WHAT NEXT,

WHEN BASAL INSULIN FAILS?

John MF
Adam

Sub-Division of Endocrinology and Metabolism,

Department of Internal Medicine, Hasanuddin
University, Makassar

TREATMENT OF DIABETES
MELLITUS

Non-pharmacology
Medical nutrition therapy,
Exercise or
increased activity

Pharmacology
Oral hypoglycemic agents

Insulin
Education

LESSONS FROM UKPDS:

BETTER CONTROL MEANS FEWER
COMPLICATIONS
EVERY 1%
reduction in
A1C

1
%

REDUCED
RISK*

Deaths from
diabetes

-21%

Heart
attacks

-14%

Microvascular
complications

-37%

Peripheral vascular
disorders

UKPDS 35. BMJ 2000; 321: 405-12.

-43%
*p<0.0001

Frederick
Banting
and

Charles Best

(Toronto, 1921)

Marjori
e

The insulin
1922 -- 2013

Leonard Thompson

The first patient to receive insulin

in January 1922, Canada

CHANGING PATTERN
OF TYPE 2 DIABETES MANAGEMENT
For decades the treatment depends on
the diabetic clinics or even personal
experience
Standard
treatment,
the
nonpharmacology and pharmacology, was
used since the invention of insulin and
oral anti-diabetic drugs
Even though, no international consensus
of
medical
management
of
hyperglycemia, how or which drug to
start
New OHA and new insulin,
needs

ELLIOT T P JOSLIN, and frontpiece of his 1916 textbook

Old Book
JOSLINS
DIABETES
MELLITUS
Before 2006
there was no
algorithm

THE JOSLINS CLINIC TREATMENT OF

DIABETES MELLITUS IN YEAR 1971

The teaching program in the

Hospital
Teaching Unit:
1. The diet
Emphasis is placed on the necessity for
careful
adherence to diet

2. Insulin
Joslins Diabetes Mellitus, General plan of treatment
3. Oral hypoglycaemic agents
diabetes, Marble A et al, 1971

of

THE ALGORITHMS
First international algorithm, introduced
in 2006 by ADA and EASD
Since 2006, at least 4 algorithms was
introduced
by
the
International
Diabetes Association
All the algorithms, two important
informations:
Metformin, was the first line Anti-Diabetic
Agents

Insulin, when to start and which insulin to

choose ??

ADA/EASD: Metabolic Management of Type 2 Diabetes 2006

Lifestyle Intervention + Metformin
(Reinforce at every visit)

STEP 1

No

Add Basal
Insulin
(Most effective)

STEP 2
No

STEP 3

A1C 7%

A1C 7%

Intensive
Insulin
No

Yes*

Add
Sulfonylurea
(Least
expensive)
Yes*

No

A1C 7%

Add Glitazone

A1C 7%

*Check A1c every 3 month until < 7% and then

at
least every 6 month

although 3 oral agents can be used,

initiation an intensification of insulin
therapy is preferred based
Intensive
on effectiveness and expense

Yes*

Yes*

Yes*

Add Glitazone
(No
hypoglycemia)
No

A1C 7%

Add
Basal Insulin
No

Yes*

Add
Sulfonylurea

A1C 7%

Yes*

Add Basal or Intensive Insulin

Insulin+ Metformin + Glitazone

Nathan DM et al. Diabetes Care. 2006; 29: 1963-

Initial drug
monotherapy

HEALTHY, EATING, WEIGHT CONTROL, INCREASED PHYSICAL ACTIVITY

Metfomin

If needed to reach individualized HbA1c target after 3 months, proceed to two-drug combination (order not
meant to denote any specific preference)

Two-drug
combinations

Metfomin
+
SUb

Metfomin
+
TZD

Metfomin
+
DPP-4 I

Metfomin
+
Insulin basal

Metfomin
+
GLP-1 RA

If needed to reach individualized HbA1c target after 3 months, proceed to three-drug combination
(order not meant to denote any specific preference)

Three-drug
combinations

Metfomin
+
SUb
+
TZD
or
DPP-4 I
or
Insulind
or
GLP-1 RA

Metfomin
+
TZD
+
SUb
or
DPP-4 I
or
Insulind
or
GLP-1 RA

Metfomin
+
DPP-4 I
+
SUb
or
TZD
or
Insulind

Metfomin
+
Insulin basal
+
TZD
or
DPP-4 I
or
GLP-1 RA

Metfomin
+
GLP-1 RA
+
SUb
or
TZD
or
Insulind

If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months,
proceed to more complex insulin strategy, usually in combination with one or two non-insulin agents

More complex
insulin strategies

Insuline (multiple daily doses)

Inzucchi SE, et al. ADA and EASD. Diabetes Care 2012; 19 April

THE INSULIN

THE ANALOG
INSULIN
Rapid acting insulin
Aspart (Novorapid), Glulisine
(Apidra ),
Lispro (Humalog)

Long acting insulin

Glargine (Lantus), Detemir
(Levemir )

Premix insulin
Novomix
Humalog Mix 25

Insulin analog kerja cepat

(aspart, glulisine, lispro [4-6 jam])
Insulin manusia kerja pendek
(insulin regular [6-8 jam])

Kadar insulin
plasma

Insulin manusia kerja menengah

(NPH [12-20 jam])
Insulin manusia kerja
panjang
(ultralente [18-24 jam])
Insulin analog kerja
panjang
(glargine, detemir [24
jam])

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

KONSENSUS

Waktu
(jam)
Profil farmakokinetik insulin manusia dan
insulin analog
TERAPI INSULIN - PERKENI

INSULIN INJECTION

RAPID ACTING INSULIN

INJECTION
After
noon

INSULIN EFFECT

Mornin
g

Breakfas
t

Lunch

dinner

Evening

Night

INSULIN EFFECT

BASAL INSULIN

Breakfast

Nigh
t

Detem
ir

Lunch

Dinner

INSULIN EFFECT

PREMIX INSULIN
INJECTION

Breakfas
t

Lunch

Premix = Novomix

Dinner

INDICATIONS OF INSULIN
FOR TYPE 2 DIABETES
Acute complications ketoacidosis etc
Diabetes and pregnancy
Diabetes and infections acute septic
infections, tuberculosis
Preparing for operation

Failed (poor control) with oral antidiabetic agents ( the most cases in
clinical practice )

INSULIN INITIATION
FOR THE TREATMENT OF HYPERGLYCEMIA
IN TYPE 2 DIABETETES MELLITUS
PATIENT- CENTERED APPROACH
ADA EASD STATEMENT 2012

WHEN TO START INSULIN ???

INSULIN INITATION
FOR THE TREATMENT OF HYPERGLYCEMIA
IN TYPE 2 DIABETIC
Due to the beta-cell dysfunction that
characterizes type 2 diabetes, insulin
replacement
therapy
is
frequently
required (Int J Clin Pract 2008;62:845-857)
Ideally, the principle of insulin use is the
creation of as normal glycemic profile as
possible without unacceptable of weight
gain or hypoglycemia (Diabetology 2002;45:937938)

WHAT NEXT,
WHEN BASAL INSULIN
FAILS ?

INSULIN CAN BE USED

ANYTIME

Traditionally insulin had been reserved as the last line of

Considering the benefits of normal glycemic status, insulin
be initiated earlier, as soon as is required.

Inadequate
Lifestyle

1 OAD

Initiate

2 OAD

3 OAD

Insulin

Indication1. Fasting BG > 250

mg/dL
s
2. Random BG > 300
mg/dL
3. Hb A1c > 10 %
4. Weight loss ++

Initial drug
monotherapy

HEALTHY, EATING, WEIGHT CONTROL, INCREASED PHYSICAL ACTIVITY

Metfomin

If needed to reach individualized HbA1c target after 3 months, proceed to two-drug combination (order not
meant to denote any specific preference)

Two-drug
combinations

Metfomin
+
SUb

Metfomin
+
TZD

Metfomin
+
DPP-4 I

Metfomin
+
Insulin basal

Metfomin
+
GLP-1 RA

If needed to reach individualized HbA1c target after 3 months, proceed to three-drug combination
(order not meant to denote any specific preference)

Three-drug
combinations

Metfomin
+
SUb
+
TZD
or
DPP-4 I
or
Insulind
or
GLP-1 RA

Metfomin
+
TZD
+
SUb
or
DPP-4 I
or
Insulind
or
GLP-1 RA

Metfomin
+
DPP-4 I
+
SUb
or
TZD
or
Insulind

Metfomin
+
Insulin basal
+
TZD
or
DPP-4 I
or
GLP-1 RA

Metfomin
+
GLP-1 RA
+
SUb
or
TZD
or
Insulind

If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months,
proceed to more complex insulin strategy, usually in combination with one or two non-insulin agents

More complex
insulin strategies

Insuline (multiple daily doses)

Inzucchi SE, et al. ADA and EASD. Diabetes Care 2012; 19 April

WHAT NEXT
WHEN INSULIN BASAL FAILS ???
1. Basal insulin + 2 OAD ? - Metformin + TZD
2. Basal bolus insulin ?? - Levemir +
Novorapid

3. Premix insulin, 2 - 3 times daily ???

INTENSIFICATION
PROGRAMS

BASAL BOLUS
INSULIN

Intensification programs

4:00

insulin
Lunch
Breakfast

Dinner

Basal bolus
insulin

Breakfast Lunch

8:00

12:00

16:00 20:00 24:00 4:00

Dinner

Plasma insulin

Plasma insulin

Starting insulin
programs
Basal

4:00

8:00

12:00 16:00
Time

20:00 24:00 4:00

Starting insulin programs for type 2 diabetes.

Basal insulin, 3-times daily prandial insulin.
Intensification programs : basal bolus insulin.
The background of each diagram depicts the
normal pattern of insulin levels in nondiabetic
individuals eating 3 daily meals. The arrows
show the progression from starting to
intensification insulin programs in the 4-T trial,
as described in the text.

Intensification programs

Starting insulin
programs
Basal
Plasma insulin

insulin
Lunch
Breakfast

Basal bolus
insulin

Dinner

4:00

8:00

12:00

16:00 20:00 24:00 4:00

Basal bolus
insulin

8:00
Dinner

Plasma insulin

Breakfast Lunch

4:00

8:00

12:00 16:00
Time

Dinner

Plasma insulin

Breakfast Lunch

20:00 24:00 4:00

12:00 16:00
Time

20:00 24:00 4:00

INTENSIFICATION
PROGRAMS

PREMIX INSULIN 2-3

TIMES

Intensification programs

4:00

Intensified premixed
insulinLunch Dinner
BreakfastLunch
Breakfast
NovoRapi
d

Plasma insulin

Plasma insulin

Starting insulin
programs
Premixed
insulin
Lunch Dinner
Breakfast

8:00

12:00 16:00 20:00 24:00 4:00

Time

4:00

8:00

12:00 16:00 20:00 24:00 4:00

Time

Starting insulin programs for type 2 diabetes. Twice daily analogue premix.
Intensification programs : twice daily premixed analogue with prandial insulin added
at lunch. The background of each diagram depicts the normal pattern of insulin levels
in nondiabetic individuals eating 3 daily meals. The arrows show the progression from
starting to intensification insulin programs in the 4-T trial, as described in the text.

Leahy Jl. Insulin therapy in type 2 diabetes mellitus. In Endocrinology and Metabolism Clinics of North
America, Insulin Therapy. LeRoith D, Leahy JL, Cefalu WT, eds. Saunders company, Philadelphia,
Pennsylvania; 2012. P119 144.

WHAT NEXT,
WHEN BASAL INSULIN
FAILS ?

Non-insulin regimens

Number
Regimen
of injection complexity

Basal insulin only

(usually with oral agents)

Basal insulin + 1
(Mealtime) rapid-acting
insulin injection

Pre-mixed insulin
twice daily

Basal insulin + > 2

(Mealtime) rapid-acting
insulin injections

More flexibel

Less flexibel

Low

Mod

3+

High

Flexibillity

Sequential insulin strategies in type 2 diabetes. Basal insulin alone is usually the optimal initial regimen, beginning at 0.10.2 units/kg body weight,
depending on the degree of hyperglycemia. It is usually prescribed in conjunction with one to two noninsulin agents. In patients willing to take more
than one injection and who have higher HbA1c levels ($9.0%), twicedaily premixed insulin or a more advanced basal plus mealtime insulin regimen
could also be considered (curved dashed arrow lines). When basal insulin has been titrated to an acceptable fasting glucose but HbA1c remains
above target, consider proceeding to basal plus mealtime insulin, consisting of one to three injections of rapid-acting analogs (see text for details). A
less studied alternativedprogression from basal insulin to a twice-daily premixed insulindcould be also considered (straight dashed arrow line); if
this is unsuccessful, move to basal plus mealtime insulin. Thegure describes the number of injections required at each stage, together with the
relative complexity and exibility. Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the
prevailing glucose levels as reported by the patient. Noninsulin agents may be continued, although insulin secretagogues (sulfonylureas,
meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilized. Comprehensive education regarding selfmonitoring of blood glucose, diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient on insulin therapy. Mod.,
moderate. Inzucchi SE, et al. Diabetes Care 2012; 19: 1-16

PROGRAM FOR INTENSIFICATION OF

INSULIN THERAPY
The daily used regimen

The

basal - bolus regimen

Starting with basal and add rapid insulin

Frequently used in daily office practice
for better glycemic control

The

bolus - basal - regimen

Mostly in hospital cases, need rapid

glycemic control (for operation )

Mr. J, 55 yrs came to see the

doctor with classical diabetic
symptoms, polyuria. loosing
weight, polidypsy
His FBS 165 mg/dL, A1c 8.0%
Treament ?
Lifestyle modification +
metformin
or
Lifestyle modification +
metformin +
basal insulin ?

Ny. S, 50 tahun datang dengan

bisul di punggung. TD 120/80
mmHg
Hasil laboratorium
GDP 180 mg/dl, A1C 10,4

Pengobatan ??
Bolus - basal insulin

A patient mr. A with diabetic ketoacidosis

Patient A, 33 yrs, with severe weakness, unconcious, BP 90/60 mmHg,
RBG 645 mg/dL

Diabetic ketoacidosis
Treatment
Continuous insulin drips
Rapid acting
Basal - bolus

Mr. A 36 yrs, 3 yrs

later

How is the insulin

regimen??
Multiple insulin
injections
Novorapid 3 times +
Levemir in the
evening

Malang APRIL 28,

2013

MKS 28 04 2013

Intensification programs

4:00

Breakfast Lunch

Dinner

Basal bolus insulin

Breakfast Lunch

8:00

12:00

16:00 20:00 24:00 4:00

Prandial insulin
Breakfast Lunch

Dinner

4:00

Plasma insulin
4:00

8:00

12:00 16:00
Time

20:00 24:00 4:00

Dinner

Plasma insulin

Plasma insulin

Starting insulin
programs
Basal insulin

8:00

12:00 16:00
Time

20:00 24:00 4:00

Intensification programs

Starting insulin programs

Premixed insulin
Breakfast Lunch

Intensified premixed insulin

Dinner

Breakfast Lunch

Dinner

4:00 8:00

Plasma insulin

Plasma insulin

NovoRapid

12:00 16:00 20:00 24:00 4:00

Time

4:00 8:00

12:00 16:00 20:00 24:00 4:00

Time

Starting insulin programs for type 2 diabetes. Twice daily analogue premix. Intensification programs : twice
daily premixed analogue with prandial insulin added at lunch. The background of each diagram depicts the
normal pattern of insulin levels in nondiabetic individuals eating 3 daily meals. The arrows show the progression
from starting to intensification insulin programs in the 4-T trial, as described in the text. Leahy Jl. Insulin therapy in
type 2 diabetes mellitus. In Endocrinology and Metabolism Clinics of North America, Insulin Therapy. LeRoith D, Leahy JL, Cefalu
WT, eds. Saunders company, Philadelphia, Pennsylvania; 2012. P119 144.

Intensification programs
Basal bolus insulin
Dinner

Lunch

Plasma insulin

Breakfast

4:00

8:00

12:00

16:00

20:00

24:00

4:00

Time
Starting insulin programs for type 2 diabetes. Basal insulin, 3-times daily prandial insulin. Intensification
programs : basal bolus insulin. The background of each diagram depicts the normal pattern of insulin levels in
nondiabetic individuals eating 3 daily meals. The arrows show the progression from starting to intensification
insulin programs in the 4-T trial, as described in the text. Leahy Jl. Insulin therapy in type 2 diabetes mellitus. In
Endocrinology and Metabolism Clinics of North America, Insulin Therapy. LeRoith D, Leahy JL, Cefalu WT, eds. Saunders
company, Philadelphia, Pennsylvania; 2012. P119 144.

EVERY 1%
reduction in A1C

1%

REDUCED
RISK*

Deaths from diabetes

-21%

Heart attacks

-14%

Microvascular complications

-37%

Peripheral vascular disorders

-43%
*p<0.0001

Intensification
programs

4:00

Breakfast Lunch

Dinner

Basal bolus insulin

Breakfast Lunch

8:00

12:00

16:00 20:00 24:00 4:00

Prandial insulin
Breakfast Lunch

Dinner

4:00

Plasma insulin
4:00

8:00

12:00 16:00
Time

20:00 24:00 4:00

Dinner

Plasma insulin

Plasma insulin

Starting insulin
programs
Basal insulin

8:00

12:00 16:00
Time

20:00 24:00 4:00

Insulin basal
Makan
malam

Insulin plasma
4:00

Makan Makan
pagi
siang

Makan
malam

Insulin plasma

Makan Makan
pagi
siang

Basal bolus insulin

8:00 12:00 16:00 20:00 24:00 4:00

Waktu

4:00

8:00

12:00 16:00 20:00 24:00 4:00

Waktu

Insulin prandial
Makan
siang

Makan
malam

4:00

Makan
pagi

Makan
siang

Makan
malam

Insulin plasma

Insulin plasma

Makan
pagi

Basal bolus insulin

8:00 12:00 16:00 20:00 24:00 4:00

Waktu

4:00

8:00 12:00 16:00 20:00 24:00 4:00

Waktu