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FOREWORD
PREFACE
GUIDE OBJECTIVES
GUIDE WORKING COMMITTEE
EXTERNAL REVIEWERS
SUMMARY OF TREATMENT ALGORITHM
i
ii
iii
iv
v
vi
SECTION 1
BACKGROUND
SECTION 2
SECTION 3
10
SECTION 4
15
SECTION 5
SECTION 6
22
INSULIN INTENSIFICATION
(SWITCHING INSULIN REGIMENS)
31
6.1 Switching from basal to basal plus regimen
6.2 Switching from basal to basal bolus regimen
6.3 Switching from basal to premixed regimen
6.4 Switching from premixed to basal bolus regimen
6.5 Switching from single to multiple premixed regimen
6.6 Intensification of premixed regimen with addition
of pre-meal bolus
6.7 Intensification of prandial regimen with addition
of basal insulin
TABLE OF CONTENTS
SECTION 7
42
SECTION 8
48
SECTION 9
SPECIAL SITUATIONS
9.1
Sick days
9.2
Travel
9.3
Exercise
9.4
Fasting (Ramadan)
9.5
Pregnancy
55
64
APPENDIX
75
Carbohydrate counting
INDEX
77
GLOSSARY OF TERMS
81
ACKNOWLEDGEMENTS
82
SOURCES OF FUNDING
82
FOREWORD BY
THE DIRECTOR GENERAL OF HEALTH OF MALAYSIA.
In Malaysia, the prevalence of diabetes mellitus among adults aged 30 years and above
had risen by almost 80% in the last decade to 14.9%. This translates to one in six adult
Malaysians above 30 years with diabetes, an estimated 1.4 million in number. It is
estimated that 95% of those with diabetes in Malaysia have Type 2 Diabetes.
With increased duration of disease, oral anti-diabetic medications often lose effective
ness and consequently there is a need to add insulin to maintain glycemic control. The
use of insulin therapy among patients with Type 2 diabetes within the Ministry of Health
has continued to increase with the recognition of the need to maintain good glycaemic
control towards prevention of long-term diabetes-related complications, as recommended by recent local and international diabetes guidelines. However, insulin use in
primary care, both public and private, is still generally low in Malaysia and varies across
different states in the country. This may be due to poor acceptance of insulin therapy
among patients and healthcare providers, probably due to lack of awareness, knowledge
and guidance. Diabetes-focused health education and counseling will definitely improve
awareness, acceptance and adherence to insulin therapy among patients with diabetes.
Despite the increase in insulin use, the majority of insulin-treated patients are not able
to attain and maintain satisfactory long-term glycaemic control, as seen from recent
audits. I understand that one of the main reasons is the lack of a standardised way in
initiating, optimising and intensifying insulin therapy. There is therefore an urgent need
to have a set of guidelines in place for this provision.
I would like to congratulate our MOHs (Ministry of Health) endocrinologists who have
worked tirelessly to develop this practical guide for insulin therapy for patients with
Type 2 diabetes. I am sure this will provide simple and clear steps for all healthcare
providers to initiate insulin safely, optimise doses well and intensify insulin regimens
promptly to ensure that insulin therapy is administered in a cost effective manner in
MOH. In addition I believe this will enable more patients to achieve and maintain good
glycaemic control, with reduction of the risk of long-term complications which equally
presents a huge economic burden.
I urge all of you to make full use of this new practical guide for insulin therapy in Type
2 Diabetes, as it represents another important clinical tool for improving quality of
diabetes care in the country.
TAN SRI DATO SERI DR. HJ. MOHD ISMAIL MERICAN
ii
PREFACE
iii
GUIDE OBJECTIVES
Objectives
The aim of the practical guide is to assist health care providers, particularly primary
care physicians in making key decisions to initiate, optimise and intensify insulin
management and decrease long-term morbidity risk in patients with Type 2 diabetes.
Clinical Questions
The clinical questions of these guidelines are:
1. Why is insulin therapy needed in Type 2 diabetes?
2. How to initiate insulin therapy?
3. How to optimize insulin doses?
4. How to intensify insulin regimens?
5. How to monitor glycemia in patients on insulin therapy?
6. What are the problems and practical issues related to insulin therapy?
Target Population
This practical guide is applicable to children, adolescents and adults with T2DM
Target Group
This practical guide is meant for all health care professionals involved in treating
patients with T2DM which includes medical officers, family medicine specialists,
primary care physicians, general practitioners, public health personnel, general
physicians, endocrinologists, cardiologists, nephrologists, neurologists, geriatricians,
obstetricians and gynaecologists, paediatricians, ophthalmologists, nurses, assistant
medical officers, podiatrists, pharmacists, dieticians and diabetic nurse educators.
MEMBERS
(Alphabetical Order)
Consultant Endocrinologist,
Hospital Selayang
Selangor
Consultant Endocrinologist,
Hospital Seremban
Seremban
Consultant Endocrinologist,
Hospital Melaka
Melaka
Consultant Endocrinologist,
Hospital Putrajaya
Putrajaya
Consultant Endocrinologist,
Hospital Putrajaya
Putrajaya
Consultant Endocrinologist,
Hospital Ampang
Selangor
EXTERNAL REVIEWERS
Glycemic
abnormality?
FPG, SMBG
High Fasting /
prebreakfast BG
Normal daytime BG
Normal Fasting /
prebreakfast BG
High daytime BG
High Fasting /
prebreakfast BG
High daytime BG
Start
PREMIXED
OD
(predinner)
Start
PREMIXED
BD
(prebreakfast
& predinner)
Start
BASAL
BOLUS
(premeals,
bedtime)
Optimise
dose
Optimise
dose
Optimise
dose
Optimise
dose
Optimise
dose
Sequential
addition of
prandial
insulin
BASAL PLUS
(premeal and
bedtime)
Optimise dose
Start
BASAL
only
(bedtime)
Start
PRANDIAL
only
(usually TDS
premeals)
PREMIXED TDS*
(premeals)
Optimise dose
PREMIXED BD
PLUS PRANDIAL
(prelunch)
Optimise dose
BASAL BOLUS (prandial insulin at premeals, basal insulin at bedtime) Optimise dose
* refers to insulin analogues only
Note:
1. Metformin should be continued while on insulin therapy unless contraindicated or
intolerant
2. Sulphonylureas / Meglitinides should be withdrawn once prandial insulin is used
regularly with meals
3. Insulin dose should be optimized prior to switching / intensifying regimens
Section
BACKGROUND
Practical Guide to
Insulin Therapy in
Type 2 Diabetes Mellitus
BACKGROUND
In Malaysia, the Third National Health and Morbidity Survey (3rd NHMS) in
2006 showed that the prevalence of T2DM for adults aged 30 years old and
above had risen by almost 80% in the last decade to 14.9%1. In this population
survey of those with diabetes, 73.5% attended government health facilities
and 20% received treatment from private health facilities. The majority, 77%
were treated with oral anti-diabetic medications only and a mere 7% were
receiving insulin therapy at the time of the survey. The National Medicines Use
Survey (NMUS) in 2006 reported that insulin therapy contributed to only 8.2%
of overall anti-diabetic drug utilisation for the country2. These figures represent
low rates of insulin use when compared to other countries.
A nationwide audit done by the Institute of Health Management (IHM) 3, MOH in
2005 and 2008 showed that the use of insulin in MOH health facilities (primary,
secondary and tertiary) was 13% and 19% respectively, mainly prescribed in
tertiary hospitals with low use in primary and secondary care. A recent MOH
audit in primary care (NCD Diabetes Clinical Audit 2009) found that insulin use
in primary care was about 11.8% with marked differences between states. Use
of insulin therapy in tertiary care was much higher at 54%4 (DiabCare 2009) and
has doubled compared to 28% 5 (DiabCare 2003) in patients attending specialist
clinics in MOH state hospitals and academic instituitions. The NMUS also
showed that insulin use was far greater in the public sector compared to the
private sector reflecting the burden of patients seen and managed by the public
sector.
Local audits and hospital based surveys have shown that more than 80% of
patients were receiving less intensive insulin regimens. The most prescribed
regimens were the basal only insulin regimen (1 injection daily) in about 39%
of patients and premixed insulin regimen in 45% of patients. More intensive
regimens requiring 3 - 4 injections per day were prescribed in only 13% of
patients attending physician practice (IDMPS 2006) 6. The majority ( > 80%) of
patients on insulin did not achieve HbA1c of less than 6.5%. There are many
problems in our current practice with insulin therapy that represent barriers to
achieving good glycaemic control such as poor patient acceptance, treatment
inertia, hypoglycemia, inadequate dosing, lack of optimisation of insulin regimens,
inappropriate timing of injections, non-adherence to insulin regimens and others.
REFERENCES
1. The Third National Health and Morbidity Survey 2006 (NHMS III). Institute for
Public Health, National Institute of Health, Ministry of Health, Malaysia.
2. GR Letchumanan, P.K.Yap Muruga V, SP CHan, Oiyammal C, Loh KM, Ariza Z,
Emieda MH, Selva Malar, Zanariah H, M Badrulnizam. Chapter 5 Use
Antidiabetics.-Report of National Medicines Use Survey. Malaysian Statistics
on Medicine 2004 Pg 9-11. (Published April 2006).
3. Haliza AM et al. Management of patients with type 2 diabetes mellitus in
Ministry of Health hospitals and health centres. Journal of Health
Management. Vol 4 no 1/ 2008 Institute of Health Management, Malaysia.
4. Results of Diabcare(Malaysia) 2009. Novo Nordisk data on file.
5. Mafauzy M. Diabetes Control and Complications in Public Hospitals in
Malaysia. For the Diabcare-Malaysia Study Group. Med J Malaysia Vol 61
No 4 October 2006.
6. Juliana Chan et al. Multifaceted Determinants for Achieving Glycemic Control.
The International Diabetes Management Practice Study (IDMPS). Diabetes
Care 2009; (32):227-233.
Section
RATIONALE FOR
INSULIN THERAPY
IN T2DM
Practical Guide to
Insulin Therapy in
Type 2 Diabetes Mellitus
Insulin resistance and impaired insulin secretion form the two key factors to
developing T2DM. These two factors are already present at an early stage in
those with pre-diabetes, and worsen with time. At diagnosis, as seen in the
UKPDS, pancreatic beta cell function was found to be approximately 50 % of
normal, with a decline of approximately 5% per year1. It was estimated that the
reduction in beta-cell function begins 10-12 years prior to diagnosis and
approached less than 25 % of normal function 6 years after diagnosis2.
(Figure 2.1)
Figure 2.1
Progressive Decline in
Beta-cell Function in Type 2
100
75
50
25
IGT
0
-12
-10
Type 2
Diabetes
Postprandial
Hyperglycemia
-2
10
14
Figure 2.2
Overview of factors influencing stages from insulin resistance to progression
of T2DM
Lifestyle factors:
diet, exercise,
smoking, alcohol
Insulin
resistance
Genetic
factors
Glucose
toxicity
Genetic and
environmental
factors cause
susceptibility
Lipotoxicity
Beta cell
dysfunction
Amyloid
deposition
Declining beta
cell function
Progression of
type 2 diabetes
Insulin is widely accepted as the most effective treatment option available to help
people with T2DM achieve treatment targets for glycemic control. Insulin therapy
is suitable at all stages of T2DM, for all ages, and with a wide range of treatment
options and regimens. Insulin has a well documented safety profile and is generally
well tolerated in those with T2DM. The glucose lowering effects of insulin are
unmatched and no maximum dose exists. Insulin can be usefully combined with
other oral anti-diabetic agents and recently has also been shown to give
improved glycemic control when combined with the other injectable agents,
GLP-agonists or mimetics4.
Numerous randomised controlled trials and large observational studies have
shown that good glycemic control can be achieved in patients with T2DM who
are treated with insulin or insulin analogues using treatment algorithms5,6.
As most people with T2DM will ultimately require long-term insulin therapy due
to the progressive nature of the disease, it seems rational to add insulin therapy
earlier rather than later. Therefore, the Malaysian CPG on Management of T2DM
2009 recommends to initiate insulin in those newly diagnosed with HbA1c of
more than 10% or fasting blood glucose (FBS) > 13mmol/L or in those on
combination OADs who are unable to achieve target HbA1c (See Figure 2.3).
Figure 2.3
Treatment Algorithm for the Management of Type 2 Diabetes Mellitus
(From Management of T2DM CPG 2009)
OAD MONOTHERAPY
COMBINATION
THERAPY***
COMBINATION
THERAPY + BASAL
/ PREMIXED
INSULIN THERAPY
Metformin**
ORAGI / DPP-4
Inhibitor / Glinides /
SU / TZDs
Optimise dose of
OAD agent in the
subsequent 3-6
months
Follow-up with
HbA1c after 3-6
months
If HbA1c 6.5%,
continue therapy
If HbA1c > 6.5%,
consider
COMBINATION OAD
Therapy
Metformin with
other OAD agents
(AGI / DPP-4
Inhibitor / Glinides
/ Incretin Mimetic /
SU / TZDs) or with
insulin
Optimise dose of
OAD agents in the
subsequent 3-6
months
OR
INTENSIVE
INSULIN THERAPY,
continue
Metformin
Follow-up with
HbA1c after 3-6
months
If HbA1c 6.5%,
continue therapy
If HbA1c > 6.5%,
consider addition of
INSULIN THERAPY
Footnote:
If symptomatic (weight loss, polyuria, etc) at any HbA1c and FPG level, consider
insulin therapy.
Try to achieve as near normal glycaemia without causing hypoglycaemia
* Consider metformin/AGI/other insulin sensitiser in appropriate patients
** Metformin is the preferred 1st line agent, and SU should preferably not be used
as 1st line
*** Although 3 oral agents can be used, initiation and intensification of insulin
therapy is preferred based on effectiveness and expense
It is important to discuss the role of insulin therapy with your patients even at the
time of diagnosis of T2DM. (Refer Table 2.1)
Table 2.1
Issues for patient discussion at time of diagnosis - role of insulin
therapy
Introduce your patient to the eventual need for insulin so that it is
not used as a punishmnent
Type 2 DM results from insufficient insulin secretion due to beta cell
dysfunction
Over time beta cell function continues to deteriorate resulting in
increasing blood glucose levels
Elevated glucose levels can lead to diabetes complications, progression
of disease and deteriorating health
Treatment of elevated blood sugars slows the gradual worsening of
health
Insulin injections will eventually be required to replace the bodys
own insulin, control blood sugar and slow disease progression
(derived from Practical Guidance to Insulin Management Primary Care Diabetes
4 Supplement 1 ( 2010) S43 56)
Short term use of insulin therapy in patients with T2DM may also be considered
in the following conditions:
Acute illness, surgery, stress and emergencies
Pregnancy
Breast-feeding
As initial therapy in T2DM with marked hyperglycemia
Severe metabolic decompensation (eg. DKA, HHS)
REFERENCES
Section
BARRIERS TO
INSULIN THERAPY
Practical Guide to
Insulin Therapy in
Type 2 Diabetes Mellitus
11
Insulin is the most effective drug available to achieve glycemic targets in patients
with T2DM yet there is reluctance among patients and physicians to initiate
insulin. There are many barriers to insulin treatment among health care providers
and patients.
12
Possible barriers
Insulin as a
personal failure
Insulin causes
complications
and death
Insulin injections
are painful
Fear of
hypoglycaemia
Change in lifestyle
1) Restricts
independence
2) Concern of
injecting insulin in
public places
Insulin is not
effective
Insulin causes
weight gain
13
14
REFERENCES
Section
INSULIN TYPES
AND REGIMENS
Practical Guide to
Insulin Therapy in
Type 2 Diabetes Mellitus
16
Conventional
Prandial
Rapid-acting
- Novorapid (Aspart)
- Humalog (Lispro)
- Apidra (Glulisine)
Basal
Intermediate-acting or Neutral
Protaminated Hagedorn (NPH)
Insulin
- Insulatard
- Humulin N
Long-acting
- Lantus (Glargine)
- Levemir (Detemir)
Premixed
Analogue
17
Onset
Peak (Hr)
Duration
(Hr)
Timing of
insulin
30 min
30 min
1-3
2-4
8
6-8
30 mins
before meal
10-20 min
0-15 min
5-15 min
1-3
1
1-2
3-5
3.5-4.5
3-5
5-15 mins
before or
immediately
after meals
c) Intermediate-acting, NPH
- Insulatard*
- Humulin N*
1.5 Hr
1 Hr
4-12
4-10
18-23
16-18
Pre-breakfast /
Pre-bed
d) Long-acting analogue
- Glargine*
- Detemir*
2-4 Hr
1 Hr
peakless
peakless
20-24
17-23
Same time
everyday at
anytime of the
day
30 min
30 min
dual
dual
18-23
16-18
10-20 min
dual
18-23
a) Short-acting, regular
- Actrapid*
- Humulin R*
b) Rapid-acting analogue
- Novorapid (Aspart)*
- Humalog (Lispro)*
- Apidra (Glulisine)
f) Premixed analogue
- NovoMix 30
(30% aspart + 70%
aspart protamine)*
- Humalog Mix 25
(25% lispro + 75%
lispro protamine*
30-60 mins
before meals
5-15 mins
before meals
0-15 min
dual
16-18
18
19
Characteristics
Conventional
Analogue
PRANDIAL INSULIN
Onset
Delayed
Immediate
With meals
++
Inter-meal hypoglycemia
++
Inter-meal hyperglycemia
++
Dosing flexibility
++
Pharmacokinetics
Less physiological
More physiological
Lower
Higher
Administration
Postprandial glycemic control
Cost
BASAL INSULIN
Duration
Peak
Nocturnal hypoglycemia
< 24Hr
~24Hr
Pronounced
Absent / minimal
++
Absorption
Variable
Reproducible
Weight gain
++
+/- (detemir)
Less physiological
More physiological
Lower
Higher
Pharmacokinetics
Cost
PREMIXED INSULIN
Administration
Postprandial glycemic control
With meals
++
++
Dosing flexibility
++
Dosing interval
Pharmacokinetics
Less physiological
More physiological
Lower
Higher
Inter-meal hypoglycemia
Cost
20
Insulin regimen
BASAL
BASAL
PREMIXED OD
BASAL
PREMIXED BD
BASAL-PLUS (1)
BASAL-PLUS (2)
PRANDIAL
PREMIXED TDS
PREMIXED-PLUS
PREMIXED-PLUS
BASAL-BOLUS
BASAL-BOLUS
Apart from insulin pump therapy, basal bolus therapy using the combination of
long-acting basal and rapid-acting analogue offers the regimen that most closely
mimics the endogenous insulin action at the expense of increased number of
injections.
REFERENCES
21
Section
INSULIN INITIATION
AND OPTIMISATION
Practical Guide to
Insulin Therapy in
Type 2 Diabetes Mellitus
23
Pre-Breakfast
Daytime
High
Normal
High
High
Normal
High
Starting T2DM patients on basal insulin is a well established treatment option for
improving glycemic control when OADs fail2. Supplementation with basal insulin
allows the reduction of HbA1c, primarily by targeting fasting plasma glucose
(FPG) concept of 3Fs Fixing the Fasting First.
For those patients who desire an easier insulin regimen but can cope with rigidity
of lifestyle, a premixed insulin regimen can be initiated2.
24
Treatment
Dose
Initiation
Monitoring
and targets
Monitor pre-breakfast BG
Target pre-breakfast BG is at 4 - 6 mmol/L
Optimisation
Optimal dose
Caution
25
26
Treatment
Dose
Initiation
Monitoring
and targets
Optimisation
Optimal dose
Caution
27
28
Treatment
Dose
Initiation
Monitoring
and targets
Optimisation
Optimal dose
Caution
29
Treatment
Dose
Initiation
Monitoring
and targets
Optimisation
i: Prandial insulin:
Adjust insulin doses after 3 consecutive pre prandial BG values
obtained
- < 4 mmol/L ( > 1 value ) reduce dose by 2 units
- 4-6 mmol/L ( all values ) maintain current dose
- > 6 mmol/L ( >1 value, no hypos ) increase by 2 units
Adjust the dose of prandial insulin of the preceding meal
(eg: if pre-lunch BG is high, adjust pre-breakfast prandial insulin)
ii: Basal insulin :
Adjust insulin doses after 3 consecutive BG values obtained
(every 3 7 days)
- < 4 mmol/L ( > 1 value ) reduce dose by 2 units
- 4-6 mmol/L ( all values ) maintain current dose
- > 6 mmol/L ( >1 value, no hypos ) increase by 2 unit
Aim for normal pre-breakfast BG first by adjusting the dose of bedtime basal insulin before adjusting the prandial (bolus) insulin dose.
Optimal dose
There is no limitation for insulin dose5, however, 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, intermeal hypoglycemia with rebound hyperglycemia pre-meal, expired
insulin, inappropriate insulin or inaccurate BGM and occult infections.
30
REFERENCES
Section
INSULIN
INTENSIFICATION
Practical Guide to
Insulin Therapy in
Type 2 Diabetes Mellitus
32
INSULIN INTENSIFICATION
33
BASAL BOLUS
BASAL PLUS
(1 PRANDIAL)
BASAL PLUS
(2 PRANDIAL)
BASAL BOLUS
(3 PRANDIAL)
PREMIXED BD
PREMIXED TDS
(FOR ANALOGUES)
PREMIXED BD
PLUS
PRELUNCH / PRANDIAL
34
INSULIN INTENSIFICATION
Fix Fasting Blood Glucose (FBG) first using basal insulin (dose optimisation)
Goal FBG 4 6 mmol/L
Consider adding bolus / meal insulin when:
Hb A1c > 7% and FBG at goal or basal insulin dose > 0.5U/kg
35
If HbA1c > 6.5 - 7% after 3 months despite titrating prandial doses or prandial
doses > 30 units per meal, consider:
Resume titration / optimisation of basal insulin up to 0.7 U/kg
Perform 7- point BG profile
36
INSULIN INTENSIFICATION
BASAL OD or BD
HbA1c 6.5 8%
FPG > 6 mmol/L
Switch to PREMIXED
TWICE DAILY
Total dose transfer
Split dose 50:50
pre-breakfast : pre-dinner
Titrate dose once / twice a
week to next preprandial goal
Stop SU, continue metformin
Consider premixed analogue
37
The initial total daily dose following the switch may be guided by using a simple
dose calculation of 0.5units/kg or by a total dose for dose transfer from the prior
total daily dose on the previous regimen. Following determination of total dailydose requirement, proportion of basal to prandial insulin requirement may be
estimated using a ratio of 50:50. A smaller proportion of basal insulin may also
be used such as between 25 40% of total daily dose in certain circumstances.
The basal dose is usually administered at bedtime (conventional insulin) and the
prandial portion is divided into three to cover the three main meals, administered
pre-meals. Estimation of the pre-meal dose should take into consideration the
size of the meal, in terms of the carbohydrate content. Subsequently the basal
and pre-meal insulin should be titrated or optimised accordingly towards attaining
glycemic targets (Figure 6.5).
38
INSULIN INTENSIFICATION
PREMIXED OD (pre-dinner) or BD
39
PREMIXED OD (pre-dinner) or BD
40
INSULIN INTENSIFICATION
PRANDIAL TDS
Optimised prandial doses
REFERENCES
41
Section
TARGETS
AND MONITORING
Practical Guide to
Insulin Therapy in
Type 2 Diabetes Mellitus
43
Targets
4.4-6.1 mmol/L
4.4-8.0 mmol/L
HbA1c
< 6.5%
44
45
Basal bolus
(short-acting)
Basal bolus
(rapid-acting)
Post
Lunch
Pre
Dinner
Post
Pre
Bedtime
Post
Pre
Note
Pre-breakfast glucose readings reflect adequacy of pre-bed basal insulin
Pre-lunch readings reflect adequacy of pre-breakfast short-acting insulin
Pre-dinner readings reflect adequacy of pre-lunch short-acting insulin
Pre-bed readings reflect adequacy of pre-dinner short-acting insulin
Post-prandial glucose readings reflect the respective pre-meal rapid-acting insulin
(Aspart/Lispro/Glulisine) and can also be used to fine-tune short-acting insulin
Post
Pre-mixed
Human BD
Pre-mixed
Analogues BD
Pre-mixed
Analogues TDS
Lunch
Pre
Dinner
Post
Post
Pre
Bedtime
Pre
X
Note
SMBG in Premixed regimen
Pre-breakfast glucose readings reflect pre-dinner premixed insulin
Pre-lunch and pre-dinner readings reflect pre-breakfast premixed insulin
Pre-bed readings reflect pre-dinner premixed insulin
Post-prandial testing may be recommended for fine-tuning of pre-mixed insulin
46
ADJUST
Pre Breakfast BG
2-hours Post-breakfast BG
Pre-lunch BG
2 hours Post-lunch BG
Pre-dinner BG
Post-dinner/Pre-bed BG
REFERENCES
47
1. UKPDS Study Group. UKPDS 16. Overview of six years therapy of type
2 diabetes a progressive disease. Diabetes 44, 12491258 (1995).
2. Diabetes Control and Complications Trial, NEJM 329(14), September 30,
1993.
3. The Epidemiology of Diabetes Interventions and Complications Trial, NEJM
353(25), December 22, 2005.
4. Effects of Intensive Glucose Lowering in Type 2 Diabetes, the ACCORD study
group, NEJM 2008.
5. Dluhy RG et al. Intensive Glycemic Control in the ACCORD and ADVANCE
Trials; NEJM 2008.
6. Standards of Medical Care in Diabetes 2010, American Diabetic Association.
7. Clinical Practice Guidelines (CPG) on Management of type 2 Diabetes Mellitus
(4th Edition) 2009.
Section
PROBLEMS WITH
INSULIN THERAPY
Practical Guide to
Insulin Therapy in
Type 2 Diabetes Mellitus
49
8.1 Hypoglycaemia
Hypoglycaemia is less common in people with T2DM than in those with T1DM.
However, this problem has become progressively more frequent with advanced
duration of T2DM and the use of intensive insulin therapy1. In a recent T2DM
survey, 50% of insulin-treated patients with T2DM self-reported hypoglycaemic
events in the preceding month2. In the UKPDS, intensive SU and insulin therapy
in non-obese, newly-diagnosed patients with T2DM was associated with the
highest cumulative incidences of hypoglycaemia over a six-year period, occurring
in approximately three-quarter of patients receiving insulin therapy and almost
half of those receiving SU. The incidence of major hypoglycaemia was much
greater with insulin therapy (11.2%) compared to SU therapy (3.3%) 3.
Hypoglycaemia has a negative impact on physical and psychological well-being.
Hypoglycaemic episodes are associated with several serious consequences such
as cardiovascular death, MI, cardiac arrhythmias, cardiac ischaemia, progressive
neuroglycopenia and autonomous nervous system abnormalities4. Hypoglycaemia
and fear of hypoglycaemia are important limiting factors in glycemic management
and may become significant barriers to treatment adherence. For instance,
patients may stop taking their anti-diabetic medication resulting in poor glycemic
control. In the Diabcare-Asia 2003 survey involving 15,549 patients with diabetes
(96% had T2DM), 54% of patients were anxious about the risk of hypoglycaemia
most of the time5.
There is no current consensus on a definition for hypoglycaemia. Recent
definitions by the American Diabetes Association (ADA), Canadian Diabetes
Association (CDA) and the European Medicines Agency (EMEA) have assigned
a threshold for the diagnosis of hypoglycaemia as a blood glucose level less than
3.9 mmol/L6.
Hypoglycaemia manifests as neuroglycopenic or neurogenic symptoms or both.4,7
(Table8.1a)
Table 8.1a Clinical manifestations of hypoglycaemia
Neurogenic / Autonomic
Adrenergic
Palpitations
Tremor
Anxiety/arousal
Cholinergic
Sweating
Hunger
Paresthesia
Neuroglycopenic
Cognitive dysfunction
Behavioral changes
Psychomotor abnormalities
Seizure
Coma
Brain damage
Death
50
51
52
53
54
REFERENCES
Section
SPECIAL
SITUATIONS
Practical Guide to
Insulin Therapy in
Type 2 Diabetes Mellitus
56
SPECIAL SITUATIONS
57
9.1.3
Indications for hospital referral / admission
The following circumstances may indicate the need for hospital referral and
admission in insulin-treated patients with acute inter-current illness
9.2
Travel1
During long distance travel, patients requiring insulin therapy will need to plan
travel and holidays in advance and seek advice wherever necessary. Ideally
glycaemia, blood pressure and lipids should be under control. It is important to
find out the types, formulations and strengths of insulin which are available in the
area of destination. The following table indicates the appropriate advice and
instructions to be given to insulin-treated patients who are intending to travel
long distance. (Table 9.2)
Table 9.2
Preparations for long distance travel for insulin users
Take twice as much insulin, syringes or pens, needles or tablets as will
be needed
If travelling with others, split the amount between each passengers hand
luggage just in case one of the bags is lost
Bring a cool bag for storing insulin
Bring adequate BG monitoring equipment (with strips, lancets, spare
battery)
High altitude, heat and humidity can sometimes affect meters and test
strips. Be aware of possible false readings
Bring carbohydrate (glucose tablets, sweets, snacks and juices) in the
hand luggage to cover any travelling delays in case of hypoglycaemia
A diabetes identity card or medic alert bracelet.
58
SPECIAL SITUATIONS
9.3
Exercise2
59
60
9.4
SPECIAL SITUATIONS
61
Those patients at very high risk of complications are strongly advised to avoid
fasting whilst those insulin-users with satisfactory glycemic control and low risk
of severe hypoglycaemia may be allowed to perform fasting with strong
recommendations for more frequent blood glucose monitoring and appropriate
insulin dose adjustments. Use of insulin analogues (basal, short acting or premix
analogues) during fasting has been associated with less hypoglycaemia and
more effective postprandial BG control.
SMBG is advised for the following times
Pre Sahur (pre-dawn meal) and 2 hours post Sahur
Pre Iftar (Sunset) and 2 hours post Iftar
Insulin dose adjustments during fasting are as recommended in Table 9.4b4.
Table 9.4b
Dose adjustments for insulin regimens during fasting
Insulin Regimen
Premixed insulin
twice daily
Basal bolus
All patients must always and immediately end their fast if:
Hypoglycaemia (BG <3.5 mmol/l)
BG reaches < 3.9 mmol/l in the first few hours after the start of the fast,
especially if insulin, has been taken at pre-dawn
Blood glucose exceeds 16 mmol/l as higher risk for acute hyperglycaemic
complications and dehydration
62
SPECIAL SITUATIONS
9.5 Pregnancy
Diabetes during pregnancy presents major risks for poor fetal, neonatal, and
maternal outcomes. However, the risk can be greatly reduced by early institution
of medical nutritional therapy and insulin treatment. In a T2DM patient planning
to get pregnant, preconception counselling with optimisation of glycaemic control
prior to conception is of utmost importance. There is a need to consider initiating
insulin prior to conception and work towards achieving and maintaining target
HbA1c < 6.5%. Maintaining maternal glycaemia as near to normal as possible
reduces the risk of congenital anomalies, macrosomia, neonatal hypoglycaemia,
and large-for-gestational-age infants.
Insulin is considered the gold standard treatment in managing gestational
diabetes mellitus (GDM) and T2DM during pregnancy. In pregnancy, the common
insulin regime is basal bolus regime which enables easier insulin dose
adjustment and potentially better glycaemic control. The prandial insulins that can
be used are short-acting regular human insulin and the rapid-acting insulin
analogues. The basal insulin used in pregnancy is usually NPH as the evidence
for the use of long- acting insulin analogues in pregnancy is not as extensive5.
When estimating the starting insulin dose, the maternal weight and the pregnancy
gestation / trimester should be considered (Table 9.5). There is increased insulin
requirement as pregnancy progresses as a result of insulin resistance. In some
patients there may be a need for more than 1 unit / kg day total daily dose during
pregnancy, especially in obese women with T2DM and other features of metabolic
syndrome6.
Table 9.5a
Estimation
total daily insulin requirement by gestation / trimester
Pregnancy of
gestation
Pregnancy gestation
1st trimester
2nd trimester
3rd trimester
The insulin regimes used must be able to maintain good glycaemic control without
hypoglycaemia. SMBG is an important aspect in managing diabetes in pregnancy.
The targets of blood glucose during pregnancy are as outlined in CPG Management
of T2DM 2009 (Table 9.5b).
REFERENCES
63
10
Section
PRACTICAL
ISSUES
Practical Guide to
Insulin Therapy in
Type 2 Diabetes Mellitus
PRACTICAL ISSUES
65
66
PRACTICAL ISSUES
Unopened
Opened /
Unopened
(Days)
Do not refrigerate
Do not refrigerate
Do not refrigerate
Do not refrigerate
Do not refrigerate
Do not refrigerate
Do not refrigerate
Do not refrigerate
Do not refrigerate
Do not refrigerate
28
28
28
28
42
42
42
28
30
42
Product name
Humulin N
Humulin 30/70
Humalog
Humalog 25/75
Actrapid
Insulatard
Mixtard 30/70
Novorapid
Lantus
Levemir
Room
temperature
67
10.2
The site of insulin injection greatly influences the absorption level and effectiveness of the insulin. Insulin injection site rotation is as important as the amount
of insulin taken.
General tips with regards to injection sites.
1. Give injections in the abdomen, thighs and back of the upper arm
whenever possible.
Insulin is most rapidly absorbed when injected in the abdomen, followed by
the upper arm and thigh area. Injections in hip and buttock areas are more
slowly absorbed. Never inject within two inches of navel.
2. Choose a slightly new location for each injection.
This is called site rotation. For example, if all injections are given in the
abdomen, note of where the last injection was given and move the next one
about an inch to one side or the other. Continue to move the injection site
until all the available sites are covered before starting a new area.
3. Always inject insulin into fatty tissue instead of muscle.
Thats why the abdomen, upper back of the arms and outer thigh are
preferred. These areas are easy to reach and have ample amounts of
fatty tissue (called subcutaneous fat). These areas also reduce the risk of
injecting insulin too close to a large blood vessel or nerve.
4. Give your injections in the same general area at the same time each day.
For example, take the morning insulin in the abdomen and the afternoon or
evening insulin in the arm. This consistency helps the body better absorb
the insulin over random injections.
5. Keep accurate records of site rotation.
This will help avoid injecting the same area repeatedly. Doing so is likely to
result in the development of fat deposits that can make skin look lumpy and
delay the absorption of insulin.
68
PRACTICAL ISSUES
Front
Abdomen
Abdomen
Front
and side
of thigh
Front
and side
of thigh
Back
Upper
and outer
arm
Upper
and outer
arm
Buttocks
Buttocks
Side of
thigh
Side of
thigh
69
70
PRACTICAL ISSUES
Pen Type
HumaPen
n (Ergo)
Reusable
Novopen 3
Novopen 4
Novolet
Flexpen
SoloSTAR
Insulin Type
- Humulin R
- Humulin N
- Humulin 30/70
- Humalog
- Humalog 25/75
Reusable
- Actrapid
- Insulatard
- Mixtard 30/70
- Novorapid
Pre-filled /
disposable
- Actrapid
- Insulatard
- Mixtard 30/70
Pre-filled /
disposable
- Novorapid
- Novomix 30
- Detemir
Pre-filled /
disposable
- Lantus
- Apidra
71
Comment
1. Site of injection
2. Injection volume
3. Injection depth
4. Needle length
5. Insulin type
6. Injection route
7. Exercise
8. Heat application
or Massage
72
PRACTICAL ISSUES
Solutions
Bleeding at site
of injection
Insulin is
dripping from
the pen needle
after injection
Insulin leaking
from injection site
The injection
device is clogged
Pen needles should be removed after each use to prevent air from entering the
cartridge and to prevent insulin from leaking out.
73
74
REFERENCES
1. Grajower m et al. How Long Should Insulin Be Used Once a Vial Is Started?
Diabetes Care September 2003 26:2665-2669;
2. Insulin Storage in Europe: A comment to Grajower et al., Eli Lilly, and Novo
Nordisk Diabetes Care May 1, 2004 27:1225-1226.
3. Holcombe JH et al : How Long Should Insulin Be Used Once a Vial Is Started?
Response to Molitch. Diabetes Care May 2004 vol. 27 no. 5 1241-1242.
4. Heinemann L. et al. Variability of insulin absorption and insulin action.
Diabetes Technol Ther. 2002;4(5):673-82.
5. Self-monitoring of blood glucose. American Diabetes Association. Diabetes
Care 1990;13(Suppl 1):S416.
6. William A et al. Assuring the Accuracy of Home Glucose Monitoring. J Am
Board Fam Pract 2002; 15:16.
APPENDIX
Practical Guide to
Insulin Therapy in
Type 2 Diabetes Mellitus
76
APPENDIX
Serving
Calories
(kcal)
Carbohydrate
content (g)
Approx.
Carbohydrate
Exchanges*
*1 carbohydrate
food exchange
= 15 g
Cooked rice
1 bowl (159g)
207
48
Roti canai
1 piece (95g)
301
46
Chappati
1 piece(100g)
300
47
Curry mee
1 bowl (450g)
549
55
Fried noodles
(mee/mee hoon)
1 plate (170g)
281
41
Bread
(white/wholemeal) 1 slice (30g)
70
15
Biscuits,
unsweetened
2 pieces (18g)
80
14
Curry puff
1 piece (40g)
128
17
>1
Potato
1 medium (90g)
90
16
Dhall (raw)
cup (98g)
98
64
187
18
131
12
100
16
Condensed milk,
sweetened
2 tablespoon (40g)
126
21
1.5
Apple/ orange
1 medium (114g)
40
<1
Banana
(pisang mas)
1 small (50g)
40
<1
Star fruit
1 medium (260g)
56
11
Langsat/ grapes/
longan
8 small (233 g)
52
12
Guava
fruit (100g)
50
11
Watermelon/
papaya/ pineapple 1 slice ( 160g)
56
11
Mango
50
11
1 small ( 100g)
77
INDEX
References are to page numbers within the booklet.
Page
Barriers
insulin absorption
insulin therapy
- solutions
patient barriers
provider barriers
- solutions
71
2; 11; 12
12
11
12
13
28; 29
Basal insulin
basal bolus regimen
initiation and optimisation
intensification
basal plus regimen
premix regimen
35
24
33
34
36
Beta cells
progressive decline
5; 8
Diagnosis
role of insulin therapy
8
Exercise
benefits
insulin dose adjustment
58
59
60
61
60
65; 66
78
INDEX
Page
Hypoglycaemia
clinical manifestations
insulin therapy
prevention
risk factors
severity
49
49
51
50
50
Injection site
practical issues
problems
67
53
Insulin
absorption
comparison of conventional insulin and insulin analogues
effectiveness
handling and storage
initiation and optimisation
intensification
pen devices and needles
preparations
regimen
types
- pharmacokinetic profiles
71
18; 19
6
65; 66
23; 24
32
69
16
20
16
17
Insulin absorption
affecting factors
71
71
Insulin analogues
18
Insulin injection
problems
72
Insulin regimen
20
Insulin resistance
progression of T2DM
79
INDEX
References are to page numbers within the booklet.
Page
Insulin therapy
barriers
- solutions
current practice
implementation
intensification
monitoring
practical issues
- injection site
- insulin absorption
- insulin handling and storage
- pen devices and needles
problems
- allergy and hypersensitivity
- hypoglycaemia
- injection site
- insulin injection
- weight gain
rationale
role
short-term use
special situations
- exercise
- fasting and Ramadan
- pregnancy
- travel
utilisation
2; 11; 12
12; 13
2
23
32
44
67
71
65; 66
69
53
49
53
72
52
5; 6; 8
8
8
56
58
60
62
57
2
Intensification
basal bolus regimen
basal regimen
multiple premixed regimen
basal plus regimen
prandial regimen
premix regimen
37
35
38
34
40
36
Monitoring
continuous glucose monitoring
insulin therapy
self-monitoring of blood glucose
- accuracy
- glucose meters
46
44
44
73
73
69
80
INDEX
Page
Pharmacokinetic profiles
insulin
17
Prandial insulin
initiation and optimisation
intensification
26; 27; 28
40
Pregnancy
insulin therapy
- management
- risks
62
62
62
Premixed insulins
addition of prandial insulin
basal bolus regimen
initiation and optimisation
intensification
multiple premixed regimen
39
37
25; 26
33
38
44
73
73
46
46
45
Sick days
hyperglycaemia
hypoglycaemia
sick days rules
56
56
56
Targets
glycaemic targets
43
Travel
insulin therapy
- long distance air travel
- preparations
58
57
8
7
Weight gain
insulin therapy
52
GLOSSARY OF TERMS
BD
BG
BMI
BP
CHD
CVD
DCCT
DKA
DM
DN
DPP-4
ECG
ED
FPG
GDM
GI
HbA1c
HDL
IDF
IFG
IGT
LDL
MNT
NCEP
NPH
OAD
OD
OGTT
OM
ON
PPAR-Y
PPG
RPG
S/C
SMBG
SU
T1DM
T2DM
TDS
TG
TZD
UKPDS
WC
WHO
81
82
ACKNOWLEDGEMENTS
The members of the working committee of this guide would like to
express their gratitude and appreciation to the following for their
contributions:
Panel of external reviewers who reviewed the draft
All those who have contributed directly or indirectly to the
development of this guide
SOURCES OF FUNDING