Initiation of Basal Insulin in

Type 2 Diabetes

T2DM is a progressive
condition
Glucose
(mg/dl)

350
300
250
200
150
100
50

Relative
-cell
function
(%)

250
200
150
100
50
0

DIAGNOSIS

Post-meal
glucose

Insulin resistance
Insulin
level

-cell failure
Obesity

Clinical
features
Years

Fasting
glucose

IGT

T2DM

Uncontrolled
hyperglycaemia

Risk for diabetes complications

10

10

15

20

25

30

IGT = impaired glucose tolerance

Adapted from Bergenstal RM. In: Int. Textbook of Diabetes Mellitus, third edition: John Wiley &
Sons; 2004: p9951015.

The Ominous Octet

Decreased
Incretin Effect

Islet -cell

Increased
Lipolysis

Impaired
Insulin Secretion

Islet -cell

Increased Glucose
Reabsorption

Increased
Glucagon
Secretion

Increased
HGP

DeFronzo RA. Diabetes 2009; 58: 773-795

Neurotransmitter
Dysfunction

Decreased Glucose
Uptake

Chronic Complications in Newly Diagnose

Diabetes
Mellitus
50% of patients had 1 complications
Stroke or TIA: 1%
NEWLY
DIABET
ES

Plasma creatinine
>120mol/l: 3%
Intermittent
Claudicasio: 3%
Foot skin ischemia : 6%

Retinopathy: 21%
Hypertension: 35%

Abnormal ECG : 18%

Erectal Dysfuntion : 20%

Pedal pulse (-) : 13%

abetes Res. 1990 Jan;13(1):1-11. J Hypertens 1993 Jun;11(6):681.

a Iranica, 44(6): 415-419; 2006 International Journal of Diabetes Mellitus, 2010 April; 2(1):61-3

Tertiary
prevention

Secondary
prevention

Primary
prevention

Early
diagnosis isis
Early
intervention
important!!
important

MANAGEMENT of TYPE
2 DM:
Early Intervention

Treatment target

HOW LOW SHOULD WE

GO ?

TREATMENT TARGET
The Indonesian Society of Endocrinology
(PERKENI)Consensus 2011

THE STUDIES OF TIGHT GLYCEMIC

CONTROL
Diabetes Control and Complication Trial (DCCT)
United States
Type 1 Diabetes

United Kingdom Prospective Diabetes Study (UKPDS

United Kingdom
Type 2 Diabetes
Kumamoto Study
Japan

Type 2 Diabetes

Multifactorial Intervention and Cardiovascular

Disease In Patients With Type 2 Diabetes (The Steno
2 Study)
Denmark
Type 2 diabetes

Intensive therapy in Diabetes

Mellitus lower the rate of
complications
DCCT

Kumamoto

UKPDS

A1c

9% 7,2%

9% 7%

8% 7%

Retinopath
y
Nephropat
hy

63 %

69 %

54 %

70 %

17% 21%
24% 33%

Neuropath
y
CVD

60 %

improve

41 %

16%

The benefits of early tight control:

UKPDS 10-year post-trial follow-up

1
2

Holman et al. N Engl J Med 2008;359:157789;

UKPDS Study Group. Lancet 1998;352:83753

Impact of Intensive Therapy

for Diabetes: Summary of
Major Clinical Trials
Study
UKPDS
DCCT /
EDIC* T1DM
ACCORD
ADVANCE
VADT

Microv
asc

CVD

Mortalit
y

longterm FU
shortKendallDM,BergenstalRM.InternationalDiabetesCenter2009UKProspectiveDiabetesStudy(UKPDS)Group.Lancet1998;352:854.
term FU

Blood pressure

Lipid

Blood glucose

A1C
<7%

FPG
80 <100
mg/dL

Body weight
Others

Konsensus Perkeni 2011

PPG
80 < 140
mg/dL

Guidelines for Glycemic, BP, &

Lipid
Control
Parameter
CV Risks (-)
CV Risks (+)
IMT (kg/m2)

18,5 - <23

18,5 - <23

< 130

< 130

< 80

< 80

Fasting Blood Glucose (mg/dL)

< 100

< 100

Post Prandial Blood Glucose

(mg/dL)

< 140

< 140

<7

<7

LDL (mg/dL)

< 100

< 70

HDL (mg/dL)

Male > 40
Female > 50

Male > 40
Female > 50

< 150

< 150

BP Sistolik (mmHg)
BP Diastolik (mmHg)

HbA1c (%)

Trigliseride (mg/dL)

CV = Cardiovascular, BP= Blood Pressure

Konsensus Perkeni 2011

MANAGEMENT of TYPE
2 DM :
Early Intervention

Reaching the target

WHEN and HOW SHOULD WE

DO ?

A traditional stepwise approach leads to

unacceptable delays in changing therapy
Even with treatment, 61% and 63% of patients in
Europe and the USA, respectively, did not achieve
recommended
OAD +
HbA1c targets1,2

HbA1c (%)

Diet and OAD

OAD
OAD +
OAD
multiple daily
exercise monotherapy uptitrationcombinationbasal insulininsulin injections

1
0
9
8
HbA1c =
7.0%1c = 6.5%
HbA

7
6
Duration of diabetes
Adapted from Campbell3

1. Liebl A, et al. Diabetologia 2002;45:S238

2. Saydah SH, et al. JAMA 2004;291:3354
3. Campbell IW. Br J Cardiol 2000;7:6253

Delayed treatment can

increase
risk
A meta-regression of data from ACCORD, ADVANCE,
PROactive, UKPDS and VADT shows that a longer duration of
diabetes at enrolment was associated with a negative effect
of intensified glucose control on cardiovascular mortality
0.40

MH odds ratio
(log transformed)

0.32
0.24
0.16
0.08
0.00
0.08
0.16
0.24
0.32
0.40
0

10

Duration of diabetes (years)

Mannucci et al. Nutr Metab Cardiovasc Dis 2009;373:176572

ACCORD, Action to Control Cardiovascular Risk in Diabetes Trial;

ADVANCE, Action in Diabetes and Vascular Disease; PROactive,
PROspective pioglitAzone Clinical Trial in macroVascular Events;
VADT, Veterans Affairs Diabetes Trial; MH, MantelHaenszel

Natural History of Type 2 Diabetes

Years from
diagnosis

-10

-5
Onset

10

15

Diagnosis

Insulin resistance

nsulin secretion
Impaired Fasting
Glucose

Post-Meal glucose

Fasting
glucose

Microvascular complications

Cardiovascular Complications
Pre-diabetes

Type 2 diabetes

-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789

n DM. N Engl J Med. 2002;347:1342-1349

Just a reminder.

INSULIN
- Basal
- BolusPrandialMealtime

Physiologic Insulin
Secretion:
24-hour Profile
50
Insulin
(U/mL) 25

Prandial insulin

Basal Insulin

0
Breakfast

150

Lunch

Dinner

Post Prandial Glucose

Glucose
(mg/dL) 100
50
07

Basal Glucose
8 9 101112 1 2 3 4 5 6 7 8 9
AM
PM

Time of day

FIX FASTING FIRST:

Rationale for Basal
Insulinization

Contribution of fasting hyperglycaemia to overall

glycaemia increases with worsening diabetes

290 patients with T2DM treated with diet or OHAs

Baseline (normal) PG defined as 6.1 mmol/l (110 mg/dl) threshold defined
by ADA as the upper limit of normal PG at fasting or preprandial times

Relative contribution (%)

100

70%

50

Fasting
30%
0

<7.3

7.38.4 8.59.2 9.310.2

HbA1c (%) quintiles

ADA=American Diabetes Association; OHA=oral hypoglycaemic agent; PG=plasma glucose.

Adapted from Monnier L, et al. Diabetes Care 2003;26:8815.

>10.2

Treating fasting hyperglycaemia lowers

the entire
24-hour plasma glucose profile
400

T2DM

300

15
200

Hyperglycaemia due to an increase in fasting glucose

10

100

Normal
0
6

Meal

Meal

10

14

Meal

18

Plasma glucose (mmol/l)

Plasma glucose (mg/dl)

20

0
22

Time of day (hours)

Comparison of 24-hour glucose levels in control subjects vs patients with diabetes
(p<0.001).
Adapted from Polonsky K, et al. N Engl J Med 1988;318:12319.

A stepwise approach for the treatment of

patients with type 2 diabetes
A1C
<7.0%
Preprandial capillary PG
70130 mg/dl
Peak postprandial capillary PG
<180 mg/dl
ADA-2011

Basal Insulin
Once daily
(optimized)

OHA
mono or
combination
therapy
Diet and
exercise
HbA1c
uncontrolled

Basal Bolus
Basal Plus
Basal Plus
One prandial
for largest
glucose
excursion

Two prandial
for largest
glucose
excursion

Basal +
three prandial

HbA1c uncontrolled, FBG on target

PPBG>8.8 mmol/l (>160 mg/dl)
Time
Raccah D. Diabetes Ob Met 2008; 10: 76-82

Insulin
serum
U/ml Prandial secretion
Breakfa
st
Lunch
40

Dinne
r

Snack

Basal
24
hour

Insulin secretion

Basal Insulin

will cover fasting blood glucose

& between
meals

Human Insulin
Humulin N, Insulatard HM
Analog Insulin:
Insulin Glargine (Lantus), Insulin
Detemir (Levemir)

Bolus / Prandial / Mealtime Insulin

will cover prandial glucose

Insulin Human
Humulin R, Actrapid
Insulin Analog
Humalog, Novorapid, Apidra

Long Acting Insulin Analog

Insulin Glargine
(Lantus)

Peakless
Clear solution
Basal Insulin
Could be given 1 2
times a day
Not for intravenous
use

MANAGEMENT of TYPE
2 DM :
Early Intervention

Reaching the target

WHEN and HOW SHOULD WE

DO ?

KADAR HbA1c
<7%

7-8%

GHS

GHS

8-9%

>9%

9-10%

>10%

GHS
Konsensus
+
GHS
AGI,
Kombina
Pengelolaan
dan
Glinid,
si
+
TZD,
2 obat
GHS
Kombina
Met,
SU,
Pencegahan
DPP-IV
si
+
AGI,
3 obat
Kombina
Met,
SU,
DiabetesGlinid,
Melitus
tipe
2
TZD,
si
AGI,
DPP-IV
2 obat
Glinid,
Met,
SU,
di Indonesia
TZD,
AGI,
DPP-IV
Glinid,
2011
TZD
+
GHS

Gaya Hidup
Sehat

Monoter
apiSU,
Met,

Penurunan
berat
badan
Mengatur
diit
Latihan
Jasmani
teratur
Catatan
1.Dinyatakan gagal bila
dengan terapi 2-3 bulan
tidak mencapai target
HbA1c <7%
2.Bila tidak ada
pemeriksaan HbA1c
dapat digunakan
pemeriksaan glukosa
darah. Rata-rata glukosa
+
Basal
darah sehari
Insulin
dikonversikan ke HbA1c
Insulin
menurut kriteria ADA
Intensif*
*insulin intensif : penggunaan insulin basal bersamaan dengan insulin prandial
2010

Konsensus Perkeni 2011

Correlation of A1C with average

glucose

A calculator for converting A1C results into eAG, in either

mg/dL or mmol/L, is available at
http://professional.diabetes.org/eAG

PROPOSED ALGORYTHM
ADA-EASD Position Statement:
Management of Hyperglycemia in T2DM

ANTI-HYPERGLYCEMIC THERAPY
Implementation strategies:

Initial therapy

Advancing to dual combination therap

Advancing to triple combination thera

Transitions to & titrations of insulin

DiabetesCare,Diabetologia.19April2012[Epubaheadofprint]

DiabetesCare,Diabetologia.19April2012

Antihyperglycemic Therapy: General Recommendations

[Epubaheadofprint]

Basal
insulin

DiabetesCare,Diabetologia.19April2012

Antihyperglycemic Therapy: General Recommendations

[Epubaheadofprint]

Basal
Insulin

Basal
Insulin

Basal
Insulin

Basal
Insulin

DiabetesCare,Diabetologia.19April2012

Antihyperglycemic Therapy: General Recommendations

[Epubaheadofprint]

Basal
Insulin

Basal
Insulin

Basal
Insulin

DiabetesCare,Diabetologia.
19April2012[Epubaheadofprint]

Basal
Insulin

BASAL INSULIN ?

How to
Start?

APAN MEMULAI TERAPI INSULIN?

sedikitnya 3 bulan
terapi GHS + 2 OHO:

A1c >7 % dan

Glukosa Puasa>100

Glukosa Darah

A1c > 9 %
GHS: Gaya Hidup
Sehat
Konsensus Perkeni 2011

The simple way to add basal

insulin

Initiate insulin with a single injection of a

basal insulin
Bedtime or morning long-acting insulin
OR

INITIATE

Bedtime intermediate-acting insulin

Daily dose: 10 units or 0.2 units/kg
Check FBG
Daily

Increase dose by 2 units every

3 days until
TITRATE FBG is 3.897.22 mmol/L (70
130 mg/dL)
If FBG is > 10 mmol/L (> 180
mg/dL),
increase dose
by 4and
units every
Continue
regimen
days HbA every 3 months
MONITOR 3
check

In the event of
hypoglycemia or FBG
level < 3.89 mmol/L
(< 70 mg/dL)
Reduce bedtime
insulin dose
by 4 units, or by
10% if > 60 units

1c

FBG, fasting blood glucose

Adapted from Nathan DM, et al. Diabetologia

Guidelines a new sense of urgency

Shorten delays in treatment changes
Achieve and maintain normal glycemic
goals
Add medications, transition to new
regimens quickly
Whenever HbA1c levels are 7%
STEP 1:
STEP 2:
STEP 3:

Lifestyle intervention + metformin

Add another agent basal insulin, SU or TZD
Intensify therapy

mely basal insulin therapy for patients not meeting targets

Nathan DM, et al. Diabetologia 2006;49:171121

Summary
Diabetes mellitus is a chronic and progressive
disease with steadily worsening glycemia
Shorten delays in treatment changes to achieve
and maintain normal glycemic goals
A single daily injection of basal insulin glargine is
a simple and effective way to start insulin therapy
Maintains targets with a low risk of hypoglycemia

Thank you