatic islet

Insulin is directly secreted into hepatic portal vein in response to

increase portal glucose level
Properties of ideal insulin analogues
Rapid-acting insulin analogues
• Onset of action < 0.5 after SC injection
• High peak activity
• Duration of action < 4 h

Long-acting insulin analogues

• Onset of action > 4 h after SC injection
• Duration of action 24 h (one injection per day)
• No pronounced peak activity
• Almost constant action over time

General
• Small intra-individual variability of insulin action
• Metabolic effect greater than mitogenic effects
• No significant immunogenic effects
• Chemically stable
• No problem with miscibility
 Greater HbA1c, Greater Contribution of FPG

Most insulin is
initiated when
HbA1c >8.5 %

100
% contribution to HbA1c

40% 30%
80 50% 45% PPG
70%
60 FPG

40 70%
50% 55% 60%
20 30%
0
<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2
HbA1c range (%)

Adapted from Monnier et al. Diabetes Care 2003;26:881–5.

 Insulin Detemir

LysB29(N-tetradecanoyl)des(B30)human insulin
Phe Phe Gly Arg
Tyr Glu
Thr Gly
Pro
Pro Cys
Lys Val
Thr
B29 A21 Asn Cys
Tyr Leu
Gly Lys
A1 Asn Tyr
Ile Glu Leu
Val Leu Ala
Glu Gln Glu
Gln Tyr Val
Cys Leu
Cys Ser Leu
Thr Ser Ile Cys
His
Ser
Gly
Cys
Asn Gln His Leu
B1 Phe Val
 Basal Insulin Analogue Profile

3.0
Insulin detemir
2.5 0.4 U/kg
Glucose infusion rate

Insulin glargine
2.0
(mg/kg/min)

1.5
1.0
0.5
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (h)
Klein O et al. Diab Obes Metab 2007; 9:290-299
 Insulin Detemir Provides Optimal HbA1c Reduction

Soewondo P et al. Clinical experience with insulin detemir: Result from the Indonesian cohort of the international A1chieve study. Diabetes Res Clin
Pract;suppl.S192013) S47-S53.
 Insulin Detemir Reduces Nocturnal Hypoglycaemia
by up to 65% compared to NPH

NPH vs. Insulin glargine NPH vs. insulin detemir

-29% -44% -53% -65%
Relative Risk

Insulin detemir
Insulin NPH
Insulin glargine

Riddle et al., 2003 Phillis-Tsimikas et al., 2006

NPH: Neutral Protamine

Phillis-Tsimikas. Clin Ther 2006;28(10):1569–81; Riddle et al 2003. Diabetes Care; 26 (11): 3080-6 Hagedorm, Insulatard Novo
 How To Start Basal Insulin?

Start Titrate

Titrate the dose every 3 days, if

Insulin Detemir
10 U or 0.1-0.2 U/kg Average FPG > 110mg/dl = increase 3 units
Average FPG < 80 mg/dl = decrease 3 units

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

Meneghini L et al. Diabetes Obes Metab, 9, 2007, 902-913

Safety is my highest
priority now

Levemir® has been approved for diabetes

gestational and children > 2 years
(BPOM, FDA, EMEA)

Levemir®. Indonesia Prescribing Information. 2014

 Outlines

• Fix the fasting with basal insulin analogue

• Simple intensification option with biphasic insulin
analogue
• Understand the basal bolus regimen
• Conclusions
How Do We Define Insulin Intensification?

INITIATE Starting insulin therapy

Dose titration to ensure that the patient

OPTIMISE receives the maximum benefit from the
prescribed treatment

Modification of the insulin regimen,

INTENSIFY e.g. adding to or changing the therapy in order
to maintain glycaemic control
 Why Do We Need Intensify from Basal Insulin?

Within 1 year,
the majority of basal
insulin patients will
need another insulin to
reach target1

Biphasic insulin
offer a simple intensification
of one insulin in one device2

1. Holman et al. N Engl J Med 2007;357:1716–30

2 Garber AJ, et al. Diabetes, Obesity and Metabolism, 8, 2006, 58–66.
 Biphasic Insulin Aspart 30

Biphasic insulin aspart 30 is a mixture of :

30%

Protaminated insulin aspart

70% insulin aspart

 Biphasic Insulin Aspart 30 Targets Both FPG and PPG1

Physiological insulin
profile: Physiological insulin profile
• Basal component Basal insulin Biphasic insulin
• Meal-related peaks Biphasic insulin aspart 30 aspart 30 closely
Plasma insulin level
mimics
physiological
insulin response
(basal & meal-
related insulin
response)
Time

1. Garber et al. Diabetes Obes Metab 2006;8:58–66; 2. Garber et al. Diabetes Obes Metab 2007;9:630–9
 Sequential Insulin Strategy in Type 2 Diabetes
# Injections Basal Insulin Complexity
1 (usually with metfromin)
low
Start: 10U/day or 0,1-0,2 U/kg/day
Adjust : 10-15% or 2-4 U once-twice weekly to reach FBG target

Add 1 rapid insulin injection If not controlled, Change to premixed insulin

2 before largest meal treat PPG twice daily
mod
Start : Divide current basal dose into 2/3 AM, 1/3 PM
Start: 4 U, 0,1 U/kg, or 10% basal dose. If A1c < 8%, or 1/2 AM,1/2 PM
consider basal by same amount Adjust: dose by 1-2 U or 10-15% once-twice weekly
Adjust: dose by 1-2 U or 10-15% once-twice weekly until SMBG target reached
until SMBG target reached

If not controlled, Add ≥ 2 rapid insulin injections before If not controlled,

consider basal- meals (“basal-bolus”) consider basal-
3+ bolus bolus high
Start : 4U, 0,1 U/kg, or 10% basal dose/meal
If A1c < 8%, consider basal by same amount
Adjust dose by 1-2 U or 10-15% once-twice weekly until SMBG target reached

Flexibility more flexible less flexible

For hypo: Determine and address cause: dose by 2-4 U or 10-20% SMBG: self monitoring of blood glucose
ADA Standards of Medical Care 2015
 Biphasic insulin aspart 30:
A Consensus Statement Simple Algorithms for Intensification

Basal insulin OD or BID

HbA1c 7-8% HbA1c > 8.0%

FPG > 110 mg/dL FPG: 73-110 mg/dL

Switch to Biphasic insulin aspart 30 BID

Titrate basal to achieve
FPG 110 mg/dL

*If recurrent hypoglycaemia limits up-titration of the basal dose, or the daily
dose reaches 0.5 U/kg (insulin units per kg body weight), switching to BIAsp 30
twice daily can be considered

Adapted from Unnikrishnan et al. Int J Clin Pract 2009: 63(11):1571-77.

Intensifying basal insulin patients to Biphasic insulin aspart 30 is simple
In basal insulin patients: start with the same total daily dose

Intensify to

Others consideration
unit unit
basal insulin Biphasic insulin aspart 30
•Titrate the dose preferably once a week.
Pre-Breakfast Pre-Dinner •Administer Biphasic insulin aspart 30 just before
meals
Split total daily dose 50% 50% •Continue metformin.
•Discontinue sulfonylureas (SUs).
Twice daily Biphasic insulin aspart 30 •Consider discontinuing TZDs as per local guideline
and practice.

Adapted from Unnikrishnan et al. Int J of Clin Prac 2009; 63:1571–7

 Adjusting The Dose of Biphasic Insulin Aspart 30

Recommended dose titration Guidance:

• Dose adjusment can be made once

FBG and predinner SMBG Biphasic insulin aspart 30
dose adjustment weekly until target is reached

mg/dL Units • The lowest of three previous days’

<80 -2 premeal levels should be used for

80–110 0 dose adjusment
111–140 +2 • The dose should not be increased if
141–180 +4
hypoglycaemia occurs
>180 +6
• Only one dose at a time should be
changed: the evening dose should be
titrated first, followed by the breakfast
dose

Adapted from Unnikrishnan et al. Int J of Clin Prac 2009; 63:1571–7

 LATEST OBSERVATIONAL DATA

“Novo Nordisk Analogue insulin

have been tested for its
efficacy and safety benefit
over Indonesian population”
 Biphasic Insulin Aspart 30 ± OAD:
Indonesia Efficacy Results

HbA1c (%) FPG (mg/dl) PPG (mg/dl)

Baseline values 9.4 204 278

Week 24 7.3 132 168

0,0
-10
Change from baseline to

-30
week 24

-1,0 -50

-70

-72*
-90
-2,0

-2.1*
-110
-110*
-130

-3,0 -150

Soewondo et al. DRCP 2013: S54-S59 *p<0.001 Insulin user

 Biphasic insulin aspart 30 ± OAD:
Indonesia Hypoglycaemia Results

Overall Major Nocturnal

Insulin users Insulin users Insulin users

No. of pt w/hypo 29 1 0 0 16 0

3.0
Events/patient-year

2.3
1,64
1.5
0.7 0,51
0,03 0,00 0,00 0,00
0.0
Baseline
24 weeks
Soewondo et al. DRCP 2013: S54-S59
 A1chieve: Self-rated Health in Insulin Users
(Biphasic Insulin Aspart 30)

Best imaginable health

100
90
24 weeks
80
Baseline
70
60
Biphasic insulin aspart 30 :
50
real world
40 improvement in
30 patients quality of life
20
10
Worst imaginable health
0
Soewondo et al. DRCP 2013: S54-S59 Baseline 24 weeks
 Outlines

• Fix the fasting with basal insulin analogue

• Simple intensification option with biphasic insulin
analogue
• Understand the basal bolus regimen
• Conclusions
 Initiating and Adjusting Insulin
Bedtime intermediate acting insulin, or bedtime or morning
long acting insulin
(initiate with 10 units or 0.2 units per kg)

Check FG and increase dose until in target range

If HbA1c < 7% If HbA1c ≥ 7%

Continue regimen; check HbA1c If FBG in target range, check BG before lunch, dinner, and bed.
every 3 months Depending on BG Results, add second injection
(can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range)

Pre-dinner BG out of range: add NPH

Pre-lunch BG out of range: add Pre-bed BG out of range: add
insulin at breakfast or rapid-acting
rapid-acting insulin at breakfast rapid-acting insulin at dinner
insulin at lunch

If HbA1c < 7% If HbA1c ≥ 7%

Continue regimen;
Recheck pre-meal BG level and if out of range, may need to add another injection; if HbA 1c continues
check HbA1c every 3
to be out of range, check 2-hr postprandial levels and adjust preprandial rapid-acting insulin
months
 Initiating and Adjusting Insulin
Bedtime intermediate acting insulin, or bedtime or morning
long acting insulin
(initiate with 10 units or 0.2 units per kg)

Check FG and increase dose until in target range

If HbA1c < 7% If HbA1c ≥ 7%

Continue regimen; check HbA1c If FBG in target range, check BG before lunch, dinner, and bed.
every 3 months Depending on BG Results, add second injection
(can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range)

Pre-dinner BG out of range: add NPH

Pre-lunch BG out of range: add Pre-bed BG out of range: add
insulin at breakfast or rapid-acting
rapid-acting insulin at breakfast rapid-acting insulin at dinner
insulin at lunch

If HbA1c < 7% If HbA1c ≥ 7%

Continue regimen;
Recheck pre-meal BG level and if out of range, may need to add another injection; if HbA 1c continues
check HbA1c every 3
to be out of range, check 2-hr postprandial levels and adjust preprandial rapid-acting insulin
months
The Basal Plus Concept

 When basal insulin added to oral agents

does not sustain target A1c
 Add mealtime insulin stepwise:
 Basal +1 — 2nd injection before the largest meal
 Basal +2 — 3rd injection before 2nd largest meal
 Basal +3 — 4th  Basal Bolus injection before
3rd meal (basal bolus)

Meal related insulin (short-/rapid-acting insulin)

 How To Titrate Prandial Insulin?

Injection Time BG Check Time Dosage adjustment

Breakfast Before lunch Next pre-breakfast
Lunch Before dinner Next pre-lunch
Dinner Before bed time Next pre-dinner

Pre-meal (mg/dL) Prandial Titration Dose

< 80 -1

80-130 0

> 130 +1

Pfutzner A. Int J Clin Pract. 2009, Update from ADA 2015

 Tambahkan
Suntikkan 10 UInjeksi
Levemir NovoRapid di setiap
sekali sebelum tidur.makan (4 U) (+3
Atur dosisnya
atau -3)Basal
untuk setiap 3– Bolus
mengendalikan
hari sampai Concept
Gula
dgndarah dengan
2 jam
GDP mencapai PPtarget
mencapai
GDP < 100
Levemir
target < 140 ® -(Perkeni
mg/dL
mg/dL NovoRapid
(Perkeni ®
2011)2011)
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)
BASAL - BOLUS Regimen

Advantages:
The most ideal therapy, has similarity with the profile of insulin endogen
More superior in blood glucose control
Easy and flexible to adjust the dose of basal or bolus insulin if patients do some variety
in meal contect & timing

Disadvantages:
Burden of injection, up to 4 injection daily
Less patient compliance, unsuitable for patient with low education or poor motivation
Higher risk of hypo and weight gain

Pfutzner A. Int J Clin Pract. 2009

 Outlines

• Fix the fasting with basal insulin analogue

• Simple intensification option with biphasic insulin
analogue
• Understand the basal bolus regimen
• Conclusions
 Conclusions

• Giving insulin earlier to reach glycemic targets are now being encouraged by
leading institutions such as ADA and EASD

• Starting with basal insulin after metformin to reach better glycemic control.
Insulin detemir is a long acting insulin and has better profile in terms of duration
of action, efficacy, safety, predictability with neutral weight gain

• Basal bolus therapy is an ideal treatment option for diabetes management

because provide optimal PPG, FPG, HbA1C control, but has a limitation with 4
times injection daily.

• Insulin treatment should be titrated and tailor made to reach individual target
TERIMA KASIH TEMAN TEMAN