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Initiation of Basal
Insulin in Type 2
Diabetes

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BACKGROUND FACTS ABOUT DIABETES

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Diabetes mellitus is a chronic and progressive disease with

steadily worsening glycemia
Addition of medication is needed to maintain treatment
goals
Long term damage, dysfunction and failure of various organ
Requires continuing medical care and ongoing patient selfmanagement education and support to prevent acute
complications and to reduce the risk of long-term
complications

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Natural History of Type 2 Diabetes

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

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

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T2DM is a Progressive Disease

IGT = impaired glucose tolerance

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

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Chronic Complications in Newly Diagnose Diabetes

Mellitus
50% of patients had 1 complications

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

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

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Class

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Insulin

Mechanism

Advantages

Activates
Universally
insulin
effective
receptor
Unlimited
Peripheral
efficacy
glucose
Microvascular
uptake
risk

Disadvantages

Cost

Hypoglycemia
Weight gain
? Mitogenicity
Injectable
Training
requirements
Stigma

Variable

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General Practitioners and Specialists Resistance

to Initiating Insulin Therapy

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I prefer to delay initiation of insulin until absolutely essential

(% agreeing)

Adapted from Peyrot M, Rubin RR, Khunti K. Primary Care Diabetes 2010; 4: 11-18
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Barriers to Insulin Use: Concerns vs Responses

DCCT = Diabetes Control and Complication Trial

DIGAMI = Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction
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Comparison of Pharmacokinetics and Dynamics of Basal

Insulin Analog Glargine and Detemir at Steady State in Type
1 Diabetes: Double-Blind, Randomized, Crossover Study

Detemir

Glargine P-value

Onset of action (h)

1.3

1.3

0.818

Minimal duration of action

15.5

24

0.000

End of action (time at which PG>150mg/dL (h)

17.5

24

0.000

End of study time (time at which PG>180mg/dL (h)

21.5

24

0.000

(time at which

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PG>118mg/dL (h)

Porcellati F, et al. Diabetes Care. 2007;30:2447-2452

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Treatment Target

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The Indonesian Society of

Endocrinology (PERKENI) Consensus
2011

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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

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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
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Intensive Therapy in Diabetes Mellitus Lower the

Rate of Complications

DCCT

Kumamoto

UKPDS

9% 7,2%

9% 7%

8% 7%

Retinopathy

63 %

69 %

17% - 21%

Nephropathy

54 %

70 %

24% - 33%

Neuropathy

60 %

improve

CVD

41 %

16%

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A1c

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The Benefit of Early Tight Control: UKPDS 10year-post-trial Follow-Up

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

UKPDS Study Group. Lancet 1998;352:83753

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Impact of Intensive Therapy

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

Microv
asc

CVD

Mortalit
y

KendallDM,BergenstalRM.InternationalDiabetesCenter2009UKProspectiveDiabetesStudy(UKPDS)Group.Lancet1998;352:854.

longterm
FU
shortterm
FU

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Guidelines for Glycemic, BP, & Lipid

Control
Parameter

CV Risks (-)

CV Risks (+)

IMT (kg/m2)

18,5 - <23

18,5 - <23

BP Sistolik (mmHg)

< 130

< 130

BP Diastolik (mmHg)

< 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

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HbA1c (%)

Trigliseride (mg/dL)
CV = Cardiovascular, BP= Blood Pressure

Konsensus Perkeni 2011

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A traditional stepwise approach leads to

unacceptable delays in changing therapy

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Even with treatment, 61% and 63% of patients in Europe and

the USA, respectively, did not achieve recommended HbA1c
targets1,2

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

2. Saydah SH, et al. JAMA 2004;291:33542| 25
3. Campbell IW. Br J Cardiol 2000;7:62531

Delayed Treatment can Increase Risk

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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

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

ACCORD, Action to Control Cardiovascular Risk in Diabetes Trial; ADVANCE, Action in| 26
Diabetes and Vascular Disease; PROactive, PROspective pioglitAzone Clinical Trial in
macroVascular Events; VADT, Veterans Affairs Diabetes Trial; MH, MantelHaenszel

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Physiologic Insulin Secretion: 24-hour Profile

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Contribution of Fasting Hyperglycemia to Overall

Glycemia Increases with Worsening Diabetes

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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

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

Adapted from Monnier L, et al. Diabetes Care 2003;26:8815. | 29

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.

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Stepwise Approach for the Treatment of Patients

with T2DM

Raccah D. Diabetes Ob Met 2008; 10: 76-82

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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)

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Peakless
Clear solution
Basal Insulin
Could be given 12 times a day
Not for intravenous use

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Struktur Insulin

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Struktur Insulin Glulisine

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Becker RHA . Diabetes Ther & Tech 2007;9(1)109-21

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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
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ANTI-HYPERGLYCEMIC THERAPY

Implementation strategies:

Initial therapy

Advancing to dual combination

therapy

Advancing to triple combination

therapy

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Transitions to & titrations of insulin

DiabetesCare,Diabetologia.19April2012[Epubaheadofprint]
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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 ?

The INSIGHT Study

405 insulin-nave patients with type 2 diabetes

Randomized to early insulin glargine or optimization

of existing OADs

Patients self-titrated their bedtime insulin glargine by

1 U per day to target FPG <5.6 mmol/L (< 100 mg/dL)

HbA1c 6.5% in 20% of patients

HbA1c 7.0% in 50% of patients

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Timely initiation of insulin achieves glycemic control more rapidly

than OADs

Gerstein H et al. Diabetic Med 2006;23:73642

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Consistent Achievement of Glycemic Targets

with Basal Insulin

1. Riddle M, et al. Diabetes Care 2003;26:30806. 2. Yki-Jrvinen H, et al. Diabetes Care 2006;49:44251.
3. Bretzel RG, et al. Lancet 2008;371:107384. 4. Janka H, et al. Diabetes Care 2005;28:2549.
5. Rosenstock J, et al. Diabetes Care 2006;29:5549. 6. Yki-Jrvinen H, et al. Diabetes Care 2007;30:1364
69.
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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

Algoritme LANMET

Dosis insulin dinaikkan

setiap 3 hari sebanyak 2

unit jika target GDP
belum tercapai pada
pengukuran 3 hari
berturut-turut

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Titrasi dilakukan jika GDP

tidak mencapai dibawah
72mg/dl dalam satu
minggu terakhir.

Yki-Jarvinen H et al. Insulin glargine or NPH combined with metformin in type 2

diabetes: the LANMET study. Diabetologia 2006;49:442-51.
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Algoritme INSIGHT

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Dosis insulin dinaikkan

setiap malam 1 Unit
sampai target GDP
tercapai

Gerstein HC et al. A Randomized Trial of Early Glargine Use to Achieve Optimal A1c Levels
in Insulin Naive People with Type 2 Diabetes. ADA Annual Congress 2005; abstract 273OR.
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Algoritme Treat-to-Target / Riddle

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Intensify insulin if HbA1c

is 7% after 23 months

STEP 3
Adjust
therapy

HbA1c
7%

Start or
intensify
insulin
therapy

If FBG is in range check pre-meal BG

levels, and add 1 prandial insulin
shot,
at a selected meal
Add 1 shot of rapid-acting insulin
At BREAKFAST if pre-lunch BG is out of
range
or LUNCH if pre-dinner BG is out of range
or At DINNER, if pre-bedtime BG is out of
range

If still uncontrolled after effective

titration, add another prandial insulin
shot, then
add a third shot to accomplish basal
bolus
Adapted from Nathan DM, et al. Diabetologia

Guidelines 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: Lifestyle intervention + metformin

STEP 2: Add another agent basal insulin, SU or
TZD
STEP 3: Intensify therapy
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Timely basal insulin therapy for patients not meeting targets

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

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Teknik Injeksi

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Teknik Injeksi (2)

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Lokasi Injeksi Insulin

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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

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Maintains targets with a low risk of hypoglycemia

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