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Tahseen A. Chowdhury

The Royal London Hospital

London

United Kingdom

ISBN 978-1-4471-4868-5

ISBN 978-1-4471-4869-2 (eBook)

DOI 10.1007/978-1-4471-4869-2

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Preface

Diabetes is a potentially deadly condition, leading to huge

personal, societal and economic costs, and many words have

been written on the epidemic of diabetes worldwide. I, like

many clinicians “at the coal face” of diabetes care feel that we

are experiencing in “tsunami” of diabetes threatening to over-

whelm diabetes services, and at current rates of growth, poten-

tially overwhelm health services with a plethora of diabetic

complications. Worryingly, the rapid growth in obesity and

diabetes shows no sign of abating, and indeed younger people

appear to be developing the condition at an alarming rate.

Despite the seemingly overwhelming nature of the pan-

demic of diabetes, the present is a wonderful time to be

involved in diabetes care. Burgeoning research into the

pathogenesis, treatment and prevention of the condition is

leading to genuine advances in our understanding, and sig-

nificant improvements in diabetes care and therapy. Diabetes

complications may now be prevented or at least delayed by

individualized management and a partnership approach with

the patient. New technologies are showing promise for

improved treatment and possibly even cure.

With the huge amounts of published literature on the topic

of diabetes, it can often be difficult to stay abreast of the most

important advances. It is with this in mind, that I approached

a number of authors to write chapters on the “state of the art”

in various aspects of diabetes care. Whilst it is important to

ensure that authors are authoritative and well known in the

field, I also made a conscious effort to approach authors who

are highly respected practicing diabetologists, running high

quality diabetes services.

vii

viii

Preface

Each chapter is a discrete essay on an important aspect of

diabetes care. In Chap. 1, we start, appropriately, with

prevention of diabetes - perhaps the most important public

health challenge of our time. Chapters 2 and 3 deal with

aspects of management to reduce the risk of diabetic compli-

cations - including glycaemic management, which is the sub-

ject of intense debate and controversy in the literature at the

moment. Chapters 4 and 5 deal with management of some of

the chronic complications of diabetes, in which there has

been significant progress in recent years. Finally, Chap. 6

deals with managing diabetes in hospitalized patients - an

area where the greatest financial burden of diabetes occurs.

I hope that upon reading the book, readers will feel they

are bang up to date with some of the latest aspects of diabetes

research and care. Whilst diabetes care has often been

reduced to a series of pathways and guidelines, I also hope

that the reader will also understand that there is much more

to care for people with diabetes than just a cocktail of pre-

scriptions. People with diabetes need compassion, support,

education and personalized care to deal with this potentially

devastating long-term condition.

I would welcome any feedback or comments on the text.

London, UK

Tahseen A. Chowdhury

Chapter 1

Preventing Diabetes

Girish Rayanagoudar and Graham A. Hitman

Abstract The prevalence of diabetes is increasing globally.

While environmental factors including obesity and sedentary

lifestyle are clearly responsible for this epidemic, the reasons

for rise in incidence of Type 1 diabetes (T1D) are less clear.

Once considered a disease of affluent countries, diabetes is

now disproportionally affecting low and middle-income coun-

tries. The last couple of decades have seen significant progress

in our understanding of the pathogenesis of these conditions.

Randomised trials have demonstrated that Type 2 diabetes

(T2D) can be delayed if not prevented. Prevention of T1D,

however, has proven more elusive. LADA and gestational

diabetes are also under intense scientific scrutiny.

Keywords Diabetes • Type 1 diabetes • Type 2 diabetes •

Latent autoimmune diabetes in adults • Gestational diabetes •

Epidemiology • Prevention

G. Rayanagoudar, MBBS, MRCP(UK)

G.A. Hitman, MBBS, MD, FRCP (

)

Centre for Diabetes, Barts and the London School of Medicine

and Dentistry, Queen Mary University of London,

Blizard Institute, London, UK

e-mail: g.a.hitman@qmul.ac.uk

T.A. Chowdhury (ed.),

Diabetes Management in Clinical Practice,

DOI 10.1007/978-1-4471-4869-2_1, © Springer-Verlag London 2014

G. Rayanagoudar and G.A. Hitman

Introduction

Diabetes is defined by the World Health Organization

(WHO) as a metabolic disorder characterized by chronic

hyperglycemia with disturbances of carbohydrate, fat and

protein metabolism resulting from defects in insulin secre-

tion, insulin action, or both. Type 2 diabetes Mellitus (T2D),

Type 1 diabetes Mellitus (T1D), and Gestational Diabetes

Mellitus (GDM) are commonly encountered in clinical prac-

tice. Other causes of diabetes include genetic defects in beta

cell function (e.g. Maturity Onset Diabetes in the Young

[MODY]) genetic defects in insulin action (e.g. Type A insu-

lin resistance), diseases of exocrine pancreas, endocrinopa-

thies, drugs, infections etc. Latent Autoimmune Diabetes in

Adults (LADA) is a subgroup of adult-onset diabetes cur-

rently classified by WHO as T1D.

Table 1.1 outlines the WHO and American Diabetes

Association (ADA) diagnostic criteria for diabetes and inter-

mediate hyperglycemia.

Diabetes is associated with reduced life expectancy, and

causes significant morbidity due to microvascular and macro-

vascular complications and diminished quality of life. The condi-

tion is gaining increasing importance due to rapidly increasing

prevalence fuelled by obesity and sedentary lifestyles. More

than 371 million people have diabetes worldwide (prevalence

8.3 % among those aged 20-79 years) compared to an estimated

153 million in 1980 of which T2D accounts for 90 % of all people

with diabetes. The epidemic of diabetes is not restricted to T2D,

as both T1D and GDM are also increasing in prevalence. Due to

the rising prevalence of diabetes and its associated socioeco-

nomic impact on individuals and health systems, efforts to pre-

vent diabetes are a public health priority.

T1D (Excluding LADA)

T1D is a multifactorial autoimmune disease characterized by

autoimmune destruction of pancreatic beta cells in geneti-

cally susceptible individuals.

G. Rayanagoudar and G.A. Hitman

Epidemiology

T1D accounts for 5-10 % of diabetes worldwide, and is the

dominant type of diabetes in children and adolescents. The

incidence of T1D has been on the rise and there is also signifi-

cant variation between different geographical areas.

Major international collaborative efforts such as WHO

DIAMOND (Multinational Project for Childhood Diabetes)

and EURODIAB (The Epidemiology and prevention of

Diabetes) projects have significantly contributed to our

knowledge of the epidemiology of T1D. DIAMOND, a proj-

ect involving 57 countries, showed that between 1995 and

1999, the average annual increase in incidence of T1D was

3.4 % compared to 2.4 % in 1990-1994. The overall age-

adjusted incidence varied from 0.1/100,000/year in China and

Venezuela to 40.9/100,000/year in Finland. The incidence

increased with age, with 10-14-year olds having almost twice

the risk than 0-4-year olds. The annual increase in incidence

was, however, highest in the youngest age group (4 % in 0-4

years and 2.1 % in 10-14 years). The SEARCH for Diabetes

in Youth Study in United States found that, in 2002-2003, the

incidence rates of childhood T1D were higher than those

reported in DIAMOND registry between 1990 and 1994.

Data from the EURODIAB registers also showed an increase

in incidence of 3-4 % annually in childhood T1D in the

European registries between 1989 and 2008. Although risk

declines after 15 years of age, around a quarter of T1D

patients are diagnosed as adults.

Etiopathology

Genetic Susceptibility

The risk of T1D in a sibling of an affected individual is

around 6 %, as compared to 0.4 % risk in the background

population, which translates to a 15-fold increase in relative

risk. A child has a 7 % risk of developing T1D if father is

Chapter 1. Preventing Diabetes

affected and 2 % risk with affected mother. There appears to

be a strong genetic component and HLA class II alleles are

responsible for up to 30-50 % of genetic T1D risk. HLA

alleles contributing to disease susceptibility include HLA

DR3, DQB1*0201, and DR4, DQB1*0302 as compared to

some associated with disease protection, e.g. HLA DR2,

DQB1*0602. Multiple non-HLA loci including insulin,

PTPN22, CTLA4, IL2RA and IFIH1 also contribute to dis-

ease risk. In fact, with the advent of genome wide association

studies (GWAS), more than 50 non-HLA loci associated with

T1D susceptibility have been found. Many of these genes

have a role in the immune response and may contribute to

autoimmunity in general.

Environmental Factors

Though genetic factors are important, disease concordance in

monozygotic twins is only up to 50 % and approximately

90 % of T1D cases lack family history of the condition. This,

along with the recent sharp increase in incidence of child-

hood T1D, suggests that exogenous influence or gene-

environment interaction may be important. Furthermore,

migrating populations have been shown to have similar risk

of developing T1D as people in their adopted geographical

area. Over the years, numerous environmental triggers for

T1D including viral infections, vitamin D deficiency, cow’s

milk consumption, intake of N-nitroso compounds, lack of

breast-feeding have been proposed. The ‘hygiene hypothesis’

suggests that reduced exposure to infectious diseases in the

west could be contributing to rising incidence of autoimmune

diseases including T1D. The role of intestinal microbiomata

in facilitating islet autoimmunity is also being explored.

Despite numerous studies of environmental influences on

T1D, there is still no convincing evidence regarding etiology.

The ongoing multicenter, prospective TEDDY

(The

Environmental Determinants of Diabetes in the Young)

study may provide some useful insights.

G. Rayanagoudar and G.A. Hitman

Autoimmunity

T1D is caused by cell-mediated autoimmune destruction of

pancreatic beta cells in the islets of Langerhans. Gepts, in

1965, noted pancreatic insulitis in recent onset T1D and pro-

posed autoimmunity as a possible mechanism. It was in 1974

that islet cell antibodies

(ICA) were discovered which

reinforced the role of autoimmunity. ICA and antibodies to

glutamic acid decarboxylase (GADA), insulin (IAA), insuli-

noma- associated protein 2 antigen (IA-2A) and islet antigen

zinc transporter-8 (ZnT8A) identify individuals at a high risk

of T1D. These autoantibodies can be present in infancy and

they often precede T1D by several years. ICA and GADA

are detected in 70-80 % of individuals with new-onset T1D

where as IAA is more common in younger children with

new-onset T1D than in adults.

Prevention of T1D

With increasing incidence of T1D worldwide along with greatly

improved knowledge of pathogenesis, efforts to prevent T1D

have gained momentum. Studies have been conducted at vari-

ous stages prior to development of antibodies (primary preven-

tion), after evidence of autoimmunity (secondary prevention),

and in recently diagnosed or established T1D (tertiary preven-

tion). Primary prevention studies have typically involved inter-

ventions based on epidemiological associations with T1D

including cow’s milk protein, vitamin D deficiency, gluten expo-

sure etc. A pilot study found that when hydrolyzed formula

milk was substituted for standard cow’s milk formula, fewer

genetically susceptible children developed beta cell autoimmu-

nity. Based on this, a large study, TRIGR (Trial to Reduce

IDDM in the Genetically at Risk) is ongoing. In another study,

delaying gluten exposure for 12 months after birth failed to

show any benefit. A pilot study is testing if omega-3 fatty acid

supplements during pregnancy and early life can prevent beta-

cell autoimmunity. Vitamin D deficiency is being associated

with several diseases including T1D. A meta-analysis of

Chapter 1. Preventing Diabetes

observational studies showed that the risk of T1D was signifi-

cantly reduced in infants supplemented with vitamin D.

Prospective study, however, has failed to confirm this link

between vitamin D intake/25-hydroxy vitamin D level and inci-

dence of T1D. Further randomized controlled trials of longer

duration are needed to clarify the association.

Secondary prevention strategies involve attempts

at modulating the dysfunctional immune system and

associated inflammatory responses characteristic of T1D.

Nicotinamide was found to arrest beta cell injury in animal

models but two major trials showed no benefit. Insulin is

one of the many antigens for which ‘self tolerance’ is lost

in T1D. The diabetes prevention trial (DPT-1) tested if

parenteral or oral insulin administration in individuals

with autoimmunity would prevent T1D. Though both were

unsuccessful, a subset of individuals on oral insulin, with

high autoimmunity had a delay in developing T1D and this

is being explored further in another trial. Nasal insulin has

been found ineffective in preventing T1D but a further

trial

(INIT II) is in progress. Novel approaches such as

peptide immunotherapy, using relevant short peptides like

proinsulin peptide, rather than whole antigens are being

studied. Non-antigen specific immunomodulatory meth-

ods such as anti CD3 monoclonal antibody (Teplizumab)

are also being examined. Table 1.2 has some examples of

primary and secondary prevention trials.

The aim of tertiary prevention studies is to preserve the

remaining beta cells. It is established that immune intervention

can delay progression of T1D. For example, in 1990, cyclosporine

was shown to induce remission and insulin independence but the

effect lasted only for the duration of treatment. Newer agents

like the fusion protein CTLA4-Ig (Abatacept) are also effective

but only in the short-term. A phase III trial with a heat shock

protein (HSP) peptide, DiaPep277, has met its primary endpoint

and has demonstrated safety and efficacy in preserving c-peptide

after

24 months. A confirmatory phase III trial is ongoing.

Another antigen-based immunotherapy, GAD-Alum vaccina-

tion failed to slow progression of T1D. Recently, engineered

DNA plasmid encoding proinsulin was shown to induce antigen-

G. Rayanagoudar and G.A. Hitman

Table 1.2 Primary and secondary prevention studies in T1D

Intervention

Study

Primary

Hydrolysed formula milk

TRIGR

Delaying gluten exposure

BABYDIET

Omega-3 fatty acid supplementation NIP

Secondary

Nicotinamide

ENDIT, DENIS

Subcutaneous insulin

DPT-1

Oral insulin

DPT-1, Trialnet

Nasal insulin

DIPP, INIT II

Teplizumab

Trialnet

TRIGR trial to reduce IDDM in the genetically at risk, BABYDIET

primary prevention of T1D in relatives at increased genetic risk, NIP

nutritional intervention to prevent T1D, ENDIT European nicotin-

amide diabetes intervention trial, DENIS the Deutsche nicotinamide

intervention study, DPT-1 diabetes prevention trial - 1, DIPP diabetes

prediction and prevention, INIT II intranasal insulin trial

specific suppression of immunity to proinsulin and preserve

c-peptide; however the study was short and longer trials are

needed. Therapies targeting T-cell immunomodulation such as

Teplizumab and Otelixizumab (anti-CD3) showed promising

results with c-peptide preservation for up to 2-4 years in phase II

trials though the specified outcomes were not met in phase III

trials. Interleukin-1 receptor antagonists, Anakinra and

Canakinumab also failed to show any benefit though blockade of

TNF-alpha using Etanercept has shown some promising results.

Table 1.3 lists some examples of tertiary prevention trials.

Latent Autoimmune Diabetes in Adults

(LADA)

Some adult patients who do not need insulin on diagnosis of

diabetes may have a form of autoimmune diabetes called

latent autoimmune diabetes in adults

(LADA); currently

Chapter 1. Preventing Diabetes

Table 1.3 Tertiary prevention trials in T1D

Mechanism

Example

Immunosuppression

Cyclosporine

Antigen specific approach

GAD-alum

DiaPep277

Proinsulin-expressing engineered

plasmid

Co-stimulation inhibition

CTLA-4 Ig (Abatacept)

T-cell modulation

Anti-CD3 (Teplizumab, Otelixizumab)

Anti-inflammatory

Anti-Interleukin-1 (Anakinra,

Canakinumab)

TNF-α blockade (Etanercept)

classified by the WHO as T1D. These patients have one or

more circulatory antibodies (more often GAD antibodies) and

need insulin earlier than those with T2D. Nearly 10 % of

patients in UKPDS cohort had GAD or ICA antibodies and

the majority needed insulin by 6 years of diagnosis. However,

unlike T1D, they may be insulin independent for several

months to years. The current criteria for diagnosis of LADA

are: age > 30 years, presence of diabetes-associated autoanti-

bodies and insulin independence for at least 6 months after

diagnosis.

LADA may account for 2-12 % of all causes of diabetes in

adults. A recent study showed a prevalence of nearly 10 %

among adult-onset diabetes patients diagnosed between 30

and 70 years of age, attending hospitals in European centers.

Patients with LADA share some genetic determinants of

T1D (HLA, INS, PTNP22, CTLA4) and T2D (TCF7L2).

Beta cell function and insulin secretory capacity in LADA

decline faster than T2D but slower than T1D. Due to the

initial non-dependence on insulin and absence of weight loss

and ketoacidosis, patients with LADA may be misdiagnosed

as T2D. Several clinical parameters are found to occur more

frequently in LADA than in T2D: age of onset <50 years,

G. Rayanagoudar and G.A. Hitman

acute symptoms

(polyuria/polydipsia, weight loss), BMI

<25 kg/m², personal history of autoimmune disease, family

history of autoimmune disease and reduced prevalence of

metabolic syndrome.

LADA has similar vascular complications associated with

T1D and T2D. Hence the aims of treatment are similar; opti-

mizing glycemic control and preserving beta cell function.

Studies have found better preservation of beta cell function in

those treated initially with insulin compared to sulfonylureas

although glycaemic control may not necessarily improve.

Thiazolidinediones have shown improvement in c-peptide

when added to insulin compared to treatment with insulin

alone. GLP-1 agonists and Il-1 receptor antagonists have also

shown promise though more evidence is needed. Because of

the autoimmune nature of LADA, it is potentially possible to

use immunomodulatory approaches being tested for T1D. For

example, GAD-alum was shown to improve and maintain

c-peptide levels for up to 5 years in patients with LADA. As

the prevalence of LADA is more than classic T1D, it is impor-

tant to explore the treatment options further.

Summary

Major progress has been made in the last two to three

decades, in our understanding of pathogenesis and preven-

tion of T1D. No single agent, however, has shown sustained

effect and combination therapies are possibly needed. Some

trials have shown transient benefits and some others are

ongoing. Ideally therapy should induce stable beta-cell spe-

cific immune tolerance rather than generalized immunosup-

pression. It is also felt that inducing immune tolerance may

be insufficient by itself in the absence of beta cell regeneration.

There has been much progress in beta cells generation from

stem cells, with ability of these cells to synthesize insulin,

sense glucose and to release insulin accordingly. The timing of

intervention is also important as the benefit is likely to be less

with longer duration of diabetes.

Chapter 1. Preventing Diabetes

T2D

Epidemiology

The number of people with T2D is increasing in every coun-

try, with almost half of them unaware of the diagnosis. The

greatest number of people with diabetes are in the 40-59

year age group, and around 80 % of people with diabetes live

in low and middle-income countries. It follows that the

countries with highest populations have the maximum num-

ber of people with diabetes. Compared to the background

population, people in the lowest socio-economic groups

have 2.5 times higher risk and black/minority ethnic groups

up to 6 times higher risk, of developing diabetes.

Rapid urbanization with changes in lifestyle and poor abil-

ity of healthcare systems to cope are contributing to the

global burden of diabetes. Sedentary lifestyle and consump-

tion of energy dense food has also resulted in increasing

obesity. A recent study shows increase in mean BMI of

0.4 kg/m2 in men and 0.5 kg/m2 in women per decade from

1980 to 2008. The overweight/obesity epidemic is also affect-

ing the paediatric population and its prevalence increased up

to 2-3 times in most developed countries between the 1970s

and 1990s. Since 1990, there has been a relative increase of

60 % in prevalence of childhood overweight and obesity

from 4.2 to 6.7 % globally, leading to a parallel increase in

prevalence of T2D in childhood and adolescence. While pre-

viously the condition was exclusively a disease of adults, it

now accounts for up to 45 % of diabetes in adolescents in

some populations.

Etiopathology

T2D is a chronic progressive metabolic disorder character-

ized by insulin resistance and impaired insulin secretion. It is

caused by a complex interaction between genetic factors with

the environment. The significant rise in prevalence in the

G. Rayanagoudar and G.A. Hitman

recent decades can only be attributed to a change in environ-

ment acting at different times in the life-course of a person

from in-utero to later life.

Genetic Factors

The lifetime risk of an offspring developing T2D is 40 % if

one parent is affected and almost 70 % if both parents have

diabetes. The concordance rate in monozygotic twins is

around 70 % compared to 20-30 % in dizygotic twins. These

factors along with variations in prevalence by ethnic groups

point towards a strong genetic component in T2D. Prior to

2007 despite 20 years of gene hunting only four candidate

genes for T2D had been reliably characterized (IRS1, PPARG,

CAPN10 and TCF7L2). With the advent of GWAS and

whole genome sequencing, over 60 new T2D associated loci

have now been identified. Despite these advances, genetic

association studies have accounted for only 10 % of esti-

mated heritability. Apart from possibility of undiscovered

rare genes, other potential explanations for this ‘missing heri-

tability’ include gene-gene interactions, gene-environment

interactions and epigenetic changes.

Gene-gene interaction, or epistasis, is important because a

gene examined in isolation may not show any effect if its

mechanism of action involves interaction with other genes.

Studies looking into epistatic influences have had mixed

results, with main limitation being the need for extremely

large samples for adequate power.

Gene-environment interaction may also be important but

has been poorly investigated due to logistic difficulties in

testing a large number of potential environmental factors.

Epigenetic Factors

Epigenetic modifications are heritable changes in gene func-

tion that occur without a change in the DNA structure of the

gene. These changes can be precipitated by environmental

factors like nutrition, and mechanisms include DNA methyl-

Chapter 1. Preventing Diabetes

ation, histone deacetylation and histone methylation. For

example, in women exposed to the Dutch famine, changes in

methylation levels of several genes including IGF2, were

found almost six decades later.

Environmental Factors

It is being increasingly recognized that early life environment

plays a major role in future development of cardiometabolic

disorders including diabetes. Hales and Barker first presented

the evidence for this more than two decades ago, when they

found a direct link between low birth weight and develop-

ment of T2D as adults which was particularly marked in those

with high ‘catch-up’ growth in the first year of life. Their

‘thrifty phenotype hypothesis’ suggested that poor nutrition

in early life caused permanent changes in glucose-insulin

metabolism. Subsequent epidemiological and animal studies

have confirmed and expanded their observations. More

recent studies show a U-shaped relationship whereby T2D

risk increases with low and high birth weight. This pattern

may become increasingly common with increasing preva-

lence of maternal diabetes causing higher birth weight.

The epidemic of diabetes has been mainly driven by rapid

socioeconomic development predisposing to obesity and sed-

entary lifestyle. Individuals, who are epigenetically pro-

grammed for fat accumulation in early life, are unable to

adjust to a later life of energy excess brought on by imbalance

between diet and activity. This may explain the rapid rise of

prevalence of T2D in developing countries and also high-

lights that diabetes prevention programs should be targeted

to those at risk during the entire life-course from conception

to later life.

Foods with higher glycemic load and trans-fat have been

implicated in T2D pathogenesis. Along with problems of

overnutrition, deficiency of micronutrients such as vitamin D

and vitamin B12 has been linked to T2D. A meta-analysis

showed that current smoking increases the risk of T2D by

45 %. Other environmental factors like pesticides and plasti-

G. Rayanagoudar and G.A. Hitman

cizers have also been suggested as contributory. Gut micro-

biota is also being increasingly recognized as a potential

environmental factor though the association is unclear.

Prevention of T2D

Prevention of T2D is undoubtedly cost effective. Several

large clinical trials have demonstrated that T2D can be

delayed or prevented by lifestyle intervention or medications.

Most of these studies involved subjects with impaired glucose

tolerance (IGT). Almost 40-50 % of those with IGT progress

to T2D during their lifetime.

Lifestyle Intervention

One of the earliest trials, The Da Qing study in China, demon-

strated reduction in risk of T2D with diet, exercise or both, by

31-46 %. The Finnish Diabetes Prevention Study (DPS) showed

a risk reduction of 58 % at 4 years in the intervention group

compared to controls. It involved 522 subjects and the interven-

tion targeted at five goals; (1) modest weight loss of 5 %, (2)

decrease fat intake to <30 %, (3) decrease saturated fat to

<10 %, (4) increase fibre and (v), moderate physical activity of

at least 30 min per day. Furthermore, the DPS demonstrated

that the reduced risk was proportional to the number of lifestyle

goals obtained. The Diabetes Prevention Program (DPP), one

of the largest randomized control trials, studied 3,234 American

multiethnic obese subjects with IGT with a median follow-up of

2.8 years. It showed similar risk reduction of 58 % with intensive

lifestyle as in DPS. It has to be noted that in all the above trials,

the benefit persisted for several years after cessation of active

intervention. The Indian Diabetes Prevention Program (IDPP)

also showed that lifestyle and metformin independently reduced

progression of IGT to T2D. Though the above trials have proven

that behavior modification can slow the progression to T2D, the

intensive personal contact methods used by them may not be

universally adaptable due to inadequate resources. Reassuringly,

Chapter 1. Preventing Diabetes

a recent study in India has demonstrated that less expensive

methods like mobile phone messaging can be successfully used

to reduce the risk of T2D. In this randomized controlled trial,

lifestyle advice through regular text messaging was acceptable

to the participants and reduced the risk of progression to T2D

by 36 % over 2 years. As the study was conducted on working

men with impaired glucose tolerance in an urban population, it

remains to be seen if it is acceptable and effective in other popu-

lations. However it is an exciting prospect considering the rapid

increase in mobile phone ownership, particularly in developing

countries with poor health care infrastructure where the impact

can be substantial.

Medications

Medications used in treatment of T2D and obesity have also

been found useful in prevention, although all have significant

side effects. Since not all people who are at risk of diabetes

will develop diabetes it therefore becomes important to con-

sider the risk-benefit ratio. Currently, in the UK and many

countries across the world, no medication is licensed for use

in those people at high risk of diabetes.

Metformin at a dose of 1,700 mg/day was effective in DPP

with 31 % risk reduction and the benefit was more pro-

nounced in younger, more obese subjects and in women with

prior gestational diabetes. The IDPP showed that metformin

was also effective in a lower dose of 500 mg/day in reducing

the progression to T2D in Asian Indians.

Thiazolidinediones (troglitazone, rosiglitazone and piogli-

tazone) have proven very effective with a 50-70 % reduction

in IGT conversion to diabetes in various trials, as has acar-

bose, though adverse effects are common. Orlistat in combi-

nation of lifestyle changes, reduced the progression to diabetes

by 52 % when compared to lifestyle and placebo; however this

drug was poorly tolerated by the participants. Incretin based

therapies (GLP-1 agonists and DPP-4 inhibitors) are being

increasingly used for their beneficial effects on weight and

glycemic control in T2D, but their role in prevention of T2D

G. Rayanagoudar and G.A. Hitman

remains largely to be explored. Liraglutide has been shown to

achieve significant weight loss and reduction in prevalence of

prediabetes in obese subjects. Nonetheless, there are also cur-

rent safety concerns with the use of these drugs in people with

established disease (see Chap. 3).

Bariatric Surgery

Several studies have shown benefit of bariatric surgery in

resolution of T2D and arresting progression to T2D in obese

subjects. The Swedish Obese Subjects (SOS) study demon-

strated a reduction in risk of developing T2D of 75 % at

10-year follow up in the surgical group. In practice, bariatric

surgery is recommended in selected subjects with obesity and

co-morbidities including conditions like T2D but not for pre-

vention of T2D by itself.

Vitamin D

Vitamin D is found to be inversely associated with risk of T2D.

A recent meta-analysis of 11 prospective studies found that

risk of T2D was 41 % lower for those in top quartile com-

pared to bottom quartile of circulating 25-hydroxyvitamin D

levels. The DPP group also demonstrated negative association

even with multiple measurements of 25-hydroxyvitamin D

and adjustment for weight loss/lifestyle. The trials on effects of

vitamin D supplementation on risk of T2D have, however,

yielded inconsistent results. Though it has been found to

reduce insulin resistance, improve beta-cell function and

attenuate HbA_1c rise, there is a need for large randomized tri-

als with adequate doses of vitamin D over longer periods to

establish if supplementation can reduce risk of T2D.

Summary

The epidemic of T2D along with growing evidence that it is

preventable has triggered international efforts to adapt the

Chapter 1. Preventing Diabetes

Table 1.4 General lifestyle recommendations for prevention of

T2D

Weight

If obese/overweight, aim to lose 5-10 % of body weight

loss

initially; continue to lose weight until BMI is in the

normal range and maintain weight loss

Physical

Aim for moderate physical activity such as walking/

activity

cycling/swimming for at least 150 min/week

Diet

Increase intake of fibre (wholegrain bread, cereals, lentils

and beans)

Reduce intake of fat and saturated fat

Choose fish and lean meat instead of fatty meat

Reduce portion sizes particularly if overweight/obese

Include fruits and vegetables

research findings to ‘real world’ conditions. The diabetes pre-

vention trials, in general, involved intensive individualized

interventions. Translational research has shown that less

expensive, group based lifestyle interventions are also effec-

tive in achieving weight loss, thereby reducing risk of T2D.

Some common lifestyle interventions to reduce progression

to T2D are summarized in Table 1.4.

Screening for T2D and ‘at risk’ population, followed by

appropriate intervention is likely to be cost effective. Individuals

with prediabetes (IGT, IFG or an HbA_1c of 5.7-6.4 % according

to ADA) should be referred to a support programme aiming

for weight loss of 7 %, dietary modification (total fat, saturated

fat and fibre) and modest physical activity (e.g. walking) of

150 min/week. Metformin may be considered particularly if

BMI >35 kg/m², age <60 years and in women with prior GDM

although it would be re-assuring to have the evidence base that

metformin also reduced the risk of associated cardiovascular

disease. From the public health point of view, it is important

that the health sector, government and relevant stake holders

such as the food industry, develop community-based efforts

and national action plans to prevent this growing epidemic of

T2D especially in high risk communities.

G. Rayanagoudar and G.A. Hitman

Gestational Diabetes

Gestational Diabetes Mellitus (GDM) is glucose intolerance

with onset or first recognition during pregnancy. Though the

definition encompasses pre-existing diabetes diagnosed in

pregnancy, it usually refers to glucose intolerance that arises

during second half of pregnancy and disappears at least

temporarily post-partum. GDM affects about 1-14 % of

pregnancies globally with prevalence being as high as 30 % in

some high risk groups. The increasing prevalence of GDM

reflects similar trends of rise in maternal obesity and T2D.

GDM arises when there is failure to compensate for the insu-

lin resistance produced by hormonal and inflammatory

changes of pregnancy. GDM increases risk of maternal and

perinatal morbidity and also indicates subsequent higher risk

of T2D in both mother and offspring. The pregnancy-related

morbidities include increased risk of preeclampsia, gesta-

tional hypertension and caesarean sections in the mother,

and macrosomia, birth injury, respiratory distress syndrome

and neonatal care unit admissions in the offspring.

There is a lack of consensus with regard to the diagnosis

and management of GDM. To address this, The International

Association of Diabetes and Pregnancy Study Group

(IADPSG) formulated new guidelines for diagnosis of GDM.

It suggested universal screening with a 2-h OGTT and a diag-

nosis of GDM to be made if any blood glucose value reached

specified level

[fasting

≥5.1 mmol/l

(92 mg/dl);

1-h

≥10.0 mmol/l (180 mg/dl); 2-h ≥8.5 mmol/l (153 mg/dl)]. The

recommendations were largely based on the recent multina-

tional Hyperglycemia and Pregnancy Outcome (HAPO)

study of around 25,000 women, which demonstrated a linear

relationship between maternal glycemia and pregnancy out-

comes. The WHO criteria for diagnosis of GDM include fast-

ing venous plasma glucose ≥7.0 mmol/l (126 mg/dl) or a 2-h

≥7.8 mmol/l (140 mg/dl).

GDM is similar to T2D in relation to risk factors and

pathophysiology; hence interventions known to prevent T2D

may potentially prevent GDM. Though there are limited

Chapter 1. Preventing Diabetes

studies, existing evidence suggests that dietary counseling and

exercise programs may be beneficial. Another important con-

sideration is prevention of subsequent T2D in women with

history of GDM. As the risk is sevenfold higher compared to

women who do not have GDM, it is important to monitor this

high-risk group. The ADA recommends an OGTT at 6-12

weeks post-partum followed by 1-3 yearly follow-up depending

on the results. Patients with prediabetes (IGT, IFG or HbA_1c

of 5.7-6.4 %) should be referred to an effective ongoing sup-

port program targeting weight loss of 7 % of body weight and

increasing physical activity to at least 150 min/week of mod-

erate activity such as walking. Metformin is suggested for

very high-risk individuals including those who are very obese

and/or have non-diabetic hyperglycaemia. Clinical trials are

required to help develop evidence-based strategies to pre-

vent T2D in women who have had a previous episode of

gestational diabetes.

Key References

Alberti KG, Zimmet PZ. Definition, diagnosis and classification of dia-

betes mellitus and its complications. Part 1: diagnosis and classifica-

tion of diabetes mellitus provisional report of a WHO consultation.

Diabet Med. 1998;15(7):539-53.

Alberti KG, Zimmet P, Shaw J. International diabetes federation: a consensus

on Type 2 diabetes prevention. Diabet Med. 2007;24(5):451-63.

American Diabetes Association. Position statement. Diagnosis and classi-

fication of diabetes mellitus. Diabetes Care. 2013a;36 Suppl 1:S67-74.

American Diabetes Association. Standards of medical care in diabe-

tes-2013. Diabetes Care. 2013b;36 Suppl 1:S11-66.

Berends LM, Ozanne SE. Early determinants of type-2 diabetes. Best

Pract Res Clin Endocrinol Metab. 2012;26(5):569-80.

Cervin C, Lyssenko V, Bakhtadze E, Lindholm E, Nilsson P, Tuomi T, et al.

Genetic similarities between latent autoimmune diabetes in adults,

type 1 diabetes, and type 2 diabetes. Diabetes. 2008;57(5):1433-7.

Daneman D. Type 1 diabetes. Lancet. 2006;367(9513):847-58.

Fall CH. Non-industrialised countries and affluence. Br Med Bull.

2001;60:33-50.

Fourlanos S, Dotta F, Greenbaum CJ, Palmer JP, Rolandsson O, Colman

PG, et al. Latent autoimmune diabetes in adults (LADA) should be

less latent. Diabetologia. 2005;48(11):2206-12.

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Galtier F. Definition, epidemiology, risk factors. Diabetes Metab.

2010;36(6 Pt 2):628-51.

Groop L, Pociot F. Genetics of diabetes - are we missing the genes or the

disease? Mol Cell Endocrinol. 2014;382:726-39.

Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull.

2001;60:5-20.

Hirschhorn JN. Genetic epidemiology of type

1 diabetes. Pediatr

Diabetes. 2003;4(2):87-100.

International Diabetes Federation. IDF Diabetes Atlas. 5th ed. Brussels:

International Diabetes Federation; 2012. Available from: http://www.

idf.org/diabetesatlas .

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM,

Walker EA, et al. Reduction in the incidence of type 2 diabetes with

lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403.

Merger SR, Leslie RD, Boehm BO. The broad clinical phenotype of type

1 diabetes at presentation. Diabet Med. 2013;30(2):170-8.

Ramachandran A, Snehalatha C, Ram J, Selvam S, Simon M, Nanditha

A, et al. Effectiveness of mobile phone messaging in prevention of

type 2 diabetes by lifestyle modification in men in India:a prospec-

tive, parallel-group, randomised controlled trial. Lancet Diabetes

Endocrinol Available online 11 Sept 2013, ISSN 2213-8587. http://

dx.doi.org/10.1016/S2213-8587(13)70067-6. http://www.sciencedirect.

com/science/article/pii/S2213858713700676 .

Skyler JS. Primary and secondary prevention of Type 1 diabetes. Diabet

Med. 2013;30(2):161-9.

Skyler JS, Ricordi C. Stopping type 1 diabetes: attempts to prevent or

cure type 1 diabetes in man. Diabetes. 2011;60(1):1-8.

Staeva TP, Chatenoud L, Insel R, Atkinson MA. Recent lessons learned

from prevention and recent-onset type 1 diabetes immunotherapy

trials. Diabetes. 2013;62(1):9-17.

Steck AK, Rewers MJ. Genetics of type 1 diabetes. Clin Chem. 2011;

57(2):176-85.

Thrower SL, Bingley PJ. Prevention of type 1 diabetes. Br Med Bull.

2011;99:73-88.

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the clinic. Hum Genet. 2011;130(1):41-58.

Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-

Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in

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2011;57(2):168-75.

Chapter 2

Preventing Diabetes

Complications: Non-glucose

Interventions

David Levy

Abstract Evidence from a cohort of randomised trials in the

past decade has challenged the accepted framework for the

prevention and management of Type 2 diabetes (T2D) com-

plications, in particular the requirement for consistently rigor-

ous glycaemic control, and even very low blood pressure. The

results of several recent studies compel a broader approach

to T2D with an individualised emphasis on risk factors that

will reduce meaningful outcomes, especially cardiovascular

disease (CVD), disability from limb loss and end-stage renal

disease. The Steno-2 trial is our main clinical guide, which

confirms that relatively cheap and practical interventions can

generate significant cardiovascular benefits. Clinicians must

be particularly vigilant for the definite adverse consequences

of over-vigorous control of glycaemia and blood pressure,

while acknowledging that strenuous LDL-cholesterol reduc-

tion is the most cost-effective and safest individual therapy

currently available in the majority of people with T2D, where

the greatest risk is premature macrovascular disease. New

guidelines should incorporate this compelling new evidence.

The only contexts in which the now-habitual term ‘aggressive

control’ can be justified in relation to risk factor reduction in

D. Levy, MD, FRCP

Gillian Hanson Centre for Diabetes & Endocrinology, Barts

Health, Whipps Cross University Hospital, London, UK

e-mail: david.levy@bartshealth.nhs.uk

T.A. Chowdhury (ed.),

Diabetes Management in Clinical Practice,

DOI 10.1007/978-1-4471-4869-2_2, © Springer-Verlag London 2014

D. Levy

diabetes are smoking cessation (where we have been notably

and regrettably unsuccessful) and LDL reduction.

Keywords Epidemiology • Risk factors • Individualised

targets • Glycaemia • Blood pressure • Lipids • Anti-platelet

agents • Multiple risk-factor intervention

Introduction

The publication of a series of major Type 2 intervention stud-

ies around 2008 (ACCORD, ADVANCE and VADT) has

served to further distinguish Type 1 diabetes (T1D) and Type

2 diabetes (T2D), not so much on their pathogenesis but in

respect of the responsiveness of vascular complications to

intensive blood glucose lowering. The totality of these studies,

all modern-era RCTs, would have been wholly persuasive to

the diabetes community because of the homogeneity of their

outcomes, had it not been for the simultaneous publication of

the long-term follow up of the United Kingdom Prospective

Diabetes Study (UKPDS), which demonstrated the advan-

tages of ‘intensive’ glycaemic control (mean HbA _1c 7.0 %) in

marginally reducing some macrovascular risk in newly-diag-

nosed patients. There was a more significant reduction in a

basket of broad microvascular outcomes that was maintained

well beyond the end of the randomisation period. The worthy

attempt to meta-analyse these studies into some kind of

framework for the practising physician still leaves many

questions unanswered; however, it looks as if the era of

heroic glycaemia studies is over, and we and our patients may

have to live with some uncertainty, which will be reflected in

different emphases given in different healthcare encounters.

Fortunately, in T1D there is no need for equivocation. The

microvascular outcomes reported in 1993 in the Diabetes

Control and Complications Trial (DCCT) are decisively in

favour of good glycaemic control, that is, a sustained HbA _1c

7 % in the intensive-treatment group. The long-term

Epidemiology of Diabetes Intervention and Complications

(EDIC) study followed up the DCCT cohort and established

Chapter 2. Non-glucose Interventions

that, albeit with a latent period of 15-20 years, compared with

6-10 years for the DCCT, macrovascular events were also

significantly reduced. Regrettably there has been a tendency

in recent discussions to link the crystalline DCCT results with

the more opaque results in T2D. There is no justification for

this.

Practical Epidemiology of Diabetes

Complications

T1D

Microvascular Complications

The natural history of advanced diabetes complications in many

countries has changed dramatically over the past 30 years. In the

Wisconsin Epidemiologic Study of Diabetic Retinopathy

(WESDR), reporting in the mid-1980s, around 40 % of Type 1

patients with 20 years diabetes had vision-threatening levels of

retinopathy, whereas a later study, the Wisconsin Diabetes

Registry Study (WDRS, examinations in 2007-2011) found only

about 20 % with the same severity of retinopathy after the same

duration. The same trends have been reported in Europe: prolif-

eration had occurred in only 11 % of patients examined between

2002 and 2003 in the Oslo study 25 years after diagnosis, though

nearly all patients had some retinopathy by this stage.

Encouraging trends in end-stage renal disease have also been

widely reported: for example, fewer than 1 % of Swedish Type 1

patients diagnosed between 1977 and 1985 have end-stage renal

disease. Neuropathic foot ulceration probably shows the same

pattern, though there are few reliable data.

Macrovascular Complications

Type 1 patients are, thankfully, more likely to survive without

microvascular complications for 20 or more years, but myo-

cardial infarction and stroke risk are at least as common in

T1D1 as T2D for a similar duration of follow-up. Previously,

D. Levy

macrovascular events were usually encountered in patients

with advanced nephropathy, but other factors are clearly

important - coronary artery disease has remained constant in

Type

1 patients, while nephropathy has decreased.

Conventional risk factors play a role, but inflammatory mark-

ers (e.g. C-reactive protein [CRP], interleukin-6 [IL-6]) are

probably involved, and premature central arterial stiffening

resulting from advanced glycosylation processes can be iden-

tified early in the course of T1D as increased pulse pressure;

it increases in the presence of other complications.

T2D

Microvascular Complications

In contrast to T1D, microvascular complications in T2D are more

resistant to the beneficial effects of tight glycaemic control.

UKPDS reported a 20 % prevalence of microvascular complica-

tions at diagnosis, and little has changed at least with respect to

retinopathy in the UK. Multimodal management of early dia-

betic complications is now mandatory (Steno-2, see below) and

this broader approach may be the reason why end-stage renal

disease (ESRD) in the USA has fallen by 2-4 % each year

between 1996 and 2006. Visual impairment due to retinopathy -

mostly maculopathy - is still quoted as the commonest cause of

blindness in working age people, and was until 2004, but it is not

clear whether it is falling now. There are no studies of the epide-

miology of neuropathy and neuropathic foot ulceration, but dis-

tal sensorimotor neuropathy is the complication most resistant

even to multimodal intervention, and any changes in the end-

stage complications of neuropathy are unlikely to be as encour-

aging as retinopathy and nephropathy.

Macrovascular Complications

Classical risk factors for coronary artery disease have improved

in the general population, at least in the USA - especially smok-

ing and total cholesterol levels, though there is less consistent

evidence for improvement in hypertension control. Coronary

Chapter 2. Non-glucose Interventions

risk has fallen in patients with diagnosed diabetes (UKPDS

estimate down from 21 to 14 %), and encouragingly in men,

women and in all ethnic groups, during the decade 1999-2008. In

Sweden, risk factor intervention in routine care over the first

3 years of diagnosis has reduced modifiable coronary risk from

38 to 19 %, though absolute 10 years risk has not changed (13-

14 %). In the UK, hospital admissions with coronary disease

have fallen to the same extent in people with and without diabe-

tes, but stroke admissions in diabetes are static. The incidence of

macrovascular events in current diabetes clinical trials is consis-

tently low, but the relative increased risk for CHD in diabetes

may not have changed much from the usually quoted rates of

between twofold and fourfold.

Risk Factors for Vascular Complications

Glycaemic Control

The controversial issue of glucose control and vascular compli-

cations in T1D and T2D is covered in Chap. 3.

Blood Pressure

T1D

Hypertension most often occurs as unrelated essential hyper-

tension, detected earlier than in non-diabetic patients because of

frequent monitoring. Once microalbuminuria is established, BP

is inevitably elevated, but often in young people not to a clini-

cally evident degree. Percentile charts for BP in young people

are important to identify those with pre-hypertension, and teen-

agers should have BP regularly monitored, regardless of the age

of onset of T1D. Arterial stiffening, occurring 15-20 years earlier

than in non-diabetic people, can be inferred by the combination

of increased systolic and decreased diastolic pressures, yielding

wider pulse pressures. By early middle age (30-34 years) pulse

pressure was higher than controls at all levels of microalbumin-

uria, and increased with its degree. This factor may be very

D. Levy

important in determining premature cardiovascular endpoints

in patients without evident microvascular complications.

Treatment should be instituted promptly after careful evalua-

tion (which should usually include 24 ambulatory blood pres-

sure monitoring), especially in people gaining weight with

intensive insulin treatment, where increased BP is associated

with more extensive coronary calcification and increased

carotid-intima thickness.

T2D

Hypertension is a persistent scourge in all aspects of T2D,

driving both microvascular and macrovascular complications,

as shown unequivocally in UKPDS, though in the context of

this chapter we should recall that mean baseline BP in

UKPDS was 160/94 mmHg. The majority of patients with

T2D have definite hypertension (≥140/90 mmHg) at diagno-

sis, presumably as an association of the metabolic syndrome,

as only around 20 % will have micro- or macroalbuminuria at

this stage. Nearly all patients with proteinuria are unequivo-

cally hypertensive, many with resistant hypertension (see

below).

The paradox seen in T2D with glycaemic control - that

while epidemiological studies show an unequivocal associa-

tion with progression of complications, RCTs are unable to

demonstrate equivalent benefit - is also seen in the newer

trials. For example, in ACCORD, intensive BP control (tar-

get SBP <120) was not different to standard control (target

SBP 130-139) in determining microvascular outcomes.

Intensive BP control was associated only with a reduction

in microalbuminuria. In patients without heavy proteinuria,

therefore, systolic target BP is <140 mmHg.

Lipids

T1D

Patients with stable T1D often have enviable lipid profiles,

with low triglyceride and high HDL levels. In fact there is

a consistent association in long-term natural history studies

Chapter 2. Non-glucose Interventions

between complication-free survival and high HDL levels,

and “Golden year” cohorts (50+ year survival) in both the

UK and USA have astonishingly high HDL levels (mean

1.85 mmol/L). An equally interesting and unexplained

finding in several cross-sectional and cohort studies is that

an insulin-resistant lipid phenotype (low HDL, relatively

normal total cholesterol and LDL, but elevated triglycer-

ides) is consistently associated with increased risks of

microvascular complications

(nephropathy, retinopathy

and even neuropathy). Lipid lowering therapy is therefore

a vexed question in Type 1 diabetic patients - unless, of

course, there is established micro- or macroalbuminuria, in

which case the enormously increased vascular risk demands

intensive statin therapy.

T2D

Although LDL levels are not significantly higher than in

non-diabetic control subjects, admittedly old data

(e.g.

MRFIT from the 1970s) hint that, like BP, CV risk is

increased at any given LDL level. The characteristic dys-

lipidaemia of low HDL and elevated triglycerides is, like-

wise, an additive risk factor for vascular outcomes, at any

given level of LDL, and most strongly when associated

with an LDL: HDL ratio >5. Therapeutically, while the

benefits of LDL lowering are unequivocal, treating the

dyslipidaemia, on the other hand, has been frustrating in

macrovascular outcome studies, but curiously may be of

value in some microvascular complications.

Haemostatic Factors

There is no evidence that patients with T1D have clinically

significant risk factors for thrombosis. Much energy, however,

has gone into researching the multiple pro-thrombotic fac-

tors associated epidemiologically with augmented inflamma-

tion and impaired fibrinolysis, leading to accelerated

vasculopathy in T2D. Although they are of great interest (see

Table 2.1) there are no specific chronic interventions, other

than the powerful antiplatelet agents (aspirin and clopidogrel),

D. Levy

Table 2.1 Putative prothrombotic factors in T2D

Plasminogen activator inhibitor type 1 (PAI-1) antigen and activity

Tissue plasminogen activator (tPA)

Fibrinopeptide A

D-dimer

Fibrinogen

C-reactive protein

Tissue factor-microparticle-mediated pathway

Platelet-derived factors e.g. soluble P-selectin, platelet-derived

microparticles

and for the moment they remain a cluster of potentially tar-

getable abnormalities. CRP is potentially modifiable, though

not in a predictable way, by statins, and it is still not clear

whether, as with the other identified factors, it is a marker of

rather than a participant in the inflammatory vascular

process.

Smoking

T1D

Progression of retinopathy and to microalbuminuria are

associated with smoking, but these are minutiae compared

with the risk to the macrovasculature. In the EDIC follow up

of DCCT, 14-18 % of subjects (then in their early 40s) with

more than 20 years duration were still smoking. Startlingly,

this proportion was unchanged compared with the baseline

DCCT assessment in the mid-1980s - unlike the general

population, where there was a significant reduction in smok-

ing over this period. There is no lack of awareness of the

impact of smoking on general health and specific diabetic

complications, but professionals have clearly been unable to

translate this into meaningful cessation.

Chapter 2. Non-glucose Interventions

T2D

The situation in Type 2 patients is equally depressing. About

20 % of the general UK population are current smokers. In the

USA 22 % of all diabetic patients were smoking in 2010, and

as in T1D, the proportion had not significantly fallen since the

turn of the millennium. The flat-lining of smoking prevalence

is hard to explain, but mechanistic mystery in no way absolves

professionals. Encouragingly and remarkably, smoking preva-

lence was reduced from 18 % to 2-3 % in the long VADT

study, with equal success in both intensive and routinely-

treated groups, so it can be achieved (in fact the multimodal

intervention in VADT was generally remarkable, and has been

rather overlooked compared with the glycaemia story).

Blood Pressure

Hypertension is an almost invariable accompaniment of T2D.

% of patients at diagnosis elevated BP (around

140/90 mmHg or more) will be accompanied by microalbu-

minuria or proteinuria. Long-term studies, especially from

the USA, confirm that BP control has substantially improved

over the past decade. There is no evidence that lower is better

in people with established diabetes (with the exception of

stroke reduction, for which no threshold can be established),

and ACCORD, the best large-scale modern-era BP study in

people with T2D, surprisingly established that SBP target

<120 conferred no advantage except in stroke, compared with

140 - even in retinopathy outcomes.

A prospective cohort study, however, following up white

and African-American diabetic patients for an average of

6 years uncovered a U-shaped association between BP and

CHD risk, which became a frankly inverse correlation in

those over 60. Aggressive lowering of BP, for example, to

<120/70 mmHg should therefore be avoided. (The objection

to this conclusion, similar to that raised in the cholesterol

controversy of 20 years ago, is that low BP may be a marker

D. Levy

of serious non-CV disease; this cannot be the case in

ACCORD.)

As with glycaemia, there is a risk that the perfect will be

the enemy of the good: BP levels such as the baseline values

in the UKPDS (160/94 mHg), already mentioned, and still

surprisingly common, must be vigorously controlled, espe-

cially in the presence of proteinuria, and although we do not

know what target we should be aiming for in patients with

proteinuria, 125/75 mmHg or lower (British Hypertension

Society-IV guidelines) might be appropriate.

Dual angiotensin blockade has been fashionable on the

basis that two BP- and proteinuria-lowering agents are likely

to be better than one (and some small early studies of dual

blockade supported this). Hard renal endpoints e.g. dialysis

were found to be more common in the large high-risk general

population in the ONTARGET study (2008), but an analysis

of the 9,000 diabetic patients in the trial indicated that while

there were no adverse cardiovascular or hard renal endpoints,

as in the main trial, acute dialysis, hyperkalaemia and hypo-

tension were more common. A definitive trial of dual block-

ade in proteinuric Type 2 patients (VA NEPHRON-D) has

confirmed the lack of benefit of dual blockade on renal out-

comes, and further highlighted the increased risk of hyperka-

laemia and acute kidney injury. This combination should be

discontinued in patients taking it, and no longer initiated.

Principles of Treatment

1. Use once-daily agents.

2. Combination therapy with two different classes of agents is

often more effective than doubling the dose of one agent.

3. Use fixed-dose combinations if possible.

4. Like statins, antihypertensives have log-linear dose-

response relationships: intermediate doses of agents

between formal dosage steps are unlikely to help BP

reduction and unnecessarily increase tablet burden.

5. Home BP monitoring and 24 h ambulatory BP monitoring

are valuable, and can guide treatment more rationally than

casual office BP readings.

Chapter 2. Non-glucose Interventions

Practical Pharmacology

Angiotensin-Blocking Agents, ACE-inhibitors (ACE-i)

and Angiotensin Receptor Blockers (ARB)

1. Preferred treatment. A long-term follow-up of ALLHAT

confirmed that they do not have CV outcome benefits, but

they are renoprotective in hypertensive Type 2 patients,

and reduce renal end points in all proteinuric diabetic

patients.

2. Use maximum recommended doses of angiotensin block-

ing agents. Use an ACE-i first, and then an ARB in patients

with cough or other adverse effects. This is especially impor-

tant in patients with nephropathy: maximum angiotensin

blockade will bring some patients into ‘remission’, even

those with heavy proteinuria (eg nephrotic range protein-

uria, >2.2 g albumin/day, >3.5 g urinary protein/day) - with

accordingly prognostic benefit. The unresolved concern

about possible increase cardiovascular risk with ARB com-

pared with ACE-i therapy carries a clear message.

3. The only major factors precluding their use are severe

hyperkalaemia (K⁺ >5.5, which occurs in about 5 % of

patients, especially those with eGFR <90 mL/min), marked

deterioration in renal function

(check renal function

7-10 days after starting; increases in serum creatinine up to

30 % above baseline are acceptable and may be prognosti-

cally favourable) and angio-oedema.

4. Black and older patients, with low renin levels, have slightly

weaker responses to angiotensin blocking agents compared

with thiazides (e.g. around 4 mm difference in systolic BP in

ALLHAT), but they are still first-line treatment.

5. The direct renin blocker aliskiren is not currently

recommended.

Calcium-Channel Blockers

1. Especially valuable in isolated systolic hypertension and in

black people, where there is associated angina, and if there

is concern about secondary causes of hypertension.

D. Levy

2. Use high-dose agents with care as they often cause symptom-

atic peripheral oedema. Gum hypertrophy is quite common.

3. Dihydropyridines e.g. amlodipine have no useful antipro-

teinuric effects.

4. The non- dihydropyridine diltiazem is valuable over a wide

dose range (in UK, prescribe modified-release preparations,

and by brand name) and has mild antitproteinuric effects.

Diuretics

1. Sometimes irrationally avoided because of unfounded

concerns about adverse metabolic effects: they emerge

from studies with at least as good, and frequently better

CV outcomes than other agents, in diabetic as well as non-

diabetic patients.

2. The major adverse effect is insidious hyponatraemia, espe-

cially in the hospitalised elderly, and which can be severe,

and hypokalaemia (less of a problem in diabetes).

3. They are inexpensive and there are no modern-era com-

parative clinical trials. The thiazide-like agents chlortali-

done and indapamide are now preferred when starting or

changing diuretics according to NICE blood pressure

guidelines. Chlortalidone was the diuretic used in most

major hypertension trials.

Beta Blockers

1. Less favoured because of adverse effects, lower effective-

ness in low-renin states and weaker effects on central (aor-

tic) blood pressure and adverse metabolic profile (glucose,

lipids - though these are minor and not usually detectable

in people with diabetes).

2. The vasodilating ‘third-generation’ agents, eg carvedilol

and nebivolol are metabolically preferable but have no

end-point studies.

3. They are still valuable agents, with possibly some antipro-

teinuric action, and should be prescribed in preference to

alpha blockers.

Chapter 2. Non-glucose Interventions

Other Agents

1. Alpha blockers (mostly doxazosin in the UK) are very

widely used, sometimes even in preference to CCBs and

angiotensin blocking agents, and although effective in the

ASCOT study (mean fall in BP 12/7 - similar to other

agents), it should be used in modified-release form, and in

doses of 4 or 8 mg daily only.

2. Potassium-sparing diuretics. Probably for secondary care

use only, though previously widely used (usually in combi-

nation with a thiazide). Valuable in patients with thiazide-

induced hypokalaemia.

3. Centrally-acting agents. Apart from alpha-methyldopa,

which is restricted to use in pregnancy, only moxonidine is

used. Central effects are limiting.

4. Labetalol - for use in pregnancy only.

Resistant Hypertension

Resistant hypertension is especially common in diabetes.

The numerical definition is arbitrary (BP > 130/80). Since

this target is no longer operative, a reasonable functional

definition is BP >140/90 on 3 drugs (including a diuretic),

especially if there is evidence of vascular complications or

diabetic nephropathy. In ACCORD BP (Fig. 2.1) around

40 % of patients in the standard treatment group (SBP

target <140) needed 3 or more drugs. While many of these

will by definition have been at target, it nevertheless high-

lights the need for multiple drug therapy for hypertension

in diabetes. Hardly surprisingly, compliance is often poor

(Fig. 2.1).

Renal artery denervation is emerging as a possible

approach to the truly resistant hypertensive patient. Mean

fall in BP at 6 months has been reported as −25/10 mmHg,

but systematic investigations into durability, safety and cost-

effectiveness are still in progress. Carefully addressing all the

modifiable risk factors in resistant hypertensive subjects is

still currently the mainstay (Table 2.2).

Chapter 2. Non-glucose Interventions

most patients) with a target LDL of >30 % reduction from

baseline or <2 mmol/L. In general, this delicate decision

should be taken in conjunction with secondary care diabe-

tologists. Naturally, in the presence of other established CV

risk factors - smoking, hypertension, micro- or macroalbu-

minuria, statins should be offered as they would in any

patient with T2D - recognising that they must not be used

without secure contraception in women of child-bearing

age.

T2D

In T2D, although there is continuing debate about whether

it should be regarded as a coronary equivalent (epidemio-

logically it probably no longer is, though it may have been

historically) all patient should aim for LDL around

2.0 mmol/L

(CARDS study), and <1.7-1.8 mmol/L in

patients with clinical manifest macrovascular disease (NCEP

ATP III, 2004 revision). The long-standing concern about

the concomitants of ultra-low LDL levels (suicide, homicide

etc.), have long been assuaged. In fact even the argument

over coronary equivalence is now mostly irrelevant; the

Cholesterol Treatment Trialists’ (CTT) Collaborators meta-

analysis of LDL lowering people at low vascular risk con-

cluded that there was

~20 % risk reduction in major

vascular events for 1.0 mmol/L LDL reduction that was

mostly independent of age, sex, baseline LDL or previous

vascular disease. The higher absolute risk of people with

T2D mandates statin therapy in all Type 2 patients, an aspi-

ration already enshrined in national guidelines. Analyses of

secondary prevention studies provide impressive evidence

for continuing event reduction with LDL levels as low as

1.0 mmol/L. An earlier publication from the CTT concluded

that ‘further reductions in LDL-C safely produce definite

further reduction [in CV events]... There was no evidence of

any threshold within the cholesterol range studied, suggest-

ing that reduction of LDL-C by 2-3 mmol/L would reduce

risk by about 40-50 %.’

D. Levy

Intervention in the dyslipidaemia of T2D (elevated triglyc-

erides, low HDL), strong in historical clinical trial terms, can

no longer be generally supported. Definitively, the ACCORD

lipid study, combining a statin with fenofibrate, found no ben-

efit for CV events, though, as in several other studies, post-

hoc analyses indicated benefit for additional fibrate treatment

in patients with marked dyslipidaemia

(e.g. HDL

<0.75 mmol/L, triglycerides >3.2 mmol/L), or other evidence

of insulin resistance. This cannot be translated into clinical

practice until there are formal prospective studies - but there

is an intriguing and fairly consistent effect of fibric acid drugs

in retinopathy (ACCORD-Eye and FIELD study) and even

in peripheral vascular disease (FIELD). Combination treat-

ment in ACCORD was very well tolerated, so cautious use in

patients with definite vascular disease and mixed dyslipidae-

mia, especially if there is associated retinopathy, can be con-

sidered reasonably evidence-based.

Non-statin Lipid Modifying Drugs

The other lipid-modifying drugs previously in widespread

use can now be dealt with briefly and definitively. Niacin

carried no benefit in the AIM-HIGH study, and mono-

therapy and the fixed dose combination with laropiprant

have been withdrawn. Despite encouraging results from

early studies, low dose omega-3 fatty acids have been

found to be of little value in primary or secondary preven-

tion, though in higher doses (e.g. 4-8 g daily) they are valu-

able in severe hypertriglyceridaemia

(as are fibrates),

conferring ~10 % triglyceride reduction at 2 g daily, and

40 % reduction at 8 g, though the benefits are the possible

reduction in risk of acute pancreatitis, not CV events. The

bile-acid sequestrant colesevalam improves glycaemia a

little

(fasting glucose lowered by

~1 mmol/L, HbA _1c

~0.5 %), as well as modestly lowering LDL; it has a lower

risk of the gastrointestinal side effects that severely lim-

ited adherence to the older drugs, must be assumed to have

a beneficial effect on long-term cardiovascular outcomes,

Chapter 2. Non-glucose Interventions

as was shown many years ago for other drugs in the class,

is ideal in combination with a statin, but is prohibitively

expensive.

Statins and Ezetimibe

Simvastatin, atorvastatin and pravastatin are all now avail-

able generically in the UK. Simvastatin and atorvastatin have

similar side-effect profiles and interactions, so patients with-

out side-effects can be transferred dose for dose to the more

potent atorvastatin if they are not at target on simvastatin. At

80 mg, both agents have only minor additional LDL lowering

effects compared with 40 mg, and there is a higher risk of

abnormal LFTs (and severe muscle side effects with simvas-

tatin, though not atorvastatin). It is relatively easy to predict

whether an individual patient will reach their LDL target:

simvastatin 40 mg daily will achieve a mean LDL reduction

of 36 %, while the same dose of atorvastatin will achieve

nearly 50 % reduction. Most high-risk patients will require

this degree of LDL reduction to reach LDL <1.8 mmol/L.

The role of the cholesterol-absorption inhibitor ezetimibe

has been significantly reduced with the availability of generic

atorvastatin, though it can still be used in secondary preven-

tion patients intolerant of all statins; but there is no RCT

evidence yet for its value in ‘routine’ cardiovascular disease.

Pravastatin is well tolerated, as is rosuvastatin, the latter

being the most potent LDL-lowering drug currently avail-

able. Both are less inclined to interact with other commonly-

used drugs (e.g. calcium channel blockers) and they should be

used more widely in patients intolerant of simvastatin or

atorvastatin and where there is high vascular risk.

Anti-platelet Agents

Again, the accumulation of evidence has modified the once-

universal lifetime prescription of aspirin usually from the

time of diagnosis of T2D. This has occurred as a result of accu-

D. Levy

rate assessment of the rather modest risk reductions (e.g. relative

risk of reduction of 9 % for CHD, and about 15 % for stroke)

in comparison with the approximately 50 % increased risk of

GI bleed in those without such a history, and the slightly

increased risk of non-fatal haemorrhagic stroke. In particular,

aspirin in patients with no evidence of vascular disease is now

restricted to those with 10 years CV risk >10 %. This, how-

ever, will still include a substantial proportion of patients

with T2D. In practice the American Diabetes Association

recommends aspirin use broadly in most men >50 years and

women >60 years with one or more additional risk factor

(family history of CVD, hypertension, smoking dyslipidaemia

and albuminuria).

Clopidogrel 75 mg is used in people with documented

aspirin allergy, and combination aspirin and clopidogrel for

up to a year after acute coronary syndrome. The volume of

literature concerning aspirin and clopidogrel resistance and

drug interactions with clopidogrel is probably disproportion-

ate to its importance in usual clinical practice.

Multiple Risk Factor Intervention

Because the societal and medical costs of T2D are driven

overwhelmingly by end-stage complications, especially renal,

foot and cardiovascular complications, it can be argued that

meaningfully intercepting early complications is more effec-

tive for physicians than primary prevention in people who in

most instances are not going to develop complications; these

latter may be more effectively tackled by public health initia-

tives over diet, obesity management and exercise (the furore

over the polypill is unlikely to be resolved soon). The argu-

ment becomes even more relevant in this post-glycaemic era

of diabetes management. I have already mentioned the

astonishing success of intensive multimodal intervention in

the VADT (though it was not a trial of this), but the approach

has been thoroughly vindicated in the Steno-2 study. Here, a

small cohort of patients with early definitive complications -

Chapter 2. Non-glucose Interventions

Table 2.3 Steno-2 study: targets and values at baseline and end of

follow-up (13.3 years)

Baseline (mean

End of

Variable

Target

or median)

follow-up

Urinary albumin excretion

(mg/24 h)

Systolic BP (mmHg)

<130-140 146

140

Diastolic BP (mmHg)

<80

HbA _1c (%)

<6.5

8.4

7.7

Fasting plasma glucose

10.1

8.9

(mmol/L)

Total cholesterol (mmol/L) <4.5-4.9 5.4

3.8

LDL cholesterol (mmol/L)

3.4

1.8

Triglycerides (mmol/L)

<1.7

1.8

1.1

i.e. mid-range microalbuminuria (mean 24 h urinary albumin

78 mg) - were randomised to intensive or less intensive mul-

timodal intervention for a mean of 8 years. CV events and

deaths and the need for laser treatment for retinopathy were

reduced by about 50 % in the 6 years following the end of

randomisation - another example of legacy effects, but cer-

tainly not related just to glycaemia. End-stage renal failure,

autonomic neuropathy, coronary interventions and amputa-

tions were all markedly reduced, though the achieved levels

of risk factors were rather modest (Table 2.3). Notably, mean

HbA _1c in the intensive group at the end of the full study was

7.7 % (baseline 8.4 %), entirely consistent with the results of

the major studies that were published shortly after Steno-2. It

also reminds us that we must identify those patients with

early complications and intervene intensively in them (the

annual incidence of CV events in the standard-treatment

group was high at around 6 %). While the same kind of inter-

ventional model has been widely used in patients with rela-

tively advanced diabetic nephropathy in hospitals, this

represents a very late stage of complications, and interven-

tions, especially with glycaemia and even very vigorous LDL

D. Levy

reduction, do not pay the dividends that can be achieved in

the same patients with lesser complications perhaps only

5 years earlier.

Conclusions

In order to reduce vascular complications of T2D, multifacto-

rial intervention is required, focussing on improvements in

diet and exercise, lipid lowering, blood pressure reduction,

smoking cessation and perhaps least importantly of all, glu-

cose management. The message for primary care, where the

vast majority of these patients have their care delivered, is

clear; efforts should focus on patients with early established

complications. Whether we can translate that message is less

clear, especially when our attention tends to be persistently

diverted to minor differences in glycaemic control between

inventive new agents and insulins, and in primary care, at

least in the UK, to time-consuming regulatory box-ticking

requirements in low risk patients that have not yet been

proven to be of long-term value. If we can persistently focus

our efforts on outcomes that are significant for patients, as is

happening very encouragingly in randomised trials, we will

undoubtedly start making real progress.

Key References

ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, et al.

Effects of combination lipid therapy in type 2 diabetes mellitus.

N Engl J Med. 2010;362:1563-74. PMID: 20228404.

Burrows NR, Li Y, Geiss LS. Incidence of treatment for end-stage renal

disease among individuals with diabetes in the U.S. continues to

decline. Diabetes Care. 2010;33:73-7.

Cholesterol Treatment Trialists’

(CTT) Collaboration, Baigent C,

Blackwell L, Emberson J, et al. Efficacy and safety of more intensive

lowering of LDL cholesterol: a meta-analysis of data from 170,000

participants in 26 randomised trials. Lancet. 2010;376:1670-81. PMID:

21067804.

Colhoun HM, Betteridge DJ, Durrington PN, CARDS Investigators,

et al. Primary prevention of cardiovascular disease with atorvastatin

Chapter 2. Non-glucose Interventions

in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study

(CARDS): multicentre randomised placebo-controlled trial. Lancet.

2004;364:685-96. PMID: 15325833.

Ford ES. Trends in the risk for coronary heart disease among adults with

diagnosed diabetes in the U.S.: findings from the National Health and

Nutrition Examination Survey, 1999-2008. Diabetes Care. 2011;34:

1337-43. PMID: 21505207.

Gaede P, Lund-Andersen H, Parving HH, Pederson O. Effect of a multi-

factorial intervention on mortality in type 2 diabetes. N Engl J Med.

2008;358:580-91. PMID: 18256393.

Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year

follow-up of intensive glucose control in type 2 diabetes. N Engl

J Med. 2008;359:1577-89. PMID: 18784090.

Juutilainen A, Lehto S, Rönemaa T, Pyörälä K, Laakso M. Similarity of

the impact of type 1 and type 2 diabetes on cardiovascular mortality

in middle-aged subjects. Diabetes Care.

2008;31:714-9. PMID:

18083789.

LeCaire TJ, Palta M, Klein R, Klein BE, Cruickshanks KJ. Assessing

progress in retinopathy outcomes in type 1 diabetes: comparing find-

ings from the Wisconsin Diabetes Registry Study and the Wisconsin

Epidemiologic Study of Diabetic Retinopathy. Diabetes Care.

2013;36:631-7. PID: 23193204.

Mann JF, Anderson C, Gao P, et al., ONTARGET Investigators. Dual

inhibition of the renin-angiotensin system in high-risk diabetes and

risk for stroke and other outcomes: results of the ONTARGET study.

J Hypertens. 2013;31:414-21. PMID: 23249829.

Purnell JQ, Zinman B, Brunzell JD, DCCT/EDIC Research Group. The

effect of excess weight gain with intensive diabetes mellitus treat-

ment on cardiovascular disease risk factors and atherosclerosis in

type 1 diabetes mellitus: results from the Diabetes Control and

Complications Trial/Epidemiology of Diabetes Interventions and

Complications Study (DCCT/EDIC) study. Circulation. 2013;127:

180-7. PMID: 23212717.

Raz I, Riddle MC, Rosenstock J, et al. Personalized management of

hyperglycemia in type 2 diabetes: reflections from Diabetes Care

Editors’ expert forum. Diabetes Care.

2013;36:1779-88. PMID:

23704680.

Reaven PD, Moritz TE, Schwenke DC, et al., Veterans Affairs Diabetes

Trial. Intensive glucose-lowering therapy reduces cardiovascular dis-

ease events in veterans affairs diabetes trial participants with lower

calcified coronary atherosclerosis. Diabetes. 2009;58:2642-8. PMID:

19651816.

Turnbull FM, Abraira C, Anderson RK, et al. Intensive glucose control

and macrovascular outcomes in type

2 diabetes. Diabetologia.

2009;52:2288-98. PMID: 19655124.

Chapter 3

Glycaemic Therapy

for Diabetes

Tahseen A. Chowdhury

Abstract Diabetes is characterised by hyperglycaemia.

Whilst chronic hyperglycaemia is a significant risk factor for

vascular complications of diabetes, therapeutic management

of hyperglycaemia has been traditionally quite difficult due

to the limited number of therapies available, and their poten-

tial adverse effects. The value of tight glucose control in type

1 diabetes (T1D) is unquestioned. There is, however, ongoing

debate about the value of tight glucose control in patients

with type 2 diabetes (T2D), particularly amongst the elderly,

or those patients with co-morbidities.

This chapter describes the debate and evidence around

management of hyperglycaemia, and current and potential

future strategies to treat high glucose levels.

Keywords Type 1 diabetes •Type 2 diabetes • Hyperglycaemia

• Microvascular disease • Macrovascular disease • Insulin

• Oral hypoglycaemics • GLP-1 • DPP-4

T.A. Chowdhury, MD, FRCP

Diabetes and Metabolism, The Royal London

Hospital, London, UK

e-mail: tahseen.chowdhury@bartshealth.nhs.uk

T.A. Chowdhury (ed.),

Diabetes Management in Clinical Practice,

DOI 10.1007/978-1-4471-4869-2_3, © Springer-Verlag London 2014

T.A. Chowdhury

Introduction

Hypotheses surrounding the pathophysiology of type 1 dia-

betes (T1D) and type 2 diabetes (T2D) are protean, and their

detailed description is beyond the scope of this book. Both

conditions are, however, likely to involve a complex interplay

of genetic, epigenetic, environmental and immunological fac-

tors. A great amount of research effort is aimed at determin-

ing the nature of these pathogenic factors, in order influence

the natural history of the two conditions.

T1D is characterised by immune destruction of pancreatic

beta cells, leading to absolute insulin deficiency, and the need

for exogenous insulin therapy (Fig. 3.1). Whilst therapy for

T1D has focussed on optimal insulin replacement therapy

matched to diet and lifestyle, recent studies suggest that

immunological interventions centred on reducing the immune

mediated attack early in the disease may help with manage-

ment of the condition. Insulin therapy will be discussed later

Genitic Predisposition

Environmental Factors

MHC genes

Other genes

Microbiological

Chemical

diasease susceptibility

diasease resistance

Immune Response

pathogenic

protective

−

Autoreactive T cells

Regulatory T cells

−

Islet Inflammation (insulitis)

cell

Type 1

β-cells

death

diabetes

Figure 3.1 Pathogenesis of T1D (Reproduced with permission from

Cell Biochemistry and Biophysics . 2007;48;159-63)

Chapter 3. Glycaemic Therapy for Diabetes

Diabetes genes

Adipokines

β-cell

Inflammation

dysfunction

Hyperglycaemia

Free fatty acids

Other factors

Pancreas

Insulin

Lipolysis

resistance

Glucose

Glucose uptake

Production

Liver

Fat

Muscle

Fatty acids

Blood glucose

Figure 3.2 Pathophysiology of T2D (Reproduced with permission

from Lancet. 2005;365:1333-46)

in this chapter, as will immune therapies as part of the section

on future treatments.

T2D is characterised by peripheral insulin resistance

(muscle, liver and adipocytes), and associated defects in insu-

lin secretion due to decline in beta-cell function and ulti-

mately beta-cell failure (Fig. 3.2). Insulin resistance is a phe-

nomenon that appears to occur early, with its seeds sown in

childhood, whilst pancreatic beta-cell function declines over

time eventually leading to impaired glucose regulation and

hyperglycaemia. Physiological mechanisms proposed for

exacerbation of insulin resistance include elevation in free

fatty acids, reduction in adiponectin levels, inflammatory

cytokines and defects in mitochondrial function. Decline in

beta-cell function may also be due to glucotoxicity, (whereby

hyperglycaemia reversibly modifies the function of the beta-

cell), lipotoxicity (increased circulating free fatty acids caus-

ing beta-cell damage), and the involvement of islet amyloid

T.A. Chowdhury

polypeptide (amylin). Many other pathogenic factors have

been implicated in the development of T2D, including peroxi-

some proliferator-activated receptor-gamma (PPARg) acti-

vation and glucagon excess.

In this chapter, I will discuss the evidence behind glycae-

mic management in T1D and T2D, use of older and newer

drug classes for treatment of T2D, insulin therapy and poten-

tial future therapies.

Treatment of Hyperglycaemia:

How Low Should We Go?

T1D

The seminal study of intensive glucose control in people with

T1D was the Diabetes Control and Complications Trial

(DCCT), which demonstrated that tight glycaemic control

(HbA_1c <7 %) in young adults with T1D reduced the inci-

dence of microvascular disease, compared to conventional

therapy. Observational follow up of the DCCT cohort post

intervention (the EDIC trial) showed that these beneficial

were maintained in the long term, despite deterioration in

glycaemic control in the intensively treated cohort.

Therefore tight glycaemic control, (HbA_1c <53 mmol/mol

[7 %]) remains a central aim of diabetes care in people with

T1D. Many studies have shown how challenging this aim can

be, particularly amongst children and young adults with the

condition.

T2D

Macrovascular Disease

The United Kingdom Prospective Diabetes Study (UKPDS)

has illuminated many facets of the epidemiology and man-

agement of T2D care over the last two decades, including the

Chapter 3. Glycaemic Therapy for Diabetes

effect of blood pressure, lipids and ethnicity on diabetes

complications. There is clear epidemiological evidence cor-

relating levels of HbA_1c with cardiovascular disease - a 1 %

increase in HbA_1c correlates with a 14 % increased risk of

myocardial infarction and 12 % increased risk of stroke.

What remains unclear, however, is the effect of pharmaco-

logical glucose reduction on the risk of developing these

complications.

The original report in 1998 from the intervention study of

the UKPDS showed a significant risk reduction on the devel-

opment of microvascular complications with intensive glu-

cose control, but little impact on the development of

macrovascular disease. Subsequent 10 year follow up of the

UKPDS cohort, however, showed significant relative risk

reductions in all cause mortality and myocardial infarction in

the intensively treated cohort, leading to the suggestions of a

“legacy effect” of tight glucose control early in the disease -

also called a “metabolic memory”.

More recent data, however, from large randomised con-

trolled trials of patients with longer duration of diabetes

(around 10 years from diagnosis to randomisation into the

trials) have given contrasting results, and may suggest that

there may be little benefit in very tight glucose control 10

years into the disease, and possible evidence of harm.

Action to Control Cardiovascular Risk in Diabetes

(ACCORD) found that intensive glycaemic control (target

HbA_1c <6.5 %) led to an increase in all-cause mortality of

around 22 %. This finding was not replicated in the Action

in Diabetes and Vascular Disease: Preterax and Diamicron

MR Controlled Evaluation (ADVANCE) study, although

no significant benefit of improved glucose control on coro-

nary heart disease rates was seen. The Veteran Affairs

Diabetes Trial (VADT), whilst smaller, suggested that 5

years of intensive glucose control had no impact on onset

of macrovascular and microvascular complications in peo-

ple with T2D.

A number of meta-analyses of combined data totalling

over

140,000 patient years shows that intensive glucose

T.A. Chowdhury

control can reduce coronary events, but does not have an

impact on cardiovascular or total mortality. Indeed, an inten-

sive glucose control regime may not be cost effective, as

numbers needed to treat (NNT) with intensive glucose con-

trol for 5 years to prevent 1 cardiovascular event equates to

119, which contrasts sharply with that for cholesterol lower-

ing (NNT 44) and blood pressure lowering (NNT 33).

Furthermore, there is some concern around tight glucose

control amongst elderly people with diabetes. Mortality

amongst people with diabetes diagnosed over the age of 70 is

not increased above that of the baseline population, and most

clinical trials of glycaemic control have not included large

numbers of patients over the age of 75 years. Therefore

unnecessary prescribing of expensive therapy, which may also

increase risk of adverse effects (particularly hypoglycaemia),

should be avoided in the elderly.

Data from a large primary care database in the UK

suggests that a U-shaped curve of HbA_1c and mortality

exists, with a glycated haemoglobin of around 58 mmol/

mol (7.5 %) being associated with the lowest mortality,

and lower HbA_1cs associated with higher mortality

(Fig. 3.3).

Microvascular Complications

The benefit of glucose control on microvascular complica-

tions of diabetes are more readily demonstrated by the

available trial data. Whilst the UKPDS and ACCORD sug-

gested a 25 % risk reduction in microvascular complica-

tions, as these complications occur less frequently in people

with T2D compared to cardiovascular complications, and

hence the numbers needed to treat are substantially more

- 272 people for 5 years to prevent 1 episode of blindness,

and 627 people for 5 years to prevent 1 episode of end stage

renal failure. Furthermore, once microvascular disease is

established, there is little evidence that microvascular com-

plications of diabetes can be reduced by intensifying glu-

cose control.

Chapter 3.

Glycaemic Therapy for Diabetes

2.0

Yearly mean‡

2.0

Mean of all values

Updated mean

†

1.8

1.6

1.4

1.2

1.0

0.8

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

10.0 10.5 11.0 11.5

HbA

1c (deciles)

HbA

1c (%)

2.0

1.8

†

1.6

1.4

†

1.4

1.2

1.0

0.8

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

10.0

10.5 11.0 11.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

10.0 10.5 11.0 11.5

HbA

1c (%)

HbA

1c (%)

Figure 3.3

Mortality according to glycated haemoglobin level in

patients with T2D

(Reproduced with permission from Lancet.

2010;375:481-9)

What Do the Guidelines Say?

The American Diabetes Association (ADA) and European

Association for the Study of Diabetes (EASD) recommend

that an HbA_1c goal of 53 mmol/mol (7.0 %) should be a target

for most patients with T2D to reduce the incidence of micro-

vascular disease. More stringent targets (42-48 mmol/mol

[6.0-6.5 %]) are suggested for people with short duration of

disease, long life expectancy and no co-morbidities, and less

stringent targets (58-64 mmol/mol [7.5-8.0 %]) for patients

with longer duration of disease, problematic hypoglycaemia

T.A. Chowdhury

or extensive co-morbidities. The UK National Institute for

Health and Clinical Excellence (NICE) guidelines suggest a

general target of 6.5 % (48 mmol/mol), but individualised to

the patient.

So What Is the Bottom Line?

Taken together, current evidence suggests that early tight

glucose control from diagnosis, may provide some benefit

in reduction of complications, but from around 10 years

from diagnosis, attempts to tighten glycaemic control may

lead to adverse outcomes. Whilst we must avoid therapeu-

tic nilihism when treating glucose in people with long

standing diabetes, it may be appropriate to adopt an indi-

vidualised targets for glycaemic control according to the

patients’ clinical state and other factors. A number of fac-

tors may be considered when deciding who might benefit

from tight glucose control, such as age, duration of diabe-

tes, motivation, capacity for self care, and social support

(Fig. 3.4).

Oral Glucose Lowering Agents

In this section I review the mechanism of action, indica-

tions and potential adverse effects of oral glucose lowering

agents. The place in therapy of these drugs varies accord-

ing to guidelines, but EASD and ADA pathways, and

NICE guideline pathways are shown in the figures. The

glucose lowering effects of metformin, sulfonylureas and

glitazones tends to be higher

(1-1.5

%) compared to

meglitinides, alpha-glucosidase inhibitors and dipeptidyl-

peptidase-IV inhibitors (0.5-1.0 %). Table 3.1 summarises

the major classes of hypoglycaemic agents, with the poten-

tial advantages and adverse effects. Figure 3.5 summarises

the NICE guidelines for hypoglycaemic therapy, and

Fig. 3.6 summarises the ADA/EASD guidelines.

Chapter 3. Glycaemic Therapy for Diabetes

Approach to management

Less

of hyperglycaemia:

stringent

Patient attitude and

High motivated, adherent,

Less motivated, non adherent,

expected treatment efforts

excellent self-care capacities

poor self-care capacities

Risks potentially associated

Low

High

with hypoglycaemia, other

adverse events

Disease duration

Newly diagnosed

Long-standing

Life expectancy

Long

Short

Important comorbidities

Absent

Few / mild

Severe

Estadlished vascular

Absent

Few / mild

Severe

complications

Resources, support system

Readily available

Limited

Figure 3.4 An approach to the individualised management of

hyperglycaemia in patients with T2D (Reproduced with permission

from Diabetologia. 2012;55:1577-96)

Metformin

In skeletal muscle metformin appears to stimulate glucose

uptake, and in the liver, it appears to suppress hepatic gluco-

neogenesis. Metformin has been shown to have a beneficial

effect on mortality and cardiovascular disease in obese

patients with T2D, and is deemed first line therapy in most

people with T2D and a body mass index (BMI) above 23 kg/

m². Metformin can be continued in conjunction with all other

oral and injectable therapies, and in particular, use of metfor-

min with insulin is desirable, as it leads to reduced weight

gain and lower insulin dosage. Metformin is safe in stable

heart failure, and should only be discontinued in patients with

severe progressive renal impairment (estimated glomerular fil-

Chapter 3. Glycaemic Therapy for Diabetes

Healthy eating, weight control, increased physical activity

Step 1:

mono-therapy

Metformin

Step 2:

Thiazol-

DPP-4

GLP-1

Insulin

dual-therapy

Sulfonylurea

idinediones

inhibitors

receptor agonist

(usually basal)

Step 3:

combination

TZD

therapy

DPP-4-i

TZD

DPP-4-i

GLP-1-RA

Insulin

GLP-1-RA

Insulin

Step 4:

complex insulin

Insulin

strategies

(multiple daily doses)

Figure 3.6 ADA and EASD guidelines on management of hyper-

glycaemia (Reproduced with permission from Diabetologia. 2012;55:

1577-96)

tration rate [eGFR] less than 30 ml/min) or liver cirrhosis. A

reduction in dose could be considered at an eGFR or 40 ml/

min. The gastrointestinal side effects of metformin can be

reduced or obviated by slow titration and post prandial

administration of the drug. Metformin modified release can

be used if side effects from standard metformin are prohibi-

tive. Maximum effective dose is around 2.5 g daily.

Sulfonylureas

Sulfonylureas are insulin secretagogues. They act on the sul-

fonylurea receptor on the pancreatic beta cell to cause clo-

sure of ATP-sensitive potassium channels, and hence release

of insulin. Their action therefore depends on the presence of

residual pancreatic beta-cell function. They should be used

as a first line drug when patients are not able to tolerate

metformin, or are not overweight

(BMI <23 kg/m²).

Sulfonylureas may reasonably be used in overweight patients

T.A. Chowdhury

with T2D and significant osmotic symptoms, as their effect is

rapid, and will help alleviate acute symptoms of diabetes.

Sulfonylureas are used as second line agents when control is

inadequate with metformin alone. The commonest used are

Gliclazide, Glimepiride and Glibenclamide. Sulphonylureas

may cause weight gain - typically 1-3 kg, and therefore

should be used with caution in obese patients. The risk of

significant hypoglycaemic events is increased in people with

erratic eating habits or good glycaemic control. Dosage

should be reduced in the elderly, or in patients with hepatic

or renal impairment.

Meglitinides

Meglitinides are insulin secretagogues, which also act on

the sulphonylurea receptor, but are very short acting, and

are said to work in a glucose dependent manner. Thus, if

prevailing glucose is high, they will stimulate insulin, and if

low, they will cause less insulin stimulation. Because their

cost is generally higher than sulfonylureas, their usage is

limited to patients with more erratic eating times to aid

with meal time flexibility. They may also be useful in

Muslim patients who wish to fast during Ramadan, as they

may induce less hypoglycaemia. Commonly used prandial

glucose regulators are nateglinide and repaglinide.

Meglitinides are relatively side effect free, but can cause

some modest weight gain and occasional hypoglycaemia.

They should be used in caution with moderate renal and

hepatic impairment.

Thiazolidinediones

(glitazones) are PPAR-g agonists.

Stimulation of these receptors leads to significant enhance-

ment of insulin sensitivity through activation of intra-cellular

pathways involved in insulin sensitivity. The effect is not

Chapter 3. Glycaemic Therapy for Diabetes

rapid, and glitazones may take around 3-6 months to have

their maximal hypoglycaemic effect. Glitazones do not

induce hypoglycaemia, and their effect may be more durable

than metformin or sulfonylureas. Glitazones are licensed for

use as monotherapy, and dual or triple therapy with metfom-

rin and sulfonylurea, or use with insulin. Pioglitazonde is the

only glitazone currently available on the market. Troglitazone

was withdrawn due to serious hepatic toxicity, and concern

over the potential cardiac effects of rosiglitazone led to the

withdrawal of the drug some years ago.

Pioglitazone does not appear to have similar cardiovascu-

lar concerns, but other potential adverse effects have recently

been reported, including increased risk of fractures in post

menopausal women, and increased risk of bladder cancer.

Therefore, in addition to an absolute contra-indication of

glitazones in patients with heart failure (due to their propen-

sity for inducing or exacerbating heart failure), glitazones

should probably be avoided in post menopausal women with

reduced bone mineral density, and in anyone with past his-

tory of bladder cancer or current haematuria. They should be

used with caution in patients with known ischaemic heart

disease.

Glitazones can cause significant weight gain of 3-5 kg, and

water retention leading to oedema, heart failure and a dilu-

tional anaemia.

Alpha-glucosidase Inhibitors

Alpha-glucosidases break down complex carbohydrates in

the small intestine for absorption into the bloodstream.

Acarbose inhibits this enzyme, resulting in a delay in diges-

tion of carbohydrates and a relative decrease in blood glu-

cose levels especially post-prandially. Acarbose is rarely

effective on its own, and is limited to those who are unable to

tolerate other glucose lowering medications. Side-effects are

dose related, and a result of the reduced digestion of carbo-

hydrates leading to bloating, flatulence, diarrhoea and

T.A. Chowdhury

Response to GLP-1 is reduced

Healthy people

People with type 2 diabetes

Oral glucose load

iv glucose infusion

120

180

120

180

⁰1

Time (min)

Figure 3.7 The incretin effect in humans (Reproduced with permis-

sion from Primary Care Diabetes. 2012;6:187-91)

abdominal pain, which can lead to poor concordance.

Acarbose is should be avoided in people with bowel prob-

lems and is contra-indicated in severe renal failure as well as

hepatic failure.

Dipeptidyl-Peptidase-IV (DPP-IV) Inhibitors

The role of the gastrointestinal tract in regulating the secre-

tion of insulin is demonstrated by the observation that insulin

secretion is substantially increased in response to oral glu-

cose, compared to intravenous glucose administration. This

difference is known as the incretin effect (Fig. 3.7). These

peptides are secreted from endocrine cells (L-cells) in the

gastrointestinal tract, and are released in response to inges-

tion of food. The two main incretin hormones are glucagon-

like peptide-1 (GLP-1) and glucose-dependent insulinotropic

polypeptide (GIP), with GLP-1 being responsible for most of

the incretin effect on pancreatic beta-cell function. GLP-1

regulates glucose homeostasis in the postprandial period by a

number of mechanisms, including stimulation of insulin syn-

thesis, inhibition of glucagon secretion, delay in gastric emp-

tying, and promotion of satiety.

Chapter 3. Glycaemic Therapy for Diabetes

In vivo, GLP-1 is rapidly broken down by the enzyme

DPP-IV, and inhibition of DPP-IV leads to elevation of endog-

enous GLP-1 and hence enhanced insulin secretion. Gliptins

are a class of oral hypoglycaemic agent that inhibit DPP-IV,

therefore enhancing and prolonging the physiological actions

of incretin hormones. Gliptins are licenced for use as add on to

metformin, sulfonylurea or insulin. A logical place to use them

might be second line to metformin, or third line to metformin

and sulfonylurea in obese people with poorly controlled diabe-

tes. Sitagliptin (Januvia) is the most commonly used gliptin.

Gliptins appear to be safe and well tolerated, with few reported

side effects such as cold/flu-like symptoms, headache and diz-

ziness. Importantly however, recent data linking acute pancre-

atitis with gliptin therapy has emerged, and careful surveillance

for this complication is required.

Sodium Glucose Transporter-2 Inhibitors

(SGLT-2) Inhibitors

Sodium glucose transporter-2 inhibitors are the newest class of

oral hypoglycaemic agent. Reabsorption of glucose from the

proximal tubule depends on the action of SGLT-2 - a low affin-

ity, high capacity transporter found on the luminal surface of the

proximal renal tubule. Antagonism of this transporter will lead

to glycosuria, with a renal loss of around 180 g of glucose per day.

This can have a significant effect on plasma glucose levels and

weight. Dapagliflozin is the first drug in class, and in addition to

metformin, can lead to a 0.5-0.9 % reduction in HbA_1c, with a

3-4.5 kg weight loss. Adverse effects of this drug include an

8-13 % incidence of urinary tract infection and genital candidia-

sis, and a potentiation of the effect of diuretics, leading to dehy-

dration. Their place in therapy is as yet unclear.

Other Oral Therapies

Colesevalam is a bile acid sequestrant, commonly used

in hyperlipidaemia. It is also licenced for use as an oral

T.A. Chowdhury

hypoglycaemic agent in the US, although it’s mechanism of

action on glucose levels is unclear. An HbA_1c reduction of

0.4-0.8 % has been seen in randomised trials, with a concomi-

tant reduction in LDL cholesterol. Triglyceride levels may

rise, however, and hence this needs to be used with caution in

hypertriglyceridaemic patients. Side effects tend to be gastro-

intestinal - with constipation predominating.

Bromocriptine is licenced as an oral hypoglycaemic agent in

the US. Its mechanism of action in glucose lowering is poorly

understood, but may act on the circadian neuronal rhythm of

the hypothalamus, to reset an abnormally elevated hypotha-

lamic drive for increased plasma glucose, free fatty acids, and

triglycerides in insulin-resistant patients. Randomized trials

suggest that slow release bromocriptine improves HbA_1c by

0.4-0.8 %. The doses used to treat diabetes are up to 4.8 mg

daily, and nausea is the main adverse effect.

Injectable Agents

Glucagon-Like Peptide-1 (GLP-1) Analogues

As stated above, following oral ingestion of nutrient,

patients with T2D have a decreased incretin effect due to a

reduction in the secretion of GLP-1, resulting in inappropri-

ately low insulin secretion, inadequate for glucose homeo-

stasis. GLP-1 administration is effective in people with T2D,

with an increase in insulin secretion and reduction of both

fasting and postprandial plasma glucose. Administration of

GLP-1 in vivo, however, is problematic as it is rapidly inac-

tivated by the proteolytic enzyme DPP-IV, which cleaves

the N-terminal amino acids of GLP-1, and is widely

expressed in many tissues including the capillary bed of the

gut mucosa. Its close presence to GLP-1 secreting endocrine

cells results in the rapid degradation of GLP-1 within min-

utes of release. In order to overcome this, long acting GLP-1

receptor agonists, resistant to the cleavage of DPP-IV have

been developed.

Chapter 3. Glycaemic Therapy for Diabetes

Exenatide is one such analogue that is licensed for use in

patients with T2D, who have inadequate glucose control with

metformin, sulphonylurea or both. It is administered as a

twice daily fixed dose injection, and leads to a modest reduc-

tion of HbA_1c (0.8 %), and around 2.5 kg weight loss. Once

daily liraglutide and lixisenatide are also available. Head to

head studies suggest liraglutide is perhaps slightly more

potent than exenatide. A long acting exenatide preparation -

exenatide LAR - has been formulated, and is administered

weekly.

Whilst T2D itself is associated with an increased risk of

pancreatitis, recent reports suggest a possible twofold risk of

pancreatitis is seen with GLP-1 analogues. Whilst the abso-

lute risk of pancreatitis is small, the effect can be severe, and

care should be taken to monitor for signs of this

complication.

More worrying is data around the potential for carcino-

genesis with GLP-1 analogues. Pancreatic acinar and ductal

metaplasia, and subclinical pancreatitis may be an issue.

Pancreatitis itself is a risk factor for pancreatic cancer, and a

signal for increased risk of pancreatic cancer has been sug-

gested from US and German regulatory databases.

GLP-1 analogues are costly, and may have long term

adverse side effects. Their use, therefore, must be targeted at

individuals with most to gain. In the UK, NICE guidelines

suggests a trial of GLP-1 therapy in patients with poorly con-

trolled diabetes (HbA_1c >58 mmol/mol [7.5 %]), and a BMI

>35 kg/m². The trial of therapy should be continued beyond 6

months only if the patient has lost around 2.5 % of body

weight or dropped HbA_1c by 10 mmol/mol (1 %).

Insulin

Insulin therapy is the mainstay of treatment for people

with T1D, and frequently required for people with long

standing T2D. Regimes and delivery methods have

improved and simplified management to enable insulin

T.A. Chowdhury

therapy to fit in with people’s lives. The advent of rapid

acting insulin analogues in conjunction with carbohydrate

counting education programmes has enabled people with

T1D to have a freedom of management far greater than

they ever used to. Long acting insulin analogues may have

modest benefits in reducing hypoglycaemia in people with

T1D. For most people with T1D, use of multiple dose insu-

lin

(MDI) with analogue insulins is deemed first line

treatment. Recent development of ultra-long acting

analogue insulins (degludec) with prolonged pharmacoki-

netic profiles may also allow flexibility of timing of dosing

of basal insulin, although their cost may outweigh the

modest benefit they provide, and a slight worry around

increased cardiovascular risk has emerged recently with

insulin degludec.

Whilst analogue insulins may enhance the care of T1D,

their role in T2D is more contentious. Insulin therapy may

be deemed necessary in some people with T2D and poor

glucose control, particularly if they have symptomatic

hyperglycaemia. In recent years, use of analogue insulins

has been favoured as first line insulin therapy in many units

in the UK and Europe, with an incremental cost of £625 mil-

lion per year in the UK. No significant improvement in

glucose control has been demonstrated with these agents. A

modest effect on nocturnal hypoglycaemia may be seen, but

this does not impact significantly on cost effectiveness.

NICE guidelines recommend the use of human insulin first

line for people with T2D, and is based on that fact that

hypoglycaemia is uncommon in patients with T2D treated

with insulin. Use of human insulin first line in all patients

with T2D could save significant costs, without major

disbenefits.

When instituting insulin therapy, NICE guidelines suggest

a clear structured programme should be offered, covering all

aspects of insulin therapy, from the mechanics of injecting, to

methods of disposing of sharps, to care with driving. A sug-

gested curriculum to be discussed with a patient starting

insulin is outlined in Table 3.2.

Chapter 3. Glycaemic Therapy for Diabetes

Table 3.2 Questions

What is insulin?

patients may ask when

Why do I need to give it?

commencing insulin

How/where do I give it?

When do I give it?

How much do I give?

How do I store the insulin (including

travel to hot countries)?

What do I do with sharps?

What are the side effects? - e.g. hypos

What do I do if I am ill and can’t eat?

Can I drive?

Do I need to inform my employer?

How often should I test my blood?

Continuous Subcutaneous Insulin Infusion (CSII)

Therapy

CSII, or insulin pump therapy has been available for many

years, and uptaken with vigour in many European coun-

tries, although use in the UK has been significantly less.

Recent improvements in technology have led to CSII

becoming the mainstay of treatment for T1D in many pae-

diatric centres, and an option for adults with T1D with dif-

ficulties on MDI therapy. NICE guidelines in the UK

suggest use of CSII in patients on MDI regimes, in whom

tight glycaemic control cannot be achieved

(HbA_1c

>58 mmol/mol [7.5 %]), or in whom problematic hypogly-

caemia unawareness ensues.

Use of sensor augmented CSII has recently been shown to

be a significant advance. Continuous glucose sensors are able

to monitor subcutaneous glucose levels and wirelessly send

the readings to the insulin pump. This could be of particular

benefit in patients with problematic hypoglycaemia, and the

T.A. Chowdhury

concept of insulin infusion suspend in people with poor hypo

awareness has been tested in the research setting, with prom-

ising results.

Equally promising is the use of closed loop systems to

manage glucose in patients with T1D, using individualised

algorithms to deliver insulin via the pump, according to sen-

sor glucose readings - akin to an “artificial pancreas”. Whilst

studies so far have been proof of concept studies in small

numbers of predominantly paediatric patients, the results

suggest that the system is workable, and larger phase 2 stud-

ies are proceeding.

Pancreatic Transplantation

Simultaneous pancreas and renal transplantation (SPK) is a

well-established treatment for patients with T1D, who are

undergoing renal transplantation for end stage renal failure.

Whilst the operation is more arduous than a simple renal

transplant, and careful pre-operative selection may be

required, post operative results are excellent, with 10 year

patient survival of over 90 %, and 10 year graft survival of

over 70 %, with insulin independence.

Pancreatic beta cell transplantation, whilst a much less

arduous procedure, has more varied results. They are recom-

mended for consideration in patients severe life threatening

hypoglycaemia, not responsive to MDI or CSII therapy. The

Edmonton protocol for anti-rejection therapy has allowed

improved graft survival and fewer side effects from anti-

rejection drugs. Five-year graft survival of around 30-50 % is

reported, with insulin-independence rates of 20-25 % at 5

years.

Whilst pancreatic islet transplantation is a promising

therapeutic approach to insulin therapy, the number of donor

islets available cannot meet demand, and hence there is a

search for renewable sources of high-quality β-cells, such as

the generation of new β-cells from embryonic stem cells.

Intensive research is ongoing in this area, although progress

in human models has been slow.

Chapter 3. Glycaemic Therapy for Diabetes

Pramlintide

Islet amyloid polypeptide, or amylin, is co-secreted with insu-

lin from islet beta cells, in response to glucose. Amylin secre-

tion is also stimulated by glucagon, GLP-1, and inhibited by

insulin. Amylin has a glucoregulatory role, by inhibiting gas-

tric emptying, reducing glucagon release and inhibiting food

intake. The amylin analogue, pramlintide, is approved for

treatment of type 1 and insulin requiring T2D in the US.

Effects on glycaemic control are modest - in T1D, glycated

haemoglobin reductions of 0.3 % are achieved, with around

1.5 kg weight loss. In T2D, 0.4 % glycated haemoglobin

reduction is achieved, with around 2.5 kg weight loss. In par-

ticular, post-prandial hyperglycaemia appears to be improved

by pramlintide. Nausea is a common side effect, which can be

reduced with gradual dose titration. Post-prandial hypogly-

caemia can be problematic if the dose of insulin is not

adjusted.

Pramlintide appears to have found a niche in the US in

type 1 patients with problematic post prandial hyperglycae-

mia. Co-administration with prandial insulin can improve

post prandial excursions considerably. Despite its availability

for some time, the drug has not developed a wide use as yet,

due to its modest effects.

Future Agents to Treat Hyperglycaemia

Inhaled/Oral Insulin

The inhaled route for insulin administration was first sug-

gested in the 1920s, when it was recognized that by virtue of

its’ large surface area and rapid access to the systemic circula-

tion, the lungs could be a very attractive site for peptide

administration. It has taken many decades of technological

advances to achieve a standard particle size and precise dos-

ing. Insulin is the first non-pulmonary drug to be licensed for

administration by the inhalation route. Exubera was the first

T.A. Chowdhury

inhaled insulin to market, but was withdrawn due to poor

sales, and concerns over possible mitogenicity in the lungs.

A newer system - the Mannkind Technosphere Insulin

system uses insulin encapsulated in “technospheres” (a car-

rier molecule), which are inhaled via a breath activated,

mobile phone size device. The insulin has a rapid onset/offset,

and early studies suggest no change in FEV1. Studies in

smokers, asthmatics and patients with chronic obstructive

pulmonary disease (COPD) are planned.

Oral insulin is being developed, although progress has

been slow. Theoretically, oral insulin has a major advantage in

having no requirement for needles and delivery of insulin to

the liver via the portal vein, mimicking normal physiology.

Insulin is rapidly degraded by gastric acid and proteolytic

enzymes. This may be overcome by inhibiting degradation

(protease inhibitors), enhancing absorption (using “enhanc-

ers”), or using carriers (such as capsules, microspheres or

liposomes). One formulation of oral insulin that looks prom-

ising is Capsulin (Diabetology Ltd). This is an enteric coated

capsule, which dissolves in the small intestine, and releases

150 unit of insulin, plus a solubilisation agent. In a study of

patients 16 patients with T2D treated with oral hypoglycae-

mic agents, a hypoglycaemic response in excess of 6 h was

seen, and over 10 days, replacement of oral hypoglycaemic

agent with capsulin did not result in deterioration of glycae-

mic control.

Glucagon Receptor Antagonists

Antagonism of the glucagon receptor is a potential therapeutic

target in diabetes therapy, and this will have a hypoglycaemic

effect. In patients with T2D, lack of suppression of glucagon may

lead to postprandial hyperglycemia due to accelerated glycoge-

nolysis. Studies of pharmacological glucagon receptor antago-

nists have shown a hypoglycaemic effect in rodent models of

diabetes. Phase 2 studies in humans have shown a modest hypo-

glycaemic effect in combination with metformin.

Chapter 3. Glycaemic Therapy for Diabetes

Glucokinase Activators

Glucokinase is a glucose-phosphorylating enzyme which has

an important role in glucose homeostasis as a glucose sensor in

pancreatic β-cells, and as a rate-controlling enzyme for hepatic

glucose clearance and glycogen synthesis, processes that are

impaired in patients with T2D. In the liver, glucokinase medi-

ates gluconeogenesis, glucose utilization and glycogen synthe-

sis, and in the pancreas, glucokinase is the rate-limiting enzyme

in glucose-stimulated insulin release. Glucokinase activators

may also antagonizing apoptosis in B cells. The effect of gluco-

kinase activators may be to improve glucose-sensitive insulin

secretion, and reduce hepatic gluconeogenesis. As glucokinase

has a lower affinity for glucose than other hexokinases and is

not inhibited by its product, it lowers glucose levels by enhanc-

ing the capability of pancreatic islet beta cells to sense blood

glucose concentrations and thus determining the threshold for

insulin secretion. Glucokinase activity increases with rising

postprandial glucose concentrations to elevate hepatic glucose

uptake while suppressing hepatic glucose production. Phase 1

studies suggest a potent hypoglycaemic effect of glucokinase

activating drugs.

11β Hydroxysteroid Dehydrogenase Type 1

Inhibitors

11β-Hydroxysteroid dehydrogenase type

(11β-HSD1)

catalyses the intracellular conversion of the physiologi-

cally inactive cortisone to physiologically active cortisol.

Overexpression of 11β-HSD1 in adipose tissue in rodents

leads to significant metabolic consequences in rodents, and

hence inhibition of 11β-HSD1 has been proposed to be a

potential therapeutic target in patients with T2D. Phase 2

studies suggest that such inhibitors can improve glucose

and other cardiometabolic risk factors in patients with

T2D.

T.A. Chowdhury

GPR119 Agonists

GPR119 is G protein-coupled receptor expressed primarily

in the pancreas and gastrointestinal tract. Activation of

GPR119 increases the intracellular accumulation of cAMP,

leading to enhanced glucose-dependent insulin secretion

from pancreatic β-cells and increased release of incretin hor-

mones GLP-1, GIP and polypeptide YY (PYY). Oral admin-

istration of GPR119 agonists has been shown to improve

glucose tolerance in both rodents and humans.

Immune Therapies

Autoimmunity against pancreatic beta cells is the hallmark of

T1D, and this is closely linked with the HLA-DQ risk alleles

and a variety of possible environmental triggers.

Autoantibodies against insulin, GAD65, IA-2 or the ZnT8

transporter mark islet autoimmunity, and immune therapy

can be targeted at three risk groups. Primary prevention

involves treatment of individuals at increased genetic risk.

Secondary prevention targets individuals with persistent islet

autoantibodies, with nonautoantigen-specific therapies, such

as Bacillus Calmette-Guérin vaccine anti-CD3 monoclonal

antibodies, or autoantigen-specific therapies such as oral and

nasal insulin or alum-formulated recombinant human

GAD65. Long-term preservation of β-cell function has not

yet been achieved in studies so far reported.

Conclusions

Management of hyperglycaemia is critical to the prevention

of complications in patients with T1D, and relies on MDI

therapy, frequent glucose monitoring, combined with adjust-

ments in dose for carbohydrate intake and glucose level. CSII

can be an option in people struggling with erratic control or

hypoglycaemic unawareness. Progress in pancreas beta cell

transplantation is occurring, but the availability of donors is

Chapter 3. Glycaemic Therapy for Diabetes

rate limiting. Slow progress is being made in the generation

of beta cells from human embryonic stem cells, or xenografts,

but use in routine care is many years away.

Management of hyperglycaemia in T2D has undergone a

significant revision in recent years, since the advent of large

trials suggesting that tight glucose control is not only difficult

to attain, but may be damaging to health in the elderly or

those with co-morbidities. Nonetheless, new targets for phar-

macological intervention in hyperglycaemia have been found,

and are being heavily researched. It is important however,

that these new drugs do not just demonstrate the ability to

lower glucose, but also demonstrate long term safety and

efficacy, as well as improvements in cardiovascular and

microvascular outcomes.

Recent safety concerns over glitazones remind all physi-

cians using new drugs for any chronic disease that long-term

pharmacovigilance with these drugs is necessary, and long

term outcome studies are required to evaluate the effects of

cardiovascular mortality and morbidity.

Key References

Action to Control Cardiovascular Risk in Diabetes Study Group. Effects

of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;

358:2545-59.

ADVANCE Collaborative Group. Intensive blood glucose control and

vascular outcomes in patients with type 2 diabetes. N Engl J Med.

2008;358:2560-72.

Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD,

et al. Glucose control and vascular complications in veterans with

type 2 diabetes. N Engl J Med. 2009;360:129-39.

Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year

follow-up of intensive glucose control in type 2 diabetes. N Engl

J Med. 2008;359:1577-89.

Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferranini E, Nauck

M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of

hyperglycaemia in type 2 diabetes: a patient centred approach.

Position statement of the American Diabetes Association (ADA)

and European Association for the Study of Diabetes (EASD).

Diabetologia. 2012;55:1577-96.

T.A. Chowdhury

The Diabetes Control and Complications Trial Research Group. The

effect of intensive treatment of diabetes on the development and

progression of long-term complications in insulin-dependent diabe-

tes mellitus. N Engl J Med. 1993;329:977-86.

The National Institute for Health and Clinical Excellence. NICE clinical

guideline 87 2009. Type 2 diabetes. The management of type 2 diabe-

tes.

http://www.nice.org.uk/nicemedia/live/12165/44320/44320.pdf .

Accessed 26 June 2013.

The National Institute for Health and Clinical Excellence. NICE short

clinical guideline 87. Type 2 diabetes: newer agents. Type 2 diabetes:

newer agents for blood glucose control in type 2 diabetes. http://www.

nice.org.uk/nicemedia/live/12165/44318/44318.pdf . Accessed 26 June

2013.

UKPDS Study Group. Intensive blood glucose control with sulphonyl-

ureas or insulin compared with conventional treatment and risk of

complications in patients with type 2 diabetes. Lancet. 1998;352:

837-53.

Chapter 4

Preventing and Managing

Renal Disease in Diabetes

Richard A. Chudleigh, Pranav Kumar, and Stephen C. Bain

Abstract Diabetic nephropathy is the leading cause of end

stage renal disease worldwide. The current epidemic of type 2

diabetes (T2D) will lead to further increase in the prevalence

of this condition.

In this chapter we review the pathology of diabetic

nephropathy in patients with type 1 diabetes (T1D) and T2D.

The staging according to presence of albuminuria and chronic

kidney disease (CKD) classification is also discussed. We

outline the principles of annual screening, investigation and

management of patients with diabetes at risk of nephropathy,

patients with microalbuminuira and also those with estab-

lished diabetic nephropathy. The need for preventative ther-

apy including blood glucose and blood pressure control is

addressed, and we discuss the importance of ACE inhibitors

and angiotensin-2 receptor blockers in the management of

these patients. The importance of cardiovascular risk factor

management is also highlighted.

R.A. Chudleigh, MD, MRCP • P. Kumar, MRCP

Diabetes, Singleton Hospital, Swansea, South Wales, UK

S.C. Bain, MA, MD, FRCP (

)

Diabetes, Singleton Hospital and Institute of Life Science,

Swansea, South Wales, UK

e-mail: s.c.bain@swansea.ac.uk

T.A. Chowdhury (ed.),

Diabetes Management in Clinical Practice,

DOI 10.1007/978-1-4471-4869-2_4, © Springer-Verlag London 2014

R.A. Chudleigh et al.

Keywords Type 1 Diabetes • Type 2 Diabetes • Diabetic

nephropathy • Chronic Kidney Disease • CKD • Renal

disease • Cardiovascular disease

Introduction

Diabetic Nephropathy (DN) is the leading cause of chronic

kidney disease (CKD) in the UK, and second most common

cause of end stage renal disease (ESRD). This patient group

are at significant cardiovascular risk and often succumb to

this, rather than progress to ESRD, especially patients with

type 2 diabetes (T2D).

DN is defined by an increase in urinary albumin excretion

(UAE), rising blood pressure and a decline in glomerular

filtration rate (GFR). DN in Type 1 diabetes (T1D) is divided

into five stages according to the presence of glomerular

hyperfiltration, morphological lesions, increasing UAE,

established DN and ESRD.

Fundamental differences in clinical phenotype between

patients with T1D and T2D are recognised. Similarly, the

pathological manifestations of DN are different between the

two groups. In T1D, DN may present with the classical mani-

festations whereas patients with T2D usually have significant

co-morbidity often predating diabetes. Patients are often

obese, hypertensive or have cardiovascular disease. They may

have features of hypertensive nephropathy or renovascular

disease. As such nephropathy is often of mixed aetiology and

maybe better termed as chronic kidney disease.

The National Kidney Foundation (NKF) recommends

clinical staging of CKD according to estimated GFR (eGFR)

values (Table 4.1). In the UK the Renal Association have also

adopted this classification.

Epidemiology

The incidence of ESRD in the UK has doubled in the past

10 years and is projected to continue to rise. The increasing inci-

dence of T2D contributes significantly to this as DN affects up

Chapter 4. Preventing and Managing Renal Disease

Table 4.1 Stages of CKD

Stage^a Description

GFR (ml/min/1.73 m²)

Kidney damage with normal or

≥90

increase of GFR

Kidney damage with normal or

60-89

mild reduction of GFR

Moderate reduction of GFR

45-59

30-44

Severe reduction of GFR

15-29

Established renal failure

<15 (or dialysis)

^aUse the suffix (p) to denote the presence of proteinuria when

staging CKD

to one third of patients with T1D or T2D. The prevalence of

ESRD actually underestimates the entire burden of CKD; in a

cross-sectional study of approximately 34,000 adults with diabe-

tes in London, the prevalence of CKD stages 3-5 was 18 %. In

another study of 7,596 people with diabetes from Salford stage

3-5 CKD was observed in 27.5 %. As the total number of people

with diabetes increases, the prevalence of DN will rise dramati-

cally, with increase in the associated cardiovascular mortality

and incidence of ESRD. This will have significant social and

economic ramifications.

Natural History

The earliest biochemical manifestation of DN is the appearance

of albuminuria, this being the most sensitive marker of CKD

due to diabetes and is common to nephropathy in both T1D &

T2D. It is defined by a urinary albumin loss of between 30 and

300 mg a day. Loss above this level is termed macroalbuminuria.

Urinary albumin measurement is most often assessed by deter-

mining the albumin/creatinine ratio (ACR) (described below).

An elevated ACR on more than one occasion confirms microal-

buminuria. Longitudinal studies suggest progression from nor-

moalbuminuria to microalbuminuria occurs at a rate of 4 % per

year. Although baseline UAE, blood pressure and serum

R.A. Chudleigh et al.

cholesterol may all influence such progression, glycaemic con-

trol appears key in reducing the incidence of microalbuminuria.

In those with persistent microalbuminuria the rate of progres-

sion to macroalbuminuria varies from 5 to 10 % per year, with

approximately 20 % of patients having macroalbuminuria at

5 years. It might be supposed that those factors which influence

rate of progression to macroalbuminuria would be similar to

those for microalbuminuria; results have however proven incon-

sistent. Improved glycaemic control may retard progression,

though control of blood pressure may be of greater significance.

Established albuminuria promotes further deterioration in renal

function with the rate of decline in renal function being related

to albuminuria. Finally, patients with T2D & DN are more likely

to succumb to cardiovascular disease, which is strongly associ-

ated with the presence of microalbuminuria. Meanwhile patients

with T1D and proteinuria are more likely to progress to ESRD.

Hypotheses abound concerning potential pathogenic mecha-

nisms involved in DN, which are beyond the scope of this chap-

ter. Genetic factors may be important, particularly in T1D.

Figures 4.1 and 4.2 outlines some potential pathogenic factors

which may contribute to the development of DN.

Detection

Patients with diabetes should have screening at diagnosis and

then undergo annual screening for the development of DN

by spot urine testing to measure albumin:creatinine ratio

(ACR). To compensate for variations in urine concentration

in spot urine samples, it is helpful to compare the amount of

albumin against the concentration of creatinine. The ACR is

more convenient than performing timed urine collections

which are often inaccurate.

An ACR of 2.5-30.0 mg/mmol in males and 3.5-30.0 mg/

mmol in females defines microalbuminuria. The different

ranges are seen due to the greater muscle bulk seen in men,

which leads to higher levels of urinary creatinine. Quantitative

measurement of ACR allows for longitudinal monitoring.

Chapter 4. Preventing and Managing Renal Disease

Microinflammation

P-selectin

ICAM-1

E-selectin

VCAM-1

Macrophages

Endothelial cells

Inflammatory

Genes for renin-

Genes for glucose

cytokine gene

angiotensin system

metabolism

Genes for protein

Genes for

kinase C signals

ROS system

Genetic factors?

Genes for

Unknown

lipid metabolism

genes

Environmental factors

Reduced glomerular

filtration, albuminuria

Figure 4.1 Microinflammation and diabetic nephropathy. A combi-

nation of multiple genetic and/or environmental factors is consid-

ered to contribute to the pathogenesis of diabetic nephropathy.

Inflammatory cytokine genes, such as IL-6, might be good candi-

dates for conferring susceptibility to diabetic nephropathy. ICAM-1

intercellular adhesion molecule-1, VCAM-1 vascular cellular adhe-

sion molecule-1, ROS reactive oxygen species (Reproduced with

permission from Kidney Int. 2008;74:413-5)

Increasing levels confer a greater chance of progression,

whilst decreasing levels of albuminuria suggest lower risk of

decline in kidney function. When UAE consistently exceeds

30 mg/mmol (in both men and women) patients have estab-

lished DN. The urinary protein concentration can be used to

quantify disease progression, with higher levels suggesting

greater renal damage with more chance of progressive

nephropathy and ESRD.

Serum creatinine is also measured to enable estimation of

GFR (eGFR). eGFR is the best measure of kidney function,

Chapter 4. Preventing and Managing Renal Disease

Figure 4.2 The molecular mechanism involved in induction and

progression of diabetic nephropathy. TNF-α indicates tumor necro-

sis factor-α, Ang II indicates angiotensin II, TGF-β indicates trans-

forming growth factor-β, NADPH oxidase indicates nicotinamide

adenine dinucleotide phosphate-oxidase, PKC indicates protein

kinase C, MCP-1 indicates monocyte chemoattractant protein-1,

JAK-STAT signaling indicates Janus kinases-signal transducer and

activator of transcription signaling, IL-1β indicates interleukin-1β,

PAI-1 indicates plasminogen activator inhibitor-1, MCP-1 indicates

monocyte chemoattractant protein-1, VEGF indicates vascular

endothelial growth factor, ICAM-1 indicates intercellular adhesion

molecule-1, NF-κB indicates nuclear factor kappa B, PA indicates

plasminogen activator, MMP-2 indicates matrix metalloproteinase-

2, ROS indicates reactive oxygen species (Reproduced with permis-

sion from Vascular Pharmacology. 2013;4:259-71)

with any change a good index of progression of CKD. The

Modification of Diet in Renal Disease (MDRD) equation,

which utilises age, gender and ethnicity to estimate GFR, has

gained favour in the majority of international guidelines for

this purpose. MDRD does, however underestimate higher

levels of GFR, and hence is not particularly specific for iden-

tifying early nephropathy but is useful for measuring pro-

gression of established nephropathy. Staging according to

eGFR is useful to highlight those at risk of specific

complications.

Prevention

Glycaemic Control

In patients with normoalbuminuria and preserved eGFR

management focuses on preventing DN. Several studies indi-

cate improved glycaemic control reduces the incidence of

microalbuminuria in T1D and T2D.

R.A. Chudleigh et al.

The DCCT trial of patients with T1D demonstrated inten-

sive diabetes treatment delays the onset of nephropathy. In

those with normoalbuminuria intensive treatment reduced

the cumulative incidence of microalbuminuria by 34 %, dur-

ing a mean follow up of 6.5 years. The risk of developing

microalbuminuria increases rapidly with an HbA_1c value of

above 8.1 % (65 mmol/mol). Follow up studies of patients

with T1D show the strongest predictors for development of

microalbuminuria are baseline UAE, glycaemia and blood

pressure over 7 years of follow up.

UKPDS examined intensive glycaemic control in subjects

newly diagnosed with T2D. Intensive treatment, achieving an

HbA_1c of 7.0 % (53 mmol/mol) produced a 25 % risk reduc-

tion in microvascular end points. Significant differences in the

incidence of microalbuminuria, macroalbuminuria and dou-

bling of serum creatinine after 12 years of follow up were

observed. Post trial observation noted that benefits of early

glycaemic control persist for up to 10 years after the period

of strictest intervention.

Hypertension

In patients with T1D, hypertension is often an early indicator

of DN. Elevated systolic BP at diagnosis predicts subsequent

microalbuminuria. A close correlation between systemic blood

pressure at baseline and subsequent nephropathy in patients

with childhood T1D has been demonstrated. Hypertension is

common in subjects with microalbuminuria, - 30 % of patients

with microalbuminuria have BP >160/95 mmHg.

In T2D hypertension often predates the diagnosis of dia-

betes. In UKPDS, controlling hypertension produced a 29 %

reduction in risk of microalbuminuria at 6 years. A lower

incidence of proteinuria in patients with T2D treated with the

antihypertensive agent ramipril, has been demonstrated.

Treatment of hypertensive patients with T2D and normoal-

buminuria treated with trandolapril, perindopril and indap-

amide reduces incidence of microalbuminuria.

Chapter 4. Preventing and Managing Renal Disease

Microalbuminuria

The presence of persistent microalbuminuria confers a 10-20

greater risk of developing DN. In T1D, microalbuminuria

develops in about 30 % of patients by 20 years. Early work

suggested that microalbuminuria conferred a risk of 60-85 %

of progressing to macroalbuminuria with progressive decline

in GFR by 6-14 years. More recent work with larger numbers

of patients and longer follow up suggests a more modest rate

of progression of 20 % with a large proportion regressing to

normoalbuminuria.

Glycaemic Control

Achieving HbA_1c target of <7.0 % (53 mmol/mol) can pre-

vent progression to macroalbuminuria and increase the

chances of regression to normoalbuminuria. HbA_1c values of

<8.0 % (64 mmol/mol) show highest rates of regression, with

values of 7.5-8.0 % (58-64 mmol/mol) having lower rates of

progression.

In T2D benefit from good metabolic control has been

established. In a Japanese study a mean HbA _1c of 7.2 %

(55 mol/mol) reduced progression from microalbuminuria to

macroalbuminuria. In the Steno-2 study of Danish patients

with T2D and microalbuminuria, subjects were divided into

intensive or conventional multifactorial intervention with

attention to lifestyle, glycaemic, blood pressure and lipid con-

trol, smoking cessation and aspirin therapy. This study found

intensive treatment reduced microvascular complications at

4 years.

Hypertension

The primary goal of therapy in patients with microalbumin-

uria is to decrease blood pressure below 130 mmHg systolic

and 80 mmHg diastolic as recommended by the National

R.A. Chudleigh et al.

Kidney Foundation. This is based on the findings of a number

of studies, which demonstrate beneficial effects of BP lower-

ing in patients with T1D & T2D in terms of reductions in

albuminuria and rates of progression of nephropathy. BP

reduction also has significant cardiovascular benefits.

Multiple classes of antihypertensive agents have been used

in patients with T1D & T2D to control hypertension associ-

ated with DN. Agents such as ACE inhibitors (ACE-I), angio-

tensin-2 receptor blockers (ARBs), beta-blockers, calcium

channel antagonists &diuretics can all effectively reduce BP

to a similar extent. A meta-regression analysis reviewed the

effects of different agents showing that blood pressure con-

trol positively impacts albuminuria, but ACE-I have had a

greater impact on proteinuria for similar BP reduction. Other

agents seem to have an effect intermediate between that of

ACE-I and placebo. Latterly, ARB’s have shown a similar

efficacy.

Renin Angiotensin System Blockade

Due to significant cardiovascular benefits and proteinuria

lowering effects, ACE-I are the first line antihypertensive

agent in patients with diabetes. A meta analysis of

randomised controlled trials of ACE-I use in normotensive

patients with T1D and microalbuminuria demonstrated that

in all studies except one ACE-I produced a reduction in UAE,

reduced progression from micro- to macroalbumniuria by a

third and had a three times higher rate of regression from

microalbuminuria to normoalbuminuria. This effect was inde-

pendent of BP lowering. Those with the highest level of ACR

had most benefit, but even those with low of ACR had benefit.

In light of these findings ACE-I are recommended as first line

therapy with all patients with microalbuminuria regardless of

BP. More recently, ARB’s have been shown to have a similar

effect in reducing microalbuminuria in patients with T1D.

In patients with T2D, ramipril has been shown to reduce

UAE and retard progression from micro- to macroalbuminuria

Chapter 4. Preventing and Managing Renal Disease

Similar benefits in terms of microalbuminuria reduction have

been demonstrated for other ACE-I.

Several studies have evaluated ARB’s as an alternative to

ACE-I to retard progression of microalbuminuria. Trials dem-

onstrate comparable antiproteinuric effects. Valsartan and

irbesartan reduce UAE and promote regression to normoal-

buminuria in patients with T2D and microalbuminuria. It is

likely ACE-I and ARB’s are equally effective as demon-

strated in the DETAIL study of Telmisartan and Enalapril in

hypertensive patients with T2D and preserved GFR and some

other small scale studies. Further large-scale trials are unlikely.

Cardiovascular Risk

Microalbuminuria confers a twofold to threefold increase in

cardiovascular risk. UKPDS demonstrated annual death

rates from cardiovascular disease of 0.7 % in normoalbumin-

uria and 2.0 % in microalbuminuria; therefore, aggressive

cardiovascular risk management is vital. Steno-2 highlighted

that early intensive multifactorial cardiovascular risk factor

management in patients with microalbuminuria reduces car-

diovascular events and death dramatically.

Diabetic Nephropathy

The multifactorial interventions described for patients with

microalbuminuria all apply once DN is established. There

may be challenges in achieving the recommended targets

using certain medications in the setting of a reduced eGFR

and also on occasion stricter targets will be recommended.

Glycaemic Control

The DCCT and EDIC trials of patients with normal UAE demon-

strated that intensive therapy (mean HbA _1c 7.2 % [55 mmol/mol])

R.A. Chudleigh et al.

produced a 54 % adjusted risk reduction in new onset macroal-

buminuria and a significantly lower rate of impaired renal func-

tion, defined as an eGFR of less than 60 ml/min per 1.73 m²,

compared with conventional treatment after 9 and 16 years of

follow up respectively. Similarly, UKPDS in patients with T2D

demonstrated intensive blood glucose control produces a risk

reduction of 34 % for progression of albuminuria and 67 %

reduction in the proportion of patients having a doubling of

serum creatinine concentration. More recently despite it’s early

termination, the Action to Control Cardiovascular Risk in

Diabetes (ACCORD) trial studied demonstrated renal benefits

from early intensive glycaemic control.

There are multiple therapeutic options for glycaemic man-

agement. Kidney function should be evaluated prior to anti-

diabetic therapy, as this will impact the choice and dosage of

medication. Patients with stage 3-5 CKD are susceptible to

hypoglycaemia when taking renally excreted medication and

should monitor blood glucose levels more frequently and

may require dose titration.

Metformin can be used in mild to moderate renal impair-

ment. Dosage should be reviewed if eGFR falls below 40 mL/

min/1.73 m² although the evidence supporting such an inter-

vention is minimal. Metformin is usually discontinued when

eGFR falls below 30 ml/min/1.73 m². Sulfonylureas should be

used with caution in mild to moderate renal impairment,

because of potentiation of hypoglycaemia; therefore long act-

ing sulphonyureas should be avoided. Pioglitazone can be

used in renal impairment without dose adjustment. It should

be used with caution, however, as fluid retention particularly

in renal disease, can be problematic.

Currently four Dipeptidylpetidase-4 (DPP-4) inhibitors

are approved for use in patients with CKD. Linagliptin does

not require dose adjustment as it is primarily excreted via

bowel and liver. The Glucagon Like Peptide-1 agonists can

only be used in mild/moderate renal impairment with indi-

vidual eGFR values recommended for discontinuation.

Often oral agents or GLP-1 agonists are contraindicated

or fail to achieve adequate glycaemic control in patients with

Chapter 4. Preventing and Managing Renal Disease

T2D, and insulin therapy is necessary. Insulin clearance is

impaired as renal failure progresses, hence blood glucose

needs careful monitoring and insulin doses should be titrated

to achieve adequate glycaemic control whilst avoiding

hypoglycaemia.

Hypertension

Hypertension markedly accelerates progression of DN, and

aggressive blood pressure control slows the rate of decline in

GFR. In patients with T1D and nephropathy, ACE-I are

reno-protective and reduce the rate of decline in GFR, pro-

gression of albuminuria and need for renal replacement

therapy (RRT) ACE-I are the first line antihypertensive

agent for patients with T1D with DN.

In patients with T2D and nephropathy there is less robust

evidence for the protective effects of ACE-I as most of the

larger studies used ARBs to block the renin angiotensin sys-

tem (RAS). Irbesartan and Losartan were both associated

with fewer renal end points including progression of protein-

uria, doubling of serum creatinine, and the development of

ESRD.

Cardiovascular Risk

Established proteinuria is associated with a cardiovascular

risk 10 times that of normoalbuminuric persons. Therefore,

patients should receive aggressive cardiovascular risk fac-

tor management from first identification of microalbumin-

uria. Importantly, a recent meta-analysis by Yudkin et al

concluded that intensive glycaemic control is a weaker risk

factor than blood pressure or cholesterol lowering.

Emerging evidence suggests the primary goal for treating

hyperglycaemia is maintaining euglycaemia, but not at the

expense of hypoglycaemia. Updated guidelines are stating

to reflect this.

R.A. Chudleigh et al.

Given that ACE-I and ARB’s provide renal and cardio-

vascular benefit in patients with T2D, there has been inter-

est in applying dual blockade of the RAS system for an

additive affect. Initial studies looked promising in terms of

albuminuria lowering. Recent studies have failed to con-

firm an additional benefit and combination therapy can be

associated with increased adverse events including hyper-

kalaemia, hypotension and renal failure. Recent investiga-

tion of direct renin inhibition to reduce proteinuria has

been undertaken. Patients with T2D, ischaemic heart dis-

ease and renal impairment treated with aliskerin in combi-

nation with usual therapy including ACE-I and ARB’s led

to increased risk of stroke, renal failure, hyperkalemia and

hypotension observed with this combination therapy. Dual

blockade is now usually at the discretion of the treating

physician in high-risk individuals, with refractory protein-

uria who may derive benefit.

Dyslipidaemia

Studies unequivocally demonstrated that lipid lowering

therapy in patients with T2D is beneficial. NICE guidelines

recommend a therapeutic for goal total cholesterol of

4.0 mmol/l, an LDL-C concentration below 2.0 mmol/l. If

lipid targets are not achieved with life style management,

statins or statins/ezetemibe in combination are the lipid-

lowering agents of choice for patients with CKD stage 1-4.

Routine use of lipid lowering treatment is not recommended

for dialysis dependent patients due to lack of evidence.

Antithrombotic Therapy

Aspirin as a secondary prevention strategy in those with dia-

betes and existing cardiovascular disease is recommended by

all relevant guidelines and supported by a strong evidence

base. The ADA and NICE recommend use of low dose

Chapter 4. Preventing and Managing Renal Disease

aspirin as primary prevention in those with microalbuminuria

for cardiovascular protection, although the evidence for this

intervention is not particularly strong.

Smoking Cessation

Smoking is a strong predictor of renal disease. In patients

presenting with newly diagnosed T2D, heavy microalbumin-

uria was more common in smokers than non-smokers. It is

also associated with progression of DN patients with T2D.

Smoking cessation is strongly recommended.

Diet, Lifestyle and Weight Loss

Obesity is strongly associated with T2D and both conditions

are associated with an increased incidence of CKD. The

recently published Look AHEAD study demonstrated that

lifestyle interventions & weight loss have a positive effect on

measures of renal function including a composite of albumin-

uria and eGFR. Target body weight should be individualized

to the patient. Life style modification should be first line and

anti-obesity medication (Orlistat) should be added if needed.

Bariatric surgery is usually reserved for severely obese

patients.

Referral to Nephrologists

Despite intervention, a proportion of patients will develop

progressive renal disease and require intervention from

nephrologists for management of complications such as renal

anaemia, bone disease and acidosis. Patients may require treat-

ment with erythropoietin, 1-alfacalcidol or sodium bicarbon-

ate; nephrologists usually supervise these therapies. Use of

CKD staging can help to inform management and referral

decisions, especially with the need for deciding on the

R.A. Chudleigh et al.

appropriateness of RRT, planning for RRT modality etc.

Patients with diabetes may have a non-diabetic cause of their

renal disease (eg glomerulonephritis), and may require renal

biopsy. A high index of suspicion for non-diabetic renal disease

should include the absence of any retinopathy, the presence of

haematuria, and rapidly progressive renal impairment.

Summary

To prevent DN, the majority of patients with diabetes should

aim to achieve target HbA_1c value of 7.0 % (53 mmol/mol)

and BP <140/80 mmHg to reduce the incidence of microalbu-

minuria, which is considered the earliest indicator of DN and

confers an elevated cardiovascular risk. Once microalbumin-

uria is established, guidelines suggest HbA_1c targets levels of

7.0 %, BP targets of 130/80 mmHg with ACE-I being recom-

mended first line in patients T1D and ACE-I or ARB’s as

first line in patients with T2D. Additional agents are recom-

mended if targets are not achieved. All patients require

aggressive cardiovascular risk factor management. When

established DN is present attenuating proteinuria is another

important consideration and more aggressive BP targets

maybe recommended, glucose lowering therapy might need

revision in light of declining eGFR especially if there is a risk

of hypoglycaemia. There should be vigilance for the compli-

cations of CKD and referral to nephrologists for those with

progressive disease who may progress to ESRD.

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nephropathy in type 2 diabetes: the United Kingdom Prospective

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indopril and indapamide on macrovascular and microvascular out-

comes in patients with type 2 diabetes mellitus (the ADVANCE

trial): a randomised controlled trial. Lancet. 2007;370:829-40.

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Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade

versus converting-enzyme inhibition in type 2 diabetes and nephrop-

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Chan JC, Ko GT, Leung DH, et al. Long-term effects of angiotensin-

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Gaede P, Vedel P, Larsen N, et al. Effect of a multifactorial intervention

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Gaede P, Lund-Andersen H, Parving HH, et al. Effect of a multifactorial

intervention on mortality in type 2 diabetes. N Engl J Med. 2008;

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Gall MA, Hougaard P, Johnsen KB, Parving HH. Risk factors for devel-

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Holman RR, Paul SK, Bethel MA, et al. 10 years follow up of intensive

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microalbuminuria and macroalbuminuria in patients with type 1 diabe-

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Mogensen CE, Christensen CK, Vittinghus E. The stages in diabetic

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update-2012.pdf . Last accesses 10 June 2013.

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Chapter 5

Managing Diabetic Foot

Disease

Frances Games

Abstract Diabetic foot disease is a serious national and

international problem, and may affect around

15 % of

patients with diabetes in their lifetime. It is not, however, a sin-

gle entity but encompasses pathologies such as diabetic neu-

ropathy, peripheral arterial disease, foot ulceration, Charcot

neuropathic osteoarthropathy, and limb amputation. Each of

these needs management by appropriately trained specialists

to improve healing of foot ulcers, which in turn reduces the

risk of major amputation. The management of foot ulceration

is therefore best done within an expert multidisciplinary foot

care team, the formation of which has been shown not only to

reduce amputation rates but to save the money.

Keywords Diabetic foot • Neuropathy • Charcot neuro-

pathic osteoarthropathy • Wound healing • Amputation

F. Games, FRCP

Department of Diabetes and Endocrinology,

Derby Hospitals NHS FT, University of Nottingham,

Uttoxeter Road, Derby, Derbyshire DE22 3NE, UK

e-mail: frances.game@nhs.net

T.A. Chowdhury (ed.),

Diabetes Management in Clinical Practice,

DOI 10.1007/978-1-4471-4869-2_5, © Springer-Verlag London 2014

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Introduction

Diabetic foot disease is considered one of the most feared

complications of diabetes, and a serious social and economic

problem all over the world. A number of pathological pro-

cesses may be involved, including peripheral neuropathy,

peripheral arterial disease, neuropathic or ischaemic foot

ulceration, Charcot neuropathic osteoarthropathy, and limb

amputation.

Current estimates (based on UK hospital episode statis-

tics) suggest that the rate of major limb amputation in

England in 2011-2012 was 0.9/10,000 patients with diabetes.

This figure, however, hides a tenfold variation between differ-

ent primary care organisations, which is, as yet, unexplained.

Epidemiology and Risk Factors for Foot

Ulceration

In the UK it is estimated that the prevalence of foot ulcers

(current or past) in patients with diabetes is around 5-7 %.

This would suggest that around 130,000-180,000 people with

diabetes currently have, or have had foot ulcers at any one

time and, whilst the annual incidence of the onset of foot

ulceration in one UK study was 2.2 %, the cumulative life-

time incidence has been estimated to be as high as 25 %.

Patients with peripheral sensory neuropathy, arteriopathy

and deformity are those most likely to develop foot ulcer-

ation, and it is these factors that are at the core of the screen-

ing programme for “at risk” feet in the UK as stipulated by

the Quality and Outcomes Framework (QOF) incentive

scheme for primary health care professionals. This scheme

defines patients with diabetes as being low, moderate or high

risk for foot ulceration according to defined criteria

(Table 5.1). Patients should then be directed to appropriate

services for regular review and treatment as necessary to try

and reduce risk of ulceration. Although the “at risk” status of

the foot may be identified with these simple tests the event

Chapter 5. Managing Diabetic Foot Disease

Table 5.1 Risk classification for the diabetic foot

Risk

Clinical features

Action

Low

Normal sensation,

Annual screening by a suitably

palpable peripheral

trained Healthcare Professional.

pulses, no deformity,

Agreed self management plan.

no previous ulcer

Provide written and verbal

education with emergency

contact numbers.

Appropriate access to

podiatrist if/when required.

Increased

One risk factor

Annual assessment or 3-6

risk

present e.g. loss of

monthly according to need by a

sensation or signs of

podiatrist or member of a foot

peripheral vascular

protection team. Agreed and

disease without callus

tailored management/treatment

or deformity

plan by podiatrist or the foot

protection team according

to patient needs. Provide

written and verbal education

with emergency contact

numbers. Referral for specialist

intervention if/when required

High risk

Previous ulceration

Review 1-3 monthly by a

or amputation or

specialist podiatrist or member

more than one risk

of a foot protection team. Agreed

factor present e.g.

and tailored management/

loss of sensation or

treatment plan according

signs of peripheral

to patient needs. Provide

vascular disease with

written and verbal education

callus or deformity.

with emergency contact

numbers. Referral for specialist

intervention if/when required

Active

Presence of active

Rapid referral to and

ulceration, spreading

management by a member of a

infection, critical

Multidisciplinary Foot Team

ischaemia, gangrene

or unexplained hot,

red, swollen foot

with or without the

presence of pain,

painful peripheral

neuropathy, acute

Charcot foot

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which finally precipitates ulceration is usually traumatic in

origin, and this is most commonly induced by inappropriate

footwear. Regrettably, footwear checks are not part of the

current QOF funded screening programme.

There are, in addition, other risk factors for the develop-

ment of foot ulceration that are also not included in the cur-

rent screening programme. Patients with significant visual

impairment are at particularly high risk of trauma to their

feet. In addition, patients with end stage renal disease

(ESRD) are at risk of an exponential rise in the incidence of

foot ulcers within the first year of starting renal replacement

therapy.

Ethnic differences also exist for both ulcer and amputation

incidence, both being significantly less common in people of

South Asian origin, although the reasons for this are unclear.

Peripheral Neuropathy

Whilst peripheral sensory neuropathy is the modality tested

for when screening for the “at risk” foot, motor and auto-

nomic neuropathy also frequently co-exist in the neuropathic

foot. Sensory neuropathy allows the patient to traumatise the

foot without being aware, whilst motor neuropathy leads to

muscle atrophy, foot deformity, and altered pressure distribu-

tion across the foot predisposing the foot to ulceration.

Autonomic neuropathy can lead to altered regulation of

cutaneous blood flow, loss of sweating and hence dry fragile

skin, prone to cracking, fissures and infection.

Painful peripheral neuropathy occurs in about a third of

patients with peripheral neuropathy and may exist in the

absence of any signs of motor or sensory neuropathy. Patients

complain of burning, tingling, aching or stabbing pains, or feet

feeling abnormally hot or cold. Patient often have difficulty

understanding that painful neuropathy may co-exist with

sensory neuropathy, putting them at risk of trauma even

though they perceive that they can feel their feet because

they are experiencing pain. Patients’ misperceptions about

Chapter 5. Managing Diabetic Foot Disease

Figure 5.1 Testing for neuropathy using a Semmes Weinstein

Monofilament giving standard 10 g of fine touch

neuropathy have been shown to have a negative impact on

the kind of self-care behaviour that may prevent foot ulcer-

ation and careful explanation about the nature of the pain is

required.

Neuropathic Assessment

Visual inspection of the foot of a patient with diabetes should

always precede any testing for neuropathy or arteriopathy.

Signs of muscle wasting, deformity, hair loss (caused by neu-

ropathy as well as arteriopathy), fissuring or callous, and dry

skin indicative of diminished sweating should all be noted.

The choice of subsequent tests done to assess neuropathy

depends on the context. In general the tests done at the

patients annual review are those that are designed to assess

whether or not the patients foot is “at risk” of ulceration.

Sensation in this context is usually assessed with a 10 g nylon

Semmes-Weinstein monofilament (Fig. 5.1). Inability to feel

the 10 g of force applied by the monofilament identified those

at risk of ulceration in 91 % in one study (specificity 34 %).

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Other tests which can be used in a research/audit setting

include vibration perception (using a biothesiometer), joint

position, pain and temperature sensation. Whether these tests

add anything to the monofilament test for the prediction of risk

in a clinical setting is debatable, and the simplicity of the mono-

filament test makes it the most attractive for widespread use.

Treatment of Painful Peripheral Neuropathy

(PPN) (Table 5.2)

PPN is under recognised and undertreated in patients with

diabetes. In one UK survey 12.5 % had never reported symp-

toms to their doctor and nearly 40 % had never received

treatment for their pain. A care pathway for treatment of

painful neuropathy has been published by the National

Institute for Health and Clinical Excellence (NICE) (Fig. 5.2).

Tricyclic antidepressants (TCAs) have the longest history

of use for the treatment of PPN although they are not

licensed for this indication. They are cheaper than their

newer comparators, and there is good trial evidence to

Table 5.2 Treatment of

TCAs

painful peripheral

Amitriptyline 25-150 mg/day

neuropathy

Imipramine 25-150 mg/day

SNRIs

Duloxetine 60-120 mg/day

Anticonvulsants

Gabapentin 300-3,600 mg/day

Pregabalin 900-600 mg/day

Opiates

Tramadol 200-400 mg/day

Oxycodone 20-80 mg/day

Chapter 5. Managing Diabetic Foot Disease

Care pathway

After the diagnosis of neuropathic pain and appropriate

management of the underlying condition(s)

People with painful diabetic neuropathy

People with other neuropathic pain conditions

First-line treatment

Offer oral duloxetine.

Offer oral amitriptyline* or pregabalin (see box A for dosages).

Offer oral amitriptyline* if duloxetine is

If satisfactory pain reduction is obtained with amitriptyline*

contraindicated.

but the person cannot tolerate the adverse effects, consider

See box A for dosages.

oral imipramine* or nortriptyline* as an alternative.

Consider referring the person to a

specialist pain service and/or a

condition-specific service¹at any

stage, including at initial presentation

Satisfactory

and at the regular clinical reviews, if:

Perform:

pain reduction

Continue treatment − consider

they have severe pain or

early clinical review (see box B)

gradually reducing dose over

pain significantly limits their daily

regular clinical reviews (see box C).

time if improvement is sustained

activities and participation² or

their underlying health condition

Unsatisfactory pain

has deteriorated.

reduction at maximum

tolerated dose

Second-line treatment

Offer treatment with another drug instead

Offer treatment with another drug instead of or in

of or in combination with the original

combination with the original drug, after informed discussion

drug, after informed discussion with the

with the person (see box A for dosages):

person (see box A for dosages):

if first-line treatment was with amitriptyline* or

if first-line treatment was with

imipramine* or nortriptyline*), switch to or combine with

duloxetine, switch to amitriptyline* or

pregabalin

pregabalin, or combine with pregabalin

if first-line treatment was with pregabalin, switch to or

if first-line treatment was with

combine with amitriptyline* (or imipramine* or

amitriptyline*, switch to or combine

nortriptyline* as an alternative if amitriptyline* is effective

with pregabalin.

but the person cannot tolerate the adverse effects).

Satisfactory

Perform:

pain reduction

Continue treatment − consider

early clinical review (see box B)

gradually reducing dose over

regular clinical reviews (see box C).

time if improvement is sustained

Unsatisfactory pain

reduction at maximum

tolerated dose

Third-line treatment

Refer the person to a specialist pain service and/or a condition-specific service1.

While waiting for referral:

consider oral tramadol instead of or in combination³ with second-line treatment (see box A for dosages)

consider topical lidocaine⁴ for treatment of localised pain for people who are unable to take oral medication because of medical conditions

and/or disability.

Other treatments

Do not start treatment with opioids (such as morphine or oxycodone) other than tramadol without an assessment by a specialist pain service or a

condition-specific service¹

Other pharmacological treatments that are started by a specialist pain service or a condition-specific service¹ may continue to be prescribed in

non-specialist settings, with a multidisciplinary care plan, local shared care agreements and careful management of adverse effects.

Box A Drug dosages

Box B Early clinicial review

Start at a low dose, as indicated in the table.

After starting or changing a treatment, perform an early

Tiltrate upwards to an effective dose or the person’s maximum tolerated

clinical review of dosage titration, tolerability and

dose (no higher than the maximum dose listed in the table).

adverse effects to assess suitability of chosen treatment.

Drug

Starting dose

Maximum dose

Amitriptyline^*

10 mg/day

75 mg/day^a

Box C Regular clinical reviews

Pregabalin

150 mg/day^b

600 mg/day^a

(divided into 2 doses)

Perform regular clinical reviews to assess and monitor

Duloxetine

60 mg/day^b

120 mg/day

effectiveness of chosen treatment. Include assessment of:

Tramadol^c

50-100 mg not more often

400 mg/day

pain reduction

than every 4 hours

adverse effects

aHigher doses could be considered in consultation with a specialist pain service.

work and drive)

daily activities and participation² (such as ability to

^bA lower starting dose may be appropriate for some people.

mood (in particular, possible depression and/or anxiety⁵)

therapy.

^cAs monotherapy. More conservative titration may be required if used as combination

quality of sleep

overall improvement as reported by the person.

Figure 5.2 NICE Painful Neuropathy care pathway

support their use and as such they appear in NICE guidance

for the first line management of this condition. They have,

however, significant adverse effects, such as drowsiness, dizzi-

ness and dry mouth, and may take some weeks to exert an

effect. Caution must be taken in patients with established

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cardiovascular disease due an increased risk of sudden car-

diac death.

The selective serotonin noradrenaline reuptake inhibitor

(SNRI), duloxetine has shown effective pain relief at 60 mg

and 120 mg/day, with the numbers needed to treat (NNT) for

effective (>50 %) pain relief being 4.9 for 120 mg/day, and 5.2

for 60 mg/day. Adverse effects are less common with dulox-

etine, but can still be troublesome.

The anticonvulsants Gabapentin and Pregabalin demon-

strate effective pain relief in placebo controlled clinical trials.

Pregabalin had a NNT of 4.04 for the 600 mg/day and 5.99 for

the 300 mg/day doses for effective (>50 %) pain relief.

Should pain not be relieved or the above not tolerated,

then opioids such as oxycodone or tramadol have supportive

evidence from clinical trials.

Topical agents such as capsaicin cream and lidocaine

patches have been used with variable success, but care should

be taken with topical agents to ensure that no damage occurs

to insensate skin.

Of note is the fact that effective pain relief in clinical trials

is defined as >50 % reduction in pain scores. Patients’ expec-

tations of the degree of pain relief they may achieve therefore

need to be carefully managed, as few will actually get com-

plete relief of their symptoms. Clinicians also need to be alert

to the psychological consequences of PPN and offer psycho-

logical support according to the needs of the individual.

Management of the Established Ulcer

The same pathological mechanisms, neuropathy and isch-

aemia, which are responsible for the foot (or feet) of a patient

with diabetes being “at risk” are also frequently responsible for

the failure of a wound to heal. Infection per se rarely precipi-

tates ulceration (except for tinea pedis), but frequently compli-

cates it, and may prolong healing. The relative contribution of

each of these pathologies varies from patient to patient and

each needs to be carefully assessed in the individual patient.

Chapter 5. Managing Diabetic Foot Disease

101

Arterial Assessment

Simple palpation of pulses has been shown to correlate with

outcome but can be subjective and influenced by a number of

external factors. Given the frequency of arterial disease in this

population (up to 50 %) a case can be made for ankle brachial

pressure index (ABPI) to be measured as part of any initial

work up of a diabetic foot ulcer. Whilst an ABPI of <0.9 indi-

cates ischaemia, calcification of the arteries in diabetes (asso-

ciated with neuropathy as well as renal impairment), will

cause elevation of the ratio even within the normal range.

Therefore ABPI measurement may have a poor sensitivity in

identifying significant arterial disease in this population,

where the majority of patients also have neuropathy. Other

assessments frequently suggested such as toe systolic pressure

or toe brachial pressure index rely on the patient still having

a toe to do the measurement, and may also be affected by digi-

tal arterial calcification. Doppler arterial wave form is another

non-invasive tool used to assess the vascular status, and can be

performed with a hand held Doppler probe by suitably

trained individuals within the clinic setting. The demonstra-

tion of a triphasic waveform in peripheral pulses can effec-

tively exclude significant arterial disease in >90 % of limbs.

Management of Ischaemia

Should an ulcer not heal in a patient with demonstrated

peripheral arterial disease

(PAD), then revascularisation

should be considered, the aim of which is to restore flow to at

least one of the foot arteries, preferably the artery that sup-

plies the anatomical region of the wound, to allow wound

healing. There are no randomised trials comparing open with

endovascular revascularisation techniques in patients with

diabetic foot ulcers. Available non randomised trial evidence

suggests that the outcomes of either technique may be simi-

lar, but results depend upon the anatomical distribution of

the arterial disease as well as local availability and expertise.

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Management of the Effect of Neuropathy -

“Offloading”

It is not so much the neuropathy that needs managing in a

patient presenting with a neuropathic ulcer, so much as the

effect of the neuropathy on the patients’ response to ulcer-

ation. With an insensate foot patients will continue to mobil-

ise either directly on an ulcerated area (if plantar) or in

inappropriate footwear, continually traumatising the area

and preventing healing. Reducing foot pressures, or

“offloading”, is a fundamental concept to the healing of neu-

ropathic foot ulcers. Many devices are available but their

capacity to offload the diabetic foot is variable. The degree of

pressure reduction particularly for plantar ulcers is however

strongly associated with the healing efficacy. Recent guide-

lines from the International Working Group of the diabetic

foot

(IWGDF) recommend the use of non-removable

offloading, such as a total contact cast (TCC), as the first line

treatment option. If not available, various off the shelf below

knee walkers are available, which if rendered non-removable

lead to much improved healing rates. The evidence base for

the use of half-shoes, forefoot offloading shoes or other foot

devices is not as impressive, but these offloading devices are

still recommended when below knee devices are not avail-

able, contraindicated or not tolerated. The offloading capac-

ity of normal shoes or therapeutic footwear, although

important for the prevention of foot ulcers, is not usually

sufficient for the healing of neuropathic ulcers.

Infection

Not only is infection of a foot ulcer negatively associated with

healing, it also considerably increases the risk of hospitalisa-

tion and amputation. Clinical infection is based on the classic

signs of inflammation (erythema, warmth, tenderness, pain,

or induration) or purulent secretions, although the signs of

inflammation may be blunted in those with PAD. It is

Chapter 5. Managing Diabetic Foot Disease

103

preferable that culture specimens (deep tissue samples/aspi-

rates not surface swabs) be taken prior to empirical antibiotic

therapy which can be tailored later according to culture

results. Clinically non-infected wounds, even if there is sur-

face contamination, should not be treated with antibiotics to

avoid the emergence of multi-drug resistant organisms.

Although some infections are polymicrobial, gram positive

cocci are the predominant infecting organism and empirical

antibiotic regimens should cover these bacteria. There is no

good evidence from randomised trials showing the superiority

of any particular antibiotic regimen above any other, and so

choices should be made locally, in the knowledge of likely

pathogens and known antibiotic resistance patterns. For mild

soft tissue infection 7-10 days treatment should be adequate.

More serious or deeper infections require longer. The antibi-

otic regimen is used to treat the infection and does not need

to be continued until the ulcer has healed.

If, in the presence of an infected wound, bone is visible at

the base or can be felt when the wound is gently probed with

a sterile instrument

(positive “probe to bone test”) then

osteomyelitis (Fig. 5.3) is likely. In a non-infected wound, how-

ever a positive probe test does not mean that bone infection

is necessarily present. The diagnosis of bone infection should

be suspected in any infected wound that, even if “probe to

bone” negative, does not heal despite adequate offloading, a

good peripheral circulation and initial antibiotic therapy.

Diagnosis of osteomyelitis can be difficult and is made more

problematic by the fact that X-rays may be persistently

unchanged (loss of visible cortex on a plain film only occurs

after 30-50 % of bone mineral has been lost (Fig. 5.4)), and

the changes may be difficult to distinguish from those seen in

Charcot neuropathic osteoarthropathy. Recent NICE guid-

ance suggests that if osteomyelitis is suspected and a plain film

is unhelpful, magnetic resonance (MR) scanning should be

performed. MR scans have a sensitivity of around 90 % and

specificity of about 80 % for the diagnosis of bone infection,

although it may be difficult to distinguish bone infection from

an acute Charcot with this imaging modality. The gold

Chapter 5. Managing Diabetic Foot Disease

105

standard for the diagnosis of osteomyelitis is said to be histo-

logical and microbiological examination of bone biopsy sam-

ples. This is not always possible in clinical practice, however,

and it must be borne in mind that even these techniques are

subject to sampling error.

Treatment of Osteomyelitis

The choice of primarily medical (antibiotics alone) as opposed

to primary surgical treatment of osteomyelitis of the diabetic

foot is controversial, but studies have shown that infection can

be successfully eradicated with antibiotics alone in 60-80 %.

The risks of prolonged (6-8 weeks) antibiotic therapy must be

weighed up against the risk of surgery with, in addition, the

risk of the development of new ulcers on the foot if the archi-

tecture of the foot is altered - so called “transfer ulcers”.

Patient preference should therefore also be taken into account.

Dressings, Topical Applications and Other

Techniques to Accelerate Wound Healing

Successive systematic reviews have failed to find any evi-

dence that any topical application or dressing has any advan-

tage over any other in terms of wound healing. A dressing

with the lowest acquisition cost to maintain an adequate

healing environment is therefore advised in UK guidance.

Advanced Adjunctive Wound Care Treatments

Growth Factors

The evidence to support the use of growth factors is poor.

One large trial of platelet derived growth factor did show a

significant improvement in wound healing rate when com-

pared to standard care. A second European study which

showed no such difference was never published. As the agents

are very expensive they are not currently recommended.

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Negative Pressure Wound Therapy (NPWT)

Despite very little trial evidence to support improved out-

comes with NPWT, it is in widespread use in the UK, particu-

larly for post-operative wounds. There is considerable

publication bias with almost 70 % of patient data from clini-

cal trials of this therapy never published. The cost utility of

NPWT has never been formally tested, but estimates by

NICE suggest that it would exceed the cost per QALY cut-off

for use within the NHS. Current guidance therefore recom-

mends the use of the intervention only in the context of a

clinical trial or as a rescue therapy to prevent amputation.

Hyperbaric Oxygen Therapy (HBOT)

Although there is some reasonable quality evidence from

randomised blinded trials supportive of the use of HBOT for

healing of diabetic foot wounds, the exact sub-group of

patients who would benefit from the therapy and the cost

utility has yet to be established. It is therefore not currently

recommended in the UK.

Charcot Neuropathic Osteoarthropathy

Charcot neuropathic osteoarthropathy

(CN), commonly

referred to as the Charcot foot, is a condition affecting the

bones, joints, and soft tissues of the foot and ankle, character-

ised by inflammation in the earliest phase. It is a complication

of peripheral neuropathy, and can therefore be seen in

patients with other causes of peripheral neuropathy. The con-

dition is thought to be related to uncontrolled release of pro-

inflammatory cytokines

(especially IL-1β and TNF-α)

following minor trauma, infection or surgery. Continued

mobilisation on an insensate foot leads to on-going bone

destruction, subluxation, dislocation, and eventual deformity.

Diagnosis is clinical in the first instance and the clinician

should be alert to any patient with neuropathy presenting

with a unilateral inflamed foot. As the foot is insensate

patients may not remember a history of trauma and therefore

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X-rays may be normal in the first instance, or show subtle

fractures and dislocations or later show more overt fractures

and subluxations. If the X-ray is normal an MRI scan should

be performed although the changes can be difficult to distin-

guish from osteomyelitis and, indeed, the two can co-exist.

Treatment of CN

Offloading is the most important management strategy of the

acute Charcot foot and can arrest the progression to deformity.

Ideally, the foot should be immobilised in a non-removable cast

or walker. Oedema reduction is often very rapid in the first few

days and weeks of treatment, and so the cast or walker needs

to be checked regularly, ideally within the first week and then

according to need, as the cast could become loose and trauma-

tise the insensate foot. If possible, the patient should also use

crutches or wheelchair and should be encouraged to avoid

weight bearing on the affected side. Casting is continued until

the temperature difference between the two feet has settled.

Medical Treatments

Treatment by anti-resorptive drugs has been proposed because

bone turnover in patients with active CN is excessive. Both

oral and intravenous bisphosphonates have been trialled and,

although initial pilot trials were encouraging, more recent stud-

ies have suggested that bisphosphonates even may lengthen

the resolution phase of the disease. A recent systematic review

concluded that the data are too weak to support the use of

bisphosphonates as a routine treatment for acute CN.

The “Multi-disciplinary Team”

It is clear from the above that it requires a number of differ-

ent professionals to manage a patient presenting with one of

the number of entities that make up the “diabetic foot”. In

addition it is likely that patients presenting with a foot prob-

lem are also likely to have other complications of diabetes

Chapter 5. Managing Diabetic Foot Disease

109

such as nephropathy, retinopathy, ischaemic heart disease

and cerebrovascular disease, and will therefore benefit from

a multidisciplinary approach to their care. Furthermore, there

is evidence to suggest that the incidence of major amputation

can be reduced after the formation of a multi-disciplinary

foot care team, and indeed a study looking at the estimated

health economic impact of these teams has shown that signifi-

cant cost savings can be made.

Conclusion

The Diabetic Foot is not one single entity but a spectrum of

disorders ranging from those “at risk” from the effects of

PAD and neuropathy, to the ulcerated foot, acute Charcot

neuropathic osteoarthropathy and amputation. The condition

is costly and can have serious negative impacts on quality of

life, and is best managed by rapid referral to a multi-

disciplinary foot care team.

Key References

http://yhpho.york.ac.uk/diabetesprofiles/foot/default.aspx . Accessed 20

June 2013.

http://www.sepho.org.uk/extras/maps/NHSatlas2011/pdf/8.pdf . Accessed

20 June 2013.

Kerr M. Foot care for people with diabetes: the economic case for change.

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Accessed 20 June 2013.

Abbott CA, Carrington AL, Ashe H, et al. The North-West Diabetes

Foot Care Study: incidence of, and risk factors for, new diabetic foot

ulceration in a community-based patient cohort. Diabet Med.

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Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients

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Pham H, et al. Screening techniques to identify people at high risk for

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The National Collaborating Centre for Chronic Conditions. Type 2 dia-

betes. National clinical guideline for management in primary and

secondary care

(update). http://www.nice.org.uk/nicemedia/

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methods used in screening for lowerlimb arterial disease in diabetes.

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diagnosis and treatment of peripheral arterial disease in a patient

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Cavanagh PR, Bus SA. Off-loading the diabetic foot for ulcer preven-

tion and healing. J Vasc Surg. 2010;52:37S-43.

Armstrong DG, Lavery LA, Wu S, Boulton AJ. Evaluation of removable

and irremovable cast walkers in the healing of diabetic foot wounds:

a randomized controlled trial. Diabetes Care. 2005;28:551-4.

Lavery LA, Armstrong DG, Murdoch DP, Peters EJG, Lipsky BA.

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Accessed 12 Jan 12 2013.

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Morales E, Beneit-Montesinos JV, Alvaro-Afonso FJ. Analysis of

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with bisphosphonates: a systematic review of the literature.

Diabetologia. 2012;55:1258-64.

Chapter 6

Managing Diabetes

in Hospital

M.S. Bobby Huda

Abstract Emergency presentations in people with diabetes

are relatively common. These include the traditional diabetic

emergencies such as diabetic ketoacidosis, hyperglycaemic

hyperosmolar syndrome and hypoglycaemia, as well as people

with diabetes presenting with other medical emergencies such

as a cerebrovascular accident (CVA) or an acute coronary syn-

drome (ACS). The evidence behind the clinical management of

these emergencies is often inconclusive and there is considerable

variation in clinical practice. This chapter aims to systematically

review the published evidence behind the clinical management

for the traditional diabetic emergencies and the common medi-

cal emergencies, as well as to critique existing guidelines.

Keywords Diabetic ketoacidosis

• Hyperosmolar hyper-

glycaemic syndrome • Hypoglycaemia • Cerebrovascular

accident • Acute coronary syndrome

The management of patients with diabetes whilst in hospital

is often challenging and requires a coordinated, multi-

disciplinary approach. The acute management of diabetic

M.S.B. Huda, MBChB, MRCP, PhD

Department of Diabetes, Royal London Hospital,

Barts Health Trust, London, UK

e-mail: bobby.huda@bartshealth.nhs.uk

T.A. Chowdhury (ed.),

111

Diabetes Management in Clinical Practice,

112

M.S.B. Huda

emergencies needs a careful, clear and evidence-based

approach. Similarly, diabetic patients often present with other

medical emergencies such as myocardial infarction and cere-

brovascular accident, and the diabetes specialist team is fre-

quently involved in management of such patients.

This chapter will focus on both the traditional diabetic

emergencies and the management of diabetes during other

medical emergencies. We will examine the evidence behind

current recommendations and give the reader some general

principles, based on recent evidence or consensus opinion

that can be translated into every day clinical practice.

Acute Diabetic Emergencies

Hypoglycaemia

Hypoglycaemia is a major potential complication of most

diabetes therapies, particularly insulin and sulfonylurea

based treatment. The precise definition of hypoglycaemia

can vary according to the specific clinical scenario, but for

the diabetic patient in hospital, it is pragmatic to use

4.0 mmol/l (72 mg/dl) as a lower limit. It can be further

defined as mild, if self-treated, or severe if third party

assistance is required.

Hypoglycaemia is common in diabetes, and people with

well-controlled type 1 diabetes (T1D) can experience an

average of two mild episodes a week. Hypoglycaemia is also

common in hospital due to a variety of factors including

reduced carbohydrate intake, concurrent illness and timing of

meals. The National Diabetes Inpatient Audit is the largest

clinical in-patient audit of diabetes in the world, and annually

audits the care of over 12,000 inpatients in England and

Wales. Figures from 2012 showed that 20.4 % of inpatients

with diabetes experienced mild hypoglycaemia (defined as

blood glucose 3-4 mmol/l (54-72 mg/dl)) and 10.5 % experi-

enced severe hypoglycaemia

(defined as blood glucose

<3.0 mmol/l (<72 mg/dl)).

Chapter 6. Managing Diabetes in Hospital

113

Table 6.1 The Edinburgh Hypoglycaemia Scale

Autonomic

Neuroglycopaenic

General malaise

Sweating

Confusion

Headache

Palpitations

Drowsiness

Nausea

Shaking

Odd behaviour

Hunger

Speech difficulty

Inco-ordination

Clinical symptoms can vary between individuals, but clas-

sically are divided in to autonomic, neuroglycopaenic and

malaise symptoms, and has been used to form the Edinburgh

Hypoglycaemia Scale

(see Table 6.1). Risk factors for

hypoglycaemia may be sub-divided into medical or lifestyle

issues (see Table 6.2). Some non-diabetic medications may

increase the frequency of hypoglycaemia including warfarin,

quinine, salicylates, fibrates, monoamine oxidase inhibitors,

non-steroidal anti-inflammatory drugs (NSAIDs), selective

serotonin uptake inhibitors

(SSRIs). Medical causes for

hypoglycaemia (alcohol, Coeliac disease, hypoadrenalism)

should also be considered, particularly as the latter two may

be more frequent in people with T1D.

The management of hypoglycaemia should involve the

administration of a quick acting carbohydrate such as a sugary

drink, followed by a medium/long acting carbohydrate snack

to maintain normoglycaemia. There should be at least

10-15 min before re-testing, and the cycle can be repeated until

the capillary glucose is above 4.0 mmol/l. A suggested algo-

rithm is shown in Fig. 6.1. If the patient is agitated, but con-

scious, use of glucogel may help avoid paramedical assistance

of hospital admission. This should be inserted into the buccal

mucosa but not directly into the mouth, due to the risk of aspi-

ration. Patients with poor hypoglycaemia awareness may ben-

efit from keeping glucogel nearby to allow their family to

administer when the patient shows signs of hypoglycaemia.

If the patient is unable to swallow, or is unconscious,

then intravenous glucose or intra-muscular glucagon must

Chapter 6. Managing Diabetes in Hospital

115

Capillary blood glucose level less than 4.0 mmol/1

Give one of the following:

- 100-120 ml Lucozade

- 150-200 ml fruit juice

- 3-4 teaspoons of sugar

Repeat cycle.

dissolved in a glass of water

If capillary

- Glucogel^® may be used

blood glucose

not greater

than 4.0

Recheck capillary blood glucose in 10-15

mmol/1 after 3

cycles, then

call doctor

Is capillary blood glucose is greater than

4.0 mmol/1?

Give long acting carbohydrate:

2 biscuits

half a sandwich

1 piece of fruit

200-300 ml milk

OR next meal if due

Do NOT omit next insulin dose but ask medical

staff to review doses, particularly at night

Figure 6.1 Suggested algorithm for the treatment of hypoglycaemia

in those able to swallow

be used. The use of 50 % dextrose is associated with a risk

of significant thrombophlebitis, and extravasation can lead

to tissue necrosis, so should be avoided if possible. A ran-

domised trial comparing the administration of 10 % dextrose

delivered in 50 ml aliquots versus 50 % dextrose delivered

5-10 ml aliquots, showed similar efficacy in reaching

normoglycaemia, but the use of 10 % dextrose resulted in

significantly lower post hypoglycaemia blood glucose values,

116

M.S.B. Huda

Capillary blood glucose level less than 4.0 mmol/1

If patient is unconscious, having a seizure, confused or

aggressive - call for emergency medical review -

otherwise initiate treatment and call for medical review

Give either:

Repeat cycle. If

75 ml of 20 % glucose IV

capillary blood

over 5 min

glucose not greater

150 ml 10 % glucose IV

than 4.0 mmol/1

over 5 min

after 2 cycles, then

If IV access not available consider

ask for senior

1mg Glucagon IM.

medical review

Recheck capillary blood glucose in 10-15 min

Is capillary blood glucose greater than 4.0 mmol/1?

Yes

If now able swallow safety,

give long acting carbohydrate as in Algorithm 1.

If nil by mouth then consider 10 % glucose at 100 ml/h

and ask for medical review.

Do NOT omit next insulin dose but ask medical staff to

review doses, particularly at night time insulin.

Figure 6.2 Suggested algorithm for the treatment of hypoglycaemia

in those unable to swallow

avoiding post treatment hyperglycaemia. The latest Joint

British Diabetes Societies Guidelines on management of

hypoglycaemia suggest the use of aliquots of 20 % glucose,

although availability of this solution is patchy. An algorithm

for the unconscious patient is shown in Fig. 6.2.

Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is a serious complication of

diabetes and still carries significant morbidity and mortality.

Chapter 6. Managing Diabetes in Hospital

117

Table 6.3 Fluid and

Water (ml/kg)

100

electrolyte deficits in

Sodium (mmol/kg)

7-10

diabetic ketoacidosis

Chloride (mmol/kg)

3-5

Potassium (mmol/kg)

Epidemiological studies from Italy, the United Kingdom and

the United States following temporal trends over the last

10-15 years have shown that the number of preventable dia-

betes related admissions is decreasing, but the overall in-

hospital mortality of hyperglycaemic emergencies remain

between 4 and 7 %. These oft quoted figures, however include

children, elderly patients and hyperglycaemic hyperosmolar

syndromes (HHS), and in adults with DKA alone, the mortal-

ity is much less (around 1 %) in the UK and USA. Cerebral

oedema is a major cause of mortality in children and young

adults, and hypokalaemia, adult respiratory syndrome, sepsis,

myocardial infarction are all associated with mortality in

adults. The incidence of DKA is difficult to ascertain but US

data suggest overall 4-8 episodes/1,000 diabetic patients and

13.4 per 1,000 in adults under 30 years.

DKA is characterised by hyperglycaemia, acidosis and

ketonaemia caused by absolute or relative insulin deficiency,

and accompanied by an increase in counter-regulatory hor-

mones such as glucagon and cortisol. Insulin deficiency

increases hepatic gluconeogenesis and decreases peripheral

glucose uptake, resulting in hyperglycaemia. In addition,

peripheral lipolysis, no longer inhibited by insulin, releases

non-esterified fatty acids (NEFA) into the circulation, which

in turn enter the hepatic cellular mitochondrial cycle and

ketone bodies are generated, primarily acetone and

β-hydroxybutyrate. As a consequence of hyperglycaemia,

osmotic diuresis results in excess water and electrolyte loss.

Initially the increase in hydrogen ions caused by ketonaemia

is buffered by bicarbonate, but as these stores are depleted the

pH starts to fall. A combination of acidosis and ketonaemia

lead to anorexia, nausea and vomiting - thus worsening dehy-

dration and electrolytes loss. The typical deficits in DKA are

shown in Table 6.3. A 70 kg male may be up to 7 l in deficit.

118

M.S.B. Huda

Insulin

Management of DKA is, therefore, directed towards correct-

ing insulin deficiency and replacing fluids and electrolytes.

There has been something of a paradigm shift in the manage-

ment of DKA, which traditionally focused on reducing

hyperglycaemia. As can be seen from the pathophysiology of

DKA, hyperglycaemia is one of the consequences of insulin

deficiency but it is rather the acidosis and ketonaemia that

constitute a significant portion of the DKA syndrome. With

the advent of near patient blood ketone testing, the manage-

ment can be tailored towards lowering blood ketones, rather

than focusing on hyperglycaemia. This has the added advan-

tage of simplifying treatment for those who present with

euglycaemia or minimal hyperglycaemia

(≤13.9 mmol/l

(250 mg/dl)) DKA, which is estimated to make up 10 % of

DKA admissions. Caution must be exercised in the interpre-

tation of changes in venous bicarbonate; large volumes of

isotonic NaCl solution given in DKA can eventually result in

a mild hyperchloraemic metabolic acidosis and additionally

urinary loss of bicarbonate as sodium salt, may both result in

a slower recovery of venous bicarbonate. There are data vali-

dating blood ketone measurements versus urine ketones in

the initial diagnosis of DKA and blood ketones may confer

some advantage with ease of diagnosis. One study ran-

domised a small number of patients to fixed insulin infusion

to clear ketones, using blood ketones for monitoring, versus

standard care. They showed that resolution of ketoacidosis

was significantly shorter in the fixed insulin arm, but there

were no other differences in outcome. The principles of man-

agement of DKA, however, remain the same and over-

reliance on blood ketones is also not helpful, not least

because ketonaemia can often rebound after treatment.

Insulin is started as a fixed infusion in most centres, and a

bolus of insulin is generally not needed unless there is a delay

in starting the insulin infusion. Much of the older data around

the dose of insulin was based on the use of a priming dose of

insulin and/or intra-muscular injections. A recent randomised

trial compared a bolus with 0.07 units/kg followed by 0.07 units/

Chapter 6. Managing Diabetes in Hospital

119

kg given as an intravenous infusion, with a group with no

bolus dose, and another group with 0.14 units/kg infusion.

They found that all groups were similar in time to reach blood

glucose ≤13.9 mmol/l (250 mg/dl), ph <7.3 but the 0.07 units/

kg group (without a bolus) needed extra doses of insulin. The

mean time to normalisation of blood glucose was around 4 h

and round 8 h for normalisation of pH. For a 70 kg man, there-

fore starting at 0.14 units/kg is around 10 units insulin/h. These

data were also primarily in African-American subjects in

whom insulin resistance was noted, and their applicability to

Caucasian populations should not be assumed. Aiming for a

decrease in capillary blood glucose of no more than 4-6 mmol/h

has been recommended but this is not based on evidence.

Indeed, 0.14 units/kg may well lower blood glucose rapidly in

Caucasian patients and a commonly used dose of 5-7 units/h

(0.07-0.1 units/h in a 70 kg man) may be considered.

Fluid replacement

Fluid replacement is of course the other main component of

DKA management. In one study comparing hypotonic,

hypertonic and isotonic fluids in DKA, patients given hyper-

tonic fluids developed hypernatraemia, hyperchloraemia and

hyperosmolarity and those given hypotonic fluids developed

excessive diuresis; therefore isotonic fluid replacement is

recommended. Although there are few data looking at col-

loid versus crystalloid solution in DKA, a recent meta-

analysis comparing colloid and crystalloid use in the critically

ill found no evidence of mortality benefit with colloid, and in

view of this low cost-effectiveness, crystalloid solutions are

generally favoured as the mainstay of treatment. A prospec-

tive randomised study compared fluid administration rates of

1,000 ml/h versus 500 ml/h and found no difference in mortal-

ity or rates of changes in pH. Pragmatically, with a fluid defi-

cit of 5-7 l common practice has been to replace the fluids

over the first 24 h of admission. This may be the first litre in

1 h, the 2nd litre over 2 h and the 3rd litre over 4 h. The

remaining litres are given 8 hourly, and may include glucose.

120

M.S.B. Huda

There has been much debate over isotonic NaCl solution

versus Hartmann’s solution (glucose and compound sodium

lactate) with the latter having the advantage of not promot-

ing hyperchloraemic metabolic acidosis. The addition of

potassium, however, is not possible in the standard Hartmann’s

solution, and although additional infusions of potassium may

be given in a critical care setting, this is not practical or neces-

sary in a general medical ward setting and isotonic NaCl solu-

tion is therefore preferable. More recent data comparing

saline and Ringer’s lactate found no difference in time nor-

malising pH, but did find that the arm using Ringer’s lactate

took longer to reach euglycaemia, presumably as Ringer’s

lactate

(as well as Hartmann’s solution) also contains

glucose.

When plasma glucose is less than 11.1 mmol/l (200 mg/dl)

then dextrose solution should be added. In a prospective ran-

domised study of 5 % versus 10 % dextrose in DKA, 10 %

dextrose was associated with less ketonaemia but higher

glucose and overall improvements in pH or bicarbonate did

not differ between the groups. Therefore either 5 or 10 %

dextrose solution can be used in this situation.

Potassium

Patients presenting with DKA tend to have low total body

potassium due to osmotic diuresis, anorexia and vomiting but

will often present with normo- or hyperkalaemia due to insu-

lin deficiency, with potassium primarily in the extra-cellular

compartment. Previous studies corroborate this, with 82 % of

patients with DKA presenting with normo- or hyperkalae-

mia, but 63 % going on to develop hypokalaemia during the

course of treatment. Therefore, the anticipation of hypoka-

laemia is crucial in fluid and electrolyte management. The

requirement of potassium averaged at 145 mmol in the above

study; if potassium is added from the second bag of fluid

(when initial potassium results are known), then addition of

20 mmol potassium chloride (KCl) to the first 2 h bag, and

then 40 mmol KCl to the next three bags of fluid, should

Chapter 6. Managing Diabetes in Hospital

121

suffice until the patient is eating and drinking. Data suggest

that infusion of 20 mmol KCl will increase serum potassium

by 0.25 mEq/l. There is also some concern of infusing KCl at

greater than a rate of 10 mmol/h outside of a critical care set-

ting, as there are data showing that 20 mmol KCl an hour will

induce hyperkalaemia in a small number of patients.

Uncommonly, a patient with DKA may present with hypoka-

laemia and it may be prudent to hold insulin therapy until

potassium is >3.5 mEq/l.

Bicarbonate and Phosphate

The use of intravenous bicarbonate in DKA is a controversial

area. Prospective randomised studies have not shown any

benefit of bicarbonate therapy in patients presenting with pH

6.9-7.1 and there is an association with decreased tissue oxy-

gen uptake and cerebral oedema. The brain also seems pro-

tected from acidosis, as CSF pH was found to be higher than

simultaneous serum pH. No prospective studies have looked

at outcomes in DKA with pH <6.9 and in these patients, if

clinically not responding to treatment, the outcome is uncer-

tain and bicarbonate therapy can be considered. Based on

expert consensus only, two 100 ml ampoules of 2.4 % bicar-

bonate can be given in 400 ml sterile water with 20 mEq KCl,

two hourly until pH >7.0.

Phosphate is usually low in DKA, but a prospective ran-

domised study have not shown any clinical benefit in replacing

phosphate, but did show hypocalcaemia in some patients. If

there is evidence of cardiac/skeletal muscle weakness or rhab-

domyolysis, then phosphate replacement may be indicated.

Continuing long acting insulin

Many centres now advocate the continuation of long acting

insulin in DKA during the acute episode, allowing a smoother

transition from intravenous therapy to subcutaneous insulin

and preventing rebound ketonaemia.

122

M.S.B. Huda

Complications of DKA

Complications of DKA include cerebral oedema which has a

very high mortality, causing 70-80 % of diabetes-related

deaths in children under 12 years in the UK. Whilst overt

cerebral oedema is uncommon in adults, asymptomatic cere-

bral oedema is common and prospective MRI studies have

shown that subclinical oedema may be present before treat-

ment has started. Hence, it is not clear to what extent iatro-

genic factors may contribute. Nevertheless, recent data

suggest that cerebral hypoperfusion followed by re-perfusion

may be the underlying mechanism, which may implicate fluid

administration as an aetiological factor. Pulmonary oedema

has been reported rarely and may be secondary to rapid infu-

sion of crystalloid fluid in elderly patients.

Hyperglycaemic Hyperosmolar Syndrome

Hyperglycaemic hyperosmolar syndrome (HHS), formerly

known as Hyperosmolar non-ketotic coma (HONK) has

many similar management principles to DKA but there are

important differences. The older name has been abandoned

primarily as patients may also have mild ketonaemia.

The patient with HHS usually becomes hyperglycaemic

over a longer period, are often elderly with other co-

morbidities, and the metabolic derangements and fluid defi-

cits are more extreme. HHS occurs usually in the context of

previously diagnosed type 2 diabetes (T2D), but this is not

exclusively the case; patients tend to have a relative rather

than absolute insulin deficiency and hence do not become

ketoacidotic, but many have varying degrees of ketonaemia.

HHS is uncommon, representing around 1 % of all diabe-

tes admissions, but mortality is alarmingly high, ranging

between 15 and 20 % from recent data. The mortality is due

in part to the fact that patients are older, with more co-

morbidities but there are likely to be other factors involved.

There is no precise definition of HHS and perhaps this is

appropriate, as there is clearly a spectrum and clinical judge-

Chapter 6. Managing Diabetes in Hospital

123

ment should be utilised. The recent UK based guidelines

from the Joint British Diabetes Societies, have recommended

a definition based on a survey of UK hospital guidelines:

• Osmolality

(measured as

2 × (Na) + glucose

+ urea)

>320 mOsm

• Hyperglycaemia (usually 30 mmol/l (540 mg/dl) or more)

• Severe dehydration

There is commonly mild ketonaemia (capillary blood

ketones <3 mmol/l), possibly due to starvation. Acidosis may

also be present, and is often secondary to pre-renal failure or

co-existing sepsis. It should be recognised, however, that a

mixed DKA/HHS picture may be present, which may result

from beta cell exhaustion after prolonged hyperglycaemia

and glucotoxicity. Osmotic diuresis is more prolonged in

HHS and hence the fluid and electrolyte losses can be more

extreme. Typical fluid losses are shown in Table 6.3, but a

60 kg patient can have 6-13 l deficit. There are clear data link-

ing cerebral obtundation and osmolality, and indeed if calcu-

lated osmolality is less than 320 mOsm with obtunding, then

other causes should be considered. Interestingly patients may

be more dehydrated than they appear, as hypertonicity pre-

serves intravascular volume; due to high osmolality fluid

moves from intra-cellular compartments to the extra-cellular

compartment.

Note that though laboratory measured osmolality is the

ideal measure, calculated osmolarity using the surrogate for-

mula (2 × Na + Urea + Glucose) is acceptable. Osmolality

and osmolarity are very similar when dealing with small

amounts of solute, and can be used interchangeably in this

circumstance. Urea is an ineffective osmolar solute as it is

freely permeable, but has been used in the formula as it gives

an important guide to the dehydrated state. Nevertheless,

there are different formulas, none are based on evidence and

hence clinical discretion must be used when calculating

osmolarity. For the remainder of this chapter, the term osmo-

larity will be used.

As the hyperosmolar state has developed over time, the

brain cells protect themselves from intracellular water deple-

124

M.S.B. Huda

tion by accumulating electrolytes and organic acids (the so-

called idiogenicosmoles). However, these accumulated

osmoles cannot be rapidly excreted and hence a rapid change

in serum osmolarity may result in fluid shifts into brain tissue

and lead to cerebral oedema.

Therefore, the main principle of management in HHS is to

correct the hyperosmolar state gradually over a period of

24-48 h and allow brain tissue time to adapt to the changes in

osmolarity. On that basis, both fluid and insulin administra-

tion must be carried out with care. Although the ideal rate of

fluid administration has not been completely established, it

would again appear pragmatic to first restore the patient’s

intravascular volume reasonably promptly, and then address

the remaining fluid deficit over the next 24-48 h. Patients

often have a pseudo-hyponatraemia or falsely normal sodium

level on presentation, due to the dilution effect of the osmo-

lar shift of fluid from the intra-cellular compartment to the

extra-cellular compartment. Once fluid administration begins,

the fluid shifts into the intra-cellular compartment and the

re-initiation of osmotic diuresis result in the true serum

sodium levels becoming apparent - and due to marked dehy-

dration and excessive water loss compared to salt loss, hyper-

natraemia is usually present. Hypernatraemia, as in with all

electrolyte disturbances that have occurred over time should

be corrected gradually and limiting decreases in serum

sodium to no more than 0.5 mEq/l/h (i.e. 12 mEq/l over 24 h)

has been suggested to minimise the risks of cerebral oedema.

Abrupt changes in glucose which will affect overall osmo-

larity should also be avoided. Fluid replacement itself will

lower blood glucose by 10-15 mmol/l due to re-initiating

osmotic diuresis. Therefore, insulin treatment can be delayed

until glucose is not decreasing by 3-5 mmol/h. The exception

to this is if significant ketonaemia is present (capillary blood

ketones ≥1 mmol/l or urine dipstick ≥2+), in which case a low

dose insulin infusion may be initiated. Osmolarity should be

calculated regularly to ensure that there are no rapid changes

in sodium or glucose, the two main components.

Chapter 6. Managing Diabetes in Hospital

125

Cerebral oedema, seizures and central pontine myelinosis

are uncommon but are well described in HHS, and adding

weight to the above suggestions, there is evidence that rapid

shifts in osmolality may be a precipitant.

Managing Diabetes in Other Emergencies

Diabetes and Cerebrovascular Accident

Hyperglycaemia is common post cerebrovascular accident

(CVA) with raised admission blood glucose levels in 20-50 % of

patients. Hyperglycaemia itself is an independent predictor of

adverse outcome in CVA including increases in 30-day mortal-

ity, duration of hospital stay and degree of permanent disability.

Mechanisms may include activation of the hypothalamic-

pituitary axis with surges in cortisol and catecholamines, and

damage to cerebral glucose/autonomic function regulatory cen-

tres. Unsurprisingly, patients with known pre-existing diabetes

have prolonged hyperglycaemia post CVA, often exacerbated

by high calorie enteral feeding regimens.

The benefit of tight glucose control in the post CVA set-

ting is, however, not clear. The largest prospective trial,

Glucose Insulin in Stroke Trial (GIST-UK) randomised 933

patients to intensive glucose-potassium infusion to maintain

blood glucose between 4 and 7 mmol/l (72-126 mg/dl) ver-

sus standard care post CVA. It did not show any difference

in 30-day mortality, but was hampered by under-recruitment

and the active treatment group only achieved a small

decrease in blood glucose (0.57 mmol/l) compared to the

controls, making the conclusions difficult to fully interpret.

A further two trials also showed no significant improvement

in 30-day mortality with glucose reduction, but sample sizes

in the studies were small. A larger observational study in

aneurysmal subarachnoid haemorrhage patients did find

significant improvements in clinical outcomes with tight

glucose control.

126

M.S.B. Huda

Whilst the evidence for tight glycaemic control post CVA

is currently lacking, it remains prudent to avoid overt hyper-

glycaemia as in any critically ill patient. Enteral feeding,

which is now initiated early post CVA, can be particularly

challenging and observational data show that 34.5 % of all

patients experience glucose levels >11.0 mmol/l post CVA.

The Joint British Diabetes Societies recommend the use of

isophane or pre-mixed analogue/isophane insulin to cover

enteral feeding post CVA, aiming for target glucose

6-12 mmol/l (108-216 mg/dl), but this is not currently based

on published evidence.

Diabetes and Acute Coronary Syndromes

The Diabetic Patients with Acute Myocardial Infarction

(DIGAMI) study published in 1995 found that patients ran-

domised to intravenous insulin-glucose infusion followed by

3 months of subcutaneous insulin had a 29 % reduction in

mortality at 1 year compared with standard care. A subse-

quent study, DIGAMI-2 by the same investigators, which was

designed to tease out whether the intravenous insulin-glucose

infusion or the 3 months of subcutaneous regimen was the

main component for reducing mortality, could not replicate

the results. Much of this was due to the fact that the three

arms of the study were too similar

(standard care also

included insulin in many patients at this time) and hence the

results were difficult to interpret. The HI-5 study was an

Australian study which randomised 240 subjects post myo-

cardial infarction (MI) to intravenous insulin-glucose infu-

sion for

24 h only versus standard care, and found no

difference in mortality but slightly less re-infarction and

congestive cardiac failure (CCF) at 3 months.

Other studies in acute coronary syndromes have concen-

trated on the principle that there are physiological reasons

why insulin, glucose and potassium may be beneficial in the

context of myocardial infarction. An early South American

study, ECLA-GIK (Estudios Cardiologicos Latino America)

Chapter 6. Managing Diabetes in Hospital

127

found a reduction in mortality following a glucose-potassium-

insulin infusion

(GKI) in MI, but only in patients who

received concomitant reperfusion therapy. A subsequent

large multi-centre study involving over

20,000 patients,

CREATE-ECLA also randomised both diabetic and non-

diabetic patients to GKI infusion and found a neutral effect

on mortality at 3 months. A sub-analysis of CREAT-ECLA,

and a similar study OASIS-6 GIK, showed that mortality and

CCF were higher in certain patients in the first 3 days, and

after adjusting for confounders, the volume of fluid given in

the infusion was a significant predictor.

Whilst much of the evidence is contradictory and difficult

to interpret, we can extrapolate that a non-glucose target

driven GKI regimen in all MI patients does not produce bet-

ter outcomes, and indeed may be associated with harm if

large volumes are used in older patients or those with a his-

tory of CCF. The original DIGAMI data has not been repli-

cated and the case for the blanket use of insulin for the first

3 months post-MI is not justified, and is now not often used

in clinical practice.

A pragmatic approach must be taken. It seems appropri-

ate to avoid excessive hyperglycaemia in patients with known

diabetes and in those without known diabetes, and this can be

achieved with insulin or other hypoglycaemic agents. Care

should be taken to avoid excess volumes of fluid in elderly

patients or patients with CCF.

Conclusions

The acute management of the diabetic patient with acute

diabetic emergencies or in the context of other medical emer-

gencies, remains a significant challenge. The evidence behind

optimal management is often contradictory and there is

much need for a common sense, pragmatism and individual-

ised care. It is clear that rather than strict protocol based

treatment, frequent clinical assessment, and careful clinical

judgement can improve clinical outcomes.

128

M.S.B. Huda

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Gray CS, Hildreth AJ, Sandercock PA, O'Connell JE, Johnston DE,

Cartlidge NE, Bamford JM, James OF, Alberti KG. Glucose-

potassium-insulin infusions in the management of post-stroke hyper-

glycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK).

Lancet Neurol. 2007;6:397-406.

Joint British Diabetes Societies Inpatient Care Group. Glycaemic man-

agement during the inpatient enteral feeding of stroke patients with

diabetes. www.diabetes.nhs.uk/document.php?o=3766 . Accessed 14

Aug 2013.

Joint British Diabetes Societies Inpatient Care Group. The hospital

management of hypoglycaemia in adults with diabetes mellitus. 2010.

http://www.diabetes.nhs.uk/document.php?o=217 . Accessed 14 Aug

2013.

Joint British Diabetes Societies Inpatient Care Group. The management of

diabetic ketoacidosis in adults. 2010. http://www.bsped.org.uk/clinical/

docs/DKAManagementOfDKAinAdultsMarch20101.pdf . Accessed 14

Aug 2013.

Joint British Diabetes Societies Inpatient Care Group. The management

of the hyperglycaemic hyperosmolar state (HHS) in adults with dia-

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2013.

Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A,

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Morris LR, Murphy MB, Kitabchi AE. Bicarbonate therapy in severe

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mic emergencies in diabetes mellitus. Diabetes Res Clin Pract.

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669-75.

Index

Anakinra, 8

Acarbose, 61-62

Angiotensin receptor blockers

ACR. See Albumin/creatinine

(ARB), 31

ratio (ACR)

Anti-platelet agents, 37-38

ACS. See Acute coronary

Antithrombotic therapy, 88-89

syndromes (ACS)

ARB. See Angiotensin receptor

Action in Diabetes and Vascular

blockers (ARB)

Disease: Preterax and

Artificial pancreas, 68

Diamicron MR Controlled

Aspirin, 28, 37, 88-89

Evaluation (ADVANCE)

Atorvastatin, 37

study, 22, 47

Action to Control Cardiovascular

Risk in Diabetes

(ACCORD), 47, 48

Beta blockers, 32

Acute coronary syndromes (ACS)

11β Hydroxysteroid type 1

DIGAMI-2, 126

inhibitors (11β-HSD1), 71

ECLA-GIK, 126-127

Blood pressure

insulin, 127

angiotensin blockade, 30

myocardial infarction

glycaemia, 30

(MI), 127

hypertension, 29

ADA. See American Diabetes

practical pharmacology, 31

Association (ADA)

treatment principles, 30

Albumin/creatinine ratio (ACR),

Bromocriptine, 64

77, 78, 84

Alpha-glucosidase inhibitors, 50,

61-62

American Diabetes Association

Calcium-channel blockers, 31-32

(ADA), 2, 49, 50

Canakinumab, 8

Amputation, 94, 96, 106, 109

Cardiovascular disease (CVD),

Amylin, 45-46, 69

76, 78, 85

T.A. Chowdhury (ed.),

131

Diabetes Management in Clinical Practice,

132

Index

Cerebrovascular accident (CVA)

Diabetic emergencies

GIST-UK, 125

ACS, 126-127

hyperglycaemia, 125

CVA, 125-126

pre-existing diabetes, 125

DKA, 116-122

tight glucose control, 125

HHS, 122-125

Charcot neuropathic

hypoglycaemia, 112-116

osteoarthropathy (CN)

Diabetic foot disease

diagnosis, 106-107

Charcot neuropathic

medical treatments, 108

osteoarthropathy, 106-108

treatment, 108

description, 94

X-rays, 108

“multi-disciplinary team”,

Cholesterol Treatment Trialists

108-109

(CTT), 35

ulceration (see Foot ulceration)

Chronic kidney disease (CKD)

wound healing, 105-106

and ESRD, 76-77

Diabetic ketoacidosis (DKA)

and nephrologists, 90

acidosis and ketonaemia, 117

stages, 76, 77

bicarbonate, 121

CKD. See Chronic kidney disease

blood ketone testing, 118

(CKD)

cerebral oedema, 117

Clopidogrel, 27, 38

complications, 122

Colesevalam, 63-64

epidemiology, 117

Continuous subcutaneous insulin

fluid and electrolyte deficits, 117

infusion (CSII) therapy,

fluid replacement, 119-120

67-68

hyperglycaemia, 117

CTLA4-Ig (Abatacept), 7

incidence, 117

CTT. See Cholesterol Treatment

insulin, 118-119

Trialists (CTT)

long acting insulin, 121

CVA. See Cerebrovascular

potassium, 120-121

accident (CVA)

phosphate, 121

CVD. See Cardiovascular

Diabetic nephropathy (DN)

disease (CVD)

antithrombotic therapy, 88-89

cardiovascular risk, 87-88

definition, 76

diet, lifestyle and weight loss, 89

Dapagliflozin, 63

dyslipidaemia, 88

Diabetes

glycaemic control, 85-87

definition (WHO), 2

hypertension, 87

and intermediate

and microinflammation, 78, 79

hyperglycaemia,

molecular mechanism, 78, 80, 81

diagnostic criteria, 2, 3

smoking cessation, 89

Diabetes Control and

T1DM and T2DM, 77

Complications Trial

Diabetic Patients with Acute

(DCCT), 22-23, 46

Myocardial Infarction

Diabetes Prevention Program

(DIGAMI) study, 126

(DPP), 14

DIAMOND (Multinational

Diabetes prevention trial

Project for Childhood

(DPT-1), 7

Diabetes), 4

Index

133

Dipeptidyl-peptidase-IV (DPP-IV)

Etanarcept, 8

inhibitors, 50, 62-63

EURODIAB. See The

Diuretics, 32

Epidemiology and

DKA. See Diabetic ketoacidosis

prevention of Diabetes

(DKA)

(EURODIAB) projects

DN. See Diabetic nephropathy (DN)

European Association for the

Doxazosin, 33

Study of Diabetes

Duloxetine, 100

(EASD), 49, 50

Dyslipidaemia, 88

Exenatide, 65

Exubera (first inhaled insulin),

69-70

Ezetimibe, 37

EASD. See European Association

for the Study of Diabetes

(EASD)

ECLA-GIK. See Estudios

Foot ulceration

Cardiologicos Latino

arterial assessment, 101

America (ECLA-GIK)

infection, 102-105

Edinburgh Hypoglycaemia

ischaemia, management, 101

Scale, 113

neuropathic assessment, 97-98

eGFR. See Estimated glomerular

neuropathy-“offloading”

filtration rate (eGFR)

effect, 102

Enalapril, 85

osteomyelitis treatment, 105

End-stage renal disease (ESRD)

peripheral neuropathy, 96-97

and DN, 76

PPN, 98-100

and nephropathy, 79

risk classification, 94, 95

T1DM and proteinuria, 78

The Environmental Determinants

of Diabetes in the Young

(TEDDY), 5

Gabapentin, 100

The Epidemiology and prevention

GADA. See Glutamic acid

of Diabetes

decarboxylase (GADA)

(EURODIAB) projects, 4

Gestational diabetes mellitus

Epidemiology of Diabetes

(GDM), 18-19

Intervention and

Glibenclamide, 60

Complications (EDIC)

Gliclazide, 60

study, 22-23

Glimepiride, 60

ESRD. See End-stage renal disease

Gliptins, 63

(ESRD)

Glitazones, 50, 60-61, 73

Estimated glomerular filtration

Glucagon-like peptide-1 (GLP-1)

rate (eGFR)

analogues, 64-65

and albuminuria, 89

Glucagon receptor antagonists, 70

metformin, 86

Glucogel, 113

serum creatinine, 79, 81

Glucokinase activators, 71

ECLA-GIK (Estudios

Glucose Insulin in Stroke Trial

Cardiologicos Latino

(GIST-UK), 125

America), 126-217

Glucotoxicity, 45

134

Index

Glutamic acid decarboxylase

GPR119 agonists, 72

(GADA), 6

immune therapies, 72

Glycaemic therapy

inhaled/oral insulin, 69-70

glycaemic control, 50

NICE guidelines, 58

guidelines, 49-50

T1DM, 46

hyperglycaemia, treatment

T2DM

(see Hyperglycaemia,

macrovascular disease, 46-48

treatment)

microvascular disease, 48

injectable agents

tight glucose control, 50, 51

CSII therapy, 67-68

Hyperglycaemic hyperosmolar

GLP-1 analogues, 64-65

syndrome (HHS)

insulin, 65-66

definition, 122

pancreatic transplantation, 68

fluid and electrolyte deficits,

pramlintide, 69

117, 123

oral glucose lowering agents

HONK, 122

(see Oral hypoglycaemics)

hyperosmolar state, 123-124

T1DM

ketonaemia, 124

exogenous insulin therapy, 44

osmolality and osmolarity, 123

pathogenesis, 44

pseudo-hyponatraemia, 124

T2DM

Hyperglycemia and Pregnancy

beta-cell function, decline,

Outcome (HAPO), 18

45-46

Hyperosmolar non-ketotic coma

insulin resistance, 45

(HONK). See

oral glucose lowering agents,

Hyperglycaemic

properties, 52-57

hyperosmolar

pathophysiology, 45

syndrome (HHS)

GPR119 agonists, 72

Hypertension

and nephropathy, 87

T1DM and T2DM, 82, 83

Hypoglycaemia

HBOT. See Hyperbaric oxygen

carbohydrate, 113

therapy (HBOT)

definition, 112

Heat shock protein (HSP)

dextrose, 115

peptide, 7

Edinburgh Hypoglycaemia

HHS. See Hyperglycaemic

Scale, 113

hyperosmolar syndrome

glucogel, 113

(HHS)

National Diabetes Inpatient

Hygiene hypothesis, 5

Audit, 112

Hyperbaric oxygen therapy

risk factors, 113, 114

(HBOT), 106

symptoms, 113

Hyperglycaemia, treatment

treatment algorithm, 113, 115-116

ADA and EASD guidelines, 59

future agents

11β-HSD1, 71

glucagon receptor

IA-2A. See Insulinoma-associated

antagonists, 70

protein 2 antigen (IA-2A)

glucokinase activators, 71

ICA. See Islet cell antibodies (ICA)

Index

135

Idiogenicosmoles, 124

Lipotoxicity, 45

IDPP. See Indian Diabetes

Liraglutide, 65

Prevention Program

Lixisenatide, 65

(IDPP)

Losartan, 87

Impaired glucose tolerance

(IGT), 14

Incretin effect, 45, 62

Macrovascular disease, 46-48

Indian Diabetes Prevention

Mannkind Technosphere Insulin

Program (IDPP), 14

system, 70

Inhaled insulin

Maturity Onset Diabetes in the

Exubera, 69-70

Young (MODY), 2

Mannkind Technosphere Insulin

MDI. See Multiple dose insulin

system, 70

(MDI)

Insulin (IAA), 6, 87

MDRD. See Modification of diet in

Insulin degludec (ultra-long acting

renal disease (MDRD)

analogue insulins), 66

Meglitinides, 50, 60

Insulinoma-associated protein 2

“Metabolic memory”, 47

antigen (IA-2A), 6

Metformin, 15, 51, 59-61, 63,

Insulin pump therapy. See

65, 70, 86

Continuous subcutaneous

Microalbuminuria

insulin infusion (CSII)

cardiovascular risk, 85

therapy

description, 83

Insulin therapy, 65-67

glycaemic control, 83

International Association of

hypertension, 83-84

Diabetes and Pregnancy

renin angiotensin system

Study Group

blockade, 84-85

(IADPSG), 18

Microvascular disease, 48

Irbesartan, 85, 87

Modification of diet in renal

Islet cell antibodies (ICA), 6

disease (MDRD), 81

MODY. See Maturity Onset Diabetes

in the Young (MODY)

Ketonaemia, 117-118, 120-124

Multiple dose insulin (MDI), 66

Multiple risk factor intervention,

38-40

Myocardial infarction (MI), 127

Labetalol, 33

Latent autoimmune diabetes in

adults (LADA), 8-10

Lidocaine, 100

National Diabetes Inpatient

Linagliptin, 86

Audit, 112

Lipids

Negative pressure wound therapy

CTT collaborators, 35

(NPWT), 106

non-statin lipid modifying drugs,

Niacin, 36

36-37

NICE. See UK National Institute

statins and ezetimibe, 37

for Health and Clinical

T1DM, 34-35

Excellence (NICE)

T2DM, 35-36

guidelines

136

Index

Prevention

ONTARGET study, 30

GDM, 17-19

Oral hypoglycaemics

glycaemic control, 81-82

alpha-glucosidase inhibitors,

hypertension, 82

61-62

non-glucose interventions

bromocriptine, 64

anti-platelet agents, 37-38

colesevalam, 63-64

beta blockers, 32

DPP-IV inhibitors, 62-63

blood pressure, 30, 31

meglitinides, 60

calcium-channel blockers,

metformin, 51, 59

31-32

properties, 52-57

diuretics, 32

SGLT-2, 63

lipids, 34-37

sulfonylureas, 59-60

multiple risk factor

thiazolidinediones (glitazones),

intervention, 38-40

60-61

resistant hypertension, 33

Orlistat, 15

smoking, 28-29

Osteomyelitis, treatment, 105

STENO-2 study, 38, 39

Otelixizumab, 8

T1DM (excluding LADA) (see

Type 1 diabetes (T1DM))

T2DM (see Type 2 diabetes

(T2DM))

Painful peripheral neuropathy

(PPN)

capsaicin cream and

Ramipril, 82, 84

lidocaine, 100

Renal disease

gabapentin and

ACR, 78

pregabalin, 100

CKD, 76

and SNRI, 100

diagnosis, 78

and TCAs, 98

DN (see Diabetic

treatment, 98

nephropathy (DN))

Pancreatic transplantation

eGFR and MDRD, 79, 81

beta cell transplantation, 68

epidemiology, 76-77

islet transplantation, 68

ESRD, 76

SPK, 68

microalbuminuria, 83-85

Peroxisome proliferator-activated

nephrologists, 89-90

receptor-gamma (PPARg)

prevention, 81-82

activation, 46

urinary albumin measurement, 77

Pioglitazone, 61, 86

Resistant hypertension, 33, 34

PPARg. See Peroxisome

Rosuvastatin, 37

proliferator-activated

receptor-gamma (PPARg)

activation

PPN. See Painful peripheral

Serotonin noradrenaline reuptake

neuropathy (PPN)

inhibitor (SNRI), 98, 100

Pramlintide, 69

SGLT-2. See Sodium glucose

Pravastatin, 37

transporter-2 inhibitors

Pregabalin, 100

(SGLT-2)

Index

137

Simultaneous pancreas and renal

autoimmunity, 6

transplantation (SPK), 68

environmental factors, 5

Simvastatin, 37

genetic susceptibility, 4-5

Sitagliptin (Januvia), 63

glycaemic therapy

Smoking

exogenous insulin therapy, 44

cessation, 83, 89

pathogenesis, 44

T1DM, 28

hypertension, 82

T2DM, 13, 29

LADA, 8-10

SNRI. See Serotonin noradrenaline

lipids, 34-35

reuptake inhibitor (SNRI)

macrovascular complications,

Sodium glucose transporter-2

23-24

inhibitors (SGLT-2), 63

microalbuminuria, 82, 84

SPK. See Simultaneous pancreas

microvascular complications, 23

and renal transplantation

prevention

(SPK)

DPT-1, 7

Statins, 37

primary prevention studies, 6

Sulfonylureas, 50, 59-61, 65

secondary prevention

studies, 7

‘self tolerance’, 7

tertiary prevention studies, 7

TCAs. See Tricyclic antidepressants

and proteinuria, 78

(TCAs)

smoking, 28

T1DM. See Type 1 diabetes

Type 2 diabetes (T2DM)

(T1DM)

bariatric surgery, 16

T2DM. See Type 2 diabetes

and DN, 79

(T2DM)

epidemiology, 11

TEDDY. See The Environmental

etiopathology

Determinants of Diabetes

environmental factors, 12-13

in the Young (TEDDY)

epigenetic factors, 12-13

Telmisartan, 85

genetic factors, 12

Teplizumab, 7, 8

glycaemic therapy

Thiazolidinediones, 15, 60-61

beta-cell function, decline,

‘Thrifty phenotype

45-46

hypothesis’, 13

insulin resistance, 45

Tramadol, 100

oral glucose lowering agents,

Trial to Reduce IDDM in the

properties, 52-57

Genetically at Risk

pathophysiology, 45

(TRIGR), 6

hypertension, 82

Tricyclic antidepressants

lifestyle intervention, 14-15

(TCAs), 98

medications, 15-16

TRIGR. See Trial to Reduce

and microalbuminuria, 83

IDDM in the Genetically

prevention, 14

at Risk (TRIGR)

risk factors

Type 1 diabetes (T1DM)

ACCORD lipid study, 36

definition, 4

blood pressure, 25-26

epidemiology, 4

glycaemic control, 25

etiopathology

haemostatic factors, 27-28