CHAPTER 4: INSULIN THERAPY IN TYPE 2 DIABETES MELLITUS

4.1 INTRODUCTION

The majority of people with type 2 diabetes may require insulin administration at some stage of
their natural history of diabetes. Type 2 diabetes is a progressive disease characterised by insulin
resistance and a decreasing ability of pancreatic beta cells to produce insulin that contributes to
hyperglycaemia. The progressive decline in beta cell functions ultimately causes oral agents to be
ineffective and a majority of patients require exogenous insulin treatment.

A large ten year population-based study of treatment practices for people with type 2 diabetes in
the United Kingdom, reported a median delay of 7.7 years between introduction of the first oral
medicine and the initiation of insulin. Therefore, this report concluded that many patients may
benefit from earlier transition from oral medicine to insulin 1. Other studies suggested that if insulin
was initiated early enough then β-cell damage and disease progression could be slowed down2,3.

4.2 INSULIN PREPARATIONS

Insulin currently available in Malaysia is recombinant human insulin either derived from the native
human insulin (regular human insulin) or structurally modified (insulin analog). These include the
following types of insulin:

 Rapid
 Short
 Intermediate
 Long Acting

Insulin is further divided into prandial, basal and premixed insulin based on their pharmacokinetic
profiles (Table 4.1).

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  Prandial Insulin – Administered as pre meal. It has short or rapid onset of action for
controlling the post-prandial glucose.
 Basal Insulin – Administered once or twice a day. The intermediate or long acting
insulin covers the basal insulin requirements in between meals and overnight due to
endogenous hepatic glucose production.
 Premixed Insulin – Preparations containing a fixed ratio of short-acting and
intermediate-acting forms of insulin, designed to be given either once or twice a daily
to cover both postprandial glucose and basal insulin needs simultaneously.

Table 4.1: Insulin preparations available in Malaysia.

Insulin Type Human Insulin Analog

Prandial Short acting regular human insulin Rapid Acting

 Actrapid®  Aspart (Novorapid®)
 Humulin R®  Lispro (Humalog®)
 Insuman Rapid®  Glulisine (Apidra®)

Basal Intermediate acting or Neutral Long Acting

Protaminated Hagedorn (NPH)  Glargine (Lantus®)
 Insulatard®  Levemir (Determir®)
 Humulin N®
 Insuman Basal®

Premixed Combination of short and Combination of rapid acting and

intermediate acting [30% regular protaminated analogue
human insulin, 70% isophane (NPH)  Novomix 30®(30% aspart & 70%
insulin] aspart protamine)
 Mixtard®  Humalog Mix 25®(25% lispro &
 Humulin 30/70® 75% lispro protamine)
 Insuman Combo 30®  Humalog Mix 50® (50% lispro &
50% lispro protamine)
 Insuman Basal®

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4.3 INSULIN ANALOGS

Insulin analogs are derived from human insulin, however the amino acid sequences are altered to
produce an improved pharmacokinetic profile. Newer insulin analogs mimic the profile of
endogenous insulin more closely, hence more predictable and consistent than conventional insulin
and allowed simplified insulin replacement strategies. Rapid-acting preparation shows faster onset
and shorter duration of action. Structural changes of long-acting analogs, delay the onset of action,
allow slow and continuous absorption into the systemic circulation and prolong the duration of
action. Thus, analogs can reduce the incidence of hypoglycaemia and post-prandial
hyperglycaemia, yet it will not hinder a molecule’s ability to control blood glucose level in the
body.

Table 4.2: Pharmacokinetic and pharmacodynamic profiles of various types of insulin4,5

Types of Insulin Onset Peak (Hr) Duration Administration Appearance

(Hr) relation to meals
Short Acting Insulin

 Actrapid® 30 min 1-3 8 30 minutes before Clear

 Humulin R® 2-4 6-8 meal
 Insuman Rapid® 1-4 7-9

Rapid Acting Insulin Analogue

 Aspart (Novorapid®) 10-20 min 1-3 3-5 5-15 min before or Clear
 Lispro (Humalog®) 0-15 min 1 3.5-4.5 immediately after
 Glulisine (Apidra®) 5-15 min 1-2 3-5 meal

Intermediate acting or Neutral Protaminated Hagedorn (NPH)

 Insulatard® 1.5 Hr 4-12 18-23 Pre breakfast / pre Cloudy
 Humulin N® 1 Hr 4-10 16-18 bed
 Insuman Basal® 1 Hr 3-4 11-20

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 Types of Insulin Onset Peak (Hr) Duration Administration Appearance
(Hr) relation to meals
Long Acting

 Glargine (Lantus®) 2-4 Hr peakless 20-24 Same time Clear

 Levemir (Determir®) 1 Hr 17-23 everyday at
anytime of the day
Combination of short and intermediate acting
 Mixtard® 30 min Dual 18-23 30 minutes before Cloudy
 Humulin 30/70® 16-18 meal
 Insuman Combo 30® 11-20

Combination of rapid acting and protaminated analogue

 Novomix 30® 10-20 min 1-4 18-23 5-15 min before Clear
 Humalog Mix 25® 0-15 min 1-6 16-18 meals
 Humalog Mix 50®

Figure 4.1: Pharmacokinetic profiles of human insulins compared with insulin analogs and
endogenous insulin.

Abbreviation: Hr, hour; NPH, neutral protamine Hagedorn.

Source: Data for graph were extracted from US Pharmacist5

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4.4 INSULIN REGIMEN

An ideal insulin should mimic the physiological insulin response to meals and endogenous
hepatic glucose production. The choice of insulin regimen should be individualized to suit
the patient’s glycaemic profile, dietary pattern, lifestyle as well as patient’s desired
flexibility. Basal-bolus regimen is most closely mimics the endogenous insulin action at
the expensed of increased number of injections (Figure 4.2).

Ideal Insulin Replacement Strategy

Breakfast Lunch Dinner

Natural Insulin Secretion

2 4 8 9 11 12 13 14 15 16 17 18 20 21 24 4 3 2

Figure 4.2: Ideal insulin replacement strategy. Adapted from:Polonsky. N Engl J Med. 1996:334:777-7836

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 The various types of insulin regimen can be classified as below (Table 4.3)

Table 4.3: Insulin regimens and frequency of injections per day

NUMBER OF INSULIN
TYPES OF INSULIN & TIMING
INJECTIONS REGIMEN

Basal Intermediate-acting (NPH) prebed

1 Basal Long-acting analogue OD
Premixed OD Premixed / premixed analogue predinner
Basal Intermediate-acting (NPH) prebreakfast&predinner
2 Premixed BD Premixed insulin prebreakfast&predinner
Basal -Plus (1) Basal insulin OD + 1 prandial insulin
Basal-Plus (2) Basal insulin OD + 1 prandial insulin
Prandial Prandial insulin prebreakfast, prelunch&predinner
Premixed TDS Premixed analogue prebreakfast, prelunch&predinner
3 Premixed insulin prebreakfast&predinner + 1 prandial
Premixed-Plus
insulin prelunch
Prandial insulin prebreakfast&prelunch + Premixed
Premixed-Plus
insulin predinner
Basal insulin OD + prandial insulin prebreakfast,
4 Basal-bolus
prelaunch & predinner
Intermediate-acting (NPH) insulin prebreakfast &
5 Basal -bolus predinner + prandial insulin prebreakfast, prelunch &
predinner

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4.5 INSULIN INITIATION, OPTIMISATION AND INTENSIFICATION

A three stage process is involved in implementing successful insulin therapy:

 Initiation – Starting insulin, Selection of regimen, type and initiation of dose must address
the individual’s glycaemic problem.
 Optimisation - Gradual dose titration according to SMBG towards optimum dose to ensure
maximum benefit from prescribed treatment.
 Intensification - Modification of regimen or switching to more intensive regimen to
achieve better glycaemic control.

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 NEWLY DIAGNOSED T2DM :
- symptomatic (osmotic symptoms) regardless of HbA1c and FBG
- HbA1c > 10% or FPG > 13 mmol/L
T2DM ON MAXIMAL OADs : - HbA1c > 7%

Glycemic
abnormality?
(FPG, SMBG)

Normal fasting High fasting High fasting

High daytime BG Normal daytime BG High daytime BG

Start PREMIXED BD Start BASAL-BOLUS

Start BASAL only Start PREMIXED OD
(pre-breakfast & (pre-meals &
Start PRANDIAL (bedtime) (pre-dinner)
pre-dinner) bedtime)
only (usually TDS) Optimise dose Optimise dose
Optimise dose Optimise dose
Optimise dose
Sequential Add 3
addition of prandial
prandial BASAL PLUS (pre- insulin PREMIXED TDS PREMIXED BD +
insulin meals & bedtime) (pre-meals) PRANDIAL (pre-
Add lunch) Optimise
Optimise dose Optimise dose
basal dose
insulin

BASAL-BOLUS (prandial insulin at pre-meals, basal insulin at bedtime). Optimise dose

Figure 4.3: Initiation and optimisation of insulin therapy8

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4.5.1 Insulin Initiation8

• When oral anti-diabetics fail, adding basal insulin to patient’s regimen can improve
glycaemic control and lowers HbA1c.
• Targeting the fasting plasma glucose using the concept of 3Fs – Fixing the Fasting First.
• Premixed insulin can be initiated for patients who desire an easier regimen but can cope
with rigidity of lifestyle.
• Issues to address when initiating insulin- type of regimen, type of insulin, starting dose,
time of insulin injection, time for self-monitoring of blood glucose, target blood glucose
and dose adjustment.
• The insulin regimen and insulin doses initiated are individualized, based on blood glucose
profile, patient’s lifestyle and preference.

Table 4.4: Selecting initial insulin regimen based on blood sugar profile
BLOOD GLUCOSE
PROFILE
PREFERRED INSULIN REGIMEN
PRE- DAYTIME
BREAKFAST
High Normal Pre-bed immediate / long-acting insulin (Basal)

Pre-bed immediate / long-acting insulin and later add short or

rapid-acting insulin(Basal → Basal Plus) or (Basal → Basal-
High High
Bolus)

Pre-breakfast and pre-dinner premixed insulin(Premixed BD)

Prandial short / rapid-acting insulin and later add on basal

Normal High
insulin (Prandial → Basal Plus) or (Prandial → Basal-Bolus)

4.5.2 Initiating and Optimising Pre-bed Intermediate / Basal insulin

 Start the pre-bed intermediate/basal insulin at 10 units per day, or alternatively, start
based on body weight at 0.2 units/kg8,9
 Patients are advised to perform SMBG at pre-breakfast.

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Table 4.5: Initiating insulin with basal insulin

TREATMENT DOSE

10 IU or 0.2 IU/kg at bedtime

INITIATION
(0.1 IU/kg if higher risk for hypoglycaemia)

MONITORING & Monitor pre-breakfast blood glucose (BG)

TARGETS (target pre-breakfast BG 4.4 – 7.0 mmol/L)

Adjust insulin doses after 3 consecutive BG values obtained (every 3-7

days)
• < 4 mmol/L (> 1 value) → reduce dose by 2 IU
OPTIMISATION
• 4 – 6 mmol/L (all values) → maintain current dose
• > 6 mmol/L (> 1 value, no hypoglycaemia) → increase dose by 2
IU

0.2 – 0.3 IU/kg in lean patients

OPTIMAL DOSE 0.4 – 0.5 IU/kg in most patients
Up to 0.7 IU/kg in obese patients

Watch for nocturnal hypoglycaemia. If hypoglycaemia is the limiting

CAUTION factor to achieve optimal dose, conventional intermediate-acting
insulin may be switch to basal insulin analog.

4.5.3 Initiating and Optimising Premixed Insulin

 Premixed insulin may be initiated once daily, usually at pre-dinner or twice daily at pre-
dinner and pre-breakfast
 The initial dose for once daily premixed insulin is usually 10 units or 0.2 units/kg
administered usually pre-dinner
 The initial dose for twice daily premixed insulin is usually 10 units or 0.2 units/kg twice
daily administered at pre-breakfast and pre-dinner

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Table 4.6: Initiating insulin with Premixed Insulin

TREATMENT DOSE

Once daily : 10 IU or 0.2 IU/kg at pre-dinner

INITIATION Twice daily : 10 IU or 0.2 IU/kg at pre-breakfast and pre-dinner
(0.1 IU/kg if higher risk for hypoglycaemia)

Once daily : monitor pre-breakfast BG

MONITORING &
Twice daily : monitor pre-breakfast and pre-dinner BG
TARGETS
(target pre-meal BG 4.4 – 7.0 mmol/L)

Adjust insulin doses after 3 consecutive BG values obtained (every 3-7

days)
• < 4.4 mmol/L (> 1 value) → reduce dose by 2 IU
OPTIMISATION • 4.4 – 7.0 mmol/L (all values) → maintain current dose
• > 7 mmol/L (> 1 value, no hypoglycaemia) → increase dose by 2 IU
Pre-breakfast BG determine pre-dinner dose adjustment
Pre-dinner BG determine pre-breakfast dose adjustment

Total daily dose 0.5 – 1 IU/kg in most patients

OPTIMAL DOSE
(may require > 1 IU/kg in obese, insulin-resistant patients)

Watch for in-between meal hypoglycaemia. If hypoglycaemia is the

CAUTION limitng factor to achieve optimal dose, conventional premixed insulin
may be switch to premixed analog.

4.5.4 Initiating and Optimising Prandial Insulin

 Prandial insulin therapy can be initiated at a dose of 6 units per meal, or based on body
weight at 0.1units/kg per meal administered 30 minutes prior (short-acting insulin) or just
before (rapid-acting analogue) the meal.
 Optimisation of prandial insulin doses are dependent on
o meal types and amount and
o pre-meal blood glucose levels.

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Table 4.7: Initiating insulin with Prandial Insulin

TREATMENT DOSE

6 IU or 0.1 IU/kg for each meal with short-acting or rapid-acting

INITIATION
analogue
Pre-meal and pre-bed
MONITORING & (post-meal 1.5 to 2 hours if using rapid-acting analogue)
TARGETS Target pre-breakfast BG 4.4 – 7 mmol/L
Target post-meal and pre-bed BG 4.4-8.5 mmol/L
Adjust insulin doses after 3 consecutive BG values obtained (every 3-7
days)
• < 4.4 mmol/L (> 1 value) → reduce dose by 2 IU
• 4.4 – 7 mmol/L (all values) → maintain current dose
OPTIMISATION
• > 7 mmol/L (> 1 value, no hypoglycaemia) → increase dose by 2
IU
Adjust the dose of prandial insulin of the preceding meal
(eg. If pre-lunch BG is high, adjust pre-breakfast prandial insulin dose)

Prandial dose for each meal will vary according to carbohydrate content
OPTIMAL DOSE
and amount. Dose ideally should not exceed 0.5 IU/kg/dose

Watch for in-between meal hypoglycaemia. If hypoglycaemia is the

CAUTION limiting factor to achieve optimal dose, conventional short-acting insulin
may be switch to rapid-acting analog.

4.5.5 Initiating and Optimising Basal Bolus Regimen

 Start the regimen by initiating prandial insulin at 0.1 U/kg or 6 units before each meal
and basal insulin at 0.2 unit/kg or 10 units at bedtime.
 Self Monitoring of Blood Glucose (SMBG) should be performed pre-meals at pre-
breakfast, pre-lunch, pre-dinner and at bedtime/pre-bed for 3 consecutive readings and
insulin dose can then be adjusted accordingly.

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Table 4.8: Initiating and Optimising Basal Bolus Regimen

TREATMENT DOSE

Prandial insulin : 6 IU or 0.1 IU/kg for each meal

INITIATION
Basal insulin : 10 IU or 0.2 IU/kg at bedtime

Preferably 4 times a day upon initiation

MONITORING & (pre-breakfast, pre-lunch, pre-dinner and pre-bed)
TARGETS Target pre-meals BG 4.4 – 7 mmol/L
Target pre-bed BG 4.4-8 mmol/L

Prandial insulin
Adjust insulin doses after 3 consecutive pre-prandial BG values
obtained (every 3-7 days)
• < 4.4 mmol/L (> 1 value) → reduce dose by 2 IU
• 4.4 – 7 mmol/L (all values) → maintain current dose
• > 7 mmol/L (> 1 value, no hypoglycaemia) → increase dose
by 2 IU
Adjust the dose of prandial insulin of the preceding meal
(eg. If pre-lunch BG is high, adjust pre-breakfast prandial insulin
dose)
OPTIMISATION

Basal insulin
Adjust insulin doses after 3 consecutive BG values obtained (every
3-7 days)
• < 4.4 mmol/L (> 1 value) → reduce dose by 2 IU
• 4.4– 7 mmol/L (all values) → maintain current dose
• > 7 mmol/L (> 1 value, no hypoglycaemia) → increase dose
by 2 IU
Aim for normal pre-breakfast BG first by adjust dose of bedtime
basal insulin before adjusting the prandial (bolus) insulin dose

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 Generally basal insulin would contribute 50% of total daily insulin
dose and prandial insulin would contribute the remaining 50%
(distributed over 3 main meals).
Prandial insulin
Dose for each meal will vary according to meal carbohydrate
OPTIMAL DOSE content.
Normal prandial dose should not exceed 0.5 IU/kg/dose.
Basal insulin
0.2 – 0.3 IU/kg in lean patients
0.4 – 0.5 IU/kg in most patients
Up to 0.7 IU/kg in obese patients

 There is no limit for insulin dose.

 However, requirement for high dose insulin (>1.5 IU/kg/day) should prompt
investigation for underlying causes or secondary problems : non-compliance, incorrect
dosing and administration timing, hypertrophy of injection area, inter-meal
hypoglycemia with rebound pre-meal hyperglycemia, expired insulin, inappropriate
type of insulin, improper SMBG or occult infection.

4.6 INSULIN INTENSIFICATION8

Type 2 diabetes mellitus (T2DM) is a progressive disease, with increasing duration of DM,
there will be increasing fasting and post-prandial hyperglycaemia due to progressive
pancreatic beta-cell failure. Therefore, insulin therapy needs to be a dynamic process to
address progressive insulin deficiency. The use of single insulin regimen may not ensure
durable glycaemic control over time despite optimisation of insulin dose. Intensification
enables modification of an insulin regimen, either with additional injections or switching
to different insulin types, towards achieving better glycaemic control. Insulin
intensification can be done in various ways, depending on pre-existing insulin regimen, the
abnormal glycaemic pattern, patient acceptance and lifestyle issues (Table 4.9).

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Table 4.9: Insulin intensification

EXISTING REGIMEN INTENSIFICATION

Basal ON Basal BD

Basal OD Premixed BD

Basal OD Basal + 1 Prandial

Basal OD Basal – Bolus

Premixed OD Premixed BD

Premixed BD Premixed TDS (analogue only)

Premixed BD Premixed BD + 1 Prandial

Premixed BD Basal – Bolus

Prandial TDS Basal – Bolus

4.6.1 Insulin intensification from basal insulin

Insulin intensification can be made from basal insulin to basal-plus, basal bonus and
premixed insulin (Figures 4.4 – 4.7).

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 BASAL

BASAL PLUS (1
PREMIXED BD BASAL-BOLUS
PRANDIAL)

BASAL PLUS (2
PRANDIAL)

BASAL-BOLUS

Figure 4.4: Intensification from basal to basal-plus

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a. Intensification from basal to basal-plus

 Fix Fasting Blood Glucose (FBG) first using basal insulin (dose
optimisation)
 Goal FBG 4 – 6 mmol/L
 Consider adding bolus / prandial insulin when :
HbA1c > 7% and FBG at goal or basal insulin dose > 0.5 IU/kg

 Add prandial insulin 6 IU or 0.1 IU/kg at the largest meal

 Titrate to next pre-meal / pre-bed BG target daily
 If subsequent pre-meal BG are :
< 4 mmol/L (> 1 value) → reduce dose by 2 IU
4 – 6 mmol/L (all values) → maintain current dose
> 6 mmol/L (> 1 value, no hypoglycemia) → increase dose by 2 IU
 Discontinue sulphonylurea after adding prandial insulin
 Continue metformin
Patient may need to perform SMBG up to 4 times/day

If HbA1c > 6.5 – 7% after 3 months despite dose titration or prandial

dose > 30IU/meal, consider:
 Add a second prandial at 6 IU or 0.1 IU/kg at second largest meal and
titrate
 Repeat 3rd prandial dose at final meal of the day

Figure 4.5: Algorithm of Intensification from basal to basal-plus

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b. Intensification from basal to basal-bolus

 Fix Fasting Blood Glucose (FBG) first using basal insulin (dose
optimisation)
 Goal FBG 4 – 6 mmol/L
 Consider adding bolus / prandial insulin when :
HbA1c > 7% and FBG at goal or basal insulin dose > 0.5 IU/kg

 Add prandial insulin 6 IU or 0.1 IU/kg at the largest meal

 Titrate to next pre-meal / pre-bed BG target daily
 If subsequent pre-meal BG are :
< 4 mmol/L (> 1 value) → reduce dose by 2 IU
4 – 6 mmol/L (all values) → maintain current dose
> 6 mmol/L (> 1 value, no hypoglycemia) → increase dose by 2 IU
 Discontinue sulphonylurea after adding prandial insulin
 Continue metformin
Patient may need to perform SMBG up to 4 times/day

If HbA1c > 6.5 – 7% after 3 months despite dose titration or prandial

dose > 30IU/meal, consider:
 Resume titration / optimisation of basal insulin up to 0.7 IU/kg
 Perform 7-point BG profile

Figure 4.6: Algorithm Intensification from basal to basal-bolus

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 c. Intensification from basal to premixed

Basal OD or BD

HbA1c 6.5 – 8% HbA1c > 6.5 – 7%

FPG > 6 mmol/L FPG 4 - 6 mmol/L

Titrate basal insulin to achieve FPG < 6  Switch to Premixed BD

mmol/L  Total dose transfer

 Optimal dose 0.4 – 0.5 IU/kg
 Continue OADs
 Split dose 50:50 pre-breakfast : pre-
dinner
 Titrate dose once / twice per week to
next pre-prandial dose
 Stop SU. Continue metformin
 Consider premixed analogue*

Figure 4.7: Algorithm Intensification from basal to premixed

Premixed analogs may be considered in patients experiencing hypoglycaemia when on

conventional premixed insulin and in those who desire greater flexibility (premixed analogs
can be injected prior to, during or immediately after a meal).

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4.6.2 Insulin intensification from premixed insulin

Insulin intensifcation from premixed insulin is shown in Figure 4.8 – 4.11.

PREMIXED OD

PREMIXED BD

PREMIXED BD PREMIXED
+ PRE-LUNCH TDS BASAL-BOLUS
(PRANDIAL) (ANALOGS)

Figure 4.8: Insulin intensification from premixed insulin

a. Intensification from premixed to basal-bolus

Appropriate for patients who require greater flexibility in dose adjustment as it
allows pre-meal insulin to be adjusted individually according to blood glucose level

Premixed BD or TDS (analogs)

FPG / pre-meals > 6 mmol/L

HbA1c > 6.5 – 7%

Switch to Basal-Bolus regimen:

 Starting dose 0.5 IU/kg/day or total dose transfer
 Split dose 50 : 50 for basal : prandial insulin
 Divide prandial doses into 3 main meals
 Fix FPG < 6 mmol/L using basal insulin
 Titrate bolus/prandial dose once/twice a week to achieve FPG and
pre-prandial goal < 6 mmol/L
 Continue Metformin

Figure 4.9: Algorithm intensification from premixed to basal-bolus

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 b. Intensification from single to multiple premixed regimen

Premixed OD (pre-dinner) or BD

FPG and/or pre-dinner > 6 mmol/L

FPG and/or pre-dinner 4 - 6 mmol/L
Titrate premixed OD or BD to achieve FPG
HbA1c >6.5-8%
and/or pre-dinner < 6 mmol/L

SWITCH TO PREMIXED BD OR TDS (ANALOGS ONLY)

DAILY (OD) → TWICE DAILY (BD)
 Starting dose 0.3 IU/kg/day or total
dose transfer
 Split the dose 50:50 (pre-breakfast :
pre-dinner)
 Titrate insulin dose to achieve FPG
and pre-dinner < 6 mmol/L
TWICE DAILY (BD) → THREE TIMES
DAILY (TDS)
 Add 6 IU or 10% TDD at pre-lunch
 Titrate dose once / twice a week to
next pre-prandial goal < 6mmol/L
 Down titrate morning dose (2 -4 IU)
may be needed after adding lunch
dose
 Continue Metformin

Figure 4.10: Algorithm intensification from single to multiple premixed regimen

21
 c. Intensification by adding insulin to premixed regime

Premixed OD (pre-dinner) or BD

Premixed BD (pre-breakfast and pre-

Premixed OD (pre-dinner)
dinner)

FPG 4 – 6 mmol/L
Pre-breakfast and pre-dinner > 6 Pre-dinner > 6 mmol/L
mmol/L ADD PRANDIAL INSULIN
ADD PRANDIAL INSULIN (pre-lunch)
(pre-breakfast and pre-lunch)

 Add prandial insulin 6 IU or 0.1 IU/kg at lunch

 Titrate to pre-dinner BG target daily
 If subsequent pre-meal BG are :
< 4 mmol/L (> 1 value) → reduce dose by 2 IU
4 – 6 mmol/L (all values) → maintain current dose
> 6 mmol/L (> 1 value, no hypoglycaemia) → increase dose by 2 IU

Figure 4.11: Algorithm intensification of adding insulin to premixed regime

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4.6.3 Intensification of prandial regime with addition of basal insulin

Steps in the intensification of prandial regime with addition of basal insulin is shown in
Figure 4.12.

PRANDIAL TDS
(optimised prandial doses)

FPG > 6 mmol/L

HbA1c > 6.5 – 8%

ADDITION OF BASAL INSULIN → BASAL-BOLUS REGIMEN

 10 IU of 0.2 IU/kg at pre-dinner
 Monitor FPG to target 4 – 6 mmol/L
 Adjust basal insulin doses after 3 consecutive BG values (every 3 – 7
days) :
< 4 mmol/L (> 1 value) → reduce dose by 2 IU
4 – 6 mmol/L (all values) → maintain current dose
> 6 mmol/L (> 1 value, no hypoglycemia) → increase dose by 2 IU

Figure 4.12: Algorithm intensification of prandial regime with addition of basal insulin

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4.7 INSULIN SIDE EFFECT 8,9,10

a. Hypoglycemia
b. Weight gain
c. Allergy
d. Lipoatrophy / lipohypertrophy

4.8 GENERAL GUIDELINES FOR LONG TERM USE OF INSULIN 8,10

 Factors to be considered before dose adjustment:

i. Insulin technique and side effect of insulin
ii. Diet or meal
iii. Exercise
iv. Infection or other elevated causes
v. Somogy effect or dawn phenomenon
 Insulin can, when used in adequate doses, decrease any level of elevated HbA1c to, or
close to, the therapeutic goal. There is no maximum dose of insulin beyond which a
therapeutic effect will not occur. Relatively large doses of insulin (≥1 unit/kg), may be
necessary to overcome the insulin resistance of T2DM and to reduce HbA1c to the
target level.
 Requirement of high insulin dose (>1.5 unit / kg per day) should prompt a search for
an underlying cause or secondary problems such as: non-compliance, incorrect dosing
and administration timing, hypertrophy of injection area, inter–meal hypoglycaemia
with rebound hyperglycaemia pre-meal, expired insulin, inappropriate insulin or
inaccurate blood glucose monitoring and occult infections.
 The rate of absorption from the injections depend on the site and ‘exercise activity’ of
the ‘site’. Patients should be encouraged to rotate all their injection sites in the
abdomen region.
 The basal intermediate-acting insulin should be administered pre-bed (preferably not
earlier that 10.00 pm) due to risk of hypoglycaemia in the early hours if given earlier.
 It is not necessary to have an extra meal or snack after intermediate or long-acting
insulin.
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  Self- monitoring blood glucose (SMBG) should be carried out at least 3-4 times daily
in patients on multiple insulin injections or insulin pump therapy i.e. before each meal
and before bed (10-11 pm) [Table 5]. Once pre-prandial glucose targets are achieved,
post-prandial glucose testing is recommended for fine-tuning of insulin therapy.

Table 4.10: SMBG for basal/basal bolus regimen8

Fasting Post Pre Post Pre Post Pre
breakfast lunch lunch dinner dinner bed

Basal Insulin X

Basal Bolus X X X X
(short acting
insulin)
Basal bolus X X X X
(rapid acting
insulin)

4.9 INSULIN PUMP 10,11

a. Continuous subcutaneous insulin infusion (CSII) or insulin pump:

 Another method to deliver insulin to diabetes patients.
 Intended to closely mimic physiological insulin profile.
 Utilises only rapid-acting insulin and eliminates the need of basal insulin.
 Safe and effective and can be initiated at any age.
 Combination use of insulin pump and continuous glucose sensor resulted in
improved control and less hypoglycaemia compared to basal-bolus therapy
alone.
b. Indication for insulin pump:
 Inadequate glycaemic control with multiple daily injections (MDI)

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  Recurrent severe hypoglycaemia
 Hypoglycaemia unawareness
 Dawn phenomenon
 Gastroparesis
 Frequent diabetic ketoacidosis
c. Patient’s pre-requisite for insulin pump
 Motivated with strong desire to improve his/her health.
 Demonstrates independent diabetes self-management.
 Able to practise carbohydrate counting and understands basic insulin action.
 Demonstrates emotional stability, able to attend education sessions and clinic
appointments.

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REFERENCES

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hypoglycaemic agents or insulin in primary care: retrospective cohort study. Br J Gen
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2. Hirsch I, Bergenstal R, Parkin C, et al. A real-world approach to insulin therapy in
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Insulin Secretion. J Am Osteopath Assoc. 2009;109:26-36
5. How to initiate, titrate, and intensify insulin treatment in type 2 diabetes.US Pharm.
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http://prod.uspharmacist.com/content/t/diabetes/c/10215/. Accessed December 10, 2008.
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Genetically Programmed Failure of the Beta Cell to Compensate for Insulin
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Ann Intern Med. 2006;145:125-134.
8. Practical Guide to Insulin Therapy in Type 2 Diabetes Mellitus. Malaysia 2010.Print.
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10. Clinical Practice Guidelines (CPG) on Management of type 2 Diabetes Mellitus (5th
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2014.Print

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