Early Insulin Therapy in People With Type 2 Diabetes, Why, When and How To Start?

Early
insulin therapy in people with Type 2

Diabetes, Why, When and How to Start?
Sony W Mudjanarko
Department of Internal Medicine dr Soetomo Hospital Surabaya
sonywibisono@yahoo.com
Burden of diabetes is expected to increase dramatically

within Asia Pacific by 2030
Estimated prevalence of diabetes in adults aged 2079 years
2010
Country
Prevalence* No. of cases

(%)
(millions)
Prevalence*
(%)
No. of cases
(millions)
Estimated
increase in
Estimated
increase in no.
prevalence (%) of cases (%)
India
7.8
50.77
9.3
87.04
19.2
71.4
China
4.2
43.16
5.0
62.55
19.0
44.9
Thailand
7.1
3.54
8.4
4.96
18.3
40.11
S. Korea
7.9
3.29
9.0
4.32
13.9
31.3
Australia
5.7
1.09
6.8
1.50
19.3
37.6
Taiwan
7.5
0.82
8.5
1.23
13.3
50.0
Hong Kong
8.5
0.59
10.1
0.92
18.8
55.9
Singapore
10.2
0.44
12.4
0.74
21.6
68.2
Malaysia
11.6
1.85
13.8
3.24
19.0
75.1
Vietnam
3.5
1.65
4.4
3.41
25.7
106.7
Philippines
7.7
3.40
8.9
6.16
15.6
81.2
Indonesia
4.8
6.96
5.9
11.98
22.9
72.2
10.3
26.81
12.0
35.96
16.5
34.1
USA
2030
Sicree R, et al. In: IDF Diabetes Atlas, 4 th edition, 2 009. Available at: http://www.diabetesatlas.org (accessed J an 2010).
Majority of type 2 DM patients in Asia Pacific fail to reach

HbA1c goals
DM, diabetes mellitus; HbA1c, glycated hemoglobin.

1. Bryant W, et al. MJA 2006;185:3059. 2. Kosachunhanun N, et al. J Med Assoc Thai 2006;89:S6671. 3. Lee WRW,
et al. Singapore Med J 2001;42:5017. 4. Nagpal J & Bhartia A. Diabetes Care 2006;29:23418. 5. Soewondo P, et al.
Med J Indoes 2010;19:23544. 6. Tong PCY, et al. Diab Res Clin Pract 2008;82:34652. 7. Pan C, et al. Curr Med Res
Opin 2009;25:3945. 8. Choi YJ, et al. Diabetes Care 2009;32:201620. 9. Mafauzy M, et al. Med J Malaysia
2011;66:17581.
Type 2 diabetes is NOT a mild disease

Stroke
2 to 4 fold increase
in
cardiovascular
mortality and stroke3
Diabetic
Retinopathy
Leading cause
of blindness
in working age
adults1
Cardiovascular
Disease
8/10 diabetic patients

die from CV events4
Diabetic
Nephropathy
Diabetic
Neuropathy
Leading cause of
end-stage renal disease2
Leading cause of
non-traumatic lower
extremity
amputations5
1 Fong DS, e t al. Diabetes Care 2003; 26 ( Suppl. 1):S99S102. 2Molitch ME, e t al. Diabetes Care 2003; 26 ( Suppl. 1):S94S98.
3
Kannel WB, et al. Am Heart J 1990; 120:672676. 4Gray R P & Yudkin JS. In Textbook of Diabetes 1997.
sonywibisono@yahoo.com 5
Mayfield JA, et al. Diabetes Care 2003; 26 ( Suppl. 1):S78S79.
EPIC-Norfolk: CV risk increases with A1C level

N = 10,232
40
40
Women
30
30
Events/
20
100
persons
20
10
10
0
<5
55.4 5.55.9 66.4 6.56.9
CVD events
All deaths
Men
<5
55.4 5.55.9 66.4 6.56.9
A1C (%)
1% A1C associated with: 20% CVD events, 22% mortality

PTrend < 0.001 across A1C categories for
all e ndpoints
Khaw K-T et al. A nn Intern Med. 2 004;141:413-2 0.

UKPDS 33: Glycemic control declines over time

N = 3867 with newly diagnosed T2DM
9
A1C,
median
(%)
8
ADA target
7
6.2% (upper limit of normal)
6
0
Diet (conventional treatment)
6
9
12
Years from randomization
15
Sulfonylurea or insulin (intensive treatment)

UKPDS Group. Lancet. 1998;352:837-53.
Need for insulin increases over time

UKPDS 57: N = 826 with newly diagnosed T2DM
60
Patients
40
requiring
additional
insulin
20
(%)
0
3
4
Years from randomization
Chlorpropamide
Glipizide
~53% of patients required additional insulin therapy by year 6

Wright A et al. Diabetes Care. 2 002;25:330-6 .
UKPDS 33: Effect of intensive glucose control on T2DM

complications
15
5
Relative risk
reduction
(%)
P = 0.029
P = 0.34
P = 0.44
P = 0.052
P = 0.0099
P = 0.52
-5
-15
-25
Any
T2DM-related
endpoint
T2DM-
related
death
All
deaths
MI
Stroke
Micro-vascular
endpoints
A1C 7% vs 7.9% with intensive vs conventional treatment

All P values vs conventional treatment
UKPDS Group. Lancet. 1998;352:837-53.

UKPDS 34: Glucose control and CV outcomes

n = 1704 overweight with T2DM; n = 342 metformin group
Aggregate endpoint
Favors metformin Favors

or intensive usual care
P*
All-cause mortality
0.02
Metformin
Intensive
MI
0.12
Metformin
Intensive
Stroke
Metformin
Intensive
0.03
0
*Metformin vs other intensive (sulfonylurea or

insulin)
1
Relative risk
(95% CI)
2
UKPDS Group. Lancet. 1 998;352:854-65.
DCCT/EDIC: Intensive glucose control associated with reduced

long-term CV risk
N = 1441 with type 1 diabetes, mean baseline age 27
0.12
0.12
52 e vents
42% Risk
(9%63%)
P = 0.02
0.10
0.10
Any initial
CV e vent* 0.06
0.08
CV death,
nonfatal MI, 0.06
stroke*
0.04
0.04
0.08
31 e vents
0.02
0.02
0
0
10
57% Risk
(12%79%)
P = 0.02
15
20
25 e vents
11 e vents
10
15
20
Time (years)
DCCT
ends
Conventional
A1C 7.4% vs 9.1%
Intensive
DCCT
ends
DCCT/EDIC Study Research Group.
N Engl J Med. 2 005;353:2643-53.
*Cumulative incidence
Glycemic control and vascular disease in T2DM

N = 4472; 6 randomized trials
Favors intense
glycemic control
Favors conventional
glycemic control
Any macrovascular*
T2DM
0.81 (0.730.91)
Cardiac
T2DM
0.91 (0.801.03)
Peripheral vascular
T2DM
0.58 (0.380.89)
Cerebrovascular
T2DM
0.58 (0.460.74)
0
0.5
1
Incidence rate ratio
(95% CI)
*1587 e vents; 1197 e vents; 87 e vents; 303 e vents

Stettler C et al. A m Heart J. 2 006;152:27-38.
Over time, glycemic control deteriorates in patients

with Type 2 diabetes
UKPDS
9
Median HbA 1c (%)
8.5
ADOPT
Conventional*
Glibenclamide
Metformin
Insulin
Rosiglitazone
Metformin
Glibenclamide
7.5
8
7.5
Recommended
treatment
target <7.0%
6.5
6
6.5
6.2% upper limit of normal r ange

0
2
4
6
8
Years from randomisation
10
*Diet initially then sulphonylureas, insulin and/or

metformin if FBG>15 mmol/L; ADA clinical practice
recommendations. UKPDS 34, n=1704
UKPDS 34. Lancet 1998:352:85465; Kahn et al (ADOPT). NEJM 2006;355(23):242743
2
3
Time (years)
Meta-Analysis: Probability of events of CHD with

intensive glucose-lowering vs standard treatment
Intensive treatment/
standard treatment
Weight of
study s ize
Participants
Events
UKPDS
3071/1549
426/259
8.6%
PROactive*
2605/2633
164/202
20.2%
ADVANCE
5571/5569
310/337
36.5%
892/899
77/90
9.0%
5128/5123
205/248
25.7%
17267/15773
1182/1136
100%
VADT
ACCORD
Overall
Odds ratio
(95% CI)
Odds ratio
(95% CI)
0.75 ( 0.541.04)
0.81 ( 0.651.00)
0.92 ( 0.781.07)
0.85 ( 0.621.17)
0.82 ( 0.680.99)
0.85 ( 0.770.93)
0.6
0.8 1.0 1.2 1.4 1.6
Intensive treatment
Standard treatment
better
better
* Included non-fatal myocardial infarction and death from all-cardiac mortality
Ray KK et a l. L ancet 2009;373:176572
Anti hyperglycemia agent
Insulin
ORIGIN
Outcome Reduction with an Initial Glargine Intervention (ORIGIN) Trial
Overview
Large international randomized controlled trial in patients with new or

recently diagnosed diabetes, impaired fasting glucose (IFG) or impaired
glucose tolerance (IGT) and additional CV risk factors
With follow-up of ~6 years, ORIGIN was the longest investigation of the

effect of insulin treatment on CV outcomes and cancer incidence in this
population
ORIGIN
Objectives
Assess the relationship between long-term
n-3 fatty acid supplementation and the rate
of CV events
Assess effects of insulin glargine on CV
outcomes
ORIGIN
Trial Design
Patients and Methods
12,537 patients from 573 sites treated with insulin glargine (open) vs standard
care and n-3 fatty acids (1g per day) versus placebo (double-blind)
Median follow-up, 6.2 years
Baseline characteristics
- Mean age, 63.5 years
- Females, 35%
- Median FPG, 125 mg/dL
- Median HbA1c, 6.4%
ORIGIN
Primary outcomes
CV death or MI or stroke
CV death or MI or stroke or revascularization or CHF
hospitalization
Secondary outcomes
Microvascular composite
New T2DM
All cause death
ORIGIN
Implications for Insulin Therapy

Compared with standard therapy in patients with T2DM, IGT,
or IFG, using once-daily basal insulin glargine to target FPG
95 mg/dL for a median 6.2 years:
- Maintains near normal glycemic control
- Has neutral effect on CV outcomes and cancers
- Slows progression of dysglycemia
- Modestly increases hypoglycemia
- Modestly increases weight
New position statement of the ADA and EASD on

management of hyperglycemia in type 2 diabetes
Inzucci SE, et al. Diabetologia. 2012
Algoritme Pengelolaan DM Tipe 2 di Indonesia KONSENSUS PERKENI 2015

Modifikasi pola hidup sehat
HbA1c 9 .0%
HbA1c 7 .5%
HbA1c < 7 .5%
Gejala (-)
Monoterapi* dengan
salah satu obat di bawah
ini
Kombinasi 2 obat* dengan

mekanisme kerja yang
berbeda
Kombinasi 2 obat
Kombinasi 3 obat
Glukosidase Alfa
Penghambat SGLT-2**
Tiazolidindion
Sulfonilurea
Glinid
Agonis GLP-1
Penghambat DPP-IV
Tiazolidindion
Penghambat SGLT-2
Insulin Basal
SU/Glinid
Jika HbAc1 > 6.4%

dalam 3 bulan tambahan
obat ke 2 (kombinasi 2 obat)
Kolsevelam**
Bromokriptin-QR
Metformin atau obat lini pertama y ang lain +
Penghambat
Obat
lini
kedua
+
Penghambat DPP-IV
Metformin atau obat lini pertama yang lain +
Metformin
Agonis GLP-1
Gejala (+)
Insulin obat jenis lain
Agonis GLP-1
Penghambat DPP-IV
Kombinasi 3 obat
Tiazolidindion
Penghambat SGLT-2
Insulin Basal
Mulai atau intensifikasi Insulin
Kolsevelam**
Bromokriptin-QR
Penghambat
Glukosidase Alfa
Keterangan
*Obat yang terdaftar, pemilihan dan
penggunaannya disarankan m empertimbangkan
Jika belum memenuhi sasaran
faktor keuntungan, kerugian biaya, dan
dalam 3 bulan, mulai terapi insulin
ketersediaan sesuai tabel 11
Penghambat Glukosidase Alfa

atau intensifikasi terapi insulin
** Kolsevelam belum tersedia di Indonesia

Bromokriptin QR umumnya digunakan pada terapi
Jika belum memenuhi sasaran dalam 3 bulan, masuk ke kombinasi 3 obat
Konsensus Pengelolaan d an Pencegahan Diabetes Melitus Tipe 2 di Indonesia. 2 015.
tumor hipofisis
Matching treatment to disease progression using a

stepwise approach
Basal Bolus: once-daily basal insulin glargine plus 3 injections of rapid-
acting insulin glulisine ( each injection before a meal) The Gold
Standard for advancedtype 2 diabetes
Basal Plus: once-daily basal insulin glargine
plus once-daily* rapid-acting insulin glulisine
Basal Bolus
Add prandial insulin before e ach meal
Glargiine - Glulisine
Basal Plus
If FBG has been reduced to target levels but

HbA1c values remain high
Add prandial insulin at main meal

Glargine plus Glulisine
Basal
Add basal insulin and titrate (Glargine)
Lifestyle changes plus metformin ( other agents)

Progressive deterioration of -cell function
If HbA1c is no longer controlled by Basal Plus
Adapted from Raccah D, et al. Diabetes Metab Res Rev 2 007;23:25764
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Early

insulin therapy in people with Type 2

Burden of diabetes is expected to increase dramatically

Prevalence* No. of cases

prevalence (%) of cases (%)

Majority of type 2 DM patients in Asia Pacific fail to reach

DM, diabetes mellitus; HbA1c, glycated hemoglobin.

Type 2 diabetes is NOT a mild disease

8/10 diabetic patients

EPIC-Norfolk: CV risk increases with A1C level

55.4 5.55.9 66.4 6.56.9

55.4 5.55.9 66.4 6.56.9

1% A1C associated with: 20% CVD events, 22% mortality

Khaw K-T et al. A nn Intern Med. 2 004;141:413-2 0.

UKPDS 33: Glycemic control declines over time

Diet (conventional treatment)

Sulfonylurea or insulin (intensive treatment)

Need for insulin increases over time

~53% of patients required additional insulin therapy by year 6

UKPDS 33: Effect of intensive glucose control on T2DM

A1C 7% vs 7.9% with intensive vs conventional treatment

UKPDS Group. Lancet. 1998;352:837-53.

UKPDS 34: Glucose control and CV outcomes

Favors metformin Favors

*Metformin vs other intensive (sulfonylurea or

DCCT/EDIC: Intensive glucose control associated with reduced

A1C 7.4% vs 9.1%

Glycemic control and vascular disease in T2DM

*1587 e vents; 1197 e vents; 87 e vents; 303 e vents

Stettler C et al. A m Heart J. 2 006;152:27-38.

Over time, glycemic control deteriorates in patients

Median HbA 1c (%)

6.2% upper limit of normal r ange

*Diet initially then sulphonylureas, insulin and/or

UKPDS 34. Lancet 1998:352:85465; Kahn et al (ADOPT). NEJM 2006;355(23):242743

Meta-Analysis: Probability of events of CHD with

Anti hyperglycemia agent

Large international randomized controlled trial in patients with new or

With follow-up of ~6 years, ORIGIN was the longest investigation of the

Median follow-up, 6.2 years

Implications for Insulin Therapy

New position statement of the ADA and EASD on

Inzucci SE, et al. Diabetologia. 2012

Algoritme Pengelolaan DM Tipe 2 di Indonesia KONSENSUS PERKENI 2015

HbA1c < 7 .5%

Kombinasi 2 obat* dengan

Jika HbAc1 > 6.4%

Metformin atau obat lini pertama y ang lain +

Metformin atau obat lini pertama yang lain +

Insulin obat jenis lain

Mulai atau intensifikasi Insulin

penggunaannya disarankan m empertimbangkan

Jika belum memenuhi sasaran

faktor keuntungan, kerugian biaya, dan

dalam 3 bulan, mulai terapi insulin

ketersediaan sesuai tabel 11

Penghambat Glukosidase Alfa

** Kolsevelam belum tersedia di Indonesia

Jika belum memenuhi sasaran dalam 3 bulan, masuk ke kombinasi 3 obat

Konsensus Pengelolaan d an Pencegahan Diabetes Melitus Tipe 2 di Indonesia. 2 015.

Matching treatment to disease progression using a

If FBG has been reduced to target levels but

Add prandial insulin at main meal