How to Approach Insulin Intensification

Therapy (Premixed or Basal Bolus)

R BOWO PRAMONO
Outlines
• Why intensify treatment?
• Intensifying treatment with insulin
• What are the treatment options?
 ADA 2015: recommendations for antihyperglycaemics
Monotherapy Metformin
Efficacy (↓HbA1c) High
Hypoglycaemia Low risk
Weight Neutral/loss
Side effects GI/lactic acidosis
Cost Low
If A1C target not achieved after 3 months of monotherapy, proceed to 2-drug combinatiion (order not meant to denote any
specific preference-choice dependend on a variety of patient and desease specific factors)

Metformin + Metformin + Metformin + Metformin + Metformin + Metformin +

Option to Dual Therapy SU TZD DPP-4i SGLT2 GLP-1RA Insuin Basal
rapidly Efficacy (↓HbA1c) High High Intermediate High High Highest
Hypoglycaemia Moderate risk Low risk Low risk Moderate risk Low risk High risk
progress to Gain Gain Loss Gain
Weight Neutral Gain
MDI in Side effects Hypoglycaemia Oedema, HF, Fx Rare Hypoglycaemia GI Hypoglycaemia
cases of Low High High Low High Variable
Cost
If A1C target not achieved after 3 months of dual therapy, proceed to 3-drug combinatiion (order not meant to denote any specific
severe preference-choice dependend on a variety of patient and desease specific factors)
hyperglycae Metformin + Metformin + Metformin + Metformin + Metformin + Metformin +
mia (HbA1c Triple Therapy SU + TZD + DPP-4i + SGLT2 GLP-1RA + Insulin Basal +
≥10.0– TZD SU SU SU SU TZD
12.0%)
OR DPP-4i OR DPP-4i OR TZD OR TZD OR TZD OR DPP-4i
OR
OR SGLT2 OR SGLT2 OR SGLT2 OR DPP-4i OR Insulin OR SGLT2
OR GLP-1RA OR GLP-1RA OR Insulin OR Insulin OR GLP-1RA
OR Insulin OR Insulin
If A1C target not achieved after 3 months of triple therapy and patient (1) on oral combination move to injection; (2) on GLP-1 RA add
basal insulin ; 0r (3) on optimally titrated basal insulin add GLP-1RA or mealtime insulin in refractory patients consider adding TZD or
SGLT2 Metformin +
Combination
injectable therapy Basal Insulin + Mealtime insulin or GLP-1RA

American Diabetes Association. Diabetes Care 2015

Diabetes treatment algorithm : Consensus Perkeni 2011
 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.

Insulin can be initiated at any time

 Traditionally, insulin has been reserved as the last line of therapy…

 …However, considering the benefits of normal glycemic status, Insulin can
be initiated earlier and as soon as possible

Inadequate
Lifestyle + 1 OAD + 2 OAD + 3 OAD

INITIATE INSULIN
How to Initiate
Basal Insulin
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

Levemir® Dose Titration Guidelines:

3-0-3 Algorithm

Simple Dose titration with Levemir

Mean 3-day FPG (mg/dL)

Start with Levemir 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.

The benefits of Insulin Detemir
•
Once daily efficacy
•
Low risk of hypoglycemia
•
Less weight gain
•
Low variability
 Basal insulin analogue profile
Levemir®/Glargine

3.0
Insulin detemir
2.5 0.4 U/kg
Glucose infusion

Insulin glargine
(mg/kg/min)

2.0
1.5
rate

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
HbA1c reductions observed in clinical settings
are consistent with RCTs
Powerful reductions in HbA1c
Randomised controlled trials Observational studies
9.5

9.0
HbA1c(%)

8.5 -2.2 -1.3

-1.48 -1.3
8.0
-1.22 -0.94 -1.4
7.5

7.0

6.5
Philis- TITRATETM TRANSITIONT SOLVETM A1chieve® PREDICTIVETM
Tsimikas 3.9-5.0 4.4-6.1 M EU
IDet pm mmol/L mmol/L IDet +
SITA+ MET N=14611 N=2240* N=2377
N=169 N=122/122 N=107
*Includes A1chieve patients randomised to insulin detemir only (Indonesia Data)
Phillis-Tsimikas. Clin Ther 2006; 28:1569-81;
Blonde et al. Diab Obes Metab 2009; 11:623-31;
Dornhorst et al. Int J Clin Pract 2008; 64:659-65;
Hollander et al. Diab Obes Metab 2011; 13:268-275.
Khunti et al. Diabetes Obes Metab. 2012. DOI:10.1111/j.1463-1326.2012.01665.x
 Levemir reduces nocturnal hypoglycaemia by up to
65% compared to NPH
NPH vs. glargine NPH vs. detemir

-29% -44% -53% -65%

Relative Risk

Insulin Determir
Insulin NPH
Insulin glargine

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

2003 2006
Phillis-Tsimikas. Clin Ther 2006;28(10):1569–81; Riddle et al 2003. Diabetes Care; 26 (11): 3080-6;
Weight gain is consistently lower on detemir
than other insulin therapies
Detemir
Glargine
NPH

Yki-Jarvinen et al. Diabetes Care 2000;23:1130-6; Massi-Benedetti et al. Horm Metab Res 2003;35:189–96;
Fritsche et al. Ann Intern Med 2003;138:952-9; Riddle et al. Diabetes Care 2003;26:3080–6; Hermansen et
al. Diabetes Care 2006;29:1269–1274; Philis-Tsimikas et al. Clin Ther 2006;28:1569–81; Rosenstock et al.
Diabetologia 2008;51:408–16; Swinnen et al. Diabetes Care 2010;33:1176–8; Hollander et al. Clin Ther
2008; 30:1976–87; Raslova et al. Diabetes Res Clin Pract 2004;66:193–201; Haak et al. Diab Obes Metab
2005; 7:56–64; Montanana et al. Diabet Med 2008;25:916–23
Insulin Detemir demonstrate less intra-individual
day-to-day variability
NPH NPH NPH

Glargine Glargine Glargine

Detemir Detemir Detemir

15

Adapted from Heise T et al. Diabetes. 2004;53:1614-20.

Beta-cell function progressively declines

100
Beta-cell function Diabetes
diagnosis
(%, HOMA) 80

60

40

20
Extrapolation of beta-cell function prior to diagnosis
0
–12 –10 –8 –6 –4 –2 0 2 4 6 8
Time from diagnosis (years)

HOMA, homeostasis model assessment

Adapted from Lebovitz. Diabetes Reviews 1999;7:139–53 (data are from the UKPDS population: UKPDS 16. Diabetes 1995;44:1249–58)
Relative changes in beta-cell function
and insulin sensitivity
Patients with diet failure 5–7 years after diagnosis
80 60
Beta-cell function (%)

Insulin sensitivity (%)

60
40
40
20
20

0 0
0 2 4 6 0 2 4 6
Time from diagnosis (years)

Levy et al. Diabet Med 1998;15:290–6

 The need for treatment intensification


Losing control – glycaemic control naturally deteriorates over time1
 Initiation of insulin therapy helps to maintain glycaemic control
 However, control will deteriorate over time, even with the addition of
insulin to the therapeutic regimen
 Intensification of insulin therapy therefore becomes necessary to
maintain glycaemic control in the long term


Benefits of effective glycaemic control
 Reduce CVD risk : Every 1% drop in HbA1c can reduce long-term
diabetes complications2

UKPDS 34. Lancet 1998:352:854–65; Kahn et al (ADOPT). N Engl J Med 2006;355:2427–43

*p<0.0001. 1. Adapted from Stratton et al. BMJ 2000;321:405–12 (UKPDS 35)
 Achieve good glycaemic control required
intensified treatment over time
Getting to, or maintaining, target HbA1c levels in T2DM requires intensified
treatment over time1

10 Lifestyl Mono- Dual Insulin ±

therapy therapyoral drugs
0 e for lowering
blood
function (%)

HbA1c (%)
glucose 9
Beta-cell

7
HbA1c
Beta-cell 6
0 function
0 >15
Time (years)
1. Nathan DM, et al. Diabetes Care 2009;32:193-203 2. Adapted from Heine et al. BMJ 2006;333:1200-4n
DiabCare Asia 2008: Poor glycaemic control
(HbA1c) across South-East Asia
Click icon to add table

ADA
Target

Adapted from Mafauzy et al. Med J Malaysia 2011;66:175-81; Latif et al. Bangladesh Med Res Counc Bull
2011;37:11-16; Soewondo et al. Med J Indones 2010;19:235-44; Novo Nordisk data on file.
Outlines
• Why intensify treatment?
• Intensifying treatment with insulin
• What are the treatment options?
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, e.g.

INTENSIFY adding to or changing the therapy in order to
maintain glycaemic control
 Insulin treatment strategies


Basal insulin: targets FPG > PPG
 Benefit: once daily injection

 Drawback: Patients may require prandial insulin to reach

HbA1c targets

 Prandial (mealtime) insulin: targets PPG > FPG

 Benefit: Most physiologic; best at targeting PPG

 Drawback: Most injections; requires addition of basal insulin to

target FPG
Lasserson DS, et al. Diabetologia. 2009;52(10):1990-2000.
 Optimising insulin therapy
Choose a progressive treatment for a progressive disease
Premix insulin
Premix

Premix insulin
Premix

Premix insulin Premix

Schematic representation of time action profiles. In clinical practice, the duration of insulin action may be shorter or longer than duration specified. Variations between
and within patients may occur depending upon injection site and technique, insulin dosage, diet and exercise. *Insulin profile in a person without diabetes.
†Optimised long-acting insulin regimen (one or two injections)
 Recommendations: Considerations for Future
Intensification
Factors that will determine whether future intensification should be with basal–bolus or premix insulin
analog therapy

Favours premix Considerations Favours basal-bolus

Patient preference regarding Comfortable with more frequent

Prefers fewer injections
number of injections injections

Patient preference regarding self- Comfortable with more frequent

Prefers less frequent monitoring
monitoring of blood glucose monitoring

Patient ability to inject (e.g.

Poor cognitive ability, manual Good
dexterity, need for carer)

Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0

Intensification with Premixed Insulin
ADA/EASD Position on Sequential Insulin
Strategy in Type 2 Diabetes
Non-Insulin Regimes Number of Regimen
Injections Complexity

Basal Insulin Only

Usually with OAD 1 Low

Basal Insulin + 1 mealtime rapid-

acting injection
Pre-mixed Insulin twice-daily 2 Mod.

Basal Insulin + >2 mealtime rapid- +3 High

acting injection

More Flexible Less Flexible Flexibility

Less Convenient More Convenient Convenience*

Inzucci SE, et al. Diabetologia. 2012. * Gumprecht et al. Intensification to to biphasic insulin aspart
30/70. Int J Clin Pract 2009
Consensus algorithm for BIAsp 30 intensification

BIAsp 30 OD (pre-dinner) or
BIAsp 30 BID
FPG and/or pre-dinner BG: FPG and/or pre-dinner BG:
4–6 mmol/L (73–110 mg/dL) >6 mmol/L (>110 mg/dL)

Titrate BIAsp 30 OD or BID to achieve FPG

HbA1c >7.0% and/or pre-dinner BG <6 mmol/L (<110
mg/dL)

If hypoglycaemia occurs

Switch to BIAsp 30 BID or TID

BG, blood glucose; BIAsp, biphasic insulin aspart; BID, twice daily; FPG, fasting plasma glucose; OD, once daily; TID,
three-times daily
Unnikrishnan et al. Int J Clin Pract 2009;63:1571–7
 21

Intensifying basal insulin patients to Premix is simple

In basal insulin patients: start with the same total daily dose1

Intensify to

unit unit
basal insulin NovoMix 30 Others consideration
Pre- Pre- •
Titrate the dose preferably once a week.
Breakfast Dinner •
Administer NovoMix® 30 just before meals
•
Continue metformin.
Split total daily dose 50% 50% •
Discontinue sulfonylureas (SUs).
•
Consider discontinuing TZDs as per local guideline
Twice daily NovoMix® 30 and practice.
Adapted from Unnikrishan1

*Guideline for the recommended dose adjustment included in the NovoMix® 30 SmPC3. 1. Unnikrishnan et al. Int J of Clin Prac 2009; 63:1571–7; 2. Garber et al. Diabetes Obes Metab
2006;8:58–66; 3. Novo Nordisk. NovoMix® 30 summary of product characteristics
 BIAsp 30: dosage regimen

Timing of blood glucose measurements

Dose to used for dose titration
titrate
BIAsp 30 OD BIAsp 30 BID BIAsp 30 TID

Breakfast – Pre-dinner Pre-lunch

Lunch – – Pre-dinner

Dinner Pre-breakfast Pre-breakfast Pre-breakfast

Garber et al. Diabetes Obes Metab 2006;8:58–66; Raskin et al. Diabetes Care 2005;28:260–5
 22

Adjusting the dose of NovoMix® 30

Recommended dose titration Guidence:

• Dose adjusment can be made once
FBG and predinner SMBG NovoMix® 30 weekly until target is reached
dose adjustment • The lowest of three previous days’
mg/dL Units premeal levels should be used for
dose adjusment
<80 -2 • The dose should not be increased if
80–110 0 hypoglycaemia occurs
111–140 +2 • Only one dose at a time should be
141–180 +4 changed: the evening dose should
>180 +6 be titrated first, followed by the
breakfast dose
Adapted from NovoMix® 30 SmPC1

1. Novo Nordisk. NovoMix® 30 summary of product characteristics. May 2012

Intensification with Basal Bolus
Current bolus insulin available

Insulin Onset (minutes) Peak (hours) Duration (hours)

Insulin aspart 10-15 1-1.5 3-5

Insulin glulisine 10-15 1-1.5 3-5

Insulin lispro 10-15 1-2 3.5-4.75

 Initiation and intensification: ADA/EASD
No. of
Basal insulin
injections (usually with metformin ± other noninsulin agent)
Complexity
Start: 10 U/day or 0.1–0.2 U/kg/day
1 Adjust: 10–15% or 2–4 U once-twice weekly to reach FBG Low
target
For hypo: determine & address cause;  dose by 4 U or 10–
STEP-Wise 20%
If not controlled after FBG target is reached (or if dose
study >0.5 U/kg/day), treat PPG excursions with mealtime insulin

(consider initial GLP-1RA trial)

Add 1 rapid insulin injection* before largest meal Change to premixed insulin* twice daily
Start: 4 U, 0.1 U/kg or 10% basal dose. If HbA1c <8%, Start: divide current basal dose into 2/3 AM, 1/3 PM or 1/2
consider  basal by same amount AM, 1/2 PM
2 Adjust:  dose by 1–2 U or 10–15% once to twice Mod
Adjust:  dose by 1–2 U or 10–15% once to twice weekly
weekly until SMBG target reached until SMBG target reached
For hypo: determine and address cause;  For hypo: determine & address cause;  corresponding
corresponding dose by 2–4 U or 10–20% dose by 2–4 U or FullStep
10–20% study
Add ≥2 rapid insulin* injections before meals (“basal-bolus”)
Start: 4 U, 0.1 U/kg or 10% basal dose/meal. If HbA1c <8%, consider  basal
If not by same amount If not
controlled, Adjust:  dose by 1–2 U/10–15% once to twice weekly until SMBG target controlled,
consider basal– reached consider basal–
bolus For hypo: determine & address cause;  corresponding dose by 2–4 U or 10– bolus
20%
3+ High
Flexibility: More flexible Less flexible

*Regular human insulin and human NPH-regular premixed formulations prandial (70/30) are less costly alternatives to rapid-acting and premixed insulin analogues, but their pharmacodynamic profiles
make them suboptimal for coverage of post glucose excursions. ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; FBG, fasting blood glucose; GLP-1RA,
glucagon-like peptide-1 receptor agonist; HbA1c, glycated haemoglobin; PPG, postprandial glucose; SMBG, self-monitoring of blood glucose

Inzucchi et al. Diabetes Care 2015;38:140–9.

Premixed vs Basal Bolus
D Presentation title
a
t Premixed insulin Therapy
e

•
Premixed insulin is simple and •
Less flexible (fixed dose
convenient for the patient due combination)
to one device can cover both •
Difficult to adjust the dose
fasting and prandial glucose
•
Less injection compare to
basal bolus
D Presentation title
a
t Basal Bolus Therapy
e

•
Physiologic (Ideal insulin •
Less convenient for patient
therapy for patients) due to 4 times injection per
•
More flexible (easy to titrate day
the dose)
Conclusion

 Because of the progessiveness of diabetes, Insulin regimen and dosage needs

to be monitored and intensified


NovoMix® is option for the intensification, provide simple and convenience for
the patients


Basal bolus therapy is an ideal treatment option since provide optimal A1C
control, but has a limitation with 4 times injection daily.
Conclusion

 Because of the progessiveness of diabetes, Insulin regimen and dosage needs

to be monitored and intensified


NovoMix® is option for the intensification, provide simple and convenience for
the patients


Basal bolus therapy is an ideal treatment option since provide optimal A1C
control, but has a limitation with 4 times injection daily.
1980

Diabetes Mellitus Tipe 2

Insulin > Cara pemberian insulin > Pen insulin
Pen insulin kini lebih popular dibandingkan semprit dan jarum karena
penggunaannya lebih mudah dan nyaman serta dapat dibawa kemana-
mana.Namun tidak dapat mencampur 2 jenis insulin kecuali menggunakan insulin
campuran yang sudah tersedia.
1980 2016

Thank you