ESW/MAR-17/RTD LVM-2017/001

Early Insulin Initiation in

type 2 DM Management
Speaker Name
ESW/MAR-17/RTD LVM-2017/001

Outlines

• Prevalence
• Rationale for early initiation
• T2DM management and guideline
• Insulin Levemir® & A1Chieve study
Sources :
1. IDF Diabetes Atlas, 8th ed
Number of people with diabetes worldwide and per region in
2017 and 2045 (20-79 years)

Diabetes:
A Global Emergency

Sources :
1. IDF Diabetes Atlas, 8th ed
Prevalence of Obesity and Diabetes in Indonesia:
Health Basic Research, 2013

IFG IGT UD-D D-D Total

M M DM Prevalence (%) of IFG, IGT and diabetes
(>15 years), Indonesia, 2007 and 2013
2007 - 10.2 4.2 1.5 5.7
2013 36.6 29.9 4.5 2.4 6.9

Health Basic Research, 2007 and 2013

 T2DM: Progressive loss of insulin
secretion with increasing insulin resistance1
Impaired Undiagnosed Known
glucose tolerance diabetes diabetes

Insulin resistance

Insulin secretion
PPG
FPG

Microvascular complications
Macrovascular complications

1. Adapted from: Ramlo-Halsted BA, Edelman SV. Clincial Diabetes 2000;18(2): http://journal.diabetes.org/clinicaldiabetes/v18n22000/pg80.htm
Hyperglycemia affects both micro-vascular and macro-vascular
complications

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

Diabetes Care Indonesia 2008
Diabetes related complications

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)
Risk of complications increases as HbA1c increases

1000 patient-years

Microvascular disease
Incidence per

Myocardial infarction

Updated mean HbA1c (%)

Stratton et al. BMJ 2000;321:405–12

ESW/MAR-17/RTD LVM-2017/001

Outlines

• Prevalence
• Rationale for early initiation
• T2DM management and guideline
• Insulin Levemir® & A1Chieve study
Poor glycemic control (HbA1c) is a global problem

•
Patients remain on multiple OAD therapy too long
8.9%

Clinical inertia exists

41% had HbA1c ≥9.0% despite:
Patients (%)

• The benefits of timely

glycemic control
• Guidelines encouraging
earlier use of insulin
22% had HbA1c ≥10.0%
At insulin initiation
in SOLVE:
• Average HbA1c was 8.9%

HbA1c (%) at insulin initiation

Reduction in HbA1c with OADs
−1.3%*

+0.2%
0.5%*
−1.0%*

Pre-treatment
Mean HbA1c (%)

Post-treatment

2 OADs 3 OADs 4 OADs Insulin

*p<0.001
OADs, oral antidiabetic drugs
Calvert et al. Br J Gen Pract 2007;57:455–60
 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.

Early insulin treatment prolongs beta-cell function and
promotes metabolic control

Alvarsson et al. Diabetes Care 2003;26:2231–7

Early insulin therapy improves beta-cell function and
glycemic control

CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injection; OHA, oral hypoglycaemic agent
Weng et al. Lancet 2008;371:1753–60
ESW/MAR-17/RTD LVM-2017/001

Outlines

• Prevalence
• Rationale for early initiation
• T2DM management and guideline
• Insulin Levemir® & A1Chieve study
American Diabetes Association. Diabetes Care Volume 41, Supplement 1, January 2018
Anti-hyperglycemic therapy in adults with type 2 diabetes

A1C is less than 9%, consider monotherapy.

A1C is greater than or equal 9%, consider dual therapy.

A1C is greater than or equal 10%, blood glucose is greater than or equal 300 mg/dL, or
patient markedly symptomatic, consider combination injectable therapy.

Monotherapy Lifestyle Management + Metformin

Initiate metformin therapy if no contraindications* (See table 8.1)

A1C at target Yes: - Monitor A1C every 3-6 months

After 3 months No: - Assess medication-taking behaviour
Of monotherapy - Consider dual therapy

Dual Therapy
American Diabetes Association. Diabetes Care Volume 41, Supplement 1, January 2018
Anti-hyperglycemic therapy in adults with type 2 diabetes
A1C is less than 9%, consider monotherapy.

A1C is greater than or equal 9%, consider dual therapy.

Monotherapy

Dual Therapy Lifestyle Management + Metformin + Additional Agent

ASCVD? Yes: - Add agent proven to reduce major adverse

cardiovascular events and/or cardiovascular mortality
(see recommendations with* on Table 8.1 p.S75)
No: - Add second agent after consideration of drug-spesific
effects & patients factors (see Table 8.1)

A1C at target Yes: - Monitor A1C every 3-6 months

After 3 months No: - Assess medication-taking behaviour
Of dual therapy - Consider triple therapy

Triple Therapy
American Diabetes Association. Diabetes Care Volume 41, Supplement 1, January 2018
Anti-hyperglycemic therapy in adults with type 2 diabetes
A1C is less than 9%, consider monotherapy.

A1C is greater than or equal 9%, consider dual therapy.

A1C is greater than or equal 10%, blood glucose is greater than or equal 300 mg/dL
or patient markedly symptomatic, consider combination injectable therapy.

Monotherapy
Dual Therapy
Triple Therapy Lifestyle Management + Metformin + 2 additional agent

Add third agent based on drug-spesific effects and patients factors#

(see Table 8.1)

A1C at target Yes: - Monitor A1C every 3-6 months

After 3 months No: - Assess medication-taking behaviour
Of triple therapy - Consider combination injectable therapy
(see figure 8.2)

Combination Injectable Therapy (see Figure 8.2)

American Diabetes Association. Diabetes Care Volume 41, Supplement 1, January 2018
 Combination Injectable therapy for type 2 Diabetes

Initiate Basal Insulin

Usually with metformin +/- other non insulin agent

Start: 10U/day or 0.1-0.2 U/kg/day

Adjust: 10-15% or 2-4 units once or twice weekly to
Reach FBG target
For hypo: Determine & address cause; if no clear
Reason for hypo, ꜜ dose by 4 units or 10-20%

If A1C not controlled, consider combination

injectable therapy

Add 1 rapid-acting insulin Add GLP-1 RA Change to premix insulin twice

injection before largest meals daily (before breakfast & supper
Start: 4 units, or 0.1kg, or 10% basal dose. If A1C If not tolerated or A1C Start: Divide current basal dose into 2/3 AM, 1/3 PM
<8%, consider lower basal by same amount Target not reached or ½ AM, ½ PM
Adjust: increase dose by 1-2 units or 10-15% once or change to 2 injection Adjust: increase dose by 1-2 units or 10-15% once
twice weekly until SMBG target reached insulin regimen or twice weekly until SMBG target reached
For hypo: Determine & address cause; if no clear For hypo: Determine & address cause; if no clear
Reason for hypo, reduce dose by 2-4 units or 10-20% If goals not met, consider Reason for hypo, reduce dose by 2-4 units or 10-20%
changing to injectable
If A1C not controlled, Advance to basal-bolus therapy If A1C not controlled, Advance to 3rd Injection

American Diabetes Association. Diabetes Care Volume 41, Supplement 1, January 2018
Fasting plasma glucose is having high contribution in HbA1c > 8,5%

Relative contribution to
overall hyperglycaemia
10
0
8 30%
45% 35%
0 50%
6 70%
(%)

0
4 70%
65%
0 55%
2 50%
30%
0
0
<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2
HbA1c quintiles

FPG PPG

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

 Combination Injectable therapy for type 2 Diabetes
Add 1 rapid-acting insulin Add GLP-1 RA Change to premix insulin twice
injection before largest meals daily (before breakfast & supper
Start: 4 units, or 0.1kg, or 10% basal dose. If A1C If not tolerated or A1C Start: Divide current basal dose into 2/3 AM, 1/3 PM
<8%, consider lower basal by same amount Target not reached or ½ AM, ½ PM
Adjust: increase dose by 1-2 units or 10-15% once or change to 2 injection Adjust: increase dose by 1-2 units or 10-15% once
twice weekly until SMBG target reached insulin regimen or twice weekly until SMBG target reached
For hypo: Determine & address cause; if no clear For hypo: Determine & address cause; if no clear
Reason for hypo, reduce dose by 2-4 units or 10-20% If goals not met, consider Reason for hypo, reduce dose by 2-4 units or 10-20%
changing to injectable
If A1C not controlled, Advance to basal-bolus therapy If A1C not controlled, Advance to 3rd Injection

Add >2 rapid-acting insulin injection Change to premix insulin 3 times

before meals (basal-bolus) daily (breakfast, lunch & supper)

Start: 4 units, or 0.1kg, or 10% basal dose. If A1C
<8%, consider lower basal by same amount
Adjust: increase dose by 1-2 units or 10-15% once or
twice weekly until SMBG target reached
For hypo: Determine & address cause; if no clear
Reason for hypo, reduce dose by 2-4 units or 10-20%
If goals not met, consider
changing to injectable
therapy
Start: Add additional injection before lunch
Adjust: increase dose by 1-2 units or 10-15% once
or twice weekly until SMBG target reached
For hypo: Determine & address cause; if no clear
Reason for hypo, reduce dose by 2-4 units or 10-20%

American Diabetes Association. Diabetes Care Volume 41, Supplement 1, January 2018
ESW/MAR-17/RTD LVM-2017/001

Outlines

• Prevalence
• Rationale for early initiation
• T2DM management and guideline
• Insulin Levemir® & A1Chieve study
Efficacy of Basal Insulin Focus on Detemir
 29

Detemir demonstrate well tolerability profile consistently

Levemir®
2012–2014 tolerability profile
2010–2011 demonstrated over
2007–2009 •SOLVE™
A1chieve™ >17.000 patients7 10 years
TITRATE™ >66,000
2004–2006 of clinical
>224 patients3 patients5 •DIET™8
experience and
Klein et al1 6 evidence 1–8
PREDICTIVE™ TRANSITION™
Philis- >5.604 patients4
Tsimikas et al2
ESW/MAR-17/RTD LVM-2017/001

Insulin Detemir demonstrate less intra-individual

day-to-day variability
NPH NPH NPH

Glargine Glargine Glargine

Detemir Detemir Detemir

30
Adapted from Heise T et al. Diabetes. 2004;53:1614-20.
Home et al. Diabetes Res Clin Pract 2011;94:352–63
A1chieve overview
Insulin Detemir use in Indonesia

2240 patients and 65

investigators were involved in
this study,

Soewondo et al. DRCP 2013. 100;(Suppl 1):S10-S16

ESW/MAR-17/RTD LVM-2017/001

A1chieve study overview and design

• Observational study of people with T2DM in routine clinical practice

Start a study BASELINE INTERIM FINAL

insulin Week 0 Week 12 Week 24
• Biphasic insulin
aspart 30
• Insulin detemir • Study objectives
• Insulin aspart
• Primary: number of attributed adverse drug
reactions (includes major hypoglycaemia)
• Secondary: other safety and effectiveness
measures
Detemir ± OAD:

Indonesia efficacy results 2.2% Insulin naïve

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

Baseline values 9.5 219 263

24 week 7.3 118 147

*p<0.001
Soewondo et al. DRCP 2013. 100;(Suppl 1):S10-S16
Detemir ± OAD:
Indonesia hypoglycaemia results
Baseline
24 weeks
Overall Major Nocturnal

Insulin naïve Insulin naïve Insulin naïve

No. of pt w/hypo 19 0 1 0 18 0
Percent with at least one
event

Baseline 24 weeks Baseline 24 weeks Baseline 24 weeks

Soewondo et al. DRCP 2013. 100;(Suppl 1):S10-S16

Summary
Insulin naïve participants initiated on Detemir (Indonesia)

Efficacy Safety Other

Baseline
HbA1c Δ HbA1c Δ FPG Δ PPG Hypoglycaemia Weight neutral

IDet 9.5% ↓2.2% ↓101

mg/dL
↓115
mg/dL
0.9*

Significant improvement
(p<0.001)

*p<0.001
Soewondo et al. DRCP 2013. 100;(Suppl 1):S10-S16
Initiation & titration of basal Insulin
Goal: 3.9–5.0 Goal: 4.4–6.1
mmol/L mmol/L
(70–90 mg/dL)1 (80–110 mg/dL)1

If FPG If FPG
is +3 is
unit
>5.0 mmol/L (>90 mg/dL) >6.1 mmol/L (>110
s
mg/dL)
3.9–5.0 0 4.4–6.1
maintain current
mmol/L dose
mmol/L
(70–90 (80–110
mg/dL) –3 mg/dL)
<3.9 mmol/L (<70 mg/dL) unit <4.4 mmol/L (<80
s mg/dL)

FPG, fasting plasma glucose

1. Blonde et al. Diabetes Obes Metab 2009;11:623–31
ESW/MAR-17/RTD LVM-2017/001

Summary
• Indonesia is one of the largest diabetes population

• Diabetes is a progressive disease which will lead to the need of insulin

therapy

• Insulin therapy is the most efficacious therapy and can reduce HbA1c up to
2,5%

• FIX THE FASTING FIRST with BASAL INSULIN

• Starting with basal insulin detemir 10 U once daily and titrate based on
patient condition to reach glycemic control

• In Indonesia, in real life clinical practice (A1chieve study), Levemir ® show

significant improvements in overall glycemic control in terms of HbA1c, FPG,
PPG and patient quality of life