2011 - Quick Reference Insulin Therapy

TABLE OF CONTENTS
FOREWORD PREFACE GUIDE OBJECTIVES GUIDE WORKING COMMITTEE EXTERNAL REVIEWERS SUMMARY OF TREATMENT ALGORITHM
i ii iii iv v vi
SECTION 1 SECTION 2
BACKGROUND RATIONALE FOR INSULIN THERAPY IN TYPE 2 DIABETES BARRIERS TO INSULIN THERAPY INSULIN TYPES AND REGIMENS 4.1 Insulin types 4.2 Insulin analogues 4.3 Insulin regimens INSULIN INITIATION AND OPTIMISATION (DOSE ADJUSTMENT) 5.1 Initiating and optimising with basal insulin 5.2 Initiating and optimising with premixed insulin 5.3 Initiating and optimising with prandial insulin 5.4 Initiating and optimising with basal and prandial insulin
4 10 15
SECTION 3 SECTION 4
SECTION 5
22
SECTION 6
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 Intensication of premixed regimen with addition of pre-meal bolus 6.7 Intensication of prandial regimen with addition of basal insulin
TABLE OF CONTENTS
SECTION 7
TARGETS AND MONITORING 7.1 Glycemic targets 7.2 Monitoring insulin therapy PROBLEMS WITH INSULIN THERAPY 8.1 Hypoglycemia 8.2 Weight gain 8.3 Injection site problems 8.4 Insulin allergy and hypersensitivity SPECIAL SITUATIONS 9.1 Sick days 9.2 Travel 9.3 Exercise 9.4 Fasting (Ramadan) 9.5 Pregnancy
42
SECTION 8
48
SECTION 9
55
SECTION 10 PRACTICAL ISSUES 10.1 Insulin handling and storage 10.2 Insulin injection sites 10.3 Insulin pen devices 10.4 Insulin absorption 10.5 Insulin injection problems 10.6 Self Monitoring of Blood Glucose (SMBG) APPENDIX INDEX GLOSSARY OF TERMS ACKNOWLEDGEMENTS SOURCES OF FUNDING Carbohydrate counting
64
75 77 81 82 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 denitely 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
The prevalence of diabetes in Malaysia continues to increase at an alarming rate from 1-2% in the 1960s and 1970s, 6.3% in 1986 (NHMS I), 8.2% in 1996 (NHMS II) to 14.9% in 2006 (NHMS III). More recent studies have indicated that the prevalence has risen to beyond 20%. This is largely contributed by a parallel increase in rates of overweight/obesity and high rates of physical inactivity among the adult population together with population growth, aging and urbanization. Oral anti-diabetic medications comprise the mainstay of treatment for patients with type 2 diabetes in Malaysia. The majority of patients receiving treatment have suboptimal glycaemic control, often as a result of treatment inertia with lack of optimsation of oral medications and delay in insulin initiation. Insulin use in the management of type 2 diabetes is still seriously lacking especially in primary care. Currently insulin therapy is used in an estimated 20% of outpatients with diabetes in the MOH Health facilities, noted from a survey done by Institute of Health Management (IHM) in 2008. This has increased compared to 13% in a similar survey by IHM in 2005. The increase in insulin use is expected with current treatment guidelines (CPG Management of Type 2 DM 2009) recommending earlier use of insulin therapy in patients with sub-optimal glycemic control either at presentation or with failure of oral anti-diabetic agents. Unfortunately, several local audits have shown that very few patients on insulin therapy are able to achieve good glycaemic control, as measured by HbA1c of less than 6.5%. Only 10 15% of patients on insulin therapy are able to achieve recommended glycaemic targets. Studies have also shown that in most instances insulin is prescribed using less intensive regimens without good optimisation of dose. The barriers to achieving good glycaemic control include poor medication adherence, hypoglycaemia, poor optimisation of insulin doses, lack of intensication of insulin regimens, especially the use of more intensive insulin regimens that require more frequent injections, the and use of both meal and basal insulin (basal bolus regimens). In recent years, a large proportion of diabetes care in developed countries has moved from specialist units to primary care and insulin is now frequently and successfully initiated in the primary care setting. This change has been sponsored by government policies and guidelines which encourage providers of primary care to initiate and manage insulin. This Practical Guide to Insulin Therapy has been developed to provide a clear and concise approach to all health care providers on current concepts in the use of insulin in the management of type 2 diabetes (T2DM). I hope it will help to address the current shortfalls in the management of patients with T2DM requiring insulin therapy and it will be fully utilised by all relevant health care providers, especially in primary care. Last but not least I would like to express my gratitude to everyone involved in the development of this practical guide and especially to the task force members for their immense support and contribution. Dr Zanariah Hussein Chairperson Working Committee
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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 ofcers, 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 ofcers, podiatrists, pharmacists, dieticians and diabetic nurse educators.
iv GUIDE WORKING COMMITTEE

CHAIRPERSON Dr. Zanariah Hussein
Senior Consultant Endocrinologist, Hospital Putrajaya Putrajaya
MEMBERS
(Alphabetical Order)
Dr. Foo Siew Hui

Consultant Endocrinologist, Hospital Selayang Selangor
Dr. Noor Lita Adam

Consultant Endocrinologist, Hospital Seremban Seremban
Dr. Lim Siang Chin

Consultant Endocrinologist, Hospital Melaka Melaka
Dr. Nurain Mohd. Noor

Consultant Endocrinologist, Hospital Putrajaya Putrajaya
Dr. Masni Mohamad

Consultant Endocrinologist, Hospital Putrajaya Putrajaya
Dr. Shamita Sharma

Consultant Endocrinologist, Hospital Ampang Selangor
Dr. Mohamed Badrulnizam Long Bidin

Consultant Endocrinologist, Hospital Kuala Lumpur Kuala Lumpur
Dr. Yong Sy Liang

Consultant Endocrinologist, Hospital Klang Selangor
EXTERNAL REVIEWERS
Prof. Dato Paduka Dr. Wan Mohamad Wan Bebakar

Senior Consultant Endocrinologist, Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan
Prof. Dr. Nor Azmi Kamaruddin

President Malaysian Endocrine and Metabolic Society (MEMS) Senior Consultant Endocrinologist, Pusat Perubatan Universiti Kebangsaan Malaysia, Kuala Lumpur
Dato. Dr. Santha Kumari

Senior Consultant Physician Hospital Klang Selangor
Dr. G. R. Letchuman Ramanathan

Senior Consultant Physician, Hospital Taiping, Perak
Dr. Feisul Idzwan Mustapha

Public Health Physician, Disease Control Division, Department of Public Health, Ministry of Health Malaysia, Putrajaya
Dr. Mastura Ismail

Family Medicine Specialist, Klinik Kesihatan Ampangan, Negeri Sembilan
(The following external reviewers provided feedback on the draft)
vi SUMMARY OF TREATMENT ALGORITHM

Newly diagnosed DM & Type 2 DM Symptomatic (osmotic symptoms) regardless HbA1c or FBS HbA1c > 10% or FPG > 13 mmol/L Type 2 DM on maximal OADs (single/double/triple) HbA1c > 8%
Glycemic abnormality? FPG, SMBG
Normal Fasting / prebreakfast BG High daytime BG
High Fasting / prebreakfast BG Normal daytime BG
High Fasting / prebreakfast BG High daytime BG
Start PRANDIAL only (usually TDS premeals) Optimise dose
Start BASAL only (bedtime) Optimise dose
Start PREMIXED OD (predinner) Optimise dose
Start PREMIXED BD (prebreakfast & predinner) Optimise dose
Start BASAL BOLUS (premeals, bedtime) Optimise dose
BASAL PLUS (premeal and bedtime) Optimise dose
Add 3 prandial insulin
Add basal insulin
Sequential addition of prandial insulin
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 gures 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 reecting 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 le. 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

RATIONALE FOR 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
-Cell Function (%)
75
50
25
IGT
Postprandial Hyperglycemia
-2 0
Type 2 Diabetes
2 6 10 14
0 -12
-10
Years From Diagnosis
T2DM is a progressive disease characterised by worsening glycemia. There are many reasons why beta cells continue to decline. One of the important reasons is glucose toxicity (Figure 2.2) 3.The progressive decline in beta cell function ultimately renders oral agents ineffective and the majority of patients with T2DM will require exogenous insulin treatment. Besides restoring circulating hormone levels, insulin treatment has benecial effects on insulin sensitivity, vascular function, dyslipidemia and biomarkers that predict vascular damage.
Figure 2.2 Overview of factors inuencing stages from insulin resistance to progression of T2DM
Lifestyle factors: diet, exercise, smoking, alcohol

Genetic and environmental factors cause susceptibility
Glucose toxicity Lipotoxicity Beta cell dysfunction Declining beta cell function Amyloid deposition
Insulin resistance
Genetic factors
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 prole 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)
Diagnosis of Type 2 Diabetes All patients advised LIFESTYLE
HbA1c < 6.5% OR FPG < 6 mmol/L LIFESTYLE APPROACH* Follow-up with HbA1c after 3 months If HbA1c 6.5% continue with Lifestyle Approach. If HbA1c > 6.5% on follow-up, consider OAD monotherapy
HbA1c 6.5 - < 8.0% OR FPG 6 - < 10 mmol/L OAD MONOTHERAPY 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
HbA1c 8.0 - 10.0% OR FPG 10 - 13mmol/L COMBINATION 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 Follow-up with HbA1c after 3-6 months If HbA1c 6.5%, continue therapy If HbA1c > 6.5%, consider addition of INSULIN THERAPY
HbA1c > 10.0% OR FPG > 13 mmol/L COMBINATION THERAPY + BASAL / PREMIXED INSULIN THERAPY OR INTENSIVE INSULIN THERAPY, continue Metformin
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 intensication 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 insufcient 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
1. UKPDS Group. UKPDS 16. Overview of 6 years therapy of type 2 diabetes-A progressive Disease. Diabetes 1995; 44:1249-1256. 2. Holman RR. Assessing the potential for Alpha-glucosidase Inhibitors in Prediabetes States. Diabetes Res Clin Pract 1998;40(suppl.):S21-S25. 3. Vincent P et al. Glucolipotoxicity: Fuel Excess and Beta Cell dysfunction. Endocrine Review, 2008. 4. Maria Tzafos et al. Glucagon-Like Peptide-1 Analog and Insulin Combination Therapy in the management of adults with type 2 Diabetes Mellitus. The Annals of Pharmacotherapy. 2010. 44(7); 1294-1300. 5. Ryuza Kawamori et al. IMPROVE Observational Study of Biphasic Insulin Aspart 30/70 in Patients with Type 2 Diabetes Mellitus. Expert Rev Endocrinol Metab. 2010; 5(4):507-516. 6. Schreiber SA et al. The long term efcacy of insulin Glargine plus oral antidiabetic agents in a 32-month observational study of every day clinic practice. Diabetes Technol Ther. 2008. Apr;10(2):121-127.
Section
BARRIERS TO INSULIN THERAPY

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.
3.1 Patient barriers

In a recent survey the International Diabetes Management Practises Study (IDMPS), which is a global registry performed to assess the current management practices in patients with diabetes, it was shown that one of the reasons for patients not reaching target is fear of injection1. Another recent global survey entitled the Global Attitudes of Patients and Physicians in Insulin Therapy (GAPPTM), conducted specically to assess needs and challenges relating to insulin treatment, found that more than one in three diabetes patients skip doses or fail to take their insulin as prescribed, on average three times in the last month. Being too busy or simply forgetting to take the insulin are the main reasons cited by patients missing insulin doses. Two thirds of patients taking insulin in the study were concerned about experiencing a hypoglycemic event in the future. Nine in 10 patients wished for less invasive insulin regimens where insulin could be dosed less than once a day.2 It is important to address the patients concerns regarding insulin by enquiring about the following prior to initiating insulin2: What do you need to know to consider insulin? What problems do you think you can encounter? What do you think are the benets and the negative effects of insulin? What will help you to overcome the concerns? Are you willing to consider insulin? If not, what would cause you to consider insulin? As healthcare providers, it is important to identify the patients barriers to insulin therapy and implement strategies to overcome or decrease these barriers as this will assist the patient in the decision-making process to accept and adhere to insulin therapy (Refer Table 3.1) To provide encouragement and support for insulin use it may be useful to do the following; Give your patient materials that they can use at home, such as information sheets, patient diary, and contact information for diabetes support groups or websites Involve family and friends for support Recommend that the patient join a local diabetes support group Encourage your patient to talk to someone who has been successfully treated with insulin therapy
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Table 3.1: Barriers to insulin therapy and suggested solutions
Possible barriers Insulin as a personal failure
Suggested solutions and issues for patient discussion Reassure your patient they have done nothing wrong Emphasize the pathophysiology of Type 2 DM Diabetes progression means insulin will be needed eventually Explain that starting insulin at the right time will help with glycemic control and slow disease progression Provide information to counteract this belief Acknowledging the patients fear and informing the providers experience is helpful Discuss that adding insulin does not mean health is deteriorating; rather, it is an effective step to prevent diabetes progression and complications Explain the benets of using pen / injection devices Demonstrate insulin injection technique for subcutaneous injections with a practice pen to the patients. Highlight sites of injection Let the patient try an injection test / placebo injection Reassure them that there are strategies to prevent, recognize and treat hypoglycaemia and thus avoid severe events Basal insulins have minimal risks Provide information and discuss about insulin and pen. Modern injection devices (insulin pens) are convenient, discreet and simple to use Insulin can t in with daily life Selection of insulin type and regimens with maximum exibility Inform that diabetes is an insulin-related problem and the insulin used is very similar to that produced naturally Offer a 3-month trial to get the patient used to the idea Once patients try insulin they rarely want to change, because it is successful Consult a dietician and discuss strategies to prevent weight gain Lifestyle interventions with diet and exercise continue to be important
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
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3.2 Provider barriers

Barriers to insulin therapy are also seen among health care providers. This also leads to delayed initiation of insulin therapy3. Some barriers are listed below: Lack of resources drug costs, staff, skills Time constraints Lack of familiarity/experience Lack of tools/algorithm Efcacy concern Risk of severe hypoglycaemia /adverse effects on quality of life (QoL) Concerns about patient refusal and non-compliance Concerns relating to educating patients Excess weight gain in already overweight patients Too demanding for elderly patients Convincing patients to be on insulin therapy can be challenging. Good communication between patients and health care providers is the key to overcoming psychological barriers to insulin therapy. Strategies to overcome these barriers among health care providers include: Building knowledge, experience and condence by continuous training and education of health care providers Discuss challenging and/or successful insulin initiation cases with health care provider peers Networking between diabetes educators, pharmacists and diabetes support groups Providing comprehensive patient education Arrange for timely patient follow-up to ensure patient adherence and identify and resolve potential difculties and challenges Development and implementation of comprehensive algorithms for optimisation and intensication of insulin
14
REFERENCES
1. Juliana Chan et al. Multifaceted Determinants for Achieving Glycemic Control. The International Diabetes Management Practice Study (IDMPS). Diabetes Care 2009; (32):227-233. 2. New Global Survey Reveals Over One in Three Patients Fail to Take Insulin as Prescribed -Global Attitudes of Patients and Physicians in Insulin Therapy (GAPPTM) Survey - Press Release by Newswire 21st September 2010. 3. Martha M et al. Overcoming barriers to the initiation of insulin therapy. Clinical diabetes. Vol 25, No 1, 2007. 4. Mark Peyrot el al . Resistance to Insulin therapy among patients and providers. Results of the cross national Diabetes, Attitude, Wishes and Needs ( DAWN) Study. Diabetes Care. Vol 28, No 11, 2005.
Section
INSULIN TYPES AND REGIMENS

16
4.1 Insulin Preparations

The insulin currently used in Malaysia is recombinant human insulin, either directly derived from the native human insulin, i.e. regular human insulin or structurally modied, i.e. insulin analogue. Both types of insulin are further divided into prandial, basal and premixed insulin according to their pharmacokinetic proles (Table 4.1a). Prandial insulin is administered pre-meal because of its short or rapid onset of action for controlling the post-prandial glucose excursion. It is also used in insulin pumps. Basal insulin is administered once or twice daily. The intermediate or long-acting pharmacokinetic prole covers the basal insulin requirements in between meals and overnight due to endogenous hepatic glucose production. Premixed insulin is biphasic insulin that incorporates the combination of short or rapid-acting insulin with its intermediate-acting counterpart into a single preparation to cover for both postprandial glucose excursion as well as basal insulin needs simultaneously (Table 4.1b).
Table 4.1a Insulin Preparations available in Malaysia Insulin Type
Conventional Short-acting regular human insulin - Actrapid - Humulin R Intermediate-acting or Neutral Protaminated Hagedorn (NPH) Insulin - Insulatard - Humulin N Combination of short & intermediate-acting: 30% regular insulin + 70% NPH - Mixtard 30 - Humulin 30/70
Analogue Rapid-acting - Novorapid (Aspart) - Humalog (Lispro) - Apidra (Glulisine) Long-acting - Lantus (Glargine) - Levemir (Detemir)
Prandial
Basal
Premixed
Combination of rapid-acting & protaminated analogue - NovoMix 30 (30% aspart + 70% aspart protamine) - Humalog Mix 25 (25% lispro + 75% lispro protamine)
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Table 4.1b Pharmacokinetic proles of various types of insulin1 Brand (Generic) Name
a) Short-acting, regular - Actrapid* - Humulin R* b) Rapid-acting analogue - Novorapid (Aspart)* - Humalog (Lispro)* - Apidra (Glulisine) c) Intermediate-acting, NPH - Insulatard* - Humulin N* d) Long-acting analogue - Glargine* - Detemir* e) Premixed human (30% regular insulin+ 70% NPH) - Mixtard 30* - Humulin 30/70* f) Premixed analogue - NovoMix 30 (30% aspart + 70% aspart protamine)* - Humalog Mix 25 (25% lispro + 75% lispro protamine*
Onset
Peak (Hr)
Duration (Hr)
Timing of insulin
30 min 30 min
1-3 2-4
8 6-8
30 mins before meal 5-15 mins before or immediately after meals Pre-breakfast / Pre-bed Same time everyday at anytime of the day
10-20 min 0-15 min 5-15 min
1-3 1 1-2
3-5 3.5-4.5 3-5
1.5 Hr 1 Hr
4-12 4-10
18-23 16-18
2-4 Hr 1 Hr
peakless peakless
20-24 17-23
30 min 30 min
dual dual
18-23 16-18
30-60 mins before meals
10-20 min
dual
18-23 5-15 mins before meals
0-15 min
dual
16-18
* Available at Ministry of Health, Malaysia. N.B. The time course of action of any insulin may vary in different individuals, or at different times, or at different injection locations in the same individual. Due to such variations the time periods described above should be used as general guidelines only. The short-acting and the intermediate-acting insulin can be self mixed as an alternative to the human premixed insulin although this is not encouraged due to signicant reduction in the reproducibility of insulin action.
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4.2 Comparison of Conventional Insulin and Insulin Analogues

Insulin analogue is derived from human insulin in which the amino acid sequence is intentionally altered to produce an improved pharmacokinetic prole that mimics physiological insulin secretion better. Prandial analogue mimics the rst phase of insulin secretion in response to a meal Basal analogue mimics the physiological basal insulin secretion in-between meals and overnight Premixed analogue consists of both rapid-acting and intermediate-acting insulin analogues and was developed to more closely mimic physiological endogenous insulin secretion and meet the needs of patients who require both basal and prandial insulin but wish to limit the number of daily injections The differences between prandial, basal & premixed analogues compared to human insulin are summarized in Table 4.2. Individuals with the following situations should be considered for insulin analogue therapy: a) Rapid-acting analogue - Delayed inter-meal hypoglycemia preventing achievement of postprandial glycemic target on regular short-acting insulin - Lifestyle restriction, the need to eat immediately after insulin injection due to job schedule etc. - Variable carbohydrate intake b) Long-acting analogue - Nocturnal hypoglycemia on intermediate-acting insulin (NPH) preventing achievement of target fasting blood glucose - Inadequate basal insulin coverage with once daily intermediate-acting insulin (NPH) and not willing to go on NPH twice daily
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Table 4.2 Comparison of conventional and analogue insulin2,3,4
Characteristics
Conventional
PRANDIAL INSULIN
Analogue
Onset Administration Postprandial glycemic control Inter-meal hypoglycemia Inter-meal hyperglycemia Dosing exibility Pharmacokinetics Cost
Delayed 30 min before meals + ++ + + Less physiological Lower BASAL INSULIN
Immediate With meals ++ + ++ ++ More physiological Higher
Duration Peak Nocturnal hypoglycemia Absorption Weight gain Pharmacokinetics Cost
< 24Hr Pronounced ++ Variable ++ Less physiological Lower PREMIXED INSULIN
~24Hr Absent / minimal + Reproducible +/- (detemir) More physiological Higher
Administration Postprandial glycemic control Inter-meal hypoglycemia Dosing exibility Dosing interval Pharmacokinetics Cost
30min before meals + ++ + Once to twice daily Less physiological Lower
With meals ++ + ++ Once to thrice daily More physiological Higher
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4.3 Insulin Regimen

4.4 An ideal insulin regimen should mimic the physiological insulin response to meals and endogenous hepatic glucose production. The various types of insulin regimen can be classied as below (Table 4.3). The choice of insulin regimen should be individualised, based on the patients glycemic prole, dietary pattern, personal lifestyle as well as desired exibility.
Table 4.3 Insulin regimens and frequency of injections per day No. of injections per day Insulin regimen BASAL 1 BASAL PREMIXED OD BASAL 2 PREMIXED BD BASAL-PLUS (1) BASAL-PLUS (2) PRANDIAL 3 PREMIXED TDS PREMIXED-PLUS PREMIXED-PLUS 4 BASAL-BOLUS Type of insulin and timing Intermediate acting (NPH) insulin pre-bed Long-acting analogue once daily Premixed/ premixed analogue pre-dinner Intermediate acting (NPH) pre-breakfast and pre-dinner Premixed insulin pre-breakfast and pre-dinner Basal insulin once daily + 1 prandial insulin Basal insulin once daily + 2 prandial insulin Prandial insulin pre-breakfast, pre-lunch and pre-dinner Premixed analogue pre-breakfast, pre-lunch and pre-dinner Premixed insulin pre-breakfast, pre-dinner + 1 prandial insulin pre-lunch Prandial insulin pre-breakfast and pre-lunch + premixed insulin pre-dinner Basal insulin once daily + prandial insulin pre-breakfast, pre-lunch and pre-dinner Intermediate acting (NPH) insulin pre-breakfast and pre-dinner + prandial insulin pre-breakfast, pre-lunch and pre-dinner
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 1. DeWitt DE et al. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: Scientic review. J Am Med Assoc. 2003; 289:2254-64. 2. Raskin P et al. Use of insulin aspart, a short-acting insulin analogue as the meal time insulin in the management of patients with type 1 diabetes. Diabetes Care. 2000; 23:583
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3. Manucci E et al. Short-acting insulin analgues versus regular human insulin in type 2 diabetes: a meta-analysis. Diabetes, Obes & Metab. 2009; 11:53-59. 4. Qayyum R et al. Systematic review: Comparative effectiveness and safety of premixed insulin analogues in type 2 diabetes. Ann Intern Med. 2008; 149: 549-59.
Section
INSULIN INITIATION AND OPTIMISATION

INSULIN INITIATION AND OPTIMISATION Implementing successful insulin therapy requires a 3 stage process;
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1. Initiation Starting insulin. Requires selection of appropriate insulin regimen, insulin type and starting dose to address the individuals main glycemic abnormality. 2. Optimisation1 Dose titration / adjustment. Requires gradual, safe and prompt titration of insulin dose according to self blood glucose monitoring (SMBG), towards an optimal dose to ensure maximum benet from prescribed treatment. The insulin dose should be adjusted at least weekly to get the monitored readings to target. Optimisation of the insulin dose should be an interactive process between the healthcare provider and the patient. This can be done at the diabetic resource centre or via telephone calls. It should be done within the rst few months of starting insulin. 3. Intensication Modication of an insulin regimen to achieve better glycemic control requires switching to more intensive insulin regimens for better glycemic control. There are a few choices when starting insulin (Table 4.1a). The insulin regimen and insulin doses initiated are individualized, based on blood glucose prole, patients lifestyle and preferences (Table 5.1).
Table 5.1 Selecting initial insulin regimen based on blood sugar prole: Blood Glucose Prole Pre-Breakfast High Daytime Normal Pre-bed intermediate / long acting insulin (BASAL) Pre-bed intermediate / long-acting insulin and later add on prandial short / rapid acting insulin (BASAL BASAL PLUS / BASAL BOLUS) or (PRE-BREAKFAST AND PRE-DINNER PREMIXED INSULIN) Prandial short / rapid acting insulin and later add on basal insulin (PRANDIAL BASAL PLUS / BASAL BOLUS) Preferred insulin regimen
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.
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5.1 Initiating and Optimising Pre-bed Intermediate / Basal insulin

We can simply start the pre-bed intermediate/basal insulin at 10 units per day, or alternatively, start based on body weight at 0.2 units/kg3. (In those patients who are elderly, leaner or have milder fasting hyperglycemia, an initial dose of 0.1units/kg may be reasonable to ensure lower risk of hypoglycemia) Patients are advised to perform SMBG at pre-breakfast. There should be at least 3 consecutive values before adjusting insulin dose. Monitoring-based dose adjustment should be done after 3 to 7 days of initiating the last dose. The target blood glucose is at 4 6 mmol/L. If more than 1 of 3 pre-breakfast blood glucose values are less than 4 mmol/L, reduce intermediate/basal insulin by 2 units. If all 3 values are within the targets of 4-6 mmol/L, maintain current intermediate/basal insulin dose. If more than 1 reading of blood glucose is more than 6 mmol/L without any hypoglycemia, basal insulin dose may be increased by 2 units (Table 5.2). Subsequently insulin doses are gradually increased until target blood glucose is achieved. The optimal dose of bedtime intermediate/basal insulin is generally at: Lean patient : 0.2 0.3 units/kg Most patients : 0.4 0.5 units/kg Obese patient : up to 0.7 units/kg
Table 5.2 Initiating insulin with basal insulin3,4
Treatment
Initiation Monitoring and targets Optimisation
Dose
10 units or 0.2U/kg at bedtime (0.1 units / kg if higher risk for hypos) Monitor pre-breakfast BG Target pre-breakfast BG is at 4 - 6 mmol/L 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 units 0.2 0.3 units/kg in lean patients 0.4 0.5 units/kg in most patients Up to 0.7 units/kg in obese patients Watch for nocturnal hypoglycaemia. If hypoglycemia is the limiting factor to achieve optimum dose, conventional intermediate-acting insulin may be switched to basal insulin analogue.
Optimal dose
Caution
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5.2 Initiating and Optimising Premixed Insulins3,4

Premixed insulin may be initiated once daily, usually at pre-dinner or twice daily at pre-dinner and pre-breakfast (Table 5.3). 5.2.1 Premixed insulin once daily The initial dose for once daily premixed insulin is usually 10 units or 0.2 units/kg administered usually pre-dinner. Patients are advised to perform SMBG at pre-breakfast. Titration is based on 3 consecutive readings of blood glucose (similar as for titrating intermediate/ basal insulin). The insulin dose should be adjusted weekly to get the monitored readings to target. During optimisation of pre-dinner premixed insulin: If more than 1 of 3 pre-breakfast BG is less than 4 mmol/L, reduce pre-dinner premixed insulin by 2 units. If all 3 pre-breakfast BG are within the targets of 4-6 mmol/L, maintain current pre-dinner premixed insulin dose. If more than 1 pre-breakfast BG is more than 6 mmol/L without any hypoglycemia, may increase pre-dinner premixed insulin dose by 2 units. 5.2.2 Premixed insulin twice daily 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. Patients are advised to perform SMBG at pre-breakfast and pre-dinner. Titration is based on 3 consecutive readings of blood glucose (similar as for titrating intermediate/basal insulin). The insulin dose should be adjusted weekly to get the monitored readings to target. During optimisation of pre-breakfast premixed insulin: If more than 1 of 3 pre-dinner BG is less than 4 mmol/L, reduce pre-breakfast premixed insulin by 2 units If all 3 pre-dinner BG are within the targets of 4 - 6 mmol/L, maintain current pre-breakfast premixed insulin dose If more than 1 pre-dinner BG is more than 6mmol/L without any hypoglycemia, may increase pre-breakfast premixed insulin dose by 2 units Titration for pre-dinner premixed insulin dose is similar as above.
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Table 5.3 Initiating insulin with premixed insulin3
Treatment
Initiation
Dose
Once daily : 10 units or 0.2U/kg at pre-dinner Twice daily : 10 units or 0.2U/kg at pre-breakfast and pre-dinner (0.1units/kg if higher risk for hypos) Once daily : Monitor pre-breakfast BG Twice daily : Monitor pre-breakfast and pre-dinner BG Target pre-meal BG is at 4-6mmol/L 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 units
Pre-breakfast BG determine pre-dinner premixed dose adjustment Pre-dinner BG determine pre-breakfast premixed dose adjustment
Monitoring and targets Optimisation
Optimal dose
Total daily dose of 0.5 1.0 units/kg in most patients (Maybe more than 1.0 units/kg/day in obese, insulin resistant patients) Watch for in between meal hypoglycaemia. If hypoglycemia is the limiting factor to achieve optimum dose, conventional premixed insulin may be switched to premixed analogue.
Caution
5.3 Initiating and Optimising Prandial Insulin

Prandial insulin therapy can be initiated at a dose of 6 units per meal, or alterntively, started 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 (Table 5.4). Optimisation of prandial insulin doses are dependent on: Meal types and amount Pre-meal blood glucose levels on SMBG
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If conventional short-acting insulin is used, SMBG should be performed pre-meals at pre-lunch, pre-dinner and pre-bed. But, if rapid-acting insulin analogue is used, BG may be monitored 1.5 - 2 hours post-meals. Following 3 consecutive readings, insulin dose adjustment should be done on a weekly basis until the glycemic targets are met. During optimisation of prandial insulin, insulin dose is titrated to next pre-meal (& bedtime) target: If the pre-lunch BG levels are not to target, pre-breakfast insulin dose is adjusted. (Post-breakfast BG level may be used for rapid-acting analogue) If the pre-dinner BG levels are not to target, pre-lunch insulin dose is adjusted. (Post-lunch BG level may be used for rapid-acting analogue) If the pre-bed blood BG levels are not to target, pre-dinner dose is adjusted. (Post-dinner BG level may be used for rapid-acting analogue) Prandial insulin dose may be adjusted as the following4: If more than one BG level is less than 4 mmol/L, reduce the prior pre-meal prandial insulin by 1- 2 units If more than one BG level is more than 6mmol/L without any hypoglycemia, may increase prior pre-meal insulin dose by 2 units If all pre-meal BG on target, dose of prior pre-meal prandial insulin is maintained Patients on prandial insulin should ideally be instructed in the following skills: Carbohydrate counting by a certied dietician. Carbohydrate counting is a recommended method of meal planning for patient who have diabetes. Carbohydrate counting allows patients to adjust the amount of prandial insulin administered based on how many grams of carbohydrate they eat at a meal or snack Insulin to carbohydrate ratio (I:C ratio) species how many grams of carbohydrate are covered by each unit of insulin. For example, a 1-unitper-10-grams-of-carb (1:10) ratio means that one unit of insulin covers 10 grams of carbohydrate Correctional dose adjustment for pre-meal hyperglycemia. This will allow patients to adjust pre-meal prandial insulin dose in case BG levels are already elevated or low prior to meals
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Table 5.4 Initiating with prandial insulin
Treatment
Initiation Monitoring and targets
Dose
6 units or 0.1units/kg for each meal with short-acting or rapid-acting analogue. Pre-meals and pre-bed. (Postmeals 1.5 - 2 hours if using rapid-acting analogue) Target pre-meal BG is at 4 6 mmol/L Target post-meals and pre-bed 4 8 mmol/L Adjust insulin doses after 3 consecutive pre-meal 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)
Optimisation
Optimal dose
Prandial dose for each meal will vary according to carbohydrate content and amount. Dose should ideally not exceed 0.5U/kg/dose. Watch for in-between meal hypoglycaemia. If hypoglycemia is the limiting factor to achieve optimum dose, conventional short-acting insulin may be switched to rapid-acting analogue.
Caution
5.4 Initiating and Optimising Basal Bolus Regimen

We can simply start this 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 (Table 5.5). 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. Insulin dose adjustment for prandial and basal insulin is similar as that mentioned in the prior sections 5.1 and 5.3. Aim for normal pre-breakfast BG rst by adjusting the dose of bedtime basal insulin before adjusting the prandial insulin dose. Repeat this monitoring on a weekly basis until glycemic targets are met.
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Table 5.5 Initiating with basal-bolus regimen3,4
Treatment
Initiation Monitoring and targets
Dose
Prandial Insulin : 6 units or 0.1U/kg before each meal Basal insulin : 10 units or 0.2U/kg at bedtime Preferably 4 times per day upon initiation Pre-meals at pre-breakfast, pre-lunch and pre-dinner and at bedtime Target pre-meals BG at 4 6 mmol/L Target bedtime BG at 4 8 mmol/L 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 rst by adjusting the dose of bedtime basal insulin before adjusting the prandial (bolus) insulin dose.
Optimisation
Optimal dose
Generally basal insulin would contribute 50% of total daily insulin dose and prandial insulin would contribute remaining 50% (distributed over three main meals). Prandial insulin: Dose for each meal will vary according to meal carbohydrate content. Normal prandial dose should not exceed 0.5u/kg/dose. Basal insulin: 0.4 - 0.5 units/kg in most patients Lean patients : 0.2 0.3 units/kg Obese patients : Up to 0.7 units/kg
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.
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REFERENCES
1. Arshag DM et al Narrative Review: A Rational Approach to Starting Insulin Therapy. Ann Intern Med. 2006;145:125-134. 2. Holman R et al. Three Year Efcacy of Complex Insulin Regimens in Type 2 Diabetes. N Engl J Med 2009;361:1736-47. 3. Bu BY. Type 2 diabetes mellitus-Guidelines for initiating insulin therapy. Australian Family Physician 2007; 36(7):549-553. 4. Swinnen SGHA et al. Contact frequency determines outcome of basal insulin initiation trials in type 2 diabetes. Diabetologia 2009; 52(11):2324-2327. 5. Clinical Practice Guidelines (CPG) on Management of type 2 Diabetes Mellitus (4th Edition) 2009.
Section
INSULIN INTENSIFICATION
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T2DM is a progressive disease. With increasing duration of disease, there is increasing fasting and postprandial hyperglycemia as a result of progressive pancreatic beta-cell failure. Therefore insulin therapy needs to be a dynamic process, to address progressive insulin deciency. The use of a single insulin regimen may often not ensure durable glycemic control over time despite optimisation of insulin doses. Many patients are left on an inadequate insulin regimen for too long resulting in sub-optimal glycemic control. Intensication enables modication of an insulin regimen, either with additional injections or switching to different insulin types, towards achieving better glycemic control. Key elements for successful insulin intensication Patient education Dedicated diabetes team - diabetes educator, pharmacist, dietician Self-blood glucose monitoring (SMBG) Frequent contact with health care team Support group Insulin intensication can be done in many ways. The choice would depend on the pre-existing insulin regimen, the abnormal glycemic pattern, patient acceptance and lifestyle issues.
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Basal insulin regimens can be intensied by any of the following ways (Figure 6.1a) Switching to premixed regimen (usually twice daily) Addition of three pre-meal rapid / short-acting insulin basal-bolus regimen Sequential addition of pre-meal rapid / short-acting insulin basal-plus regimen
Figure 6.1a Insulin Intensication from basal regime BASAL PREMIXED BD BASAL BOLUS BASAL PLUS (1 PRANDIAL) BASAL PLUS (2 PRANDIAL) BASAL BOLUS (3 PRANDIAL)
Premixed insulin regimens can be intensied by any of the following ways (Figure 6.1b) Additional injections of premixed insulin (twice and three times daily) Addition of pre-meal rapid / short-acting at lunch
Figure 6.1b Insulin Intensication from premixed regime PREMIXED OD
PREMIXED BD
PREMIXED TDS (FOR ANALOGUES)
PREMIXED BD PLUS PRELUNCH / PRANDIAL
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6.1 Switching from Basal to Basal plus regimen

For those patients on combination OADs and basal insulin not achieving HbA1c targets despite optimal fasting BG, addition of prandial insulin to address postprandial hyperglycemia will help improve overall glycemic control. This can be initiated with addition of single prandial insulin prior to the largest meal of the day or to address the highest postprandial BG of the day1,2. With time, additional prandial insulin can be added prior to other meals to address postprandial hyperglycemia. (Figure 6.2). Intensication of the Basal Plus regimen (sequential addition of prandial insulin) will ultimately lead to Basal Bolus regime.
Figure 6.2 Intensication from Basal to Basal Plus regimen
Fix Fasting Blood Glucose (FBG) rst 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
Add prandial insulin 6 units or 0.1unit/ kg at largest meal Titrate to next pre-meal / bedtime BG target daily If subsequent premeals BG are - < 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 Discontinue SU on addition of prandial insulin Continue metformin Patients may need to perform SMBG up to 4 times per day
If A1c > 6.5 - 7% after 3 months despite titrating doses, or prandial dose > 30 U per meal, consider: Add second prandial insulin at 6 units or 0.1 unit/kg at 2nd largest meal and titrate as before Repeat 3rd prandial insulin dose at nal meal of the day
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6.2 Switching from Basal to Basal bolus regimen

For those patients on combination OADs and basal insulin not achieving HbA1c targets despite optimal fasting BG, with post-prandial hyperglycemia identied following all main meals, addition of prandial insulin prior to each meal will help improve overall glycemic control. (Figure 6.3). Sulphonylureas should be stopped but Metformin should be continued.
Figure 6.3. Intensication from Basal to Basal Bolus regimen
Fix Fasting Blood Glucose (FBG) rst 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
Add bolus / prandial insulin 6 units or 0.1unit/kg at each meal Monitor BG up to 4 times per day Titrate to next pre-meal / bedtime BG target daily If subsequent pre-meals BG are - < 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 Stop SU and continue metformin
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 prole
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6.3 Switching from Basal to Premixed regimen

For those patients on combination OADs and basal insulin not achieving HbA1c targets despite optimal fasting BG, with post-prandial hyperglycemia, another option for intensication would be to switch to a premixed regimen. This option is usually appropriate for patients who prefer a simpler regimen and are unable to accept 3 4 injections per day. This regimen is more suitable for those with a rigid lifestyle. Sulphonylureas should be stopped but Metformin should be continued. Dose for dose transfer can be used where the total daily dose of basal insulin is used to determine premixed total daily dose. Premixed is then administered in two divided doses, usually equal in amount ie: split dose 50: 50 at pre-breakfast and pre-dinner (Figure 6.4).
Figure 6.4 Intensication from basal to premixed regimen
BASAL OD or BD
HbA1c 6.5 8% FPG > 6 mmol/L
HbA1c > 6.5 7% FPG 4-6 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
Titrate basal insulin to achieve FPG < 6mmol/L Optimal dose 0.4 0.5 u / kg Continue OADs
Premixed analogues may be considered in patients experiencing hypoglycaemia with conventional premixed insulin and in those who desire greater exibility as administration of premixed analogue does not require specic timing prior to meals and may be injected just prior to, during, or immediately after, a meal.
37
6.4 Switching from Premixed to Basal bolus regimen

For those patients on premixed regimen (twice or three times daily) and not achieving HbA1c targets despite optimised dose, another option for intensication would be to switch to basal-bolus regimen. This option is appropriate for patients who require greater exibility in dose adjustment as it potentially allows pre-meal rapid / short-acting insulin to be adjusted individually according to blood glucose level (correctional bolus) as well as the carbohydrate meal content of the meal.
Figure 6.5 Intensication from premixed regimen to basal bolus regimen PREMIXED INSULIN BD or TDS (Insulin analogue) FPG / premeals > 6 mmol/L HbA1c > 6.5 7% Switch to BASAL BOLUS REGIMEN Starting dose 0.5units/kg/day or total dose transfer Split dose 50:50 for basal and prandial insulin Divide prandial doses into 3 main meals Fix FPG < 6mmol/L using basal insulin Titrate bolus dose once / twice a week to achieve FP and preprandial goal < 6mmol/L Stop SU, continue metformin
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).
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6.5 Switching from single to multiple premixed regimen

For those patients already on a single premixed insulin regimen, usually in combination with single or multiple OADs and not achieving blood glucose and HbA1c targets despite optimising insulin and OAD doses, an option for intensication would be to initiate additional pre-meal doses of premixed insulin. For those on single dose conventional premixed insulin, usually prior to evening meals, one additional dose may be initiated prior to the morning meal. In those receiving premixed analogue insulin, additional doses may be initiated at both morning and midday meals, either sequentially or simultaneously. It is not usual to administer conventional premixed insulin more than twice daily in view of concern for between-meal hypoglycaemia3,4,5,6.
Figure 6.6 Intensication of premixed regimen
PREMIXED OD (pre-dinner) or BD
FPG and / or pre-dinner 4-6 mmol/L
FPG and / or pre-dinner > 6 mmol/L
HbA1c > 6.5 8%
Titrate Premix OD or BD to achieve FPG and / or predinner < 6mmol/L
SWITCH TO PREMIXED BD OR TDS (analogues only) DAILY (OD) TWICE DAILY (BD) Starting dose 0.3units/kg/day or total dose transfer Split the dose 50:50 pre-breakfast and pre-dinner Titrate insulin dose to achieve FPG and pre-dinner<6mmol/L TWICE DAILY (BD) THREE TIMES DAILY (TDS) Add 6 units or 10% total daily dose at lunch Titrate dose once or twice a week to next pre prandial goal < 6mmol/L Down titrate morning dose ( 2 4 units ) may be needed after adding lunch dose Continue metformin Consider premixed analogues if hypos
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6.6 Intensication of premixed regimen with addition of pre-meal bolus

For those patients already on a premixed daily regimen usually in combination with single or multiple OADs and not achieving blood glucose and HbA1c targets despite optimising insulin and OAD doses, an option for intensication would be to initiate additional injections of pre-meal rapid or short-acting insulin. Whereas for those patients already on premixed twice daily regimen and not achieving blood glucose and HbA1c targets despite optimising insulin doses, an option for intensication would be to initiate pre-lunch rapid or short-acting insulin.
Figure 6.7 Intensication of premixed regimen with addition of prandial insulin
PREMIXED OD (pre-dinner) or BD
PREMIXED ONCE DAILY (pre-dinner)
PREMIXED TWICE DAILY (pre-breakfast, pre-dinner) Pre-dinner >6 mmol/L Add PRANDIAL INSULIN (at midday meal)
FPG 4-6 mmol/L, pre-lunch and pre-dinner > 6mmol/L Add PRANDIAL INSULIN (at morning and midday meal)
Add prandial insulin 6 units or 0.1unit/kg at lunch Titrate to pre-dinner BG target daily If subsequent pre-meal BG is - < 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
40
6.7 Intensication of prandial regimen with addition of basal insulin

For those patients already on prandial only regimen usually with each meal and not achieving HbA1c and blood glucose targets (particularly fasting BG despite optimising doses of prandial insulin), an option for intensication would be to initiate basal insulin, usually at bedtime. Basal insulin analogue may be added in the daytime as an alternative to bedtime dosing. Therefore the prandial regimen is intensied to a basal bolus regimen (Figure 6.8)7.
Figure 6.8 Intensication of prandial regimen with addition of basal insulin
PRANDIAL TDS Optimised prandial doses
FPG > 6 mmol/L HbA1c > 6.5 8%
Addition of BASAL INSULIN BASAL BOLUS REGIMEN 10 units or 0.2U / kg at pre-dinner Monitor FPG , target 4-6 mmol/L Adjust basal 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 units
REFERENCES
41
1. Insulin intensication strategies in type 2 diabetes: when one injection is no longer sufcient A. J. Garber Diabetes, Obesity and Metabolism Special Issue: Perspectives in Type 2 Diabetes: Incorporating the Latest Insulin Analogue Strategies to Achieve Treatment Success Volume 11, Issue Supplement s5, pages 1418, November 2009. 2. Options for the intensication of insulin therapy when basal insulin is not enough in type 2 diabetes mellitus D. Raccah Diabetes, Obesity and Metabolism Special Issue: Insulin Glargine: Cornerstone Treatment for Type 2 Diabetes Patients Volume 10, Issue Supplement s2, pages 7682, July 2008 (basalplus). 3. Garber AJ, Wahlen J, Wahl T et al. Attainment of glycemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (The 1-2-3 study). Diabetes Obes Metab 2006; 8: 58-66. 4. Bebakar WM, Chow CC, Kadir KA et al. Adding biphasic insulin aspart 30 once or twice daily is more efcacious than optimizing oral antidiabetic treatment in patients with type 2 diabetes. Diabetes Obes Metab 2007; 9: 724-32. 5. A. G. Unnikrishnan,1 J. Tibaldi,2 M. Hadley-Brown,3 A. J. Krentz,4 R. Ligthelm,5 T. Damci,6 J. Gumprecht,7 L. Ger,8 Y. Mu,9 I. Raz10 Practical Guidance on Intensication of Insulin Therapy With BIAsp 30: A Consensus StatementInt J Clin Pract. 2009;63(11):1571-1577. 6. Intensication lessons with modern premixes: From clinical trial to clinical practice Serdar Gulera, Julius A. Vazb, Robert Ligthelmc Volume 81, Supplement 1, Pages S23-S30 (1 September 2008). 7. Intensication with prandial insulin. Pftzner A, Forst T .Int J Clin Pract Suppl. 2009 Oct;(164):11-4.
Section
TARGETS AND MONITORING

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Achieving glycaemic targets is central to reducing diabetes-related complications. In most patients insulin given in sufcient doses and carefully titrated will achieve those targets, and often more readily than with oral agents. As a general rule, therapy should be directed to achieve an HbA1c of below 6.5% as this has been shown to reduce both microvascular and macrovascular complications. It is increasingly recognised however that glycaemic targets should be individualised. Long-term follow-up of UKPDS and DCCT cohorts suggests that patients with little co-morbidity and a long life expectancy may benet from stringent glycaemic targets early in the disease1,2,3. Other recent studies4,5 assessing macrovascular outcomes indicate that less stringent targets may be appropriate in the following situations: A history of severe hypoglycaemia Patients with limited life expectancy Advanced microvascular or macrovascular complications Extensive co-morbidities Long-standing diabetics in whom glycaemic control remains difcult despite optimising patient education, adherence and dosage6.
7.1 Glycaemic targets for diabetes mellitus7

Glycemic Measures
Fasting Blood Glucose (FBG) Non-fasting Blood Glucose HbA1c
Malaysian Ministry of Health CPG, Management of T2DM 2009
Targets
4.4-6.1 mmol/L 4.4-8.0 mmol/L < 6.5%
Individualised targets for self-monitoring of blood glucose may be discussed and agreed upon after taking patient factors and limitations into consideration.
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7.2 Monitoring insulin therapy

Techniques of monitoring insulin therapy include: Fasting Plasma Glucose (FPG) Glycosylated haemoglobin (HbA1c) Self-monitoring of blood glucose (SMBG) Continuous glucose monitoring (CGM)
7.2.1 Fasting Plasma Glucose (FPG)

Measurement of FPG is an established component of glycemic monitoring in most outpatient settings. It is inexpensive and widely available. However single-point glucose measurements may not accurately depict overall glycaemic control. This is important to bear in mind when making therapeutic decisions.
7.2.2 Glycosylated haemoglobin (HbA1c)

HbA1c levels reect average glycaemic control over 2-3 months. This affords an advantage over single-point glucose measurements, however it may not reect glucose variability. HbA1c should be performed at least 6-monthly in patients who are on stable treatment and are meeting glycaemic targets. In patients not meeting targets or in whom there has been a change in therapy, HbA1c levels should be performed 3-monthly. Special situations may require monitoring at closer intervals e.g. in pregnant diabetics requiring intensive insulin therapy.
7.2.3 Self-Monitoring of Blood Glucose (SMBG)

SMBG allows patients to evaluate their individual response to lifestyle, meals and therapy, and to assess whether glycaemic targets are being achieved. It is particularly important in insulin self-titration and may help minimise hypoglycaemia. As self-monitoring is both instrument and user-dependent, involvement of a diabetes educator is crucial. 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 (1011pm). Once pre-prandial glucose targets are achieved, post-prandial BG testing is recommended for ne-tuning of insulin therapy.
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Recommended timing of SMBG in different insulin regimens Please refer to tables 7.2.3a and 7.2.3b
Table 7.2.3a SMBG in Basal / Basal bolus Regimen Breakfast Pre Basal only Basal bolus (short-acting) Basal bolus (rapid-acting) X X X X X X X X X Post Lunch Pre Post Dinner Pre Post Bedtime Pre
Note Pre-breakfast glucose readings reect adequacy of pre-bed basal insulin Pre-lunch readings reect adequacy of pre-breakfast short-acting insulin Pre-dinner readings reect adequacy of pre-lunch short-acting insulin Pre-bed readings reect adequacy of pre-dinner short-acting insulin Post-prandial glucose readings reect the respective pre-meal rapid-acting insulin (Aspart/Lispro/Glulisine) and can also be used to ne-tune short-acting insulin
Table 7.2.3b SMBG in Premixed Regimen Breakfast Pre Pre-mixed Human BD Pre-mixed Analogues BD Pre-mixed Analogues TDS X X X X X X X Post Lunch Pre X Post Dinner Pre X X X X X Post Bedtime Pre X
Note SMBG in Premixed regimen Pre-breakfast glucose readings reect pre-dinner premixed insulin Pre-lunch and pre-dinner readings reect pre-breakfast premixed insulin Pre-bed readings reect pre-dinner premixed insulin Post-prandial testing may be recommended for ne-tuning of pre-mixed insulin
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SMBG pattern management This is a systematic approach to identifying patterns within SMBG data and then taking appropriate action based upon results. It consists of four basic steps: Step 1 Identify glycemic abnormality: Priority 1 Hypoglycaemia Priority 2 Fasting hyperglycemia Priority 3 Postprandial hyperglycemia Step 2 Determine timing and frequency of occurrence Prior to meals, after meals, during night? Occurs frequently or intermittently? Step 3 Investigate potential causes Insulin and OADs, food and/or physical activity Step 4 Take action Insulin and OADs, food and/or physical activity SMBG and insulin titration / adjustment
Table 7.2.3 c SMBG and Insulin Titration TO CONTROL Pre Breakfast BG 2-hours Post-breakfast BG Pre-lunch BG 2 hours Post-lunch BG Pre-dinner BG Post-dinner/Pre-bed BG ADJUST Pre-bed intermediate/long-acting insulin or pre-dinner premixed Pre-breakfast rapid-acting or premixed insulin analogue. Pre-breakfast short-acting or premixed insulin. Pre-lunch rapid-acting or pre-breakfast premixed insulin. Pre-lunch short-acting or pre-breakfast premixed insulin. Pre-dinner rapid-acting or pre-dinner premixed insulin.
7.2.4 Continuous Glucose Monitoring (CGM)

CGM is not widely available but is an evolving technology which may benet selected patients. It employs interstitial glucose measurement via sensors placed subcutaneously in the abdomen. These readings are transmitted to a monitor and generally correlate well with plasma glucose. However, SMBG is still recommended to calibrate CGM and for making acute treatment decisions. Studies using CGM suggest some benet for patients with Type 1 diabetes.
REFERENCES 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.
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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

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 signicant 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 denition for hypoglycaemia. Recent denitions 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
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The severity of hypoglycaemia can be dened by its clinical manifestations. Mild - Autonomic symptoms present and the individual is able to self-treat Moderate - Autonomic and neuroglycopenic symptoms present and the individual is able to self-treat Severe - Unconsciousness may occur. Plasma glucose is typically < 2.8 mmol/L and the individual requires the assistance of another person Severe hypoglycaemia requiring hospitalisation is more common in elderly patients with T2DM. These events can have serious, sometime life-threatening, cardiovascular and neurological consequences resulting in increased healthcare costs. Elderly patients have a higher risk of complications such as falls and injury, cognitive decline, depression and deteriorating quality-of-life. Asymptomatic hypoglycaemia is the presence of biochemically low blood glucose level without any symptoms. This can be seen in some insulin-treated patients with advanced duration of diabetes or some patients who suffer from autonomic dysfunction and frequent exposure to hypoglycaemia episodes. Symptoms of hypoglycaemia may be absent despite signicantly low blood glucose levels. This phenomenon is described as hypoglycaemic unawareness. Hypoglycaemic unawareness predisposes the patients to have recurrent hypoglycaemia events which can be life threatening7. Risk factors for hypoglycaemia in people with T2DM are Concomitant use of insulin secretagogues and insulin therapy Missed or irregular meals Alcohol consumption (in the absence of sufcient carbohydrate intake) Excessive physical activity Advanced age Longer duration of diabetes Impaired renal or liver function Impaired awareness of hypoglycaemia Lack of patient and care-giver education on hypoglycaemia
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Prevention of hypoglycaemia requires risk factor reduction and individualised treatment regimens. This will include therapy adjustment, exibility in treatment or a change in regimen adapting to each persons needs and lifestyle. It is very important to educate patients with diabetes to recognize the signs and symptoms of hypoglycaemia and how to treat hypoglycaemia (Table 8.1b). Improved education and recognition could prevent and reduce frequency of hypoglycaemic events.
Table 8.1b Treatment of hypoglycaemia 1. Assess the cause and severity of hypoglycaemia 2. Treat hypoglycaemia according to BG level Mild ( BG 3.3 3.9 mmol/L ): Give 15g carbohydrate 4 ounces (120mls) orange juice or other fruit juices OR Hard candy OR 3 glucose tablets Moderate ( BG 2.5 3.2mmol/L ): Give 20g carbohydrate 6 ounces (180mls) orange juice or other fruit juices OR 4 glucose tablets OR Dextrose 50% 25 ml iv Severe ( BG < 2.5 mmol/L ): Give 30g carbohydrate 8 ounces (240ml) orange juice or other fruit juices OR 6 glucose tablets OR Dextrose 50% 25 ml iv Unconscious with severe hypoglycaemia ( BG< 2.5 mmol/L ) Dextrose 50% 25 ml IV OR Glucagon 1 mg subcutaneous or intramuscular (0.5 mg for child) - Vomiting and aspiration risk - Roll patient onto their side when used 3. Monitor BG level every 15 minutes until > 5.6 mmol/L 4. Redose glucose replacement as above every 15 minutes as necessary (PRN)
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8.2 Weight gain

Most patients with T2DM are overweight or obese. Many anti-diabetic medications contribute to weight gain over time. In the UKPDS study (UKPDS 34)9: regardless of treatment, patients gained weight. Patients who were treated with insulin showed the largest weight increase, with an average gain of 4 kg more than conventional therapy at 10 years (UKPDS 33)10. In other studies involving basal insulin use, weight gain of 2 to 3 kg has been observed. Weight gain with insulin therapy is dose related. Use of more intensive insulin regimens with increased total daily insulin requirement generally contributes to greater magnitude of weight gain. The combination of insulin with oral anti-diabetic agents such as TZDs and SUs result in greater weight gain whereas combined use of insulin with metformin may help minimize weight gain. Weight gain in insulin-treated patients may be a consequence of several factors: Improving metabolic control reduces glycosuria, thus fewer calories are lost in this manner Fear of hypoglycaemia may lead to increased snacking between meals, thus increasing calorie intake Use of insulin can increase lean body mass through its anabolic nature. Insulin use can also cause salt and water retention It is important to provide patient education on measures to counter weight gain while on insulin therapy. Important steps would be as follows Restrict calories and portion control, particularly carbohydrate and fats Appropriate advice from dietician Keep physically active and practise regular exercise Avoid high doses of insulin. Reducing carbohydrate intake and being physically active reduces insulin requirement Prevent hypoglycaemia which leads to defensive eating / snacking
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8.3 Injection site problems

Skin irregularities can sometimes occur at injection sites due to changes in the subcutaneous fat, of which there are three types. Fat hypertrophy (lipohypertrophy) appears as soft lumps at the injection sites. This unusual condition may be caused by the natural effects of insulin (one of which is to cause fat to grow) or by reuse of needles. To prevent further development of hypertrophy, rotate injection sites and avoid reuse of needles. Fat atrophy (lipoatrophy) is a loss of fat under the skins surface. This rare condition appears as a dip in the skin and has a rm texture. It occurs much more commonly with impure insulins. Scarring of the fat (also known as lipodystrophy) is caused when you inject too many times into the same site or when you reuse a needle.
8.4 Insulin allergy and hypersensitivity

In the past, when unpuried insulins were used, allergic reactions were reported in 10% to 56% of patients. Since human insulin and analogues have been introduced, insulin allergies are rare and currently reported in only 0.1% to 2% of all patients treated with insulin. In most cases, allergic reactions are restricted to the skin and are either of a local immediate or delayed reaction type. These skin reactions are often self-limited with continuation of therapy. However, systemic reactions such as urticaria or anaphylaxis have also been reported. Both types of hypersensitivity may result from the insulin molecule itself, and also from protamine, which is used in many preparations to delay insulin absorption. In patients with diabetes mellitus, subcutaneous administration of protamine-containing insulin preparations can provoke delayed, T-cell mediated skin reactions or granulomatous hypersensitivity. In addition to protamine, cresol and phenol, both preservatives in pharmaceutical products, may provoke allergic reactions. Successful treatment of insulin allergies have been reported when patients were using a continuous subcutaneous pump infusion of insulin and switching from human insulin to insulin analogues such as aspart or lispro.
54
REFERENCES
1. UK Hypoglycemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007;50(6):11401147. 2. Lundkvist J et al. The economic and quality of life impact of hypoglycemia. Eur J Health Econom. 2005;6(3):197202. 3. UKPDS Research Group: Overview of 6 years of therapy of type II diabetes: a progressive disease. Diabetes 44:12491258, 1995 4. Cryer PE. Hypoglycemia, functional brain failure, and brain death. J Clin Invest. 2007;117(4):868870. 5. Mohamed M. An audit on diabetes management in Asian patients treated by specialists: the Diabcare-Asia 1998 and 2003 studies Curr Med Res Opin 2008; Vol 24 No 2: 507514. 6. Workgroup on Hypoglycemia, American Diabetes Association: Dening and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 28:12451249, 2005. 7. Cryer PE et al. Hypoglycemia in diabetes. Diabetes Care 26:19021912, 2003. 8. Amiel SA et al. Hypoglycaemia in Type 2 diabetes . Diabet Med. 2008;25(3):245254. 9. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive bloodglucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998 Sep 12 352 854-865. 10. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):83753.
Section
SPECIAL SITUATIONS
56
SPECIAL SITUATIONS
9.1 Sick Days

There may be times when the patient cannot eat solid food or follow their regular meal plan because of concurrent illness, dental or outpatient surgery. Maintaining glycemic control during periods of short-term illness is important to prevent complications. Potential problems during sick days are the following: dehydration ketoacidosis hyperglycemia hypoglycaemia 9.1.1 Hyperglycaemia These are more common during illness particularly in viral illnesses with fever (such as inuenza or upper respiratory tract infection) or in bacterial illnesses (such as tonsillitis or otitis media). BG levels will often still be high even if the patients appetite is poor because of continuing release of glucose from the liver and insulin resistance secondary to infection. 9.1.2 Hypoglycaemia Gastroenteritis (vomiting and diarrhoea) often cause low BG levels even without fever. The BG levels are low because the patients appetite is often decreased and the food and drink that is taken is not being well absorbed. During acute inter-current illness, insulin-treated patients will need to pay special attention to monitoring and self-care practices. The following table indicates principles in managing insulin-treated patients with acute intercurrent illness (Table 9.1) Table 9.1 Sick Days Rules. Patients are instructed on the following self-care. Treat underlying illness Symptomatic treatment eg: paracetamol for headache More frequent SMBG Maintain positive uid balance: plenty of uids, especially those with high temperatures and high glucose Maintain adequate nutrition Insulin treatment may need adjustment - Start out with usual insulin dose (except if AGE) - Monitor BG pre-meals and between meals when needed - Adjust insulin doses according to SMBG - Additional rapid-acting insulin if blood glucose more than 15-16 mmol/L
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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 Voluminous or repeated vomiting Increasing levels of ketones in the blood or urine or labored breathing Blood glucose remains high despite extra insulin Absence of obvious precipitating factors Severe or unusual abdominal pain Confusion or deterioration in well being Presence of concurrent illnesses besides diabetes Exhaustion on the part of other person or their carer, eg: repeated night waking
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 nd 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
Adjustment of insulin doses during long distance air travel With long haul ights and crossing of time zones, there may need to adjust insulin doses due to changes in mealtimes and activity during the ight. Travelling North or South does not require any changes in 24 hour schedule. Travelling East will shorten the day and therefore the need for less insulin, meanwhile travelling West will lengthen the day and the need for more insulin. During travelling, the insulin-treated patient is advised the following: Frequent blood glucose monitoring Planning of activities to match the insulin and meals Careful observation and selection of food and drinks to avoid food-borne infection Advice on appropriate footwear and foot care
9.3
Exercise2
Physical activity / exercise is an integral part of the overall management of insulin-treated patients. The following table states the benets of exercise in insulin-treated patients (Table 9.3a). Table 9.3a Benets of exercise in insulin-treated patients Increases calorie expenditure with weight loss and maintenance of healthy weight Increases insulin sensitivity and reduces insulin resistance, improves glycemic control Reduces insulin requirement Improves lipid prole, reduces LDL-cholesterol and increases HDLcholesterol Lowers BP and reduces risks of CV disease and CV mortality Increases endorphin release, thereby reduces stress and improves mood Improves muscle strength Increases bone density and strength Prior to exercise, insulin-treated patients should undergo the following evaluation: Complete Physical Exam, including foot, respiratory, cardiovascular Diabetic complication screening with assessment for proliferative retinopathy, autonomic and peripheral neuropathy and nephropathy
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Insulin-treated patients may experience unstable blood glucose levels in relation to exercise with an increase risk of both hypoglycaemia and hyperglycaemia. Risk of hypoglycaemia is due to reduced insulin resistance and reduced insulin requirement while risk of hyperglycemia is a result of stress hormone release. Advice is given to patients with regards to monitoring, lifestyle and insulin dose adjustment prior to, during and after exercise as stated in Table 9.3b. Table 9.3b Recommendations on self-care and lifestyle adjustment with exercise for insulin users Optimal time for exercise would preferably be 1-3 hours following meal SMBG should be performed before, during and after exercise BG target at the start - between 5.5mmol/L to 11.1 mmol/L If BG is < 4.4 mmol/L advise to consume 15-20 grams carbohydrate 15-20 grams carbohydrate for prevention of hypoglycaemia, may need additional consumption every 30-60 minutes. Carry sweet or snacks in case of hypoglycaemia. Consider need for insulin dose reduction, vary between 25-75% reduction Watch for post-exercise hypoglycaemia If heavy exercise is planned, such as aerobics, running or handball, extra calories should be consumed. Exercise should be avoided in the following circumstances; Elevated BG > 16mmol/L Acute inter-current illness Positive ketonuria Dyspnoea. Symptomatic peripheral neuropathy - tingling, pain or numbness in the legs
60
SPECIAL SITUATIONS
9.4
Fasting and Ramadan3
Insulin-treated patients who perform fasting are at risk of hypoglycaemia, hyperglycaemia, diabetic ketoacidosis, dehydration and thrombosis. The severity of risk for developing these complications differ according to several patient factors as mentioned in Table 9.4a. Table 9.4a Severity of risk for complications during fasting for patients with diabetes3 Very high risk group Type 1 diabetes Severe hypoglycaemia within the last 3 months prior to Ramadan Patient with a history of recurrent hypoglycaemia or hypoglycaemia unawareness Ketoacidosis or Hyperosmolar hyperglycaemia within the last 3 months prior to Ramadan Patients with sustained poor glycaemic control Patients with renal insufciency, advanced macrovascular complications or co-morbid conditions that present additional risk factors Acute concurrent or recent illness such as infection Poor compliance to anti-diabetic medications Pregnancy Moderate risk Patients with moderate hyperglycaemia People living alone that are treated with insulin Patients living alone with ill health Old age with ill health Drugs that may affect mentation Patients who perform intense physical work Low risk Well controlled patients treated with diet alone, metformin, or a thiazolidinedione, who are otherwise healthy Well-controlled patients treated with prandial glucose regulators such as repaglinide or nateglinide
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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 Bedtime basal insulin with OADs Insulin Dose Adjustment Reduce basal insulin dose by 20% Insulin administered at Iftar time (sunset) Reverse OAD dose - morning to evening dose and vice versa Reverse doses morning dose given at Iftar (sunset) and evening dose at sahur Insulin dose at sahur reduced by 20-50% to prevent daytime hypoglycaemia Basal dose given at Iftar, dose reduced by 20% Sahur/ morning dose of prandial insulin reduced by 25% Mid-day/ lunch prandial insulin omitted Iftar prandial dose maintained, may be adjusted according to carbohydrate content in meals
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 rst 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 of total daily insulin requirement by gestation / trimester Pregnancy gestation Pregnancy gestation 1st trimester 2nd trimester 3rd trimester Total daily insulin requirement 0.7 units/kg/day 0.8 units/kg/day 0.9 units/kg/day
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).
Table 9.5b Glycaemic Targets in Pregnancy Timing Pre-prandial 1 hour post-prandial 2 hours post-prandial 0200-0400H
(ADA recommends pre-prandial BG <5.3 mmol/L)
Glucose Levels (mmol/L) 3.5-5.9 <7.8 4.4-6.7 3.9
REFERENCES
63
1. National diabetes education program. Available from http://www.nedep.nih. gov/media/diabetes_travel_article,pdf. 2. Diabetes and Exercise association. Available from http://www.diabetesexercise.org/presentaion/Horton_2009,pdf. 3. A population-based study of diabetes and its characteristics during the fasting month of Ramadan in 13 countries: results of the epidemiology of diabetes and Ramadan 1422/2001 (EPIDIAR) study. Diabetes Care. 2004 Oct;27(10):2306-11. 4. Recommendations for Management of Diabetes During Ramadan. Diabetes Care,2010 Aug;33(8):1895-1902. 5. Angeline L et al .Insulin analogue and pregnancy .Diabetes Spectrum Vol 2, 2007. 6. Boyd et al.Summary and Recommendations of the 5th International Workshop Conference on Gestational Diabetes Mellitus .Diabetes Care, Vol 30, Supplement 2, July 2007.
Section
10
PRACTICAL ISSUES
PRACTICAL ISSUES
65
10.1 Insulin handling and storage

Insulin comes from drug manufacturers in three basic packages; vials, pens and cartridges/ penlls. Insulin vials, either open or unopened, generally last for one month when stored at room temperature (15 30oC). All unopened vials should be stored in the refrigerator (2 8oC) away from the freezer, and are good until the expiration date printed on the label. A vial is considered open if its seal has been punctured. Once opened and stored in a refrigerator the insulin should be used within one month of being opened and discarded thereafter, regardless of the expiration date, as there may be loss in potency. Vials that are currently in use can be kept at room temperature as injecting cold insulin can be painful. Insulin past the expiration date printed on the label should not be used. Patients are advised to write the date the vial was opened on the label. With insulin pens and their cartridges / penlls, storage life ranges from seven days to one month1. There are different storage indications for every type of insulin available, depending on the particular formulation of insulin, its method of manufacture, its container and ambient storage conditions. In-use dating recommendations for insulin in vials differ from cartridges or prelled insulin pens. Pens and cartridges have shorter in-use duration than those for vials, reecting the reduced volumes and the environment to which these products might be exposed.2,3
66
PRACTICAL ISSUES
Maximum storage duration for insulin pens Refrigerated Opened Product name
Humulin N Humulin 30/70 Humalog Humalog 25/75 Actrapid Insulatard Mixtard 30/70 Novorapid Lantus Levemir 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 Until Expiration Date Stamp Until Expiration Date Stamp Until Expiration Date Stamp Until Expiration Date Stamp Until Expiration Date Stamp Until Expiration Date Stamp Until Expiration Date Stamp Until Expiration Date Stamp Until Expiration Date Stamp Until Expiration Date Stamp
Room temperature Opened / Unopened (Days)

28 28 28 28 42 42 42 28 30 42
Unopened
The following tips are useful for insulin storage Protect insulin (vials, pens, and cartridges) from extremes of hot and cold Keep insulin out of direct sunlight Never store insulin in the freezer - once insulin is frozen, it loses its potency Dont store insulin near radiators, heat-vents, ovens, air conditioners, etc. Dont leave insulin in a closed car during very warm or cold weather If going outdoors for a while in hot or cold weather, store your insulin in an insulated case Inspect insulin prior to each use. Observe for unusual appearance of insulincloudy instead of clear, clumping, stringy or has changed in color. These changes will probably lead to ineffective insulin and should be discarded immediately and a new vial / cartridge / pen should be used
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10.2
Insulin injection sites
The site of insulin injection greatly inuences 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
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10.3 Insulin pen devices and needles

Insulin injections can be given using an insulin syringe and appropriate syringe needles or with an insulin pen device and appropriate pen needles. An insulin pen is a type of delivery system for administering insulin doses that is used as an alternative to a syringe. Insulin pens use short and thin needles that usually guard against any air owing through. Insulin pens have made dispensing insulin simple for patients at home or on the go, and can generally provide a more accurate dosage than a syringe. There are a number of different brands and models of insulin pens available. Most insulin pens fall into one of two groups: reusable pens and disposable pens. A reusable insulin pen must be loaded with a cartridge / penll of insulin (available / sold in boxes of ve cartridges). Cartridges / penlls hold 300 units of insulin and may give enough insulin to last for several days. When the cartridge is empty a new cartridge is loaded. With good care a reusable pen can often be used for several years. Disposable insulin pens come pre-lled with insulin and are thrown away when they are empty. Most disposable pens used hold 300 units of insulin and are available / sold in boxes of ve. Disposable pens are generally more convenient because there is no need to load any cartridges, but usually cost more to use than reusable pens and cartridges.
70
PRACTICAL ISSUES
Table 10.3 Insulin pens available in Malaysia1 Insulin Pen HumaPen (Ergo) n Reusable Pen Type Insulin Type - Humulin R - Humulin N - Humulin 30/70 - Humalog - Humalog 25/75 - Actrapid - Insulatard - Mixtard 30/70 - Novorapid - Actrapid - Insulatard - Mixtard 30/70 - Novorapid - Novomix 30 - Detemir - Lantus - Apidra
Novopen 3 Novopen 4 Reusable
Novolet
Pre-lled / disposable Pre-lled / disposable
Flexpen
SoloSTAR
Pre-lled / disposable
71
10.4 Insulin Absorption

Variability of insulin absorption is perhaps the greatest barrier to replicating physiologic insulin secretion4. The inter-individual and intra-individual insulin absorption can pose a signicant challenge to the health care provider during insulin optimisation. Day-to-day intra-individual variation in insulin absorption is approximately 25%, and the variation between individuals may be as high as 50% 5. Factors that may affect insulin absorption include the following (Table 10.4): Table 10.4 Factors inuencing insulin absorption Factors
1. Site of injection
Comment
Abdominal injection (particularly if above the umbilicus) results in the quickest absorption; arm injection results in quicker absorption than thigh or hip injection Large volume injection is absorbed in a more unpredictable manner compared to small volume injection (i.e. < 10u) Patients should be advised to inject insulin at a consistent depth to avoid unpredictable absorption Absorption may be compromised if short needles are used for a relatively thick subcutaneous tissue. There are three needle sizes available in Malaysia, i.e. 5mm, 6mm and 8mm Insulin analogue is generally absorbed in a more predictable manner than conventional human insulin Insulin is absorbed faster when administered intravenously compared to intramuscular or subcutaneously in a descending order Exercising a muscle group before injecting insulin into that area increases the rate of insulin absorption Local application of heat or massage after an insulin injection increases the rate of insulin absorption
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
10.5 Insulin Injection problems

Beginning insulin therapy requires proper education regarding injection technique. However, even with proper education by a certied diabetes educator problems can still occur. Injection problems can occur with the use of a vial and syringe or a pen device (Table 10.5) Table 10.5 Common insulin injection problems Problems Painful injections

Solutions
Review injection technique Try injecting at a 45 angle; to prevent hitting muscle Inject quickly Check that needle is not bent Inject insulin when it is at room temperature. Cold insulin hurts Try injecting in different site Do not use needles more than once. Reusing needles can bend and dull the tip and increase pain Keep the muscles at injection area relaxed Larger doses hurt more. May benet from more frequent injection with smaller amount
Bleeding at site of injection
Do not rub the injection site Apply light pressure with nger to prevent bruising If bruising, avoid that injection site again until the bruise resolves Frequent bleeding may indicate poor technique or another medical problem; inform healthcare provider and/or diabetes educator Wait at least 10 seconds after injecting before removing the needle. Do not carry a pen with the needle attached. This causes air to enter the cartridge, thus slowing the time it will take to get the insulin dose Try using a longer needle (8mm). Try a different injection site Small amounts of insulin may be caught in the needle from a previous use. Never re-use needles There may be a clump in the insulin: If using cloudy insulin, be sure to properly mix insulin before drawing it up Cloudy insulin can dry inside the needle or syringe if drawn up too far before the time of injection. Fill syringe closer to the time 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
10.6 Self monitoring of Blood Glucose (SMBG)

Glucose meters play a central role in the management of diabetes particularly for insulin- treated patients as insulin dose adjustment is reliant on SMBG. The ADA consensus panel reported that up to 50% of SMBG determinations might vary more than 20% from the true value4 The following table (Table 10.6) describes factors to be considered to assure the accuracy of home glucose monitoring5 Table 10.6 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Code on monitor matches code on glucose test strip vial Glucose test strips stored in original container Test strips within expiry date Lateral side of nger pricked with puncture device First drop of blood is wiped off, then hanging drop is tested Blood is applied correctly to cover all of test strip Strip is inserted at appropriate time Monitor is cleaned weekly or as needed Blood glucose value properly recorded Control solution is used and control solution is within expiry date Control values are within 10% of expected
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
76
APPENDIX
Carbohydrate Content of Common Malaysian Foods

Foods Serving Calories (kcal) Carbohydrate content (g) Approx. Carbohydrate Exchanges* *1 carbohydrate food exchange = 15 g 3 3 3 4 3 1 1 >1 1 4 1 1 1 1.5 <1 <1 1 1 1 1 1
Cooked rice Roti canai Chappati Curry mee Fried noodles (mee/mee hoon)
1 bowl (159g) 1 piece (95g) 1 piece(100g) 1 bowl (450g) 1 plate (170g)
207 301 300 549 281 70 80 128 90 98 187 131 100 126 40 40 56 52 50 56 50
48 46 47 55 41 15 14 17 16 64 18 12 16 21 9 9 11 12 11 11 11
Bread (white/wholemeal) 1 slice (30g) Biscuits, unsweetened Curry puff Potato Dhall (raw) Full cream milk Low fat milk 2 pieces (18g) 1 piece (40g) 1 medium (90g) cup (98g) 1 cup (250 ml) 1 cup (250 ml)
Skim milk powder 4 tablespoon (28g) Condensed milk, sweetened Apple/ orange Banana (pisang mas) Star fruit Langsat/ grapes/ longan Guava 2 tablespoon (40g) 1 medium (114g) 1 small (50g) 1 medium (260g) 8 small (233 g) fruit (100g)
Watermelon/ papaya/ pineapple 1 slice ( 160g) Mango 1 small ( 100g)
INDEX
References are to page numbers within the booklet.
77
Page Barriers insulin absorption insulin therapy - solutions patient barriers provider barriers - solutions Basal bolus regimen initiation and optimisation Basal insulin basal bolus regimen initiation and optimisation intensication basal plus regimen premix regimen Beta cells progressive decline Diagnosis role of insulin therapy 8 Exercise benets insulin dose adjustment Fasting and Ramadan insulin therapy - complications - insulin dose adjustments - severity of risk Handling and storage insulin 58 59 71 2; 11; 12 12 11 12 13
28; 29
35 24 33 34 36
5; 8
60 61 60
65; 66
78
INDEX
Page Hypoglycaemia clinical manifestations insulin therapy prevention risk factors severity Injection site practical issues problems Insulin absorption comparison of conventional insulin and insulin analogues effectiveness handling and storage initiation and optimisation intensication pen devices and needles preparations regimen types - pharmacokinetic proles Insulin absorption affecting factors Insulin analogues Insulin injection problems Insulin regimen Insulin resistance progression of T2DM 49 49 51 50 50
67 53
71 18; 19 6 65; 66 23; 24 32 69 16 20 16 17 71 71 18
72 20
INDEX
79
Page Insulin therapy barriers - solutions current practice implementation intensication 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 Intensication basal bolus regimen basal regimen multiple premixed regimen basal plus regimen prandial regimen premix regimen Monitoring continuous glucose monitoring insulin therapy self-monitoring of blood glucose - accuracy - glucose meters Pen devices and needles 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 37 35 38 34 40 36 46 44 44 73 73 69
80
INDEX
Page Pharmacokinetic proles insulin Prandial insulin initiation and optimisation intensication Pregnancy insulin therapy - management - risks Premixed insulins addition of prandial insulin basal bolus regimen initiation and optimisation intensication multiple premixed regimen Self-monitoring of blood glucose accuracy - glucose meters insulin titration/adjustment pattern management timing in different insulin regimens Sick days hyperglycaemia hypoglycaemia sick days rules Targets glycaemic targets Travel insulin therapy - long distance air travel - preparations Type 2 Diabetes Mellitus diagnosis - role of insulin therapy - treatment and management Weight gain insulin therapy 17 26; 27; 28 40 62 62 62 39 37 25; 26 33 38 44 73 73 46 46 45 56 56 56 43
58 57
8 7 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 Twice Daily (Bis Die) Blood Glucose Body Mass Index Blood Pressure Coronary Heart Disease Cardiovascular Disease Diabetes Control and Complications Trial Diabetes Ketoacidosis Diabetes Mellitus Diabetic Nephropathy Dipeptidyl peptidase-4 Electrocardiogram Erectile Dysfunction Fasting Plasma Glucose Gestational Diabetes Mellitus Glycaemic Index Glycosylated Haemoglobin High Density Lipoprotein International Diabetes Federation Impaired Fasting Glucose Impaired Glucose Tolerance Low Density Lipoprotein Medical Nutrition Therapy National Cholesterol Education Program Neutral Protamine Hagedorn Oral Anti-diabetic Once Daily (Omni Die) Oral Glucose Tolerance Test On Morning (Omni Mane) On Night (Omni Nocte) Peroxisome Proliferator-Activated Receptor-Gamma Post-prandial Plasma Glucose Random Plasma Glucose Subcutaneous Self Monitoring Blood Glucose Sulphonylurea Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus Three Times Daily (Ter Die Sumendus) Triglycerides Thiazolidinedione United Kingdom Prospective Diabetes Study Waist Circumference World Health Organisation
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
The development of this guide was supported by an educational grant from sano-aventis

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TABLE OF CONTENTS

iv GUIDE WORKING COMMITTEE

Dr. Foo Siew Hui

Dr. Noor Lita Adam

Dr. Lim Siang Chin

Dr. Nurain Mohd. Noor

Dr. Masni Mohamad

Dr. Shamita Sharma

Dr. Mohamed Badrulnizam Long Bidin

Dr. Yong Sy Liang

Prof. Dato Paduka Dr. Wan Mohamad Wan Bebakar

Prof. Dr. Nor Azmi Kamaruddin

Dato. Dr. Santha Kumari

Dr. G. R. Letchuman Ramanathan

Dr. Feisul Idzwan Mustapha

Dr. Mastura Ismail

(The following external reviewers provided feedback on the draft)

vi SUMMARY OF TREATMENT ALGORITHM

Glycemic abnormality? FPG, SMBG

Normal Fasting / prebreakfast BG High daytime BG

High Fasting / prebreakfast BG Normal daytime BG

High Fasting / prebreakfast BG High daytime BG

Start PRANDIAL only (usually TDS premeals) Optimise dose

Start BASAL only (bedtime) Optimise dose

Start PREMIXED OD (predinner) Optimise dose

Start PREMIXED BD (prebreakfast & predinner) Optimise dose

Start BASAL BOLUS (premeals, bedtime) Optimise dose

BASAL PLUS (premeal and bedtime) Optimise dose

Add 3 prandial insulin

Add basal insulin

Sequential addition of prandial insulin

PREMIXED TDS* (premeals) Optimise dose

PREMIXED BD PLUS PRANDIAL (prelunch) Optimise dose

RATIONALE FOR INSULIN THERAPY IN T2DM

RATIONALE FOR INSULIN THERAPY IN TYPE 2 DIABETES MELLITUS

Figure 2.1 Progressive Decline in Beta-cell Function in Type 2

-Cell Function (%)

Years From Diagnosis

RATIONALE FOR INSULIN THERAPY IN TYPE 2 DIABETES MELLITUS

Lifestyle factors: diet, exercise, smoking, alcohol

Progression of type 2 diabetes

Diagnosis of Type 2 Diabetes All patients advised LIFESTYLE

RATIONALE FOR INSULIN THERAPY IN TYPE 2 DIABETES MELLITUS

BARRIERS TO INSULIN THERAPY

BARRIERS TO INSULIN THERAPY

3.1 Patient barriers

BARRIERS TO INSULIN THERAPY

Table 3.1: Barriers to insulin therapy and suggested solutions

Possible barriers Insulin as a personal failure

Insulin causes complications and death

Insulin injections are painful

Insulin causes weight gain

3.2 Provider barriers

INSULIN TYPES AND REGIMENS

INSULIN TYPES AND REGIMENS

4.1 Insulin Preparations

10-20 min 0-15 min 5-15 min

3-5 3.5-4.5 3-5

30-60 mins before meals

18-23 5-15 mins before meals

INSULIN TYPES AND REGIMENS

4.2 Comparison of Conventional Insulin and Insulin Analogues

Table 4.2 Comparison of conventional and analogue insulin2,3,4