INSULIN THERAPY

IN DIABETES MELLITUS
Dra. WIDYATI, Apt, MClin
Pharm

PENGGUNAAN INSULIN
Insulin therapy can be used to
overcome glucose toxicity
Use in acute and chronic care

Glucose toxicity

Contribute to development of insulin

resistance and impaired insulin secretion
In type 2 chronic elevation in plasma
glucose concentration leads to progressive
impairment in insulin secretion as well as
aggravation of insulin resistance due to
downregulation of the glucose-transport
system.
Thus, impairments in insulin secretory
response and insulin action are the result
of dynamic processes.
Insulin therapy can be used to overcome
glucose toxicity

GOAL of Physiological (Basal-Bolus)

Insulin Therapy

Adults
Parameter
(mg/dL)
Fasting plasma 70130
glucose

School Age
(612 years)
(mg/dL)
90180

Adolescents
and Young
Adults (1329
years)
Pregnancy
(mg/dL)
(mg/dL)
90130
6090

2 hr
<180
postprandial
plasma glucose
24 am plasma >70
glucose

Not routinely
Not routinely
120
recommended recommended
100180

90150

>60

HbA1cb

<8.0%

<7.5%d

56%

<7.0%c

Urine ketonese Absent to rare Absent to rare Absent to rare Rare

INSULIN USE IN ACUTE CASE

to reduce the symptoms and adverse effects of
glucotoxicity
Insulin therapy can be started at a dose of 0.5
U/kg/24 hr.
Patients who have more significant insulin
deficiency need a mix of rapid-acting insulin and
intermediate insulin before breakfast, rapid-acting
insulin before supper, and intermediate insulin at
bedtime to control their fasting glucose level.
Obese patients can require 100 U or more daily
When glucose control improves with temporary
insulin use, an oral medication can be introduced
gradually while blood glucose levels are
monitored and the amount of insulin is slowly
reduced.

ACUTE CASES
o Decompensation due to an
intercurrent event (eg, infection,
acute injury, stress)
o Severe hyperglycemia with
ketonemia or ketonuria
o Acute events: Acute Coronary
Syndrome (ACS), Stroke
o Upcoming surgery
o Allergy or other serious reaction to
oral agents

INSULIN USE IN CHRONIC

CARE

INSULIN USE IN DM TYPE 2

o
o
o
o
o
o

Indication: when glucose control can no longer be

maintained with oral combination
Insulin therapy overcome insulin resistance and provide
adequate insulin even in the presence of islet beta-cell
dysfunction
Indications for insulin therapy of type 2 diabetes :
Hyperglycemia despite maximum doses of oral agents
Acute Cases
Uncontrolled weight loss
Pregnancy
Renal disease
A preference for insulin therapy by the patient or physician.

Kombinasi OAD-Insulin
Setelah kombinasi OAD gagal mengontrol
gula
Kombinasi

FPG
(mg/dl)
SU+ insulin
60-80
Metformin+in 60-80
s
Acarbose+ins 0-16
Glimepiride+i 110
ns

HbA1c (%)
0,5-1.8
1,7-2,5
0,4-0,5
2,2
9

Gradual insulin initiation

For a patient who takes maximal doses of oral antidiabetic

medications in combination, insulin therapy can be initiated more
gradually
The following insulin options are available:
o NPH insulin, lente, or ultralente at bedtime
o Human analogue insulin 70/30 or 75/25 mixtures before supper or
before breakfast, or both
o Basal insulin glargine (Lantus) at bedtime, before supper, or in the
morning
Patients often have high fasting glucose levels, and therefore,
basal insulin or insulin at bedtime is a good choice.
Insulin suppresses the increased hepatic glucose production and
lowers fasting glucose concentrations.
If intermediate insulin is chosen, the amount can be calculated by
dividing a patient's body weight in kilograms by four and using
that number to determine the starting dose (resulting in one fourth
of the regular dose) or by figuring the dose according to a ratio of
0.5 U/kg and using 25% to 30% of that amount as the initial dose.
If basal insulin glargine is being used, no special calculations are
necessary. A starting dose of 1010U is prescribed, and the dose is

Comparing insulin treatment

options in type 2
NPH insulin compared with insulin glargine
similar
percentage of reduction in HbA1c of 7% or less. However,
those who received glargine experienced less hypoglycemia
overall (33% versus 27%) and less nocturnal hypoglycemia.
Insulin 70/30 and glimepiride with a combination of insulin
70/30 and placebo. At 24 weeks, reduction in HbA1c (from
9.9% to 7.6%), but the group receiving glimepiride required
35% less insulin to achieve this goal.
The new insulin analogues offer more physiologic insulin
profiles.When insulin lispro was added to sulfonylurea therapy
and compared with NPH and oral medication, patients in the
lispro group had lower postprandial glucose levels, decrease in
HbA1c levels that was statistically significant, despite higher
fasting glucose levels with the lispro therapy
11

PEMILIHAN INSULIN

Type/Duration of Action Brand Name

Rapid Acting
Insulin lispro
Humalog
Insulin aspart
NovoLog
Insulin glulisine
Apidra
Short Acting
Regular
Humulin R

Novolin R
Intermediate Acting
NPH (isophane insulin
Humulin N
suspension)

Novolin N
Long Acting
Insulin glargine
Lantus
Insulin detemir
Levemir
Combination Insulins
NPH/regular mixture
Humulin 70/30
(70%/30%)

Novolin 70/30
NPH/regular mixture
Humulin 50/50
(50%/50%)
Insulin aspart
Novolog Mix 70/30
protamine/insulin aspart
mixture (70%/30%)
Insulin NPL/insulin lispro Humalog Mix 75/25

Manufacturer
Lilly
Novo Nordisk
Sanofi-Aventis
Lilly
Novo Nordisk
Lilly
Novo Nordisk
Sanofi-Aventis
Novo Nordisk
Lilly
Novo Nordisk
Lilly
Novo Nordisk
Lilly

Insulin
Onset (hr)
Rapid acting 525 min
(insulin lispro,
aspart and
glulisine)

Peak (hr)
3090 min

Duration
(hr)
<5

Regular

0.51

23

58

Clear

NPH

24

412

1218

Cloudy

Insulin
glargine

1.5

No
2024
pronounced
peak
Relatively flat 5.723.2

Appearance
Clear

Clearb

Insulin
38
Clearb
detemir
a
The onset, peak, and duration of insulin activity may vary considerably
from times listed in this table. See text and Table 50-12.
b
Should not be mixed with other insulins or administered IV. Some
patients require twice-daily dosing.

Factors Altering Insulin absorption

Factor
Route of administration

Factors altering clearance

Renal function
Insulin antibodies

Thyroid function

Factors altering SC absorption

Comments
Onset of action more rapid and
duration of action shorter for
IV>IM>SC137
Intrapulmonary insulin has more rapid
onset and shorter duration than SC
insulin, resembling IV
pharmacokinetics72

Renal failure lowers insulin clearance;

may prolong and intensify action of
exogenous and endogenous insulin
IgG antibodies bind insulin as it is
absorbed and release it slowly, thereby
delaying and/or prolonging its
effect339
Hyperthyroidism increases clearance,
but also increases insulin action,
making control difficult; patients
stabilize as they become euthyroid
Factors that raise SC blood flow

Types of Insulin
Insulin Glulisine (Apidra, Sanofi-Aventis)
Is a rapid-acting insulin analog that differs from human insulin by substitution
of lysine for asparagine at position B3 and glutamic acid for lysine at position
B23.
Currently not FDA approved for use in pediatric patients.
It is pregnancy category C.
Lowers postprandial glucose excursions similar to insulin lispro and insulin
aspart.
Short-Acting Insulin
Onset of action of 30 to 60 minutes, a peak effect at 2 to 4 hours, and a duration
of action of 5 to 7 hours. Use of regular insulin in patients with type 1 diabetes
is much less common with the advent of the rapid-acting insulins.
Previously, an inhaled human insulin powder (Exubera, Pfizer, New York, NY)
was available. In October 2007, Pfizer announced that it would no longer make
this insulin owing to its infrequent use. In March 2008, Lilly announced that it
was cancelling the trials of its inhaled insulin.

Types of Insulin (CONTINUE)

Intermediate-Acting Insulin e.g. NPH
Onset of action is approx. 2 hours (range, 13), peak effects occur at
approx. 6 to 14 hours
DOA of NPH is approx 16 to 24 hours.
Premix Insulin
Premixed NPH and regular insulin in a fixed ratio of 70:30 are available
from Lilly as Humulin 70/30 and Novo Nordisk as Novolin 70/30. Lilly
also makes a premixed formulation in a 50:50 ratio (Humulin 50/50).
Additional premixed formulations are available wherein both insulin
lispro and insulin aspart have been co-crystallized with protamine to
create an intermediate-acting insulin similar to NPH. Humalog Mix 75/25
and Humalog Mix 50/50 (Lilly) are products with lispro protamine and
insulin lispro in a fixed ratio of 75:25 and 50:50, respectively.
These premixed insulins are available for patients who have difficulty
measuring and mixing insulins and are dosed twice daily.
These insulins are compatible when mixed together and retain their
individual pharmacodynamic profiles

Types of Insulin

(CONTINUE)

LONG ACTING INSULIN

Insulin Glargine (Lantus, Sanofi-Aventis)
Once a day SC administration for the treatment of adult and pediatric
patients (age 6) with type 1 diabetes or adult patients with type 2
diabetes who require basal (long-acting) insulin for the control of
hyperglycemia.
Administered anytime during the day, but it is important to take it at the
same time each day but commonly, befeore bed
Is an insulin analog in which asparagine in position A21 is substituted
with glycine and two arginines are added to the C-terminus of the chain
Insulin Detemir (Levemir, Novo Nordisk),
Approved in June 2005 and joins insulin glargine as the second basal
insulin
It is pregnancy category C.
Unlike other insulin analogs, in which the amino acid sequence is
modified, for insulin detemir, a fatty acid moiety is added to the last
amino acid on the end of the -chain.
More slowly absorbed in the SC tissue because the fatty acid moiety
binds to albumin, creating a long-acting insulin.

Texas Diabetes Council

Guideline

Targets
A1c 6,5 %
FPG/SMBG 110mg/dl
2 hr PPG/SMBG 140-180 mg/dl

Treatment Naive
Symptomatic
FPG 260 mg/dl
A1c 10%, ketoacidosis, recent rapid
weight loss
Pilihan:
1. Once-daily Insulin
2. Multi-dose insulin
3. Intensive insulin management

Oral Agent Failure

7,0 %> A1c < 8,5%

Pilihan:
1. Once-daily Insulin
2. Multi-dose insulin
3. Intensive insulin management

Oral Agent Failure

A1c > 8,5%

Pilihan:
1. Multi-dose insulin
2. Intensive insulin management
3. Once daily insulin

Once-Daily Insulin
At bedtime : NPH or Long-acting insulin
B efore supper: short-acting insulin or
premix 70/30
Dosis awal : 0,1-0,25 U/kg or 6-10 U untuk
manula kurus
Naikkan dosis setiap 2-3 hari.
Titration schedule: >180mg/dl 6 unit

141-180mg/dl 4 unit

121-140mg/dl -2 unit

Multi Dose Insulin

2 x suntik : NPH + Short acting
insulin
Or premix 70/30
3 x suntik (if nocturnal
hypoglycemia): Short acting insulin
before breakfast and before supper
sliding scale + NPH before breakfast
and bedtime or Long acting insulin
Starting dose: 0,3-0,5 unit/kg

Intensive Insulin
Management
1:1 basal:bolus
Basal :NPH before breakfast, before
supper or bedtime x 2 or Long acting
Insulin
Bolus: Short acting insulin at each
meal
Starting dose: 0,3-0,5 U/kg

Metode Pemberian Insulin

INSULIN USE IN DM TYPE

1

KASUS DM TYPE 1
A.H., Wanita 18th , 50kg, 160cm MRS
dg keluhan polydipsia, nocturia (6x
semalam), fatigue, penurunan BB 6kg
dalam 2 bulan. Hasil periksa Lab GDP
190mg/dl dan GDA 250mg/dl. HbA 1c,
14% (normal, 4%6%); and trace
urine ketones yg terukur dg KetoDiastix. Selanjutnya AH didiagnosis
dg DM Type 1 dg ketoasidosis ringan.

Basal-Bolus (Physiological) Insulin Therapy

A physiological insulin regimen is designed to mimic

normal insulin secretion as closely as possible
Between meals and throughout the night, the pancreas
secretes small amounts of insulin that are sufficient to
suppress lipolysis and hepatic glucose output (basal
insulin).
Two methods have been used to achieve a similar
pattern of insulin release: (a) insulin pump therapy
(previously referred to as continuous subcutaneous
infusion of insulin) and (b) basal-bolus insulin regimens
consisting of once to twice daily doses of basal insulin
coupled with pre-meal doses of rapid or short-acting
insulin

Insulin Pump Therapy

The use of an insulin pump is currently the most precise way to mimic
normal insulin secretion.
Consists of a battery-operated pump and a computer that can program
the pump to deliver predetermined amounts of regular insulin, insulin
lispro, insulin aspart, or insulin glulisine from a reservoir to a
subcutaneously inserted catheter or needle (e.g., MiniMed Paradigm 722,
Northridge, CA; Animas 2020).89,90 These systems are portable and
designed to deliver various basal amounts of insulin over 24 hours as well
as meal-related boluses. A bolus of regular insulin can be released by the
patient 30 minutes before food ingestion.
Most patients using an insulin pump, however, prefer to use the rapidacting insulin analogs in their pump. For meal coverage, the rapid-acting
insulin can be given 0 to 15 minutes before eating. The delivery of the
bolus can be adjusted depending on the type of food eaten (e.g., piece of
cake versus slice of pizza).
The preferred meal planning approach for patients using an insulin pump
is carbohydrate counting.
The insulin to carbohydrate ratio or how much carbohydrate is covered
by 1 unit of insulin must be determined. One method is to use the 500
Rule. The number 500 (or 450 for regular insulin) is divided by the total
daily dose of insulin the patient is using to determine the insulin to
carbohydrate ratio (see Question 13). Insulin pumps are capable of

Multiple Daily Injections

How can insulin injections be administered to A.H. in a way that mimics the physiological
release of insulin from the pancreas?
Endocrinologists have developed a variety of insulin regimens that are intended to mimic the release
of insulin from the pancreas. A total daily dose of insulin is estimated empirically (e.g., 0.5
unit/kg/day) or according to guidelines listed in Table 50-11. The total daily dose of insulin then is split
into several doses. In general, the basal dose comprises approximately 50% of the total daily dose.
A regimen much less commonly used in patients with type 1 diabetes involves injecting a mixture of
intermediate-acting and regular or rapid-acting insulin twice daily, before breakfast and before dinner
(Fig. 50-4A).
The morning dose of regular/rapid-acting insulin is intended to take care of the breakfast meal; the
morning dose of NPH takes care of the noon meal and provides basal insulin throughout the day; the
evening dose of regular/rapid-acting insulin takes care of the evening meal; and the evening dose of
NPH provides basal insulin levels during the night and takes care of any evening snack that is
ingested.
Because NPH is an intermediate-acting insulin and has a peak effect, it does not provide true basal
insulin coverage. Also, when NPH is injected in the morning, the patient must eat lunch on time
because of this peak effect, otherwise they will experience hypoglycemia. Also, when NPH is taken
with mealtime insulin before dinner, the patient is at risk for nocturnal hypoglycemia from the peak
effect of the evening dose of NPH. The advantage of using a rapid-acting insulin (e.g., insulin lispro,
insulin aspart, or insulin glulisine) instead of regular insulin in this regimen is to facilitate the patient
being able to take their insulin doses immediately before P.50p21

a meal. However, the peak effect of the NPH component in this combined dose still presents the same
problems. Caveat: When patients are switched to a rapid-acting insulin from regular insulin in this
type of regimen, the doses of NPH may have to be increased to minimize preprandial hyperglycemia.
This type of insulin regimen does not mimic physiological insulin release.

Insulin Therapy
Physiologic insulin replacement: to
replicate normal insulin secretion,
comprise:
Basal Insulin: insulin available
overnight and between meals to
suppress hepatic glucose production
Meal-related insulin(BOLUS): given w/
each meal to promote glucose
utilization after eating
34

Meal-Related Insulin
Replacement
Regular Insulin:
May need snacks to prevent postprandial
hypoglycemia
Longer DOA as dose increase
Slows correction of hyperglycemia
Caution w/ postprandial exercise
Contributes to basal insulin when time between
meal is long
Insulin Lispro
Postprandial glucose level improved
Consistency of action as dose increases
Less need for snacks
Less hypoglycemia
Good for exercise> 2hours after a meal
35

Basal Insulin Replacement

Intermediate acting Insulins: NPH,
Lente
Risk of hypoglycemia at time of peak
action
Not true basal insulin
Does not provide around the clock
action
Morning use as prandial insulin for
lunch can be a problem
Can be given bedtime only or twice
36

Basal Insulin Replacement

Long Acting Insulins: Glargine
Peakless insulin w/ flat, smooth
action
More predictable absorption
Can be given once at bedtime or
twice

37

Basal-Bolus (Physiological) Insulin Therapy

Basal-Bolus (Physiological) Insulin Therapy: Indications and

Precautions
Patient Selection Criteria
Type 1, otherwise healthy patients (>7 years of age) who are highly motivated
and compliant individuals. Must be willing to test blood glucose concentrations
multiple times daily and inject 4 doses of insulin daily, on average
Women with diabetes who plan to conceive
Pregnant patients with diabetes (pre-existing)
Patients poorly controlled on conventional therapy (includes type 2 patients)
Technical ability to test blood glucose concentrations
Intellectual ability to interpret blood glucose concentrations and adjust insulin
doses appropriately
Access to trained and skilled medical staff to direct treatment program and
provide close supervision
Avoid or Use Cautiously in Patients Who Are Predisposed to Severe
Hypoglycemic Reactions or in Whom Such Reactions Could be Fatal
Patients with counter-regulatory insufficiency
-Adrenergic blocker therapy
Autonomic insufficiency
Adrenal or pituitary insufficiency
Patients with coronary or cerebral vascular disease
(Note: Counter-regulatory hormones released in response to hypoglycemia
may have adverse effects in these individuals)
Unreliable, noncompliant individuals, including those who abuse alcohol or
drugs and those with psychiatric disorders

PENETAPAN DOSIS
INSULIN

Estimating Total Daily Insulin Requirement

Type 1 diabetes
Initial dose

0.30.5 unit/kg

Honeymoon phase

0.20.5 unit/kg

With ketosis, during illness, during

growth
Type 2 diabetes

1.01.5 units/kg

With insulin resistance

0.71.5 units/kg

Estimating Basal Insulin Requirements

Basal requirements vary throughout the day,approximately 50% of total
daily insulin needs. The basal requirement also is influenced by the
presence of endogenous insulin, the degree of insulin resistance, and body
weight.

ESTIMATING INSULIN DOSE

(CONT)
Estimating Premeal Insulin Requirements
The 500 rule estimates the number of grams of
carbohydrate that will be covered by 1 unit of rapid-acting
insulin. The rule is modified to the 450 rule if using
regular insulin.
500/total daily dose of insulin (TDD) = number of grams
covered
Example: For a patient using 50 U/day, 500/50 = 10.
Therefore, 10 g carbohydrate would be covered by 1 unit of
insulin lispro, glulisine, or aspart. This equation works very
well for type 1 patients in estimating their premeal insulin
requirements. Because patients with type 2 diabetes have
insulin resistance, the rule may underestimate their insulin
requirements.

ESTIMATING INSULIN DOSE

(CONT)
Determining the Correction Factor
For example, if the premeal or bedtime blood glucose target is 140
mg/dL and the patient's value is 190 mg/dL, additional units of insulin
might be added to the premeal dose or an additional supplemental
bedtime dose of rapid-acting insulin might be given. The correction
factor determines how far the blood glucose drops per unit of insulin
given and is known as the 1700 rule. For regular insulin, the rule is
modified to the 1500 rule. The equation is as follows:
1700/TDD = point drop in blood glucose per unit of insulin
Example: If a patient uses 28 U/day of insulin, their correction factor
(or insulin sensitivity) would be 1700/28 = 60 mg/dL. Therefore, the
patient can expect a 60 mg/dL drop for every unit of rapid acting
insulin administered. Patients with a higher sensitivity factor have
lower insulin requirements. Individuals with a lower sensitivity factor
(higher insulin requirements) typically achieve a smaller reduction in
blood glucose per unit of insulin.

Guidelines for Dosing Insulin

Basic Insulin Dose
Adjust the basic insulin dose (i.e., the dose that the patient will
be instructed to take daily). This assumes that diet and physical
activity are stable. Set a reasonable goal initially. This may mean
the upper limits of the acceptable concentrations may be high
initially (e.g., <200 mg/dL).
Move toward a more ideal goal slowly.
Only adjust insulin doses if a pattern of response is observed
under stable diet and exercise circumstances. That is, the same
response to insulin is observed for 3 days.
Unless all levels are >200 mg/dL, try to adjust one component of
insulin therapy at a time. Start with the insulin component
affecting the fasting blood glucose concentration.
Adjust the basic insulin dose by 12 units at a time. The amount
prescribed is based on the individual patient's response to insulin.
This can be determined by looking at the patient's total daily
dose using the 500 rule (see the following, and Table 50-11).

Guidelines for Dosing Insulin

(CONT)

Supplementary Insulin Doses

Once the basic dose of insulin has been established, supplemental
doses of rapid- or short-acting insulin can be prescribed to correct
preprandial hyperglycemia. For example, if the goal is 140 mg/dL, and
the glucose value is 190 mg/dL, administer one additional unit.
Supplemental doses also can be used when the patient is ill (Table 5022). Algorithms for correction doses are based on the patient's
sensitivity to insulin using the 1500 or 1700 rule (Table 50-11). If
premeal glucose concentrations are <6070 mg/dL, the dose of lispro,
aspart, glulisine, or regular insulin administered before the meal is
by 12 U; insulin administration is delayed until just before the meal;
the meal should include an extra 15 g of glucose if the value is <50
mg/dL. If supplemental doses before a given meal are required for 3
days, the basic insulin dose should be adjusted appropriately. For
example, if a patient taking lispro before meals requires an extra 2
units before lunch for 3 days, 2 units should be added to the
prebreakfast dose.

Guidelines for Dosing Insulin

(CONT)

Anticipatory Insulin Doses The

basic insulin dose is increased or
decreased based on the anticipated
effects of diet or physical activity.
Increase lispro/aspart/glulisine or
regular insulin by 1 unit for each
additional 15 g of carbohydrate
ingested (e.g., holiday meal) or
decrease the usual dose by 12 units
if the meal is smaller than usual

Kasus 1
Tn HM 58th 160cm 85kg, MRS karena
akan menjalani ops katarak. Pada
saat MRS hasil pemeriksaan gula
puasa 216mg/dl, GD 2jamPP
234mg/dl. Menurut pengakuan Tn
HM memang memiliki riwayat DM,
namun tidak kontrol rutin, obatpun
tidak rutin dan lebih sering meminum
Glibenklamide.

Kasus 2
Tn Y, 46th 167cm, 70kg, MRS dengan
keluhan mual muntah. Pada
pemeriksaan gula puasa di lab luar
dijumpai FPG 253mg/dl; 2jPP 315
mg/dl. Pasien mengaku memiliki
riwayat DM sudah lima tahunan
dengan obat Glibenklamide 1-1-0
dan metformin 3x500mg.
Bagaimana Pharm care untuk kasus
ini?

Kasus 3
Tn K 59th, 172cm 75kg, MRS dengan
keluhan kencing tidak lancar, disertai
rasa panas dan nyeri pada saat
kencing. Pasien mengaku memiliki
DM sudah 8tahun dan masih minum
Gliklazide 1-1-0 dan Metformin 3 x
850mg. Hasil lab: FPG 265mg/dl; 2JPP
168mg/dl; Leukosit (N),
Leukosuria(+). Hasil observasi TTV
TD 140/90; Temp (N). Bagaimana

Kasus 4
Tn N 44th 168m, 78kg MRS karena
hasil SMBG puasa 328mg/dl. Pasien
selama ini sudah menggunakan
Humulin N 24-0-16 U. Bagaimana
rekomendasi penatalaksanaan pada
kasus tersebut.

Kasus 5
Tn KP 62th, 161cm, 59kg MRS
dengan diagnosa stroke infark di
hemisphere kanan yang luas. Hasil
Lab GDP 154mg/dl sehingga
diberikan 3 x 4U s.c., namun 2 hari
kemudian pasien kejang dan hasil
GDP 189mg/dl. Pengakuan keluarga
pasien hanya memakan makanan RS.
Bagaimana dengan penatalaksanaan
DM?