DPCA 2-3_entire_v3

Diabetes
& Primary Care Australia
Vol 2 No 3 2017
The primary care diabetes journal for healthcare professionals in Australia
Free CPD module:
Dyslipidaemia
in diabetes
Explore the links between lipid levels
and cardiovascular risk, and review
the evidence for lipid management in
people with diabetes.
Page 100
Visit our suite of FREE e-learning
modules and gain CPD certificates at
pcdsa.com.au/cpd
IN THIS ISSUE
Sexual dysfunction
How to identify and treat male
and female sexual dysfunction
in people with diabetes.
Page 91
Prevention of foot ulcers
International guidance on
diabetes foot care applied in
the Australian context.
Page 111
Second-line options
A comparison of the benefits
and risks of SGLT2 and DPP-4
inhibitors in type 2 diabetes.
Page 119
WEBSITE
Journal content online at
www.pcdsa.com.au/journal

1
1
Dual Action NovoMix ® 30 2,3
PBS Information: This product is listed on the PBS for the treatment of diabetes mellitus.
NOVMIX0065/ADE/FPC
Please review Product Information before prescribing.
The Product Information can be accessed at www.novonordisk.com.au
Minimum Product Information. NovoMix ® 30 (insulin aspart (rys)). Indication: Treatment of diabetes mellitus. Contraindications: Hypoglycaemia. Hypersensitivity to insulin aspart or
excipients. Precautions: Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis. Where blood glucose is greatly
improved, e.g. by intensified insulin therapy, patients may experience a change in usual warning symptoms of hypoglycaemia, and should be advised accordingly. The impact of the rapid onset of
action should be considered in patients where a delayed absorption of food might be expected. Do not use in insulin infusion pumps. No studies in children and adolescents under the age of 18. No
clinical experience in pregnancy. When thiazolidinediones (TZDs) are used in combination with insulin, patients should be observed for signs and symptoms of congestive heart failure, weight gain
and oedema; discontinuation of TZDs may be required. Insulin administration may cause insulin antibodies to form and, in rare cases, may necessitate adjustment of the insulin dose. Interactions:
Oral hypoglycaemic agents, octreotide, lanreotide, monoamine oxidase inhibitors, non-selective beta-adrenergic blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol,
anabolic steroids, alpha-adrenergic blocking agents, quinine, quinidine, sulphonamides, oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone,
diazoxide, asparaginase, nicotinic acid. Adverse Effects: Hypoglycaemia. Dosage and Administration: Dosage as determined
by physician. NovoMix ® 30 should be administered immediately before a meal, or when necessary after the start of a meal.
Resuspend immediately before use. Discard the needle after each injection. Subcutaneous injection only. NovoMix ® 30 must
not be administered intravenously. (July 2014). References: 1. Liebl A et al. Drugs 2012; 72(11): 1495–520. 2. Wu T et al.
Diabetes Ther 2015; 6(3): 273–87. 3. NovoMix ® 30 Approved Product Information (Jul 2014). Novo Nordisk Pharmaceuticals Pty
Ltd. ABN 40 002 879 996. Level 3, 21 Solent Circuit, Baulkham Hills, NSW 2153. NovoCare ® Customer Care Centre (Australia)
1800 668 626. www.novonordisk.com.au. ® Registered trademark of Novo Nordisk A/S. AU/NM/0116/0004. January 2016. insulin aspart (rys)

Contents
Diabetes
& Primary Care Australia
Volume 2 No 3 2017
@PCDSAus
Website: www.pcdsa.com.au/journal
Editorial
Our second national conference 85
Rajna Ogrin introduces this issue and reflects on the success of the PCDSA's second national conference.
From the other side of the desk
I love my CGM: Managing my diabetes is no longer a performance 86
How continuous glucose monitoring helped Tim Burnham get his career back on track.
Meeting report
2 nd National Conference of the Primary Care Diabetes Society of Australia 88
Mark Kennedy summarises the sessions from the PCDSA's recent national conference held in Melbourne.
CPD module
Managing dyslipidaemia in the context of diabetes 100
For this issue’s free education module, Mike Kirby and Roy Rasalam explore the latest thinking on the links between dyslipidaemia and
cardiovascular risk, and review the evidence for lipid management in people with diabetes.
Articles
Sexual health and dysfunction in men and women with diabetes 91
David Edwards and Nicholas Forgione outline the identification and treatment of sexual dysfunction in people with diabetes.
Primary care practitioner guide to the International Working Group on the Diabetic Foot:
Recommendations for the Australian context 111
Rajna Ogin and Jane Tennant discuss the prevention of diabetes-related foot ulcers and translates international guidelines into the Australian
primary care setting.
The new class war: SGLT2 inhibitors versus DPP-4 inhibitors 119
Merlin Thomas compares the benefits and risks associated with SGLT2 and DPP-4 inhibitors when added to metformin in type 2 diabetes.
Editor-in-Chief
Rajna Ogrin
Senior Research Fellow, RDNS
Institute, St Kilda, Vic
Associate Editor
Gary Kilov
Practice Principal, The Seaport
Practice, and Senior Lecturer,
University of Tasmania,
Launceston, Tas
Editorial Board
Ralph Audehm
GP Director, Dianella Community
Health, and Associate Professor,
University of Melbourne,
Melbourne, Vic
Werner Bischof
Periodontist, and Associate
Professor, LaTrobe University,
Bendigo, Vic
Anna Chapman
Research Fellow, RDNS Institute,
St Kilda, Vic
Laura Dean
Course Director of the Graduate
Certificate in Pharmacy
Practice, Monash University, Vic
Nicholas Forgione
Principal, Trigg Health Care
Centre, Perth, WA
John Furler
Principal Research Fellow and
Associate Professor,
University of Melbourne, Vic
Mark Kennedy
Medical Director, Northern Bay
Health, Geelong, and Honorary
Clinical Associate Professor,
University of Melbourne,
Melbourne, Vic
Peter Lazzarini
Senior Research Fellow,
Queensland University of
Technology, Brisbane, Qld
Roy Rasalam
Head of Clinical Skills and
Medical Director,
James Cook University, and
Clinical Researcher, Townsville
Hospital, Townsville, Qld
Suzane Ryan
Practice Principal, Newcastle
Family Practice, Newcastle, NSW
Editorial team
Olivia Tamburello, Tracy Tran,
Charlotte Lindsay
Editorial Manager
Richard Owen
Publisher
Simon Breed
© OmniaMed SB and the Primary Care
Diabetes Society of Australia
Published by OmniaMed SB,
1–2 Hatfields, London
SE1 9PG, UK
All rights reserved. No part of this
journal may be reproduced or transmitted
in any form, by any means, electronic
or mechanic, including photocopying,
recording or any information retrieval
system, without the publisher’s
permission.
ISSN 2397-2254
Diabetes & Primary Care Australia Vol 2 No 3 2017 83

The PCDSA is a multidisciplinary society with the aim
of supporting primary health care professionals to deliver
high quality, clinically effective care in order to improve
the lives of people with diabetes.
The PCDSA will
Share best practice in delivering quality diabetes care.
Provide high-quality education tailored to health professional needs.
Promote and participate in high quality research in diabetes.
Disseminate up-to-date, evidence-based information to health
professionals.
Form partnerships and collaborate with other diabetes related,
high level professional organisations committed to the care of
people with diabetes.
Promote co-ordinated and timely interdisciplinary care.
Membership of the PCDSA is free and members get access to a quarterly
online journal and continuing professional development activities. Our first
annual conference will feature internationally and nationally regarded experts
in the field of diabetes.
To register, visit our website:
www.pcdsa.com.au

Editorial
Our second national conference
The Primary Care Diabetes Society of
Australia (PCDSA) was delighted to
hold its second annual conference on
6 May at the Melbourne Convention and
Exhibition Centre. The focus of the one-day
event was on meeting the PCDSA’s aim of
supporting primary care health professionals
to deliver high quality, clinically effective
care to improve the lives of people living with
diabetes.
The presentations had a strong practical focus,
underpinned by a person-centred approach.
The first session included presentations on
the emotional health of people living with
diabetes and how to engage this group of
people, including through the use of digital
health. The content included presentations
from key allied health professionals involved
in the care of people with diabetes in fields
such as podiatry, optometry, dentistry,
pharmacy and psychology.
The feedback that we received was
extremely positive and, among the many
suggestions for future conference content,
were calls to include talks on sexual health,
the management of diabetes in people who
also have renal disease, hearing and diabetes,
and complex client management. This has
provided us not only with a bank of ideas for
future events, but also for articles to include
in future issues of our journal.
A summary of this year’s conference
has been provided in the current issue of
Diabetes & Primary Care Australia by Mark
Kennedy. Additionally, future journal
issues will feature articles based on some
of the presentations provided that day.
Please bookmark the PCDSA website
(www.pcdsa.com.au) so that you can return
and read them, and keep a look out for
information about next year’s conference.
This issue covers some of the topics that the
conference delegates were most interested in
hearing about. One of the most commonly
sought-after topics was the often underdiscussed
subject of sexual dysfunction. David
Edwards and Nicholas Forgione outline the
identification and treatment of male and
female sexual dysfunction in people with
diabetes, and include guidance on how to
take a sexual history. While research into
female sexual dysfunction is unfortunately
limited, I anticipate that this article will
provide plenty of useful information for you
to call upon in your practice.
Also included is a practical guide on the
prevention of foot ulcers and lower extremity
amputation in people with diabetes.
Co-authored by myself and Jane Tennant,
the article translates international guidelines
into the Australian clinical setting in order to
encourage their implementation.
Professor Merlin Thomas provides a simple
framework to weigh up the comparative benefits
and risks of sodium–glucose cotransporter 2
(SGLT2) inhibitors and dipeptidyl peptidase-4
(DPP-4) inhibitors, when added to metformin
for the management of type 2 diabetes in
Australian general practice.
Mike Kirby and Roy Rasalam provide a
comprehensive overview of the management
of dyslipidaemia in the context of diabetes,
and this forms our CPD article for the issue.
To test your understanding of this important
topic and, to gain RACGP-accredited CPD
points, take our free multiple-choice test at
www.pcdsa.com.au/cpd. While you are there,
I suggest you take a look at the growing list of
educational modules that the PCDSA offers
and see what might be of interest.
Finally, as part of our continuing support for
the provision of a person-centred approach to
diabetes care, our “From the other side of the
desk” piece has been written by Tim Burnham,
a professional drummer with diabetes. In
it, he relates the personal and professional
challenges that he has faced since diagnosis,
and his experiences of using continuous glucose
monitoring to address them.
We anticipate that this issue will provide you
with plenty of useful, practical information to
support your clinical care delivery. n
Rajna Ogrin
Editor-in-Chief of Diabetes &
Primary Care Australia, and Senior
Research Fellow, Royal District
Nursing Service Institute,
St Kilda, Vic.
Diabetes & Primary Care Australia Vol 2 No 3 2017 85

From the other side of the desk
From the other side of the desk:
Patient perspective
I love my CGM: Managing my diabetes
is no longer a performance
Tim Burnham
Citation: Burnham T (2017) I love
my CGM: managing my diabetes is
no longer a performance. Diabetes &
Primary Care Australia 2: 86–7
About this series
The aim of the “From the other
side of the desk” series is to
provide a patient perspective and
a pause for thought to reflect on
the doctor–patient relationship.
Drumming has been my passion since I
was 13 – I have an advanced diploma
of music and have been teaching as
well as playing the drums for nearly 30 years.
My career as a drummer was pretty much
wiped out, however, when I developed type 1
diabetes.
I was diagnosed with diabetes in June 2010
and the fear and stress of unstable blood sugars
made it difficult to focus on the performance.
Having lows or highs on stage meant that my
brain wasn’t functioning properly, so I wasn’t
performing at the standard I used to in my
life before diabetes. The music industry is
tough enough without diabetes making it near
impossible. The phone soon stopped ringing.
Before I knew it, I was out of work and broke.
Things can only get better
When I was first hooked up to my continuous
glucose monitor (CGM), it only took a few
hours for me to realise that life was going to be
great again. All the stress and fear of managing
type 1 diabetes left my mind thanks to a little
black box that I kept in my pocket. I was able
to sleep all night knowing my new friend
would wake me if I was in trouble. Finally I
could get back to working full time and living
my life to the full.
Before I had my CGM, my average HbA 1c
Author
Tim Burnham, Drummer and
Music Teacher, Brunswick, Vic.
86 Diabetes & Primary Care Australia Vol 2 No 3 2017

From the other side of the desk
level was 53 mmol/mol (7%). It’s now dropped
to 37 mmol/mol (5.5%).
I can mimic the blood sugars of a normal
person about 80% of the time. The other
20% of the time I’m only slightly higher than
somebody without diabetes. The highest my
blood sugars ever get is about 8 mmol/L and
most days I don’t go above 7. This tight control
was unheard of before the CGM. Managing
blood glucose levels has become child’s play.
The best thing about wearing a CGM is
the feeling of safety provided by the alarm.
Knowing that I am not going to hypo because
an alarm will warn me in advance of low blood
glucose becoming a problem is incredibly
reassuring.
Testing blood sugar is no performance
Before I got my CGM, I had to do a finger
prick test to check my glucose levels – which
was a real performance when I was working.
I would have to stop drumming, holding up
the whole band, and, in front of hundreds of
people, sterilise and prick my finger, then wait
for the results.
Now I can check my sugars without anyone
ever knowing. When I am performing I place
my CGM and some jelly beans on the floor
behind my drum kit. When there is a gap
between songs, I simply poke the CGM button
with the end of my drumstick, glance down
and see if I’m OK. All this is done without
skipping a beat.
Cost is an issue
As I write this I am not wearing my CGM:
with a realistic cost of around $80–120 per
week, saving any respectable amount of money
is difficult. For this reason, when work is slow I
don’t wear it. This is annoying, as I go straight
back to having unstable blood sugars and the
constant anxiety of having a hypo. I love my
CGM. I just wish I could afford it.
It’s disappointing that CGMs are not
subsidised or covered by insurance for adults.
I hope that the subsidy now available to
children will be extended to include people
of all ages with type 1 diabetes. Clearly the
powers that be do not see that CGMs would
ease the burden on the healthcare system,
as tens of thousands of people with type 1
diabetes would no longer require the same
extent of medical attention as their health
could potentially improve significantly. They
also don’t understand that CGMs could get
many of these people off income support and
back into the workforce, which benefits the
whole of society. I hope the doctors I see are
as keen as I am to change the system so there
is better access to CGMs.
n
“I love my CGM. It’s
given me back my
career and my happygo-lucky
state of mind.
Diabetes & Primary Care Australia Vol 2 No 3 2017 87

Meeting report
2 nd National Conference of the Primary
Care Diabetes Society of Australia
Melbourne Convention and Exhibition Centre, Victoria, 6 th May 2017
Key speakers from a diverse area of primary healthcare came together at the 2017 Primary Care Diabetes Society of
Australia (PCDSA) national conference to share news, insights and evidence on diabetes management.
Associate Professor Mark Kennedy, Chair of PCDSA, provides a summary of the presentations.
The 2 nd National Conference
of the Primary Care Diabetes
Society of Australia (PCDSA)
saw an impressive panel of speakers
covering a wide range of areas
important in the daily management of
diabetes in the primary care setting.
Below is a summary of the day’s
presentations, which includes my review
of the latest news on diabetes.
Diabetes management and research
in primary care – key components to
improving outcomes
Associate Professor Neale Cohen, Director
of Clinical Diabetes, Baker IDI Heart and
Diabetes Institute, Melbourne, Vic
The emotional health of people living
with diabetes
Dr Christel Hendrieckx, Senior Research
Fellow, Australian Centre for Behavioural
Research in Diabetes, Melbourne, Vic
Dr Christel Hendrieckx spoke of the
high prevalence of diabetes distress and
depression in people with type 1 diabetes
(T1D) and T2D, and reminded us to
consider the emotional aspects of diabetes
management alongside the physical
aspects in our day-to-day consulting.
She highlighted the impact of
emotions in people with diabetes on
their engagement with self-care, HbA 1c
levels and quality of life, and called for
health practitioners to screen people
with diabetes for emotional problems
and other diabetes complications. She
also reminded us that often we only
need to be a sounding board for people
dealing with many of these emotional
problems rather than needing to
“solve” the complexity of issues
involved.
Associate Professor Neale Cohen spoke
of the importance of treating newly
diagnosed type 2 diabetes (T2D)
aggressively because intensive glycaemic
control leads to long-term benefits. He
also reminded us that in primary care
we are ideally placed both to detect
diabetes early and then to manage it
intensively.
He spoke of the importance of
individualised glycaemic targets and
the need to consider glycaemic control,
expected cardiovascular outcomes
and renal function when choosing
between pharmacological treatments.
He also discussed many of the factors
contributing towards clinical inertia
and poor patient adherence to therapy.
Mark Kennedy presenting “Breaking diabetes news. The latest
evidence and stories from recent months.”
88 Diabetes & Primary Care Australia Vol 2 No 3 2017

Meeting report
Engaging people with diabetes, diabetes
online community and apps for diabetes
Renza Scibilia, National Program Manager
for Type 1 Diabetes and Consumer Voice,
Diabetes Australia, Melbourne, Vic
Renza Scibilia gave a great insight
into the perspective of a person with
diabetes with respect to the impact
of the diagnosis. She explained many
of the communication challenges and
frustrations that people with diabetes
face in their interactions with health
professionals.
Breaking diabetes news. The latest
evidence and stories from recent
months
Mark Kennedy, founding member and
inaugural Chair, PCDSA; Honorary Clinical
Associate Professor, Department of General
Practice, The University of Melbourne,
Melbourne, Vic
I reviewed interesting new literature
about pharmacological and lifestyle
management of diabetes and explained
that, in several countries, governments
are starting to confront one of the root
causes of childhood and adult obesity and
diabetes by imposing taxes on
sugar-sweetened beverages.
I made a call for our own government
to step up and follow recommendations
from our own Obesity Policy Coalition,
the World Health Organization,
International Diabetes Federation and
World Cancer Research Fund to impose a
similar tax.
Technology: the great democratiser – a
brief history of glucose sensing: past,
present and future
Dr Gary Kilov, Principal, Seaport Diabetes
Practice, Launceston, Tas; founding member
of the PCDSA
Dr Gary Kilov talked about the history
of technology in the management
of diabetes and provided an exciting
insight into emerging technologies
with respect to continuous glucose
monitoring, flash glucose monitoring
and insulin pumps.
He explained artificial pancreas
developments that involve an insulin
pump under closed-loop control
using real-time data from continuous
glucose sensing technology. And he
finished with a glimpse into what’s
ahead, including the non-invasive
measurement of blood glucose using
spectrophotometry, implantable glucose
sensors that can operate for a year at a
time, and glucose sensing through skin
patches or contact lenses.
“To low carb or not to low carb: that is
the question”
Erin Jackson, Accredited Practising Dietitian,
Launceston, Tas
Erin Jackson spoke of the carbohydrate
intolerance characteristic of T2D and the
glycaemic benefits that can come from
reducing carbohydrate intake for people
with T2D. She discussed some of the
associated challenges such as ensuring
adequate fibre intake and adequate, but
not excessive, consumption of healthy
fats and protein. She also emphasised the
need to individualise any carbohydrate
restriction with the dietitian, other
health practitioners, and person with
diabetes – working together as a
multidisciplinary team.
Best practice to reduce variation of
diabetes-related amputation rates in
Australia
Dr Rajna Ogrin, Senior Research Fellow,
Royal District Nursing Service Institute,
St Kilda, Vic
Dr Rajna Ogrin showed that it is
possible to reduce major and minor
amputations and hospital admissions by
appropriately screening for amputation
risk factors and then following
appropriate management guidelines.
Risk factors include the loss of
protective sensation, co-existing
peripheral artery disease, structural
abnormalities of the foot, and past or
current foot ulceration.
The emerging importance of cardiac
failure diagnosis and management in
people with type 2 diabetes
Dr Gautam Vaddadi, Head of Heart Failure
services at Northern Health, Melbourne,
Vic; Director of Cardiac Services at Cabrini
Health, Melbourne, Vic
Dr Gautam Vaddadi highlighted the
bidirectional relationship between heart
failure and diabetes, with increased
prevalence of heart failure in people with
diabetes as well as poorer survival in
those hospitalised with heart failure and
diabetes compared to heart failure alone.
He discussed the different types of
diabetic cardiomyopathy and outlined
evidence from research trials relating
to positive and negative cardiovascular
outcomes. Within this, Gautam
highlighted that there are now significant
data showing that some agents are
associated with increased rates of heart
failure and others with decreased rates.
He also provided a useful overview of the
comparative safety of different glucoselowering
medications.
Why use optometry in this day and
age when retinal cameras and item
numbers are available?
Mitchell Anjou, Academic Specialist and
Senior Research Fellow, Indigenous Eye
Health Unit, University of Melbourne,
Melbourne, Vic
Mitchell Anjou reminded delegates
that everyone with diabetes is at
Diabetes & Primary Care Australia Vol 2 No 3 2017 89

Meeting report
risk of developing retinopathy and
potential vision loss. He explained
that good glycaemic control is critical
and regular screening is important to
enable appropriate timing of treatment.
He showed that if these are achieved,
most diabetes-related blindness is
preventable.
Mitchell also presented alarming data
showing that 37% of adult indigenous
Australians have diabetes and that
13% have already lost some vision. He
pointed out that although timely laser
surgery can prevent 98% of diabetesrelated
blindness, almost two-thirds
of indigenous Australians requiring
this treatment have not received it.
However, the new availability of
funded retinography through Medicare
provides hope that appropriate
screening through optometrists,
ophthalmologists or retinography will
be accessible by all Australians.
The role of pharmacists in diabetes
detection and management, new
government initiatives
Kirstie-Jane Grenfell, Community Pharmacist
and Diabetes Educator, Melbourne, Vic
Kirstie-Jane Grenfell discussed the
Australian Government’s Sixth
Community Pharmacy Agreement
(6CPA) $50m Pharmacy Trial
Program.
The program, which commenced in
2016, involves a comparison of three
different pharmacy-based diabetes
screening interventions to determine
their clinical and cost effectiveness
in improving the identification of
previously undiagnosed diabetes in the
community.
Dental practitioners – important
players in the diabetes
multidisciplinary care team
Associate Professor Werner Bischof,
Periodontist in Practice, Geelong, Vic
Delegate Dr Mandy Mossop enjoying looking around the exhibitions hall.
Werner Bischof presented a strong
case for periodontal disease to be seen
as the sixth complication of diabetes
along with retinopathy, neuropathy,
nephropathy, cardiovascular disease
and peripheral vascular disease. He
highlighted the bidirectional nature of
the relationship of periodontal disease
and diabetes in terms of risk and
control, and asked that we consider the
oral health of our patients, particularly
those with diabetes, and collaborate
with dentists as part of optimal
multidisciplinary care of our patients.
He also outlined other oral health
conditions associated with diabetes,
including dry mouth, dental caries,
candida, poor wound healing and
burning mouth syndrome.
A note of thanks
We would like to thank all of our
speakers, sponsors, exhibitors and
organisers for their support of the
PCDSA. Feedback from conference
delegates was very positive and
initial planning for the 2018 national
conference is already underway.
The PCDSA is your society, so do
email us at info@pcdsa.com.au with
your suggestions for what, or who,
you would like to see at next year’s
conference.
You can also contact us at the above
address if you would like an education
seminar in your area, or wish to
contribute to Diabetes & Primary Care
Australia.
We look forward to seeing you at our
national conference next year! n
Citation
Kennedy M (2017) 2 nd National Conference of
the Primary Care Diabetes Society of Australia.
Diabetes & Primary Care Australia 2: 88–90
90 Diabetes & Primary Care Australia Vol 2 No 3 2017

Article
Sexual health and dysfunction in men and
women with diabetes
David Edwards and Nicholas Forgione
Sexual dysfunction is common in people with diabetes and, although much research
has focused on erectile dysfunction, there is a paucity of knowledge regarding sexual
dysfunction in women. Despite the evidence, sexual dysfunction is poorly evaluated and
managed in patients with diabetes. Taking a basic sexual history is therefore an important
skill for a primary care clinician, as an individual’s sexual background will help to provide
the appropriate treatment, be it pharmacological or psychological. This article discusses
the identification and treatment of male and female sexual dysfunction in people with
diabetes and explores how to take a sexual history.
Sexual dysfunction is common in people
with diabetes. Much medical research
has focused on male sexual dysfunction,
particularly erectile dysfunction (ED). In
general, male sexual dysfunction is more obvious
and measurable than female sexual dysfunction.
There is also more research into ED because
effective treatments have been developed.
This gender imbalance is being addressed as
more research on female sexual dysfunction
is published. This article looks first at the
identification and treatment of male and female
sexual dysfunction and then at how best to
conduct a consultation about sexual dysfunction.
Sexual health in men with diabetes
Erectile dysfunction
An Australian survey showed that at least one
in five men over the age of 40 years has erectile
problems and about one in 10 men is completely
unable to have an erection (Andrology Australia,
2014). About 50% of men with diabetes will
suffer from ED within 10 years of the diagnosis
and this may be a manifestation of more
generalised vascular disease. ED can be defined
as the persistent inability to attain or maintain
an erection that lasts long enough for satisfactory
sexual activity (Hatzimouratidis et al, 2010). ED
affects over half of men with diabetes, (Diabetes
UK, 2013) and around 5% of men with ED have
undiagnosed diabetes (Nieschlag et al, 2006).
It is three times more common and occurs
10–15 years earlier in life in men with diabetes
than those without (Feldman et al, 1994).
An erection is initiated by sexual stimulation
and is a vascular process controlled by the
autonomic nervous system. The blood vessels in
the corpora cavernosa dilate, leading to increased
arterial inflow and reduced venous outflow.
Smooth muscle relaxation is crucial, and nitric
oxide (NO) has been identified as the agent
largely responsible for smooth muscle relaxation
in the corpora cavernosum. NO stimulates
guanylate cyclase, which leads to increased
production of cyclic guanosine monophosphate,
and it is thought that this induces smooth muscle
relaxation through the opening of calcium
channels (Price, 2010). In men with diabetes,
evidence suggests that autonomic neuropathy
and endothelial dysfunction contribute to the
failure of NO-induced smooth muscle relaxation,
resulting in ED (Sáenz de Tejada et al, 1989;
2004). The pathophysiology in diabetes is
complex, however, and knowledge has been
gradually increasing since the 1990s (Cellek et
al, 2013).
Citation: Edwards D, Forgione N
(2017) Sexual health and dysfunction
in men and women with diabetes.
Diabetes & Primary Care Australia
2: 91–8
Article points
1. Men with diabetes are more
likely to develop erectile
dysfunction, have androgen
deficiency, premature
ejaculation, balanitis,
phimosis, Peyronie’s disease
and penile fibrosis than
men without diabetes.
2. Women with diabetes may
present with sexual dysfunction,
fungal and bacterial infections,
polycystic ovarian syndrome
and fertility problems.
3. Clinicians can encourage
patients to provide a full
sexual history by listening,
looking interested, maintaining
eye contact and providing
encouraging verbal and
non-verbal cues.
Key words
– Androgen deficiency
– Contraception
– Sexual dysfunction
Authors
David Edwards is a GP at
Claridges Barn, Chipping
Norton, Oxfordshire, UK, and
Past President of the British
Society for Sexual Medicine;
Nicholas Forgione is a GP in
Perth, Western Australia with a
special interest in diabetes.
Diabetes & Primary Care Australia Vol 2 No 3 2017 91

Sexual health and dysfunction in men and women with diabetes
Page points
1. Erectile dysfunction (ED) in
men with diabetes is often
multifactorial in aetiology
and can be more severe and
resistant to treatment than in
men without ED.
2. There is evidence that ED
may be an early marker for
endothelial dysfunction, and
that cardiovascular health
should be assessed in men
presenting with ED.
3. The individual presenting with
ED must be medically assessed.
Assessment should involve a
sexual, medical, psychosocial
and cultural evaluation.
4. Three phosphodiesterase-5
(PDE5) inhibitors are currently
available in Australia –
sildenafil, tadalafil and
vardenafil
Box 1. Factors involved in erectile dysfunction
in diabetes.
l Autonomic neuropathy
l Peripheral neuropathy
l Hypertension
l Peripheral vascular disease
l Hyperlipidaemia
l Drug-related side effects
l Hypogonadism with reduced sexual desire
(double risk)
l Psychological factors including depression
l Ejaculatory disorders
l Retrograde ejaculation or anejaculation
l Reduced sensation (e.g. Peyronie’s disease,
balanitis, phimosis, fibrosis)
Assessment, management and treatment of
erectile dysfunction
The MALES (Men’s Attitudes to Life Events
and Sexuality) study demonstrated that 64% of
men with ED reported at least one comorbidity
(Rosen et al, 2004). ED in men with diabetes
is often multifactorial in aetiology (Box 1) and
is more severe and resistant to treatment than
in men without diabetes. ED may be a marker
for diabetes, depression, lower urinary tract
symptoms and cardiovascular disease, and has
an adverse impact on quality of life. It is vital
that when individuals attend for an appointment
related to their diabetes, every consideration and
opportunity is given by the primary care team
to optimise their lifestyle, including smoking
cessation and encouraging exercise. Smoking can
increase the risk of ED (Feldman et al, 1994) and
quitting smoking may improve erectile function,
though the degree of improvement is dependent
on factors such as the severity of the ED prior
to quitting and the presence of other significant
health problems.
Evidence suggests that ED may be an early
marker for endothelial dysfunction (Pegge et al,
2006), and that cardiovascular health should be
assessed in men presenting with ED. Furthermore,
the risk of developing coronary heart disease is
doubled for men with ED and type 2 diabetes
compared with men without ED (Ma et al,
2008). With this in mind, “getting fit for sex” can
be the gateway to improving overall health.
It is important that the individual presenting
with ED (whether or not he has diabetes) is
medically assessed. Assessment involves a sexual,
medical, psychosocial and cultural evaluation.
Physical examination should include a full
cardiovascular, neurological and genito-urinary
assessment. Initial blood tests that should be
considered when assessing a man with ED are
lipids, glucose, HbA 1c
and androgens. Full blood
count, liver function and thyroid function tests
can be useful additional measures. Testing
for prostate-specific antigen, creatinine and
electrolytes should also be considered. Clinicians
should adopt a “treat to target” approach to issues
such as hypertension and hypercholesterolaemia.
Drug therapy
Three phosphodiesterase-5 (PDE5) inhibitors
are currently available in Australia – sildenafil,
tadalafil and vardenafil. These are usually
prescribed as “on demand” dosing, though
tadalafil 5 mg can be used as daily dosing. The
treatment success rate with sildenafil in men with
diabetes has been reported as 56–59% (Price
et al, 1998; Rendell et al, 1999). The choice
between these treatments usually depends on
the preference of the individual. Many men with
diabetes require the maximum dose of PDE-5
inhibitor and it should also be made clear that
the drugs are only effective in combination with
sexual stimulation.
It has been suggested that men who have not
responded to treatment with a PDE-5 inhibitor
may be successful with further education and
attempts at intercourse. One study reported that
intercourse success rates in men treated with
sildenafil reached a plateau after eight attempts.
It can be concluded that men should attempt
intercourse eight times using the maximum
recommended dose of PDE-5 inhibitor before
being considered a non-responder (McCullough
et al, 2002). There is some evidence that PDE5
inhibitor use in men with type 2 diabetes may be
associated with a reduction in all-cause mortality
(Anderson et al, 2016).
92 Diabetes & Primary Care Australia Vol 2 No 3 2017

Sexual health and dysfunction in men and women with diabetes
Other treatments
It may be helpful to prescribe a vacuum erection
device (VED) for use on a daily basis as a penile
trainer to encourage blood flow into the penis
and as a confidence builder, as many people with
ED have been without erections for several years.
The VED is a suitable alternative for men who
do not want to take or have contraindications
to other pharmacological therapies. A consensus
statement that draws together recommendations
for post-surgical ED has confirmed that using a
VED either alone or in combination with other
treatments can be helpful (Kirby et al, 2013).
It is not unusual for men to require more than
one therapy for their ED, which may include
testosterone replacement.
Other forms of ED treatment include injections
into the corpora cavernosum, or penile implant
surgery. In men with neuropathy, alprostadil
injection therapy has been shown to be an
effective treatment for ED (Porst, 1996).
Other novel treatments for ED include lowintensity
extracorporeal shock wave therapy
(Vardi et al, 2012). This procedure has been
demonstrated to work on humans and may add
another dimension to treating ED. Stem-cell
therapy when related to “restoration of normal
penile vasculature and neuronal homeostasis” is
also of interest (Albersen et al, 2013). Similarly,
NO-releasing microspheres have been shown to
improve ED in diabetic rats (Soni et al, 2013).
Time will tell whether these studies become part
of routine ED management.
Guidelines for the management of ED can
be accessed on the Andrology Australia website
(www.andrologyaustralia.org).
Therapies that may cause or worsen erectile
dysfunction
Men with diabetes are commonly prescribed
medications that may include ED as a side
effect, and some people will stop taking these
medications as a result, often without telling
their doctor. Such drugs include statins,
antihypertensive and antidepressant medications
(e.g. non-selective beta-blockers and diuretics).
However, withdrawal of a drug could compromise
the treatment of another important condition
and it is important to remember that the problem
being treated, as well as the drugs prescribed to
treat it, can be associated with ED. It may be
possible to change or modify an individual’s
treatment to drugs that are less likely to impact
erectile function.
Androgen deficiency
Androgen deficiency affects about 1 in 200
men under the age of 60 and can present with
symptoms of reduced libido or ED (Nieschlag et
al, 2004). In a study by Kapoor et al (2007), 20%
of men with diabetes had a total testosterone
level of

Sexual health and dysfunction in men and women with diabetes
Page points
1. Men with poor metabolic
control are more likely to report
premature ejaculation.
2. The prevalence of female sexual
dysfunction in women with
diabetes is between 14% and
71%.
3. Low desire and reduced
lubrication are the most
commonly reported female
sexual dysfunctions.
4. Simple but effective treatment
for female sexual dysfunction
includes topical hormone
replacement therapy and/or
lubricants.
phimosis, which can make sexual activity
uncomfortable or painful. It is therefore
important that full enquiry is made regarding
these conditions.
PE is common in men with diabetes. One
study reported a prevalence of 32.4% in men with
type 2 diabetes aged under 50 years and 67.6% in
such individuals above 50 years. Men with poor
metabolic control were 9.6 times more likely to
report PE compared with those who had good
metabolic control (El-Sakka, 2003). Dapoxetine
is available for prescribing to men aged between
18 and 64 years who experience PE. It is a shortacting,
quick-onset selective serotonin reuptake
inhibitor. It is taken orally and can be used as
needed (approximately 1–3 hours prior to sexual
activity). Other longer-acting selective serotonin
reuptake inhibitors such as fluoxetine, paroxetine
and sertraline are also commonly used.
Balanitis (inflammation of the glans penis)
can have both physical and psychological effects
on ED and intercourse owing to irritation,
pain, discharge and anxiety associated with
transmitting a fungal infection to a partner.
The prevalence of balanitis in men with diabetes
was found to be 16% compared with 5.8% in
men without diabetes (Fakjian et al, 1990).
Furthermore, Drivsholm et al (2005) found
that 12% of men had suffered from balanitis in
the 2 years prior to them being diagnosed with
diabetes.
Phimosis (a condition where the foreskin
cannot be retracted) and Peyronie’s disease
(growth of connective scar tissue in the penis)
can also affect the ability to have intercourse, and
both are more common in men with diabetes.
The prevalence of Peyronie’s disease in men
with diabetes and ED has been estimated as
20.3% (Arafa et al, 2007). Data on the natural
history of Peyronie’s disease suggest that 13%
of cases will gradually resolve, 47% will remain
stable and 40% will worsen (Gelbard et al,
1990). There are various treatments available,
directed at those in whom the condition is
getting worse, including surgery and verapamil
injection.
Phimosis is common in men with diabetes.
One study showed that 32% of men presenting
at a urology clinic had diabetes and phimosis
(Bromage et al, 2008), reinforcing the need to
check fasting blood glucose levels when this
condition is discovered. Physiological phimosis
may just require an improvement in hygiene and
observation, whereas pathological phimosis will
require referral to a urologist.
Diabetes can also cause penile fibrosis due to
loss of endothelium and smooth muscle cells
from the corpus cavernosum (Burchardt et al,
2000).
Sexual health in women with diabetes
The paucity of knowledge regarding female
diabetes and sexual health is only gradually being
addressed. Research has been difficult to design
and there are many methodological problems
(De Veciana, 1998).
Nowosielski et al (2010) conducted an analysis
of 544 Polish women, as well as reviewing a
number of studies on women with diabetes.
The authors found that the prevalence of female
sexual dysfunction in women with diabetes
was between 14% and 71% (17–71% with
type 1 and 14–51% with type 2 diabetes),
but they accepted it could be either underor
overestimated. Low desire (17–85%) and
reduced lubrication (14–76%) were the most
frequently reported female sexual dysfunctions;
orgasmic and pain disorders were less common
(1–66% and 3–61%, respectively). The authors
describe possible explanations as to the causes
of this, including decreased receptivity to sexual
stimulation and endothelial deregulation due to
diabetic neuropathy (Nowosielski et al, 2010).
Caruso et al (2006) found that reduced sexual
satisfaction and sexual activity were a result
of decreased clitoral blood flow. Some authors
comment that factors such as age, body mass
index, duration of diabetes, glycaemic control,
HbA 1c
level, menopausal status, the use of
hormonal and oral contraceptives, or even the
presence of diabetes complications could be
relevant, whereas others found contradictory
results. An association has been found in
women with type 1 diabetes between retinopathy
and reduced vaginal blood flow, and in the
same study women with neuropathy were also
found to have reduced clitoral sensitivity (Both
et al, 2012).
94 Diabetes & Primary Care Australia Vol 2 No 3 2017

Sexual health and dysfunction in men and women with diabetes
Simple but effective treatments for female sexual
dysfunction include topical hormone replacement
therapy (Rees, 2009) using topical oestrogens,
vaginal lubricants or a combination of the two.
Care is required when advising or prescribing
vaginal moisturisers and lubricants (Edwards
and Panay, 2016). Many women with type 2
diabetes are post-menopausal and the symptoms
of menopause can include vaginal dryness and
a lack of libido, among others. Guidelines on
the management of post-menopausal women are
available from the Australian Menopause Society
(www.menopause.org.au).
Pre-conception care
The joint Royal Australian College of General
Practitioners/Diabetes Australia (2016) guideline
for diabetes in pregnancy recommends that
women with diabetes should be informed
about the benefits of good pre-conception
glycaemic management. In a study by Pearson
et al (2007), women who planned for pregnancy
and waited until their glycaemia was under
control before stopping contraception had
lower rates of adverse outcomes. For advice on
pre-pregnancy blood glucose targets, refer to
www.pregnancyanddiabetes.com.au.
Contraception
Women of childbearing age should be informed
about the need for effective contraception.
Women with diabetes (type 1 and type 2)
with no vascular disease can generally use any
form of contraception. However, women with
nephropathy, neuropathy, retinopathy or other
vascular disease should not use progestogenonly
injectable contraception because the side
effects can aggravate these complications. These
include a tendency to gain weight; a potential
increase in coagulation factors for prothrombin
(II), VII, VIII, IX and X; a risk of retinal
thrombosis; potential glucose intolerance; and,
rarely, abscess formation at the injection site.
Likewise, combined oral contraceptives should
only be used with consideration of the above
risk factors. Sterilisation is an option but must
be performed in a setting with healthcare
professionals experienced in managing diabetes,
as well as backup medical support. Contraception
Box 2. Case example.
Mr G, aged 28 years, presented to his GP with erectile dysfunction (ED). He has type 1
diabetes and is treated with a basal-bolus insulin regimen. He has read about the effect that
diabetes can have on erections. He has been married for 2 years and has had ED for the past
6 months but still has early morning erections.
After taking a fuller history it transpired that his mother-in-law is dying from cancer and
there is family pressure to conceive a first grandchild before she dies. This social pressure
had put psychological strain on him to perform sexually to fit in with his wife’s ovulation.
An explanation of the effect of psychological stress on performance, fertility education and
a phosphodiesterase-5 inhibitor enabled a grandson to be conceived and born prior to his
mother-in-law’s death.
– an Australian Clinical Practice Handbook
(National Health and Medical Research Council,
2012) provides further guidance on contraceptive
management.
Other diabetes-related sexual problems
Fungal and bacterial infections are common
in women with diabetes, and vulvovaginal
candidiasis occurs more often in this group
(Bohannon, 1998). Vulvovaginal candidiasis that
is chronically recurring can be a marker for
diabetes (Sobel, 1997). It may also occur as a
side effect of SGLT-2 inhibitor therapy in both
men and women. An improvement in glycaemic
control can reduce the risk of reinfection.
Polycystic ovary syndrome (PCOS) is a
common problem, affecting 5–10% of all women
of childbearing age. The most common features
are hyperandrogenism and chronic anovulation,
which can lead to infertility and sexual
dysfunction (Eftekhar et al, 2014). There is a high
prevalence of diabetes (16%) and hypertension
(40%) in women with PCOS (Carmina and
Lobo, 1999). Metformin can help improve
insulin sensitivity sufficiently to induce ovulation
and facilitate conception. Clomiphene citrate is
the drug of choice in inducing ovulation (Balen
and Rutherford, 2007a), but where there is a lack
of ovarian response, other more complicated and
expensive treatment regimens may be needed
(Carmina and Lobo, 1999). Once pregnancy is
achieved there is increased risk of spontaneous
abortion because of abnormal hormonal levels,
abnormal embryos due to atretic oocytes, and
an abnormal endometrium (Carmina and Lobo,
1999). In the established pregnancy, there
are increased rates of complications such as
Diabetes & Primary Care Australia Vol 2 No 3 2017 95

Sexual health and dysfunction in men and women with diabetes
Box 3. Taking a basic sexual history.
Below are a range of areas that should be covered to take a full sexual history.
l “So, what appears to be the problem?” – Ideally, try to obtain both the
patient’s and partner’s perspective.
l “How long has it been going on?” – Establish the severity of the problem.
l “What actually happens?”
l Confirm the duration of relationship, and the partner’s age and gender.
l If there are multiple partners, past or present, establish if the problem has
occurred with all of them.
l Establish if the partner has a problem. Is it sexual (e.g. atrophic vaginitis),
general medical (e.g. arthritis in the knees) or psychological (e.g. depression)?
l Determine if intercourse is possible and, if so, what sort (vaginal, oral
or anal)?
l Establish if there is the same problem with masturbation.
l Enquire about sexually transmitted infections past or present (in the patient
or partner) and protective measures taken.
l Ask about the need for contraception or if conception is being attempted.
l Explore the general medical and social history (past and present).
l Consider the potential impact of other medical conditions such as
cardiovascular disease, depression and cancer (in the patient and partner).
l Establish if there have been any hospital admissions or surgery (especially
genital), past or present, not forgetting obstetric or infertility aspects.
l Consider who else is at home (children, elderly relatives, flatmates or
animals)?
l Determine if there is any work or family stress, and if there have been any
changes in the patient’s situation or level of stress?
l Explore if there any cultural or religious factors regarding the patient and
partner.
l Obtain a drug history and ask about whether drugs used were prescribed or
recreational and when they were initiated or discontinued with regard to a
sexual problem.
pre-eclampsia, diabetes, premature labour and
stillbirth. In a study by Legro et al (1999), almost
a third of women with PCOS of reproductive
age had impaired glucose tolerance and 7.5%
had diabetes. Basson et al (2010) noted that
overweight but not lean women with PCOS have
an increased incidence of sexual dysfunctions,
noting that further research in such women with
PCOS was needed. The authors also commented
that an “optimal balance of hormonal milieu is
critical to normal sexual functioning” but that
hormones were only one component.
Diabetes-related infertility in men
and women
The link between diabetes and ED has already
been discussed and needs to be assessed when
couples present with fertility issues. Integrity
of the central and peripheral neurotransmitters
and autonomic nervous system are of paramount
importance for erection and ejaculation (Sáenz de
Tejada and Goldstein, 1988).
The main link between women with diabetes
and fertility problems appears to be obesity.
Weight loss improves not only the endocrine
profile but also the reproductive outcome, and
5–10% weight loss can reduce central fat by as
much as 30% (Norman et al, 2004). Insulin
resistance is an important pathophysiological
abnormality (Balen and Rutherford, 2007b) and
the greater the degree of insulin resistance, the
longer the time interval between menstrual
bleeds (Balen et al, 1995).
Effect of diabetes on psychological,
physical and social wellbeing
The pathophysiological changes of sexual
dysfunction that are associated with diabetes
are mainly due to a variable combination of
neuropathy, vasculopathy, hypogonadism
and locally-occurring pathological factors.
Although the physical effects of diabetes are well
established, it should be remembered that social
and psychological aspects can also play a part in
sexual dysfunction. This is illustrated by the case
example in Box 2.
The chronic nature of diabetes and its
complications can lead to relationship
problems, including arousal difficulties and
sexual inhibition. Men with diabetes may need
more physical stimulation, which may not be
appreciated by the partner, who might feel
unloved and less attractive. This can then lead
to poor self-esteem, anxiety and depression
(Bancroft and Gutierrez, 1996).
Consultation and referral
Discussing sex with an individual
A number of barriers that stop healthcare
professionals raising the subject of sex have been
identified (Athanasiadis et al, 2006):
l Lack of relevant training.
96 Diabetes & Primary Care Australia Vol 2 No 3 2017

Sexual health and dysfunction in men and women with diabetes
l Embarrassment.
l Time constraints.
l Conservative sexual beliefs.
l Insufficient knowledge on sexual health.
l Insufficient acceptance of the individual’s
sexual profile.
Respecting confidentiality at all times can be
especially important in this area. Furthermore,
cultural and religious attitudes need to be
considered. It is also important to enquire about
the partner’s sexual and general health. It is
always helpful to encourage the partner to attend
or offer for him or her to come to the follow-up
appointment to obtain this person’s perspective.
Adolescents with diabetes are not excluded
from having anxieties concerning sexual matters,
and particular attention needs to be paid to this
group; they may be having difficulty enough just
coming to terms with their diagnosis of diabetes.
Finally, it is worth being aware that people may
present with a “calling card” (e.g. athlete’s foot)
to test the clinician out. It is important to ask
about sexual function so that the individual has
the opportunity to voice any concerns.
Taking a basic sexual history
Every interaction between patient and clinician
will be subtly different, but in broad terms the
“art” of taking a sexual history is to listen, look
interested, maintain good eye contact and be
encouraging with both non-verbal and verbal
cues (Box 3). It is particularly important in such
conversations that the clinician adopts a nonjudgemental,
caring and professional consulting
style to minimise embarrassment.
As part of the consultation, it is vital to
ascertain what actually happens (and what does
not) during sexual activity. Also, one needs to be
prepared that consultations covering this topic
may run into other areas. For instance, ED may
be an expression of underlying psychosexual
issues, and this may need to be discussed with a
trained counsellor.
When to refer
Unlike many topics in general practice, sexual
dysfunction seems to have a wide range of referral
patterns. Some clinicians refer early to a specialist
while others will manage the majority of their
patients, carrying out investigations and treating
where necessary. Typical reasons to refer include:
l Pronounced psychosexual therapy needs.
l A desire to initiate therapies for ED such
as intracavernosal injections, and surgery
options.
l Non-response to PDE-5 inhibitors.
l Consideration of testosterone replacement
therapy.
l A requirement for specialist investigations
for comorbidities, such as exercise tolerance
testing.
l Referrals for comorbidities found during
assessment, such as prostate cancer.
l The sexual dysfunction being of a nature that
is outside the competence of the clinician.
Conclusion
Sexual problems are common in both men and
women with diabetes. Healthcare professionals
need to be comfortable asking individuals about
such problems and, where necessary, refer on
to sexual dysfunction specialists. By using the
individual skills of healthcare professionals, both
the person’s sexual difficulties and any medical
or lifestyle issues can be progressively addressed,
so that he or she is empowered and encouraged
to holistically improve not only sexual issues but
also general health.
n
Acknowledgement
This article has been modified from one
previously published in Diabetes & Primary Care
(2016, 18: 288–96).
Albersen M et al (2013) Sexual Medicine Reviews 1: 50–64
Anderson et al (2016) Heart 102: 1750–6
Andrology Australia (2014) Erectile dysfunction. http://bit.ly/2fKYxur
(accessed 21.06.2017)
Arafa M et al (2007) Int J Impot Res 19: 213–17
Athanasiadis L et al (2006) J Sex Med 3: 47–55
Balen AH et al (1995) Hum Reprod 10: 2107–11
Balen AH, Rutherford AJ (2007a) BMJ 335: 663–6
Page points
1. Respecting confidentiality at
all times can be especially
important when discussing a
patient’s sexual history.
2. It is important to ask about
sexual function so an individual
has the opportunity to voice
any concerns.
3. Health professionals need to be
comfortable asking individuals
about sexual problems and
to refer patients to specialists
when necessary.
Diabetes & Primary Care Australia Vol 2 No 3 2017 97

Sexual health and dysfunction in men and women with diabetes
“By using the
individual skills
of healthcare
professionals, both
the person’s sexual
difficulties and
any medical or
lifestyle issues can
be progressively
addressed.”
Balen AH, Rutherford AJ (2007b) BMJ 335: 608–11
Bancroft J, Gutierrez P (1996) Diabet Med 13: 84–9
Basson R et al (2010) J Sex Med 7: 314–26
Bohannon NJ (1998) Diabetes Care 21: 451–6
Both S et al (2012) J Sex Med 9(Suppl 5): 303–35
Bromage SJ et al (2008) BJU Int 101: 338–40
Burchardt T et al (2000) J Urol 164: 1807–11
Mulligan T et al (2006) Int J Clin Pract 60: 762–9
National Health and Medical Research Council (2012)
Contraception – an Australian Clinical Practice Handbook (4 th
edition). Australian Government. http://bit.ly/2sqlf3i (accessed
21.06.17)
Nieschlag E et al (2004) Hum Reprod Update 10: 409–19
Nieschlag E et al (2006) J Androl 27: 135–7
Norman RJ et al (2004) Hum Reprod Update 10: 267–80
Nowosielski K et al (2010) J Sex Med 7: 723–35
Carmina E, Lobo RA (1999) J Clin Endocrinol Metab 84: 1897–9
Pearson DW et al (2007) BJOG 114: 104–7
Caruso S et al (2006) Urology 68: 161–5
Pegge NC et al (2006) Diabet Med 23: 873–8
Cellek S et al (2013) Int J Impot Res 25: 1–6
Porst H (1996) J Urol 155: 802–15
De Veciana M (1998) Diabetes Rev 6: 54–64
Diabetes UK (2013) Sex and Diabetes. Diabetes UK, London, UK.
Available at: http://bit.ly/8Tr1bb (accessed 23.06.17)
Drivsholm T et al (2005) Diabetologia 48: 210–14
Price D (2010) Sexual function in men and women with diabetes. In:
Holt RIG, Cockram CS, Flyvbjerg A, Goldstein BJ (eds). Textbook
of Diabetes (4 th edition). Wiley-Blackwell, Oxford, UK
Price DE et al (1998) Diabet Med 15: 821–5
Edwards D, Panay N (2016) Climacteric 19: 151–61
Rees M (2009) Br J Sex Med 32: 4–6
Eftekhar T et al (2014) Iran J Reprod Med 12: 539–46
Rendell MS et al (1999) JAMA 281: 421–6
El-Sakka AI (2003) Int J Androl 26: 329–34
Rosen RC et al (2004) Curr Med Res Opin 20: 607–17
Fakjian N et al (1990) Arch Dermatol 126: 1046–7
Feldman HA et al (1994) J Urol 151: 54–61
Royal Australian College of General Practitioners, Diabetes Australia
(2016) General Practice Management of Type 2 Diabetes, 2016–
2018. East Melbourne, Vic. Available at: http://bit.ly/2egrFIW
(accessed 21.06.17)
Gelbard MK et al (1990) J Urol 144: 1376–9
Sáenz de Tejada I, Goldstein I (1988) Urol Clin North Am 15: 17–22
Hatzimouratidis K et al (2010) Eur Urol 57: 804–14
Sáenz de Tejada I et al (1989) N Engl J Med 320: 1025–30
Kapoor D et al (2007) Diabetes Care 30: 911–17
Sáenz de Tejada I et al (2004) J Sex Med 1: 254–65
Kirby M et al (2013) Int J Clin Pract 67: 606–18
Shores MM et al (2006) Arch Intern Med 166: 1660–5
Legro RS et al (1999) J Clin Endocrinol Metab 84: 165–9
Sobel JD (1997) N Engl J Med 337: 1896–903
Ma RC et al (2008) J Am Coll Cardiol 51: 2045–50
Soni S et al (2013) J Sex Med 10: 1915–25
McCullough AR et al (2002) Urology 60(Suppl 2): 28–38
Vardi Y et al (2012) J Urol 187: 1769–75
98 Diabetes & Primary Care Australia Vol 2 No 3 2017

Call for papers
Would you like to write an article
for Diabetes & Primary Care Australia?
The new journal from the Primary Care Diabetes Society of Australia
To submit an article or if you have any queries, please contact: rajna.ogrin@pcdsa.com.au.
Title page
Please include the article title, the full names of the authors
and their institutional affiliations, as well as full details of
each author’s current appointment. This page should also have
the name, address and contact telephone number(s) of the
corresponding author.
Article points and key words
Four or five sentences of 15–20 words that summarise the major
themes of the article. Please also provide four or five key words
that highlight the content of the article.
Abstract
Approximately 150 words briefly introducing your article,
outlining the discussion points and main conclusions.
Introduction
In 60–120 words, this should aim to draw the reader into the
article as well as broadly stating what the article is about.
Main body
Use sub-headings liberally and apply formatting to differentiate
between heading levels (you may have up to three heading levels).
The article must have a conclusion, which should be succinct and
logically ordered, ideally identifying gaps in present knowledge and
implications for practice, as well as suggesting future initiatives.
Tables and illustrations
Tables and figures – particularly photographs – are encouraged
wherever appropriate. Figures and tables should be numbered
consecutively in the order of their first citation in the text. Present
tables at the end of the articles; supply figures as logically labelled
separate files. If a figure or table has been published previously,
acknowledge the original source and submit written permission
from the copyright holder to reproduce the material.
References
In the text
Use the name and year (Harvard) system for references in the
text, as exemplified by the following:
● As Smith and Jones (2013) have shown …
● As already reported (Smith and Jones, 2013) …
For three or more authors, give the first author’s surname
followed by et al:
● As Robson et al (2015) have shown …
Simultaneous references should be ordered chronologically first,
and then alphabetically:
● (Smith and Jones, 2013; Young, 2013; Black, 2014).
Statements based on a personal communication should be
indicated as such, with the name of the person and the year.
In the reference list
The total number of references should not exceed 30 without prior
discussion with the Editor. Arrange references alphabetically first,
and then chronologically. Give the surnames and initials of all
authors for references with four or fewer authors; for five or more,
give the first three and add “et al”. Papers accepted but not yet
published may be included in the reference list as being “[In press]”.
Journal article example: Robson R, Seed J, Khan E et al (2015)
Diabetes in childhood. Diabetes Journal 9: 119–23
Whole book example: White F, Moore B (2014) Childhood
Diabetes. Academic Press, Melbourne
Book chapter example: Fisher M (2012) The role of age. In: Merson
A, Kriek U (eds). Diabetes in Children. 2nd edn. Academic Press,
Melbourne: 15–32
Document on website example: Department of Health (2009)
Australian type 2 diabetes risk assessment tool (AUSDRISK).
Australian Government, Canberra. Available at: http://www.
health.gov.au/preventionoftype2diabetes (accessed 22.07.15)
Article types
Articles may fall into the categories below. All articles should be
1700–2300 words in length and written with consideration of
the journal’s readership (general practitioners, practice nurses,
prescribing advisers and other healthcare professionals with an
interest in primary care diabetes).
Clinical reviews should present a balanced consideration of a
particular clinical area, covering the evidence that exists. The
relevance to practice should be highlighted where appropriate.
Original research articles should be presented with sections
for the background, aims, methods, results, discussion and
conclusion. The discussion should consider the implications
for practice.
Clinical guideline articles should appraise newly published
clinical guidelines and assess how they will sit alongside
existing guidelines and impact on the management of diabetes.
Organisational articles could provide information on newly
published organisational guidelines or explain how a particular
local service has been organised to benefit people with diabetes.
— Diabetes & Primary Care Australia —

CPD module
Managing dyslipidaemia
in the context of diabetes
Mike Kirby, Roy Rasalam
Citation: Kirby M, Rasalam R
(2017) Managing dyslipidaemia in
the context of diabetes. Diabetes &
Primary Care Australia 2: 100–10
Learning objectives
After reading this article, the
participant should be able to:
1. Outline the underlying
process in the development
of atherosclerosis and its
contribution to major adverse
cardiovascular events.
2. Define the relationship between
lipid levels and cardiovascular
risk in people with diabetes.
3. Describe the recommended
options for lipid management
in people with diabetes.
Key words
– Cardiovascular disease
– Cardiovascular risk
– Cholesterol
– Dyslipidaemia
Authors
Mike Kirby is Visiting Professor,
Centre for Research in Primary &
Community Care, University of
Hertfordshire, UK; Roy Rasalam
is Director of Clinical Studies,
College of Medicine, James Cook
University, Qld, Australia.
People with diabetes have an increased risk of cardiovascular complications, including acute
coronary syndrome, stroke, heart failure and arrhythmias. The background to this risk for the
development of cardiovascular complications is multifactorial and our understanding of the
nature of atherosclerotic disease has progressed considerably. This article explores the latest
thinking on the link between the various facets of dyslipidaemia and cardiovascular risk, and
reviews current evidence for lipid management in people with diabetes.
Cardiovascular disease (CVD) is a major
cause of death in Australia causing
approximately 45 000 deaths in 2015.
CVD kills one Australian every 12 minutes
(National Heart Foundation of Australia, 2015).
People with diabetes have an increased risk of
cardiovascular complications, including acute
coronary syndrome, stroke, heart failure and
arrhythmias. Data suggest that people with diabetes,
without prior cardiovascular disease (CVD), have
similar rates of myocardial infarction as people
without diabetes who have had previous events
(Haffner et al, 1998; Malmberg et al, 2000;
Donahoe et al, 2007). Type 2 diabetes more than
doubles the risk of heart failure hospitalisation
and death (Davis and Davis, 2015). Women with
diabetes are more likely to develop coronary heart
disease (CHD; Peters et al, 2014) and are at greater
relative risk of dying from CVD than their male
counterparts (Juutilainen et al, 2004).
The background to this risk for the development
of cardiovascular complications is multifactorial and
our understanding of the nature of atherosclerotic
disease has progressed considerably. The concept
that atherosclerosis is a gradual process, leading to
narrowing of the arteries until such a point that a
thrombus forms and occludes a vessel, is naive. The
concept was originally questioned by pathologists
who showed that most myocardial infarctions are
caused by low-grade stenosis (Falk et al, 1995).
The current approach is to define atherosclerotic
plaques as either stable, which can lead to high-grade
obstruction, or unstable, which are vulnerable to
rupture and show a high incidence of thrombosis
(Davies, 1996).
The initial phase of the development of
atherosclerosis is endothelial dysfunction caused by
hyperglycaemia, with or without hypertension, and
dyslipidaemia and the adverse effect of adipose tissuederived
inflammatory cytokines. These include
tumour necrosis factor-alpha (TNF-alpha) and
interleukin-6 (IL-6). The effect of this is to produce
adhesion molecules, inflammatory mediators
and cytokines that stimulate the involvement of
inflammatory cells such as monocytes, which then
enter the vessel wall and further stimulate the
inflammatory response by interacting with oxidised
low-density lipoproteins (LDLs).
Oxidised LDLs have long been recognised as
regulators of macrophage functions, including lipid
accumulation and foam cell formation (Vangaveti
et al, 2014). In addition, there is a reduction in
the release of nitric oxide (NO), leading to vessel
constriction (Xu and Zou, 2009). Subsequently,
the monocytes differentiate into macrophages and
foam cells, which further stimulate the release of
inflammatory mediators (Hansson, 2005). What
can be seen at this stage is a fatty streak. The
platelet hyperactivity that is present in diabetes
probably contributes to the further development of
100 Diabetes & Primary Care Australia Vol 2 No 3 2017

CPD module
lesions at this stage (Ross, 1999). Eventually, more
complicated lesions occur and the core of the plaque
becomes necrotic. This necrotic core is protected by
a fibrous cap, and it is those lesions that have a thin
and vulnerable fibrous cap that are likely to become
unstable plaques (Hansson et al, 1988).
Plaques in people with diabetes are more likely to
rupture, with consequent thromboembolic events,
because of the inflammatory process within (Moreno
et al, 2000). Techniques using intra-vascular
ultrasound with virtual histology (IVUS-VH) have
advanced our knowledge of plaque morphology
(Lindsey et al, 2009).
In addition to the effect on the wall, there is a
subset of people with diabetes who acquire diabetic
cardiomyopathy during the course of this disease.
The nature of this process in not clearly defined,
but there are functional and structural changes in
the cardiac muscle that cause cardiac enlargement,
increased stiffness and impaired diastolic function,
which eventually leads to heart failure (Devereux
et al, 2000). Heart failure is more common in the
presence of poor glucose control, suggesting that
hyperglycaemia may be an important contributor
(Lind et al, 2011).
Clearly, good blood glucose control (i.e. reducing
hyperglycaemia and avoiding hypoglycaemia in
the process), particularly in the early stages of the
disease, good blood pressure control throughout, and
attention to dyslipidaemia is critically important in
people with diabetes to prevent this atherosclerotic
Box 1. High-density lipoprotein cholesterol
functionality: Relevance to athero- and
vasculoprotection (Chapman et al, 2011).
l Regulation of glucose metabolism
l Cholesterol homeostasis and cellular
cholesterol efflux
l Endothelial repair
l Anti-inflammatory activity
l Anti-oxidative activity
l Anti-apoptotic activity
l Anti-thrombotic activity
l Anti-protease activity
l Vasodilatory activity
l Anti-infectious activity
process (Colhoun et al, 2004; Holman et al, 2008).
Lipid levels and cardiovascular risk
In diabetes, LDL cholesterol may not be significantly
elevated compared with matched individuals
without the disease, but it is a smaller, denser, more
atherosclerotic particle (Mazzone et al, 2008).
The well-established treatment approach is to focus
on the use of LDL cholesterol-lowering drugs such as
statins. There is a clear linear relationship between
the degree of LDL-cholesterol lowering achieved
with statins and benefits, with a 10% and 21%
reduction in all-cause mortality and major vascular
events, respectively, per 1.0 mmol/L reduction in
LDL cholesterol (Baigent et al, 2010).
Statin therapy reduces cardiovascular events by
22–48% (Collins et al, 2003; Colhoun et al, 2004);
however, there still appears to be an excess residual
cardiovascular risk among statin-treated people with
diabetes compared with those without the disease
(Costa et al, 2006). This residual risk may result from
lipoprotein abnormalities that occur in diabetes,
which are not adequately addressed by statin therapy
(Mazzone et al, 2008).
Dyslipidaemia in type 2 diabetes is characterised
by increased concentrations of triglyceride-rich
lipoproteins, decreased concentrations of high-density
lipoprotein (HDL) cholesterol and abnormalities in
the composition of triglyceride-rich HDL and LDL
particles (Garvey et al, 2003; Deeg et al, 2007). HDL
is a very complex lipoprotein particle and changes in its
composition may affect its atherosclerotic properties
(Mazzone, 2007). The failure of cholesteryl ester
transfer protein (CETP) inhibition with torcetrapib
to protect against cardiovascular events suggests
that HDL particle composition may be a more
important consideration than HDL cholesterol level
in the reduction of cardiovascular risk (Barter et al,
2007). However, the REVEAL trial (which will be
published in late 2017) will report on the efficacy and
safety of the last CETP inhibitor in ongoing trials,
anacetrapib, versus placebo on major coronary events
in patients taking atorvastatin (Landray et al, 2017).
Box 1 examines the relevance of HDL cholesterol
functionality to athero- and vasculo-protection.
The case for non-HDL cholesterol
It is likely that combined dyslipidaemia may confer
a higher magnitude of risk than elevated LDL
Page points
1. Plaques in people with diabetes
are more likely to rupture, with
consequent thromboembolic
events, because of the
inflammatory process within.
2. A subset of people with
diabetes develop diabetic
cardiomyopathy with cardiac
muscle changes that cause
cardiac enlargement, increased
stiffness and impaired diastolic
function, which eventually
leads to heart failure.
3. In diabetes, LDL cholesterol
may not be significantly
elevated, but it is a smaller,
more dense and atherosclerotic
particle. There are increased
concentrations of triglyceride
(TG)-rich lipoproteins,
decreased HDL cholesterol and
abnormalities in composition of
TG-rich HDL and LDL particles.
4. Cholesteryl ester transfer
protein (CETP) inhibition aims
to elevate HDL levels but, thus
far, has been unsuccessful
in lowering coronary events
without safety signals.
Anacetrapib is the last CETP
inhibitor in ongoing trials; data
is due for release in late 2017.
Diabetes & Primary Care Australia Vol 2 No 3 2017 101

CPD module
Low-density
lipoprotein
cholesterol
Very low-density
lipoprotein
cholesterol
Cholesterol content
of all atherogenic
lipoprotein particles
Intermediatedensity
lipoprotein
cholesterol
Non-HDL cholesterol
Non-HDL cholesterol = Total cholesterol – HDL cholesterol
Lipoprotein(a)
cholesterol
Figure 1. Components of non-high-density lipoprotein (non-HDL) cholesterol (redrawn with
kind permission of the author from Virani, 2011).
cholesterol alone (Assman and Schulte, 1992).
Triglycerides appear to be an independent risk factor
(Austin et al, 1998), although they may be a marker
of low HDL cholesterol. LDL cholesterol may
underestimate CVD risk, particularly in the presence
of hypertriglyceridaemia. The measurement of non-
HDL cholesterol partially overcomes this problem
(Anastasius et al, 2017). Non-HDL cholesterol may
be defined as the difference between total and HDL
cholesterol and thus represents cholesterol carried
on all the potentially pro-atherogenic particles
(Hsai, 2003; see Figure 1). By measuring total
cholesterol and HDL cholesterol, and calculating
non-HDL cholesterol, we can avoid the potential
limitations of triglycerides as a marker of CHD risk
and instead measure something that directly reflects
the cholesterol content of all the particles that may
be pro-atherogenic. Another advantage of non-HDL
cholesterol measurement is that it does not need to
be done in the fasting state. Non-HDL cholesterol
may be, therefore, a readily obtainable, inexpensive
and convenient measure of CHD risk that may be
superior to LDL cholesterol in many respects (Hsai,
2003).
A meta-analysis of individual patient data
from eight randomised trials, in which nearly
40 000 patients received statins, evaluated the relative
strength of the association between conventional
lipids and apolipoproteins (determined at baseline
at 1 year follow-up) with cardiovascular risk. One
standard deviation increases from baseline levels
of LDL, apolipoprotein B (apoB) and non-HDL
at 1 year were all associated with increased risks of
cardiovascular events, but the differences between
LDL and non-HDL were significant. Patients
reaching the non-HDL target of under 3.4 mmol/L
(130 mg/dL) but not the LDL target of under
2.6 mmol/L (100 mg/dL) were – assessed relative
to patients achieving both targets – at lower excess
risk than those reaching the LDL target but not the
non-HDL target (Boekholdt et al, 2012; see Table 1).
In other words, non-HDL cholesterol is a better
predictor of risk than LDL cholesterol.
Virani (2011) reviewed non-HDL cholesterol as a
metric of good quality of care. Non-HDL cholesterol
has been shown to be a better marker of risk in both
primary and secondary prevention studies. In an
analysis of data combined from 68 studies, non-
HDL cholesterol was the best predictor among all
cholesterol measures both for coronary artery events
Table 1. Hazard ratios for major cardiovascular events by LDL and non-HDL cholesterol
categories (Boekholdt et al, 2012).
LDL cholesterol level
Non-HDL cholesterol level
Hazard
ratio
95% confidence interval
Not meeting target
(2.6 mmol/L or higher)
Not meeting target
(2.6 mmol/L or higher)
Meeting target
(under 2.6 mmol/L)
Not meeting target
(3.4 mmol/L or higher)
Meeting target
(under 3.4 mmol/L)
Not meeting target
(3.4 mmol/L or higher)
1.21 1.13–1.29
1.02 0.92–1.12
1.32 1.17–1.50
Meeting target
(under 2.6 mmol/L)
Meeting target
(under 3.4 mmol/L)
*Reference.
HDL=high-density lipoprotein; LDL=low-density lipoprotein.
1.00*
102 Diabetes & Primary Care Australia Vol 2 No 3 2017

CPD module
and for strokes (Emerging Risk Factors Collaboration,
2009). In the IDEAL (Incremental Decrease in End
Points through Aggressive Lipid Lowering) trial,
elevated non-HDL cholesterol and apoB levels were
the best predictors after acute coronary syndrome of
adverse cardiovascular outcomes in patients on lipidlowering
therapy (Kastelein et al, 2008).
Elevated levels of non-HDL cholesterol, in
combination with normal levels of LDL cholesterol,
identify a subset of patients with elevated levels of
LDL particle number, elevated apoB concentrations
and LDL of small, dense morphology (Ballantyne et
al, 2001). The increase in the incidence of metabolic
syndrome probably reduces the accuracy of risk
prediction for vascular events when LDL cholesterol is
used for that purpose, whereas non-HDL cholesterol
has been shown to retain predictive capability in this
patient population (Sattar et al, 2004).
The use of non-HDL cholesterol to provide a
better prediction of risk and treatment response than
LDL cholesterol may be particularly relevant in the
growing number of people with type 2 diabetes in
whom an increase in atherogenic lipoproteins is not
reflected by LDL cholesterol levels (JBS3 Board,
2014). Whilst non-HDL has been recommended
Box 2. Adults with any of the following
conditions do not require absolute CVD
risk assessment using the Framingham
Risk Equation (The Royal Australian
College of General Practitioners, 2016a).
l Diabetes and aged >60 years
l Diabetes with microalbuminuria
(>20 µg/min or urine albumin-to-creatinine
ratio [UACR] >2.5 mg/mmol for men and
>3.5 mg/mmol for women)
l Moderate or severe chronic kidney
disease (persistent proteinuria or
estimated glomerular filtration rate [eGFR]
7.5 mmol/L
l Aboriginal or Torres Strait Islander peoples
aged >74 years
for CVD risk assessment in National Institute for
Health and Care Excellence (NICE) guidelines
in the UK, it is not yet endorsed, instead of LDL
cholesterol, in current Australian guidelines.
Identifying and assessing CVD risk
There are several tools available to assess risk for the
primary prevention of CVD including: Australian
CVD Risk Calculator (NVDPA/National Heart
Foundation; 45–75 years age range); QRISK (Joint
British Societies for the Prevention of CVD [JBS3]
recommendations; no specified age range); ACC
(American College of Cardiology; 40–79 years) and
SCORE (European Society of Cardiology; 40–65
years; Anastasius et al, 2017).
Australian diabetes guidelines (The Royal
Australian College of General Practitioners
[RACGP], 2016a) endorse use of the Australian
CVD Risk Calculator, which been adapted from
the Framingham Risk Equation and provides an
estimate of CVD risk over the next 5 years, for
population aged 45–75 years. Patients are categorised
as low risk (15% risk of
CVD).
Box 2 lists adults already known to be clinically
determined high risk of CVD who do not require
assessment using the Framingham Risk Equation
(RACGP, 2016a).
The need for pharmacological treatment, and
therefore who may benefit from medication, is
determined by the assessment and level of absolute
CVD risk (Carrington and Stewart, 2011).
Remember that CVD risk will be underestimated
in people taking antihypertensives or lipid-lowering
drugs, those who have recently stopped smoking
and those who have additional risk due to certain
medical conditions or treatments (e.g. people
taking medications that can cause dyslipidaemia,
such as corticosteroids, antipsychotics and
immunosuppressants). CVD risk is also increased by
severe obesity (BMI >40 kg/m 2 ).
The JBS3 risk calculator is based on the QRISK2
risk assessment tool but has some additional
features that are very helpful in explaining risk,
such as life expectancy and life years gained by
modifying risk factors. This can be accessed online
at www.jbs3risk.com.
Both total and HDL cholesterol should be
Page points
1. The use of non-high density
lipoprotein (HDL) cholesterol
to provide a better prediction
of risk and treatment response
than low-density lipoprotein
(LDL) cholesterol may be
particularly relevant in the
growing number of people
with type 2 diabetes in whom
an increase in atherogenic
lipoproteins is not reflected by
LDL cholesterol levels.
2. Australian diabetes guidelines
endorse the use of the
Australian Cardiovascular
Disease Risk Calculator to
assess risk for the primary
prevention of cardiovascular
disease.
3. Cardiovascular disease risk will
be underestimated in people
taking antihypertensives or
lipid-lowering drugs, and
those who have additional
risk due to certain conditions
or treatments. Risk is also
increased by severe obesity.
Diabetes & Primary Care Australia Vol 2 No 3 2017 103

CPD module
Page points
1. For primary prevention, it is
recommended to calculate
the Absolute Cardiovascular
Disease Risk (available at
www.cvdcheck.org.au) and
initiate therapy based on level
of risk and other clinical factors.
2. For secondary prevention, statin
therapy is recommended for
all patients with coronary heart
disease. For patients admitted
to hospital, statin therapy
should be started while they are
in hospital. In addition, patients
should be considered for low
dose aspirin, ACEi/ARB, betablocker
and management of all
modifiable risk factors.
3. Patients taking statins should
be offered annual medication
reviews. They should also
be advised to seek medical
advice if they develop muscle
symptoms.
4. Ezetimibe targets the NPC1L1
receptor in intestinal cells to
inhibit absorption of cholesterol
and plant sterols. Ezetimibe
lowers LDL cholesterol by
about 20%. The IMPROVE-IT
study demonstrated that
patients post-acute coronary
syndrome receiving ezetimibe
with simvastatin achieved LDL
1.4 mmol/L and relative risk
reduction of 6.4% (P=0.016).
measured to give the best estimation of CVD risk.
Before lipid modification therapy is offered for the
primary prevention of CVD, patients should have
a full lipid profile, including total cholesterol, HDL
cholesterol, non-HDL cholesterol and triglycerides.
Lipid management
People at high risk of, or with, CVD should
be encouraged to play a part in reducing their
personal risk through lifestyle changes, including
achieving and maintaining a healthy weight,
eating a cardioprotective diet, taking more physical
activity, stopping smoking and moderating alcohol
consumption. The management of modifiable risk
factors should also be optimised.
For primary prevention, it is recommended to
calculate the Absolute Cardiovascular Disease Risk
(available at www.cvdcheck.org.au) and initiate
therapy based on level of risk and other clinical
factors (National Vascular Disease Prevention
Alliance, 2012).
Atorvastatin 20 mg or rosuvastatin 10 mg is the
preferred option in patients with a ≥10% 10-year risk
of CVD estimated using the QRISK2 assessment
tool, including those with type 2 diabetes. This
treatment should also be considered for primary
prevention in all adults with type 1 diabetes and
offered to the following people with type 1 diabetes:
l Those who are aged over 40 years.
l Those who have had the condition for more than
10 years.
l Those who have established nephropathy.
l Those who have other risk factors for CVD.
For the secondary prevention of CVD, statin
therapy is recommended for all patients with
existing CVD. For patients admitted to hospital,
statin therapy should commence while they are in
hospital. In addition, patients should be considered
for low dose aspirin, ACEi/ARB, beta-blocker and
management of all modifiable risk factors (National
Heart Foundation of Australia and the Cardiac
Society of Australia and New Zealand, 2012). A
lower dose is recommended if there is a high risk of
adverse effects or the potential for drug interactions,
or if the patient prefers this option. The decision to
start statin treatment should follow discussion with
the patient regarding the risks and benefits, and
consideration of additional factors, such as potential
benefits from lifestyle modification, informed patient
preference, comorbidities, polypharmacy, frailty and
life expectancy (NICE, 2014).
Patients started on high-intensity statin treatment
should have their total cholesterol, HDL cholesterol
and non-HDL cholesterol checked after 3 months,
with a target >40% reduction in non-HDL
cholesterol. If a >40% reduction in non-HDL is not
achieved, look at adherence and timing of dose and/or
consider increasing the dose if the patient was started
on less than 80 mg atorvastatin and is thought to be
higher risk due to risk score, comorbidities or clinical
judgement (NICE, 2014).
For secondary prevention of CVD, all adults
with type 2 diabetes – known prior CVD (except
haemorrhagic stroke) – should receive the maximum
tolerated dose of a statin, irrespective of their lipid
levels. Note: The maximum tolerated dose should
not exceed the maximum available dose (i.e. 80 mg
atorvastatin, 40 mg rosuvastatin). Patients taking
statins should be offered annual medication reviews.
They should also be advised to seek medical advice
if they develop muscle symptoms. JBS3 provides
a step-wise therapeutic approach for patients who
require statin therapy but appear to be intolerant.
It may be appropriate to seek specialist advice about
the options for treating people at high-risk of CVD,
including those with type 1 or type 2 diabetes, who
are intolerant to three different statins.
Ezetimibe targets the NPC1L1 receptor in
intestinal cells to inhibit absorption of cholesterol
and plant sterols. Ezetimibe lowers LDL cholesterol
by about 20% (Tonkin and Byrnes, 2014).
Ezetimibe monotherapy should be considered
for people with primary hypercholesterolaemia in
whom initial statin therapy is contraindicated or not
tolerated. It is recommended as add-on therapy for
people with primary hypercholesterolaemia who have
started statin therapy if the total or LDL cholesterol
is not appropriately controlled after appropriate dose
titration of statin therapy, if appropriate dose titration
is limited by intolerance or if a change from the
initial statin therapy is required.
Recently, ezetimibe has received additional
indication: for administration in combination with
the maximum tolerated dose of a statin with proven
cardiovascular benefit in patients with coronary
heart disease and a history of acute coronary
syndrome in need of additional lowering of LDL-C
104 Diabetes & Primary Care Australia Vol 2 No 3 2017

CPD module
in the expectation of a modest further reduction
in the risk of cardiovascular events following at
least one year of therapy. This is based on the
IMPROVE-IT study (Cannon et al, 2015), which
demonstrated that treatment with ezetimibe when
added to simvastatin provided incremental benefit
in reducing the primary composite endpoint of
cardiovascular death, major coronary event or
non-fatal stroke compared with simvastatin alone
(relative risk reduction of 6.4%, P=0.016).
Proprotein convertase subtilisin/kexin type 9
(PCSK9) enzyme regulates plasma concentrations of
LDL cholesterol by interacting with LDL receptors
on liver cells. After binding to an LDL receptor,
PCSK9 directs it to lysosomal degradation. Thus, it
inhibits recycling of the receptor to the surface of the
hepatocyte and delays catabolism of LDL particles.
PCSK9 inhibitors are monoclonal antibodies that
reduce LDL-cholesterol concentrations by about
50% and require subcutaneous administration every
2 to 4 weeks (Tonkin and Byrnes, 2014).
In Australia, evolocumab and alirocumab are
available, but require specialist consultation for
prescribing (Simons, 2016). Patients with atherogenic
dyslipidaemia (elevated total triglycerides, decreased
HDL-C and normal or moderately elevated LDL-C)
have an elevated risk of CVD events. Atherogenic
dyslipidaemia may be found in type 2 diabetes
Lipid-lowering therapy for primary
prevention should (while balancing risks and
benefits) aim towards:
l Total cholesterol

CPD module
Box 3. Case example one.
Narrative
Mr B is a 62-year-old man who has had type 2 diabetes for 6 years. He weighs 98 kg
with a BMI of 30 kg/m 2 , and his HbA 1c
level is 60 mmol/mol (7.6%). His estimated
glomerular filtration rate is 58 mL/min/1.73 m 2 and his blood pressure is 146/88 mmHg.
He takes metformin 0.5 g twice daily and ramipril 5 mg daily and follows a healthy
lifestyle program diligently.
He had been on atorvastatin 40 mg but reported muscle pain and cramps in his legs.
These disappeared when the statin was stopped but his lipid profile was unsatisfactory,
with a cholesterol level of 5.4 mmol/L, high-density lipoprotein (HDL) cholesterol
0.9 mmol/L, non-HDL cholesterol 4.5 mmol/L and triglycerides 2.7 mmol/L.
Using the Australian CVD risk calculator is not necessary as he has type 2 diabetes and is
aged over 60 years. Therefore he is high risk, with >15% risk of CVD over next 5 years.
Discussion
As Mr B was symptomatic and his creatine kinase level was less than four times the
upper limit of normal, statin use was halted for 4 weeks. He remained unable to tolerate
statin at the original dose, so a lower dose of rosuvastatin (5 mg) was prescribed.
His muscle pains were no longer a problem but his targets (non-HDL cholesterol

CPD module
levels and a history of intolerance to two or more
statins. The trial started with a 24-week crossover
procedure using atorvastatin 20 mg or placebo
to identify the patients having symptoms with
the statin only (phase A). Following a 2-week
washout period, patients were randomised
to ezetimibe (10 mg/day) or evolocumab
(420 mg/month) for 24 weeks (phase B). The
co-primary endpoints were the mean percentage
change in LDL cholesterol from baseline to the
mean of weeks 22 and 24, and from baseline to
week 24 levels.
Of the 491 patients who entered phase A
(mean age 60.7 years, 50.1% female, 34.6%
with CHD, entry mean LDL cholesterol level
212.3 mg/dL [5.5 mmol/L]), muscle symptoms
occurred in 42.6% (n=209) when taking
atorvastatin but not when taking placebo. Of these,
199 entered phase B, together with 19 who were
fast-tracked to phase B due to elevated creatine
kinase (n=218; 73 randomised to ezetimibe,
145 to evolocumab, entry mean LDL cholesterol
level 219.9 mg/dL [5.7 mmol/L]; Nissen et al, 2016).
For the mean of weeks 22 and 24, the LDL
cholesterol level was 183.0 mg/dL (4.7 mmol/L)
with ezetimibe (mean percentage change −16.7%,
absolute change −31.0 mg/dL [0.8 mmol/L]) and
103.6 mg/dL (2.7 mmol/L) with evolocumab
(mean percentage change −54.5%, absolute change
−106.0 mg/dL [2.7 mmol/L]). At week 24, the
LDL cholesterol level was 181.5 mg/dL (4.7 mmol/L)
with ezetimibe (mean percentage change −16.7%,
absolute change −31.2 mg/dL [0.8 mmol/L]) and
104.1 mg/dL (2.7 mmol/L) with evolucumab
(mean percentage change −52.8%, absolute change
−102.9 mg/dL (2.7 mmol/L; P

CPD module
“Statins are very
effective at reducing
the risk of serious
and life-threatening
cardiovascular events
and when we take a
patient off statin therapy,
we may be doing them
harm.”
diabetes are at increased risk of cardiovascular
complications, and non-HDL cholesterol now
appears to be a more effective measure of risk
in this population than LDL cholesterol. The
management of dyslipidaemia in these patients
should involve a multifactorial program to improve
lifestyle and adherence to treatment. n
Acknowledgement
This article has been modified from one
previously published in Diabetes & Primary Care
(2016, 18: 184–92).
Anastasius M, Kritharides L, Sullivan D (2017) How to Treat: The
assessment of CVD risk and dyslipidaemia. Australian Doctor 5 May
Assman G, Schulte H (1992) Relation of high-density lipoprotein
cholesterol and triglycerides to incidence of atherosclerotic coronary
artery disease (the PROCAM experience). Am J Cardiol 70: 733–7
Austin MA, Hokanson JE, Edwards KL (1998) Hypertriglyceridaemia as a
cardiovascular risk factor. Am J Cardiol 81(Suppl 4A): 7B–12B
Baigent C, Blackwell L, Emberson J et al (2010) Efficacy and safety of
more intensive lowering of LDL cholesterol: a meta- analysis of
data from 170,000 participants in 26 randomised trials. Lancet 376:
1670–81
Ballantyne CM, Andrews TC, Hsai JA et al (2001) Atorvastatin
Comparative Cholesterol Efficacy and Safety Study. Correlation of
non-high-density lipoprotein cholesterol with apolipoprotein B:
effect of hydroxymethylglutaryl coenzyme A reductase inhibitors
on non-high-density lipoprotein cholesterol levels. Am J Cardiol 88:
265–9
Barter PJ, Caulfied M, Eriksson M et al (2007) Effects of torcetrapib in
patients at high risk for coronary events. N Engl J Med 357: 2109–22
Bitzur R, Cohen H, Kamari Y et al (2013) Intolerance to statins:
mechanisms and management. Diabetes Care 36: S325–30
Boekholdt SM, Arsenault BJ, Mora S et al (2012) Association of LDL
cholesterol, non-HDL cholesterol and apolipoprotein B levels with
risk of cardiovascular events among patients treated with statins: a
meta-analysis. JAMA 307: 1302–9
Cannon CP, Blazing MA, Giugliano RP et al; the IMPROVE-IT
Investigators (2015) Ezetimibe added to statin therapy after acute
coronary syndromes. N Engl J Med 372: 2387–97
Colhoun HM, Betteridge DJ, Durrington PN et al (2004) Primary
prevention of cardiovascular disease with atorvastatin in type 2
diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS):
multicentre randomized placebo-controlled trial. Lancet 364:
685–96
Collins R, Armitage J, Parish S et al (2003) MRC/BHF Heart Protection
Study of cholesterol lowering with simvastatin in 5963 people
with diabetes: a randomised placebo-controlled trial. Lancet 361:
2005–16
Costa J, Borges M, David C, Vaz CA (2006) Efficacy of lipid lowering
drug treatment for diabetic and non-diabetic patients: meta-analysis
of randomized controlled trials. BMJ 332: 1115–24
Davies MJ (1996) Stability and instability: two faces of coronary
atherosclerosis. The Paul Dudley White lecture 1995. Circulation 94:
2013–20
Davis T, Davis W (2015) Predictors and outcome of heart failure
complicating type 2 diabetes: The Fremantle Diabetes Study.
Presented at: 75 th American Diabetes Association 2015 Scientific
Sessions (abstract 1490-P). Boston, USA, 5–9 June
Deeg MA, Buse JB, Goldberg RB et al (2007) Pioglitazone and
rosiglitazone have different effects on serum lipoprotein particle
concentrations and sizes in patients with type 2 diabetes and
dyslipidaemia. Diabetes Care 30: 2458–64
Devereux RB, Roman MJ, Paranicas M et al (2000) Impact of diabetes
on cardiac structure and function: the strong heart study. Circulation
101: 2271–6
Donahoe SM, Stewart GC, McCabe CH et al (2007) Diabetes and
mortality following acute coronary syndromes. JAMA 298: 765–75
Emerging Risk Factors Collaboration (2009) Major lipids,
apolipoproteins, and risk of vascular disease. JAMA 302: 1993–2000
European Association of Cardiology (2016) New Joint European
Cardiovascular Prevention Guidelines launched today. ESC, Les
Templiers, France. Available at: http://bit.ly/25nY1tq (accessed
31.05.16)
Falk E, Shah PK, Fuster V (1995) Coronary plaque disruption. Circulation
92: 657–71
Garvey WT, Kwon S, Zheng D et al (2003) Effects of insulin resistance
and type 2 diabetes on lipoprotein subclass particle size and
concentration determined by nuclear magnetic resonance. Diabetes
52: 453–62
Haffner SM, Lehto S, Rönnemaa T et al (1998) Mortality from coronary
heart disease in subjects with type 2 diabetes and in nondiabetic
patients with and without prior myocardial infarction. N Engl J Med
339: 229–34
Carrington MJ and Stewart S (2011) Australia’s cholesterol crossroads:
An analysis of 199,331 GP patient records. Baker IDI Heart and
Diabetes Institute, Melbourne, Vic
Chapman MJ, Ginsberg HN, Amarenco P et al (2011) Triglyceride-rich
lipoproteins and high-density lipoprotein cholesterol in patients
at high risk of cardiovascular disease: evidence and guidance for
management. Eur Heart J 32: 1345–61
Chew D, Scott I, Cullen L et al (2016) National Heart Foundation
of Australia and Cardiac Society of Australia and New Zealand:
Australian clinical guidelines for the management of acute coronary
syndromes. Med J Aust 205: 128–33
Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery
disease. N Engl J Med 352: 1685–95
Hansson GK, Jonasson L, Lojsthed B et al (1988) Localization of T
lymphocytes and macrophages in fibrous and complicated human
atherosclerotic plaques. Atherosclerosis 72: 135–41
Holman RR, Paul SK, Bethel MA et al (2008) 10-year follow-up of
intensive glucose control in type 2 diabetes. N Engl J Med 359:
1577–89
Hsai S (2003) Non-HDL cholesterol: Into the spotlight. Diabetes Care
26: 240–2
108 Diabetes & Primary Care Australia Vol 2 No 3 2017

CPD module
JBS3 Board (2014) Joint British Societies’ consensus recommendations
for the prevention of cardiovascular disease (JBS3). Heart 100:
ii1–1167
Juutilainen A, Kortelainen S, Lehto S et al (2004) Gender difference
in the impact of type 2 diabetes on coronary heart disease risk.
Diabetes Care 27: 2898–904
Kastelein JJ, van der steeg WA, Holme I et al (2008) Lipids,
apolipoproteins, and their ratios in relation to cardiovascular events
with statin treatment. Circulation 117: 3002–9
Keech A, Simes RJ, Barter P et al; FIELD study investigators (2005)
Effects of long-term fenofibrate therapy on cardiovascular events
in 9795 people with type 2 diabetes mellitus (the FIELD study):
randomised controlled trial. Lancet 366: 1849–61
Landray MJ, Reveal Collaborative Group; Bowman L et al (2017)
Randomized Evaluation of the Effects of Anacetrapib through
Lipid-modification (REVEAL) – A large-scale, randomized, placebocontrolled
trial of the clinical effects of anacetrapib among people
with established vascular disease: Trial design, recruitment, and
baseline characteristics. Am Heart J 187: 182–90
National Vascular Disease Prevention Alliance (2012) Absolute
cardiovascular disease risk management. Quick reference guide
for health professionals. National Heart Foundation of Australia.
Available at: http://bit.ly/2tji63M (accessed 19.06.17)
NICE (2014) Cardiovascular disease: Risk assessment and reduction,
including lipid modification (CG181). NICE, London, UK. Available
at: https://www.nice.org.uk/guidance/cg181 (accessed 19.06.17)
Nissen SE, Stroes E, Dent-Acosta Re et al (2016) Efficacy and tolerability
of evolocumab vs ezetimibe in patients With muscle-related statin
intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA 315:
1580–90
Peters SA, Huxley RR, Woodward M (2014) Diabetes as risk factor for
incident coronary heart disease in women compared with men:
a systematic review and meta-analysis of 64 cohorts including
858,507 individuals and 28,203 coronary events. Diabetologia 57:
1542–51
Piepoli M, Hoes AW, Agewall S et al (2016) 2016 European Guidelines
on cardiovascular disease prevention in clinical practice: The Sixth
Joint Task Force of the European Society of Cardiology and Other
Societies on Cardiovascular Disease Prevention in Clinical Practice.
Eur Heart J 37: 2315–81
“The management
of dyslipidaemia in
people with diabetes
should involve a
multifactorial program
to improve lifestyle
and adherence to
treatment.”
Lind M, Bounias I, Olsson M et al (2011) Glycaemic control and
incidence of heart failure in 20,985 patients with type 1 diabetes: An
observational study. Lancet 378: 140–6
Lindsey JB, House JA, Kennedy KF, Marso SP (2009) Diabetes duration
is associated with increased thin-cap fibroatheroma detected by
intravascular ultrasound with virtual histology. Circ Cardiovasc Interv
2: 543–8
Malmberg K, Yusuf S, Gerstein HC et al (2000) Impact of diabetes on
long-term prognosis in patients with unstable angina and non-Qwave
myocardial infarction results of the OASIS (organization to
assess strategies for ischaemic syndromes) registry. Circulation 102:
1014–19
Ross R (1999) Atherosclerosis – an inflammatory disease. N Engl J Med
340: 115–26
Sattar N, Williams K, Sniderman AD et al (2004) Comparison of the
associations of apolipoprotein B and non-high-density lipoprotein
cholesterol with other cardiovascular risk factors in patients with the
metabolic syndrome in the Insulin Resistance Atherosclerosis Study.
Circulation 110: 2687–93
Sattar N, Preiss D, Murray HM et al (2010) Statins and risk of incident
diabetes: a collaborative meta-analysis of randomised statin trials.
Lancet 375: 735–42
Simons L (2016) Alirocumab and Evolocumab - a new era in cholesterol
control. Medicine Today 17: 51–3
Mazzone T (2007) HDL cholesterol and atherosclerosis. Lancet 370:
107–8
Mazzone T, Chait A, Plutzky J (2008) Addressing cardiovascular disease
risk in diabetes: insights from mechanistic studies. Lancet 371: 180–9
McFadden E, Stevens R, Glasziou P et al (2015) Implications of lower
risk thresholds for statin treatment in primary prevention: Analysis of
CPRD and simulation modelling of annual cholesterol monitoring.
Prev Med 70: 14–16
Mihaylova B, Emberson J, Blackwell L et al (2012) The effects of
lowering LDL cholesterol with statin therapy in people at low
risk of vascular disease: meta-analysis of individual data from 27
randomised trials. Lancet 380: 581–90
Moreno PR, Murcia AM, Palacios IF (2000) Coronary composition and
macrophage infiltration in atherectomy specimens from patients with
diabetes mellitus. Circulation 102: 2180–4
Stroes ES, Thompson PD, Corsini A et al (2015) Statin-associated muscle
symptoms: impact on statin therapy – European Atherosclerosis
Society Consensus Panel Statement on Assessment, Aetiology and
Management. Eur Heart J 36: 1012–22
The Royal Australian College of General Practitioners (2016a)
General practice management of type 2 diabetes: 2016–18.
RACGP, East Melbourne, Vic. Available at: www.racgp.org.au/
your-practice/guidelines/redbook (accessed 23.06.17)
The Royal Australian College of General Practitioners (2016b)
Guidelines for preventive activities in general practice (9 th
edition). RACGP, East Melbourne, Vic. Available at: www.racgp.
org.au/your-practice/guidelines/diabetes (accessed 23.06.17)
Tonkin A, Byrnes A (2014) Treatment of dyslipidemia. F1000 Prime
Reports 6: 17
Vangaveti VN, Shashidhar VM, Rush C et al (2014)
Hydroxyoctadecadienoic acids regulate apoptosis in human
THP-1 cells in a PPARy-dependent manner. Lipids 49: 1181–92
National Heart Foundation of Australia (2015) Heart disease in Australia:
Cardiovascular disease, heart disease and heart attack. Available at:
http://bit.ly/2sGV8Wt (accessed 19.06.17)
National Heart Foundation of Australia, the Cardiac Society of Australia
and New Zealand (2012) Reducing risk in heart disease: an expert
guide to clinical practice for secondary prevention of coronary heart
disease. National Heart Foundation of Australia, Melbourne, Vic.
Available at: http://bit.ly/2sOm33b (accessed 19.06.17)
Virani S (2011) Non-HDL cholesterol as a metric of good quality of care.
Tex Heart Inst J 38: 160–2
Xu J, Zou MH (2009) Molecular insights and therapeutic targets for
diabetic endothelial dysfunction. Circulation 120: 1266–86
Yusuf S, Bosch G, Dagenais J et al (2016) Cholesterol lowering in
intermediate-risk persons without cardiovascular disease. N Engl
J Med 374: 2021–31
Diabetes & Primary Care Australia Vol 2 No 3 2017 109

CPD module
Online CPD activity
Visit www.pcdsa.com.au/cpd to record your answers and gain a certificate of participation
Participants should read the preceding article before answering the multiple choice questions below. There is ONE correct answer to each question.
After submitting your answers online, you will be immediately notified of your score. A pass mark of 70% is required to obtain a certificate of
successful participation; however, it is possible to take the test a maximum of three times. A short explanation of the correct answer is provided.
Before accessing your certificate, you will be given the opportunity to evaluate the activity and reflect on the module, stating how you will use what
you have learnt in practice. The CPD centre keeps a record of your CPD activities and provides the option to add items to an action plan, which will
help you to collate evidence for your annual appraisal.
1. According to Boekholdt et al (2012), which
combination of LDL cholesterol and non-
HDL cholesterol has the HIGHEST hazard
ratio for major cardiovascular events?
Select ONE option only.
LDL cholesterol
(mmol/L)
Non-HDL cholesterol
(mmol/L)
A. 4 3
B. 2 4
C. 2 3
D. 3 2
2. When considering the primary prevention
of CVD, for which ONE of the following
people with diabetes is Australian CVD risk
tool appropriate? Select ONE option only.
A. A 30-year-old man with type 1 diabetes
B. A 45-year-old woman with
type 2 diabetes and familial
hypercholesterolaemia
C. A 62-year-old man with type 2 diabetes
and diabetic nephropathy
D. A 57-year-old woman with type 2
diabetes and hypertension
E. A 91-year-old man with type 2 diabetes
and Parkinson’s disease
3. Which ONE of the following features is
found in the JBS3 risk calculator but NOT
in the Australian CVD risk assessment tool?
Select ONE option only.
A. Ability to include diabetes as a risk
factor
B. Ability to include rheumatoid arthritis as
a risk factor
C. 5-year risk
D. Life years gained
E. 10-year risk
4. A 47-year-old man with type 2 diabetes
has a 5-year Australian CVD risk score
of 16%. Which is the MOST appropriate
INITIAL medication, if any, to reduce his
cardiovascular risk?
Select ONE option only.
A. Atorvastatin 20 mg
B. Atorvastatin 80 mg
C. Simvastatin 40 mg
D. Simvastatin 80 mg
E. Lifestyle changes alone recommended
5. For which ONE of the following people
with type 1 diabetes is a statin as primary
prevention of CVD the MOST appropriate?
Select ONE option only.
A. A 17-year-old male smoker
B. A 26-year-old female with a total
cholesterol of 6.4 mmol/L
C. A 35-year-old male with poor glycaemic
control
D. A 39-year-old male diagnosed 5 years
ago
E. A 46-year-old female with CKD stage 3
6. A 59-year-old woman with type 2
diabetes agrees to start high-intensity
statin medication today for primary CVD
prevention. When is the MOST appropriate
time-interval (in months), if any, before remeasuring
her lipid profile?
Select ONE option only.
A. 1
B. 3
C. 6
D. 12
E. No repeat lipid profile required
7. What is the MINIMUM target REDUCTION
in non-HDL cholesterol recommended for
people with diabetes starting a high-intensity
statin?
Select ONE option only.
A. 10%
B. 20%
C. 30%
D. 40%
E. 50%
8. A 61-year-old man with type 2 diabetes is
at high risk of CVD. He is intolerant of both
atorvastatin and simvastatin due to myalgia.
His creatine kinase (CK) was normal at the
time of reporting symptoms. Which is the
SINGLE MOST appropriate monotherapy to
now recommend?
Select ONE option only.
A. Fenofibrate
B. Ezetimibe
C. Nicotinic acid
D. Omega-3-acid ethyl esters
E. Rosuvastatin
9. A 49-year-old man with type 2 diabetes
has a 10-year CVD risk score of 32%.
Despite good lifestyle modification and
concordance with maximal statin dosages,
his total and LDL cholesterol remain poorly
controlled. Which is the SINGLE MOST
appropriate add-on therapy, if any, to
recommend as primary prevention? Select
ONE option only.
A. Fenofibrate
B. Bile acid sequestrant
C. Co-enzyme Q10
D. Ezetimibe
E. No add-on therapy recommended
10. A 65-year-old woman developed muscle
pain after starting simvastatin 40 mg.
Her CK was elevated at twice the upper
limit of normal. According to European
Atherosclerosis Society guidance (Stroes
et al, 2015), what is the MINIMUM
time-interval (in weeks) before a statin
re-challenge is recommended? Select ONE
option only.
A. 1
B. 2
C. 4
D. 8
E. 12
110 Diabetes & Primary Care Australia Vol 2 No 3 2017

Article
Primary care practitioner guide to the
International Working Group on the
Diabetic Foot: Recommendations for the
Australian context
Rajna Ogrin, Jane Tennant
Diabetes-related foot complications negatively impact on the lives of people with diabetes
and increase healthcare costs. Practical, evidence-based guidance has been developed
by the International Working Group on the Diabetic Foot (IWGDF), focusing on five
main topics: prevention, footwear and offloading, peripheral arterial disease, infection
and wound management. This article will discuss the prevention of diabetes-related foot
ulcers and apply the IWGDF recommendations to the Australian context for primary care
providers. By applying the evidence to the local context, the authors anticipate that these
guidelines will be more easily implemented into practice.
Currently, more than 1.2 million
Australians are estimated to be
living with diabetes (National
Diabetes Strategy Advisory Group, 2015) with
approximately 2–3 million Australians projected
to develop diabetes by 2025 (Magliano et al,
2009). Up to 25% of people with diabetes will
develop foot ulcers in their lifetime (Singh et
al, 2005) and, in 2012–13, 4402 Australians
required an amputation related to diabetes
(Australian Commission on Safety and Quality
in Health Care, 2015). The negative effect of
diabetes on quality of life is high; people with
diabetes who have foot ulcers have significantly
lower quality of life and higher rates of depression
compared to the people without diabetes and to
those who do not have foot complications (Ribu
et al, 2007). Further, people with diabetes who
have a foot ulcer or undergo a lower-extremity
amputation have double the risk of death at
5 years, compared to those without diabetes
(Faglia et al, 2001).
Prevention of foot ulceration in people with
diabetes is the most effective way to prevent the
individual and economic burden associated with
foot complications, and primary care providers
have an important role to play in doing this
(Harris, 2009). In September 2016, Diabetes &
Primary Care Australia published an article about
foot screening of people with diabetes to identify
the risk of amputation in people with diabetes
(Ogrin and Forgione, 2016). The current article
builds on this, by outlining the recommendations
for prevention of diabetes-related foot ulcers,
developed by the International Working
Group on the Diabetic Foot (IWGDF). The
IWGDF have developed guidance in five main
areas: prevention, footwear and offloading,
peripheral arterial disease, infection and wound
management. This article covers the prevention
of foot ulcers in people with diabetes at risk of
serious foot complications, and includes how the
IWGDF recommendations can be applied in the
Australian context. We anticipate that this will
make it easier for primary care providers to access
and use the recommendations.
IWGDF guidance
The IWGDF was founded in 1996 and in
2000 became a Consultative Section of the
International Diabetes Federation (IDF). The aim
of the IWGDF is to create awareness and improve
Citation: Ogrin R, Tennant J
(2018) Primary care practitioner
guide to the International Working
Group on the Diabetic Foot:
Recommendations for the Australian
context. Diabetes & Primary Care
Australia 2: 111–18
Article points
1. Primary care health
professionals have an
important role to play in the
prevention of foot ulceration.
2. If you are unsure of how
to complete a procedure
or do not have the relevant
equipment, seek a podiatry
clinic or specialist that does.
Key words
– Diabetic foot
– International guidelines
– Prevention
Authors
Rajna Ogrin is Senior Research
Fellow, RDNS Institute, St Kilda,
Vic, Australia; Adjunct Research
Fellow, University of Melbourne,
Austin Health Clinical School,
Vic; Adjunct Assistant Professor,
University of Western Ontario,
London, Canada. Jane Tennant is
an Advanced Practising Podiatrist,
East Melbourne Podiatry,
Melbourne, Vic; Austin Health,
High Risk Foot Clinic, Melbourne,
Vic, Monash University,
Melbourne, Vic.
Diabetes & Primary Care Australia Vol 2 No 3 2017 111

Primary care practitioner guide to the International Working Group on the Diabetic Foot
Page points
1. The International Working
Group on the Diabetic Foot
guidance documents aim
to support any healthcare
provider, regardless of their
level of training, to incorporate
the content into clinical
practice, and should be used
as a basis for developing local
guidance.
2. Foot screening to ascertain
the risk for amputation for all
people with diabetes should be
undertaken at least annually.
3. After screening, people with
diabetes are to be stratified
as being at low, intermediate
or high risk of serious foot
complications.
the management and prevention of diabetesrelated
foot complications. The IWGDF have
developed guidance documents, with updates
every 4 years, based on systematic reviews of
the literature combined with expert consensus,
resulting in credible evidence-based documents.
The Grading of Recommendations Assessment
Development and Evaluation (GRADE; Guyatt
et al, 2008) system was used to guide the
approach. The guidance documents aim to
support any healthcare provider, regardless of
their level of training, to incorporate the content
into clinical practice, and should be used as a
basis for developing local guidance (Bakker et
al, 2016).
Australian guidelines
The National Evidence-Based Guideline:
Prevention, Identification and Management of
Foot Complications in Diabetes guidelines (Baker
IDI Heart & Diabetes Institute, 2011) were
developed based on a literature review from
2009 and are approved by the National Health
and Medical Research Council (NHMRC).
These guidelines provide information on the
quality of the evidence, unlike the IWGDF
guidelines, which provide both the quality
and strength of the evidence behind their
recommendations. The IWGDF guidance
documents include additional information
on peripheral arterial disease and infection,
not included in the NHMRC guidelines. For
those interested in the differences between the
guidance documents, Diabetic Foot Australia
(2016) has developed an extensive, in-depth,
comparison.
IWGDF guidance recommendations
As stated earlier, the IWGDF guidelines have
been separated into five main topic groups:
l Prevention (Bus et al, 2016a);
l Footwear and offloading (Bus et al, 2016b);
l Peripheral artery disease (Hinchliffe et al,
2016);
l Infection (Lipsky ey al, 2016); and
l Wound management (Game et al, 2016).
Each topic is provided in an open-access
article, published in the 2016 January
supplementary issue of Diabetes Metabolism
Research and Reviews, and this article will focus
on the prevention topic.
Prevention of foot ulcers in at-risk
people with diabetes
1. To identify a person with diabetes at
risk for foot ulceration, examine the feet
annually to seek evidence for signs or
symptoms of peripheral neuropathy and
peripheral artery disease.
(GRADE strength of recommendation:
strong; Quality of evidence: low)
Foot screening to ascertain the risk for amputation
for all people with diabetes should be undertaken
at least annually (Baker IDI Heart & Diabetes
Institute, 2011; Bakker et al, 2016). As most
people with diabetes who develop foot ulcers
and then require amputation have developed
peripheral neuropathy and/or peripheral artery
disease, these are the focus of the IWGDF
guidance documents. Full screening for risk
factors for amputation includes a standardised
assessment of the following:
l Presence of neuropathy.
l Presence of peripheral arterial disease.
l Presence of joint or nail deformity or skin
pathology.
l Presence of foot deformities include
restricted dorsiflexion of the hallux (great
toe).
l Presence of nail and skin pathologies must
be viewed as pre-ulcerative lesions.
l Ability to self care.
l Including those with reduced vision,
restricted mobility to reach their feet and
those with cognitive deficits.
l Past history of foot ulceration
l Including past history of infection.
l Past history of lower-extremity amputation.
Further, in Australia, until adequately assessed,
all Aboriginal and Torres Strait Islander people
with diabetes are considered to be at high risk of
developing foot complications and, therefore, will
require foot checks at every clinical encounter
and active follow-up (Bus et al, 2016b).
After screening, people with diabetes are to be
stratified for risk of serious foot complications in
112 Diabetes & Primary Care Australia Vol 2 No 3 2017

Primary care practitioner guide to the International Working Group on the Diabetic Foot
the following manner (Bus et al, 2016b):
l “Low risk”: people with no risk factors and no
previous history of foot ulcer or amputation.
l “Intermediate risk”: people with one risk
factor (e.g. neuropathy, peripheral arterial
disease or foot deformity) and no previous
history of foot ulcer or amputation.
l “High risk”: people with two or more risk
factors (neuropathy, peripheral arterial disease
or foot deformity) and/or a previous history of
foot ulcer or amputation.
For more information, see Ogrin and Forgione
(2016).
Any healthcare providers, with some training,
can undertake foot screening (Baker IDI Heart
& Diabetes Institute, 2011). In Australia,
podiatrists, GPs, credentialled diabetes educators
and practice and community nurses generally
undertake these assessments. The equipment
needed to undertake these assessments includes
a 10-g monofilament and a hand-held Doppler
(Baker IDI Heart & Diabetes Institute, 2011;
McAra et al, 2016).
If your practice does not have this equipment,
we suggest you seek a podiatry clinic that
does, and also has the knowledge and skills to
undertake these assessments, as not all podiatrists
have an interest in diabetes. The Primary Health
Networks around Australia have developed,
or are currently developing, evidence-based
pathways for care for people with diabetes called
HealthPathways. The HealthPathways are worth
reviewing as they list local services, healthcare
providers and resources for people with diabetes
to access based on their needs.
2. In a person with diabetes who has
peripheral neuropathy, screen for a history
of foot ulceration or lower-extremity
amputation, peripheral artery disease,
foot deformity, pre-ulcerative signs on the
foot, poor foot hygiene and ill-fitting or
inadequate footwear.
(GRADE strength of recommendation:
strong; Quality of evidence: low)
The presence of neuropathy is the single most
common risk factor for foot ulcer development
in people with diabetes (Reiber et al, 1999).
The presence of an additional risk factor for
amputation significantly increases the risk
of individuals developing a foot ulcer and
requiring amputation (Lavery et al, 2008).
Therefore, identifying these additional risk
factors is important so that management can be
implemented to prevent escalation to serious foot
complications.
As above, in Australia, podiatrists, GPs,
credentialled diabetes educators and practice
and community nurses generally undertake
foot screening, including screening for the
listed risk factors. However, the presence of
neuropathy leads to changes in the arteries of
the lower limb; therefore, no single modality
has been shown to be optimal to identify
peripheral artery disease (Hinchliffe et al, 2016).
Measuring ankle–brachial index (ABI; with

Primary care practitioner guide to the International Working Group on the Diabetic Foot
Page points
1. Any foot condition that
develops in a person with
diabetes is best treated by a
healthcare provider with skills
and experience in this area.
2. If the person with diabetes
has inadequate vision,
poor mobility or poor
comprehension that limits their
ability to undertake safe foot
care, a referral to a podiatrist
for ongoing regular care will be
required.
include callus debridement and biomechanical
assessment and management to address the
aetiology of any callus.
If a person with diabetes develops a blister:
l Shallow blisters: Apply compressive taping
to prevent skin breaking and becoming a
potential source of infection, then review in
1 week. In addition, it is important to advise
the individual that should the area become red,
hot or swollen, urgent review is required.
l Distended blisters where peripheral tissue
exhibits evidence of erythema: Drain the blister
and dress with a non-adherent, non-occlusive
dressing and review again in 2–3 days. As
above, it is important to advise the individual
that should the area become red, hot or
swollen, urgent review is required.
For infected ingrown toenails, prescribe
appropriate antibiotics. Refer to a podiatrist or
surgeon for nail surgery for those people with
ongoing ingrown toenail problems. Thickened
nails must be reduced by a podiatrist to prevent
subungual ulcers and tissue trauma to abutting
toes.
Fungal nail infections should be identified
with microscopy and culture (Cathcart et al,
2009; Gupta et al, 2013). There is no one best
treatment for fungal nail infections, with the
decision to be made on a case-by-case basis,
with consideration given to the causative agent,
the number of nails involved, and the risks and
benefits associated with the different treatments
(Gupta et al, 2013). Oral therapy is recommended
for proximal subungual onychomycosis (when
at least 50% of the distal nail plate, the nail
matrix, or multiple nails are involved) and for
individuals whose conditions have not responded
after 6 months of topical therapy (Gupta et al,
2013). It is important to note that people with
diabetes generally use concomitant treatments
for their comorbid conditions, which increases
the risk of drug–drug interactions with the
systemic antifungal agents (Gupta et al, 2013).
Topical antifungal agents should be used for
fungal skin infections, with instructions on
avoidance of cross contamination from footwear
worn without socks.
Any foot condition that develops in a person
with diabetes is best treated by a healthcare
provider with skills and experience in this area,
such as:
l Community health service podiatry
department.
l Private podiatrist.
l Footcare nurse/healthcare provider trained in
providing diabetes footcare (particularly for
those individuals living in rural and remote
areas).
l High-risk/diabetes foot clinic.
As long as the healthcare providers in the
available local service have experience in working
with people with diabetes and are confident and
skilled in managing foot complications, they
should be able to address the foot issue initially,
until access to a dedicated multidisciplinary
team is available. Check your Primary Health
Network website for whether they have developed
HealthPathways for diabetes management, as
this might include local resources for diabetes
foot complication care.
4. To protect their feet, instruct a person
with diabetes at risk of serious foot
complications to never walk barefoot,
in socks only, or in thin-soled standard
slippers, whether at home or when outside.
(GRADE strength of recommendation:
strong; Quality of evidence: low)
This includes during any episodes of nocturia
(Tennant et al, 2015), or any other perceived
quick or short trips.
5. Instruct a person with diabetes at risk of
serious foot complications to daily inspect
their feet and the inside of their shoes,
daily wash their feet (with careful drying
particularly between the toes).
(GRADE strength of recommendation:
weak; Quality of evidence: low)
Identify if there are any cutaneous lesions or
thickened nails that need a podiatry referral. If
the person with diabetes has inadequate vision,
poor mobility or poor comprehension that limits
their ability to undertake safe foot care, a referral
to a podiatrist for ongoing regular care will be
required. For those with adequate mobility and
114 Diabetes & Primary Care Australia Vol 2 No 3 2017

Primary care practitioner guide to the International Working Group on the Diabetic Foot
vision, education on daily care should include
daily application of emollients to any dry skin,
and daily inspection looking for “anything
that was not there yesterday”. Nails should be
trimmed to the shape of the toe edge to prevent
sharp nail edge damage to abutting toes. Seek
early assistance from a specialist for any small
problem with the feet that can be managed
before it becomes problematic.
6. To prevent a first foot ulcer in a person
with diabetes at risk of serious foot
complications, provide education aimed
at improving foot care knowledge and
behaviour, as well as encouraging the
individual to adhere to this foot care
advice.
(GRADE strength of recommendation:
weak; Quality of evidence: low)
All people with diabetes need access to footcare
education, as everyone with diabetes is at greater
risk of amputation when compared to people
without diabetes (Bakker et al, 2016). Amputations
can be prevented by early identification and
intervention for individuals with foot injuries or
abnormalities. It is important to provide written
foot care information for people with diabetes at
risk of foot complications, in their language of
preference, if possible. Diabetes Australia has good
pictorial guides in many languages to support
people with diabetes in the understanding and
implementation of foot care.
For those individuals who are at increased risk
of amputation, this education needs to include
advice for protecting and caring for the feet,
and wearing appropriate footgear (Bakker et al,
2016). Early identification of foot abnormalities
by all healthcare workers enforces the principals
of protecting the feet of people with diabetes. This
will also reinforce the need for individuals with
diabetes at increased risk of amputation to wear
their prescriptive footgear (footwear, socks and
foot orthotics). Any education needs to encourage
increasing knowledge and behaviour change
(Price, 2016). Guidance for footcare education
content is available from Diabetes Australia,
National Diabetes Service Scheme (NDSS), State
Diabetes Australia websites and centres and the
Australian Podiatry Council website.
7. Instruct a person with diabetes at risk
of serious foot complications to wear
properly fitting footwear to prevent a first
foot ulcer, either plantar or non-plantar, or
a recurrent non-plantar foot ulcer. When
a foot deformity or a pre-ulcerative sign is
present, consider prescribing therapeutic
shoes, custom-made insoles or toe
orthosis.
(GRADE strength of recommendation:
strong; Quality of evidence: low)
Ill-fitting footwear is one of the leading causes
of foot ulceration (Baker IDI Heart & Diabetes
Institute, 2011). Where available, refer to a
shoe fitting service or store (e.g. sports store)
to optimise the best fitting shoe. All footwear
should be fitted and worn with socks to prevent
fungal infections and prevent blisters that may
develop into ulcers. Not all people with diabetes
will need extra depth/width footwear or bespoke
footwear. Ideally, all healthcare providers should
assess if the presenting worn footwear is creating
any pressure areas on the feet at every visit.
This enables the foot to be exposed to identify
the presence of any other footwear problems.
Those individuals with identified footwear
problems should be referred to a podiatrist or
an orthotist for footwear education, prescription
or provision. Off-the-shelf shoes from general
retailers are appropriate for individuals without
foot deformities. Extending simple advice such
as trying shoes on at the end of the day, when
the feet are at their largest, and ensuring the
footwear fits the foot shape (allowing sufficient
length of one thumb’s width beyond the longest
toe), has lace or strap fastenings and does not
rub any bony prominences is sufficient to
minimise risk of footwear causing ulceration.
Of particular importance is the presence of
peripheral neuropathy. As a learnt behaviour
during shoe fitting with intact sensation, a shoe is
tried on to see what “fits” which, in the presence
of peripheral neuropathy, is often too small or too
tight as manufacturers may have differing sizes to
the individual’s usual size. Advice on shoe fitting
is also available from Diabetes Australia and
Australian Podiatry Council websites.
For individuals where there is significant
foot deformity or partial amputation, custom-
Page points
1. All people with diabetes need
access to footcare education,
as everyone with diabetes is at
greater risk of amputation when
compared to people without
diabetes
2. Ill-fitting footwear is one of
the leading causes of foot
ulceration.
3. For individuals where there is
significant foot deformity or
partial amputation, custommade
footwear from a reputable
pedorthotist or bootmaker may
be required.
Diabetes & Primary Care Australia Vol 2 No 3 2017 115

Primary care practitioner guide to the International Working Group on the Diabetic Foot
Page points
1. A person with diabetes who has
had a foot ulcer places them at
high risk of future ulcerations
and amputations.
2. Referring to a local podiatrist,
orthotist or high risk/diabetes
foot clinic can support people
with diabetes to access any
funding that may be available
and can link in with providers
who can make the appropriate
footwear adjustments.
made footwear from a reputable pedorthotist or
bootmaker may be required. These usually include
custom insoles to balance the foot within the shoe.
Not all regions in Australia will have footwear
retailers that stock footwear appropriate for
individuals with different foot shapes. Referring to a
local podiatrist, orthotist or high risk/diabetes foot
clinic can support people with diabetes to access
any funding that may be available and can link
in with providers who can make the appropriate
footwear adjustments.
We recommend that you consider the footwear
retailers in your area, and generate a list of stores
that have some understanding of this issue. We also
recommend that you consider the podiatrists and
orthotists or other healthcare providers with training
to support people with diabetes to access appropriate
footwear. Whether the podiatry clinic has a handheld
Doppler is an important determinant in
choosing a podiatrist – not every podiatrist has
an interest in diabetes. There are also shoemakers
and repairers that have experience in adjusting
shoes who may be of help. Having this information
available to people with diabetes may help them
avoid developing serious foot problems. Check
your Primary Health Network website for whether
they have developed HealthPathways for diabetes
management, as this might include local resources
for diabetes foot complication care, including
footwear retailers or at least specialist podiatrists or
clinics who might have this information.
8. To prevent a recurrent plantar foot ulcer
in a person with diabetes at risk of serious
foot complications, prescribe therapeutic
footwear that has a demonstrated plantar
pressure-relieving effect during walking
(i.e. 30% relief compared with plantar
pressure in standard of care therapeutic
footwear) and encourage the patient to
wear this footwear.
(GRADE strength of recommendation:
strong; Quality of evidence: moderate)
Having had a foot ulcer places a person with
diabetes at high risk of future ulcerations and
amputations (Baker Institute and International
Diabetes Institute, 2011; Bakker et al, 2016).
It also increases their risk of mortality (Iversen
et al, 2009). Ideally, these individuals would be
under the care of a clinic with specialist skills in
managing people with diabetes who have serious
foot complications, such as a multidisciplinary
high-risk foot clinic or diabetes foot clinic. These
clinics are usually situated within tertiary health
services and ideally include healthcare providers
with training in footwear and orthotics to provide
effective pressure redistribution to avoid ulcer
recurrence (Schaper et al, 2016). This is a specialist
skill and not all generalist providers have it. There
are a number of people with diabetes who have
foot ulcers who choose not to attend a high-risk
foot clinic for various reasons, or who may not be
able to access a foot ulcer clinic. It is likely that
there are numerous healthcare providers involved
in the care of an individual with a diabetesrelated
foot ulcer, such as a community nurse,
GP, podiatrist, endocrinologist, dietitian, diabetes
educator and vascular surgeon. It is important
that good communication is in place to link
all healthcare providers involved in managing
the individual with a foot ulcer. Further, all
involved in this management need to understand
that a foot ulcer that does not reduce in size
within 4 weeks needs reconsideration of treatment
provided. Ideally, referral to a high-risk foot
clinic or private wound/podiatrist service with
knowledge in specialised pressure redistribution
skills is required at this stage.
As above, we recommend that you consider
the available services in your area. Do you have
a tertiary centre with a high-risk foot/diabetes
foot clinic? If not, are there healthcare providers
that have some expertise in this area? Having this
information available to people with diabetes may
help them avoid foot ulcer recurrence.
9. To prevent a recurrent foot ulcer in a
person with diabetes at risk of serious
foot complications, provide integrated
foot care, which includes professional
foot treatment, adequate footwear and
education. This should be repeated or
re-evaluated once every 1 to 3 months as
necessary.
(GRADE strength of recommendation:
strong; Quality of evidence: low)
As stated earlier, ideally individuals who have
healed a foot ulcer would be under the care of a
116 Diabetes & Primary Care Australia Vol 2 No 3 2017

Primary care practitioner guide to the International Working Group on the Diabetic Foot
clinic with specialist skills in managing people
with diabetes who have foot complications,
such as a high-risk/diabetes foot clinic,
multidisciplinary wound clinic or private
podiatrist with experience and skills in the
area. These clinics would provide professional
foot treatment, ongoing footgear assessment,
ongoing arterial assessments and education.
Once the individual is stable, referral to
community healthcare providers who have
expertise in this area, such as podiatrists, is
required for ongoing care. It is important
that healthcare providers have experience in
identifying the development of pre-ulcerative
lesions and can effectively treat foot issues and
monitor for arterial changes that arise.
Again, consider the available services in
your area. If there is tertiary centre with
a high risk foot/diabetes foot clinic, these
clinics would have an established network to
support individuals with diabetes-related foot
complications. If not, you will need to source
healthcare providers that have some expertise
in this area. This information may help people
with diabetes avoid foot ulcer recurrence and
amputation.
10. Consider digital flexor tenotomy to
prevent a toe ulcer when conservative
treatment fails in a person with diabetes
at high risk of amputation, hammertoes
and either a pre-ulcerative sign or an
ulcer on the distal toe.
(GRADE strength of recommendation:
weak; Quality of evidence: low)
Flexor tenotomies may be associated with high
healing rates, relatively low recurrence rates and
low incidences of post-operative complications
in people with diabetes (Scott et al, 2016).
These procedures can only be undertaken by
healthcare providers who have the scope of
practice and understanding of the biomechanics
of the foot to release the tendon. These are
usually orthopaedic surgeons or accredited
podiatric surgeons. The flexor tenotomy is a
fairly simple procedure to undertake. However
it is important that people with diabetes have
adequate blood flow to allow healing of the
surgical site.
11. Consider Achilles tendon lengthening,
joint arthroplasty, single or pan
metatarsal head resection, or osteotomy
to prevent a recurrent foot ulcer when
conservative treatment fails in a highrisk
patient with diabetes and a plantar
forefoot ulcer.
(GRADE strength of recommendation:
weak; Quality of evidence: low)
An example of these procedures is the Achilles
tendon lengthening, which is considered to
addresses the overloading of the forefoot for
people with recurrent ulceration where the heel
does not bear much of the load during gait. Any
person with diabetes who may fit these criteria
will need to be assessed for the appropriateness
of any of these procedures by a foot and ankle
surgeon with expertise in undertaking these
procedures in people with diabetes.
12. Instruct a person with diabetes at high risk
of serious foot complications to monitor
foot skin temperature at home to prevent
a first or recurrent plantar foot ulcer.
This aims at identifying the early signs of
inflammation, followed by action taken by
the patient and care provider to resolve
the cause of inflammation.
(GRADE strength of recommendation:
weak; Quality of evidence: moderate)
This is valuable for those with poor mobility or
vision using an infrared temperature scanner. It
enables the person with diabetes with a history
of ulceration, infection, amputation and/or
Charcot neuro-arthropathy to monitor their feet
by comparing to the same site to the contralateral
foot. Any temperature difference greater than
2°C should alert the person with diabetes to
seek professional advice (Armstrong et al, 1997).
These temperature scanners can be obtained
from some large chain hardware stores.
Conclusion
The recommendations developed by IWGDF are
based on the collective evidence of systematic
reviews and the consensus of experts. They aim
to provide guidance for healthcare providers
working with people with diabetes to prevent
foot ulcerations and amputations. At this stage,
Page points
1. It is important that healthcare
providers have experience in
identifying the development of
pre-ulcerative lesions and can
effectively treat foot issues and
monitor for arterial changes that
arise.
2. An infrared temperature
scanner may be valuable for
those with poor mobility or
vision to monitor temperature
difference between each foot.
Diabetes & Primary Care Australia Vol 2 No 3 2017 117

Primary care practitioner guide to the International Working Group on the Diabetic Foot
“This article provides
the recommendations
on prevention of
foot amputation in
at-risk individuals with
diabetes, and applies
them to the Australian
context.”
evidence based on high-quality research is still
lacking in many areas; however, people with
diabetes are presenting to primary care providers
for immediate intervention and need care.
This article provides the recommendations on
prevention of amputation in at-risk individuals
with diabetes, and applies them to the Australian
context. Further work is underway to support
the generation of evidence to better prevent and
manage people with diabetes, to work towards
reaching the aim of significantly reducing foot
ulcerations and amputations in people with
diabetes.
n
Harris M (2009) The role of primary health care in preventing the
onset of chronic disease, with a particular focus on the lifestyle
risk factors of obesity, tobacco and alcohol. Centre for Primary
Health Care and Equity, UNSW
Hinchliffe RJ, Brownrigg JRW, Apelqvist J et al (2016) IWGDF
guidance on the diagnosis, prognosis and management of
peripheral artery disease in patients with foot ulcers in diabetes.
Diabetes Metab Res Rev 32: 37–44
Iversen MM, Tell GS, Riise T et al (2009) History of foot ulcer
increases mortality among individuals with diabetes: tenyear
follow-up of the Nord-Trondelag Health Study, Norway.
Diabetes Care 32: 2193–9
Lavery LA, Peters EJ, Williams JR et al (2008) Reevaluating the way
we classify the diabetic foot: restructuring the diabetic foot risk
classification system of the International Working Group on the
Diabetic Foot. Diabetes Care 31: 154–6
Armstrong DG, Lavery LA (1997) Monitoring healing of acute
Charcot’s arthropathy with infrared dermal thermometry.
J Rehabil Res Dev 34: 317–21
Australian Commission on Safety and Quality in Health Care (2015)
Australian Atlas of Healthcare Variation. Australian Commission
on Safety and Quality in Health Care, Sydney, NSW. Available
at: https://safetyandquality.gov.au/wp-content/uploads/2015/11/
SAQ201_07_Chapter6_v7_FILM_tagged_merged_6-8.pdf
(accessed 19.05.17)
Baker IDI Heart & Diabetes Institute (2011) National Evidencebased
guideline. Prevention, identification and management
of foot complications in diabetes (part of the guidelines on
management of type 2 diabetes). Melbourne, Vic. Available at:
www.baker.edu.au/Assets/Files/Foot_FullGuideline_23062011.
pdf (accessed 16.05.17)
Bakker K, Apelqvist J, Lipsky BA et al (2016) The 2015 IWGDF
guidance documents on prevention and management of foot
problems in diabetes: development of an evidence–based
global consensus. Diabetes Metab Res Rev 32: 2–6
Bus SA, van Netten JJ, Lavery LA et al (2016a) IWGDF guidance
on the prevention of foot ulcers in at–risk patients with diabetes.
Diabetes Metab Res Rev 32: 16–24
Bus SA, Armstrong DG, van Deursen RW et al (2016b) IWGDF
guidance on footwear and offloading interventions to prevent
and heal foot ulcers in patients with diabetes. Diabetes Metab
Res Rev 32: 25–36
Cathcart S, Cantrell W, Elewski BE (2009) Onychomycosis and
diabetes. J Eur Acad Dermatol Venereol 23: 1119–22
Diabetic Foot Australia (2016) DFA Guides You Through: Australian
and International Guidelines on Diabetic Foot Disease. Diabetic
Foot Australia, West End, Qld. Available at: https://www.
diabeticfootaustralia.org//wp-content/uploads/2016/07/DFA-
Guides-you-through-guidelines.pdf (accessed 15.05.17)
Faglia E, Favales F, Morabito A (2001) New ulceration, new major
amputation, and survival rates in diabetic subjects hospitalized
for foot ulceration from 1990 to 1993: a 6.5-year follow-up.
Diabetes Care 24: 78–83
Game FL, Apelqvist J, Attinger C et al (2016) IWGDF guidance on
use of interventions to enhance the healing of chronic ulcers of
the foot in diabetes. Diabetes Metab Res Rev 32: 75–83
Gupta AK, Paquet M, Simpson FC (2013) Therapies for the
treatment of onychomycosis. Clin Dermatol 31: 544–54
Guyatt GH, Oxman AD, Vist GE et al (2008) GRADE: an emerging
consensus on rating quality of evidence and strength of
recommendations. BMJ 336: 924–6
Lipsky BA, Aragón–Sánchez J, Diggle M et al (2016) IWGDF
guidance on the diagnosis and management of foot infections in
persons with diabetes. Diabetes Metab Res Rev 32: 45–74
Magliano D, Peeters A, Vos T et al (2009) Projecting the burden
of diabetes in Australia – what is the size of the matter?
Aust N Z J Public Health 33: 540–3
McAra S, Trevethan R, Wang L, Tinley P (2016) Clinical vascular
screening of the foot: For life and limb. Diabetes & Primary Care
Australia 2: 16–23
National Diabetes Strategy Advisory Group (2015) A Strategic
Framework for Action: Advice to Government on the
Development of the Australian National Diabetes Strategy
2016–2020. Commonwealth of Australia, Canberra, ACT
Ogrin R, Forgione N (2016) Prevention, screening and referral of
people with diabetes related foot complications in primary care.
Diabetes & Primary Care Australia 1: 86–93
Price P (2016) How can we improve adherence? Diabetes Metab
Res Rev 32(Suppl 1): 201–5
Reiber GE, Vileikyte L, Boyko EJ et al (1999) Causal pathways for
incident lower–extremity ulcers in patients with diabetes from
two settings. Diabetes Care 22: 157–62
Ribu L, Hanestad BR, Moum T et al (2007) A comparison of the
health–related quality of life in patients with diabetic foot
ulcers, with a diabetes group and a nondiabetes group from the
general population. Qual Life Res 16: 179–89
Schaper NC, Van Netten JJ, Apelqvist J et al (2016) Prevention and
management of foot problems in diabetes: a Summary Guidance
for Daily Practice 2015, based on the IWGDF Guidance
Documents. Diabetes Metab Res Rev 32: 7–15
Scott JE, Hendry GJ, Locke J (2016) Effectiveness of percutaneous
flexor tenotomies for the management and prevention of
recurrence of diabetic toe ulcers: a systematic review. J Foot
Ankle Res 9: 25
Singh N, Armstrong DG, Lipsky BA (2005) Preventing foot ulcers in
patients with diabetes. JAMA 293: 217–28
Tennant J, McClelland M, Miller J (2015) Identifying nocturia as a
contributor to diabetic foot ulcer healing delays. The Diabetic
Foot Journal 18: 186–9
118 Diabetes & Primary Care Australia Vol 2 No 3 2017

Article
The new class war:
SGLT2 inhibitors versus DPP-4 inhibitors
Merlin Thomas
Over 90% of people with type 2 diabetes will need more than metformin monotherapy
to achieve their targets for optimal glucose levels. There are many second-line options for
glucose management in type 2 diabetes, including the sodium–glucose cotransporter 2
(SGLT2) inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor classes. This article provides
a framework for Australian general practices to compare the associated benefits and risks
of SGLT2 inhibitors and DPP-4 inhibitors when added to metformin for the management
of type 2 diabetes.
Over 90% of people with type 2
diabetes will need more than
metformin monotherapy to achieve
their targets for optimal glucose levels. Dual
therapy may begin early in their management,
when it is clear that metformin is insufficient
(primary failure) or later as the efficacy of
metformin gradually wanes (secondary failure).
The Royal Australian College of General
Practitioners (RACGP) and Diabetes Australia
(2014) guidelines recommend that when
optimal glycaemic levels are not met, no more
than 3–6 months should pass before a secondline
agent is added. Of course, earlier initiation
of combination therapy may be appropriate in
some cases, especially when diabetes is clearly
managed suboptimally.
There are many second-line options for
glucose management of type 2 diabetes,
including the sodium–glucose cotransporter 2
(SGLT2) inhibitor and dipeptidyl peptidase-4
(DPP-4) inhibitor classes. These newer classes
have a number of advantages compared
to older classes, including reduced risk of
hypoglycaemia and weight gain, and no need
for dose-titration. So the question, rather than
whether to use them, is which agent will be
best for the patient you have in front of you?
This article provides a framework to compare
the associated benefits and risks of SGLT2
inhibitors and DPP-4 inhibitors, when added
to metformin for the management of type 2
diabetes in Australian general practice.
Question #1: efficacy
The most obvious first question when deciding
between an SGLT2 and a DPP-4 inhibitor is how
well does each class lower glucose? Across clinical
trials, SGLT2 inhibitors have been shown to lower
HbA 1c
by 7.2 mmol/mol (−0.66%; 95% confidence
interval [CI], −0.73%, −0.58%; Vasilakou et
al, 2013). Very similar results have also been
reported for DPP-4 inhibitors in participants
who were not achieving their glycaemic target
on metformin alone (7.2 mmol/mol [−0.69%]
95% CI, −0.79%, −0.61%; Liu et al, 2012). It
has been considered that there is no significant
difference in glucose lowering achieved by either
drug class (Goring et al, 2014). However, recent
head-to-head studies have suggested that SGLT2
inhibitors may result in a greater glucose-lowering
effect than DPP-4 inhibitors in people with type 2
diabetes very suboptimally managed diabetes at
baseline (HbA 1c
>75 mmol/mol [9%]; Rosenstock
et al, 2014; DeFronzo et al, 2015). In contrast, for
people with type 2 diabetes who have an HbA 1c
around 53 mmol/mol (7%), a DPP-4 inhibitor
may achieve a greater glucose-lowering effect.
The effect of DPP-4 inhibitors on fasting plasma
glucose may be modestly greater than with SGLT2
inhibitors in combination with metformin, while
the converse may be true for post-prandial glucose
levels (Rosenstock et al, 2014; DeFronzo et al,
2015). In people with type 2 diabetes who have
renal impairment, there may be a reduction in
SGLT2 inhibitor efficacy. The glucose-lowering
effects of DPP-4 inhibitors are unaffected or
Citation: Thomas M (2017) The new
class war: SGLT2 inhibitors versus
DPP-4 inhibitors. Diabetes & Primary
Care Australia 2: 119–23
Article points
1. Over 90% of people with
type 2 diabetes will require
additional medication
after metformin.
2. Dipeptidyl peptidase-4
inhibitors and sodium–glucose
cotransporter 2 inhibitors
provide an alternative
to the older glucoselowering
medications.
3. Drug regimens should
be individualised and
patient-centred.
Key words
– DPP-4 inhibitors
– Dual therapy
– SGLT2 inhibitors
Author
Merlin Thomas is Professor,
Department of Diabetes,
Central Clinical School, Monash
University, Melbourne.
Diabetes & Primary Care Australia Vol 2 No 3 2017 119

The new class war
Page points
1. DPP-4 inhibitors have highly
favourable tolerability. This is
important, as most Australians
with type 2 diabetes are over
65 years of age, and for whom
polypharmacy, inconstant
health and comorbidities are
common.
2. Because of their mode of
action, SGLT2 inhibitors are
not recommended for glucose
lowering in people with renal
impairment.
3. While some antidiabetes
medications are potentially
weight promoting, DPP-4
inhibitors are weight neutral
and SGLT2 inhibitors are weight
negative.
even modestly improved in people with renal
impairment (Thomas et al, 2016).
Question #2: tolerability
All treatments have the potential for adverse
effects, so the doctor’s mantra must be prius minus
noceant (first do least harm). The key advantage of
using DPP-4 inhibitors is their highly favourable
tolerability (Karagiannis et al, 2012; Kawalec et
al, 2014). This is critical, given that the most
Australians with type 2 diabetes are over 65 years
of age, in whom polypharmacy, inconstant health
and comorbidities are common. Recent studies
have confirmed a very small risk of pancreatitis with
DPP-4 inhibitors (DeVries et al, 2017).
SGLT2 inhibitors block the SGLT2 protein
involved in 90% of glucose reabsorption in the
proximal renal tubule, resulting in increased renal
glucose excretion and lower blood glucose levels.
SGLT2 inhibitors also increase the urine output,
especially when therapy has just been started and
glucose levels are high. This can be a positive
experience for people using an SGLT2 inhibitor, as
within hours of taking the drug, it begins to take
effect. As glucose levels improve, the amount and
frequency of urination usually settles down.
The glucose-lowering efficacy of SGLT2
inhibitors is dependent on sufficient glomerular
filtration to deliver a glucose load to the proximal
tubule. SGLT2 inhibitors are not recommended
for glucose lowering in patients with renal
impairment (estimated glomerular filtration rate
[eGFR]

The new class war
Question #4: cardiovascular safety
Reducing the risk of cardiovascular events is a
priority of diabetes management as heart attacks
and strokes account for over a third of all deaths
in people with type 2 diabetes. If an agent reduces
glucose levels, it must be shown to not increase
the risk of cardiovascular disease, and as such, the
US Food and Drug Administration (FDA) and
European Medicines Agency (EMA) now mandate
that all new antidiabetes agents undergo rigorous
testing to demonstrate cardiovascular safety.
Cardiovascular safety data for DPP-4 inhibitors
suggest that the class does not pose an unacceptable
cardiovascular risk (Patil et al, 2012; Scirica et al,
2013), although there is a small increase in heart
failure admissions observed in trials of participants
using DPP-4 inhibitors (odds ratio, 1.13 [95% CI,
1.00–1.26]; Li et al, 2016).
Cardiovascular safety data for empagliflozin from
the EMPA-REG (Empagliflozin, Cardiovascular
Outcomes, and Mortality in Type 2 Diabetes) trial
suggested that its use may be associated with reduced
rates of heart failure and cardiovascular death
in people with established cardiovascular disease
(Zinman et al, 2016). The mechanism behind this
is still unclear and it is yet to be determined whether
such benefits will also be seen in high-risk individuals
without cardiovascular disease. CANVAS
(CANagliflozin cardioVascular Assessment Study)
recently demonstrated a reduction in major adverse
cardiovascular events with canagliflozin (Neal et al,
2017), suggesting there is a class effect. However,
it is yet to be established whether dapagliflozin
will have the same cardiovascular safety effect in
the DECLARE-TIMI 58 (Dapagliflozin Effect
on CardiovascuLAR Events – Thrombolysis in
Myocardial Infarction) trial.
Question #5: renoprotection
Chronic kidney disease (CKD) is a major
microvascular complication in diabetes. At least
half of people with type 2 diabetes in Australian
general practices have CKD, in whom its presence
and severity are strongly associated with poor health
outcomes, including premature mortality. Beyond
glucose lowering, there are data to suggest that some
agents used to treat diabetes provide renoprotection.
Reductions in albuminuria have been reported
in the SAVOR-TIMI 53 (Saxagliptin Assessment
of Vascular Outcomes Recorded in Patients with
Diabetes Mellitus – Thrombolysis in Myocardial
Infarction; Mosenzon et al, 2017) and TECOS
(Trial Evaluating Cardiovascular Outcomes with
Sitagliptin; Cornel et al, 2016) trials in over 10 000
participants using the DPP-4 inhibitors saxagliptin
and sitagliptin, respectively. However, no significant
effects were seen on declining renal function or
the incidence of renal failure. The EMPA-REG
study reported a slower decline in renal function
and fewer participants developing renal failure
or needing dialysis (Wanner et al, 2016). Similar
renal benefits were also reported in the CANVAS
trial (Neal et al, 2017). When renoprotection is a
treatment priority, such benefits may be potentially
valuable. However, it is important to remember
that, unlike DPP-4 inhibitors, SGLT2 inhibitors
are currently not recommended in people with
severe or moderate renal insufficiency because of
their reduced efficacy for lowering glucose levels in
this setting.
Question #6: cancer
Today, every new agent must go through rigorous
testing to ensure that it does not increase the
risk of cancer. DPP-4 inhibition raises the levels
of the incretins glucagon-like peptide 1 (GLP-1)
and glucose-dependent insulinotropic polypeptide
(GIP), which have the potential to promote the
growth of the rare medullary carcinoma of the
thyroid (MCT). Consequently, DPP-4 inhibitors
are contraindicated in individuals with a personal
or family history of MCT or multiple endocrine
neoplasia type 2 (Vangoitsenhoven et al, 2012).
Whether incretins have significant effects on other
cancers is debatable. Certainly, large clinical trials
have not observed any increased risk of cancers,
including pancreatic cancer (Scirica et al, 2013;
Cornel et al, 2016; Mosenzon et al, 2017), although
from a practical point of view, it is reasonable not
to prescribe a DPP-4 inhibitor in individuals with a
history of pancreatitis or pancreatic cancer.
Early studies reported numerically more cases
of bladder cancer in participants treated with
dapagliflozin than with standard therapy, and on
this basis, FDA approval for this agent was initially
withheld (Lin and Tseng, 2014). However, most
people who were diagnosed with bladder cancer
in the trial had blood in the urine before starting
Page points
1. Cardiovascular safety data for
DPP-4 inhibitors suggest that
the class does not pose an
unacceptable cardiovascular
risk, although a small increase
in heart failure admissions has
been observed in trials.
2. Cardiovascular safety data for
empagliflozin suggest that its
use may be associated with
reduced rates of heart failure
and cardiovascular death
in people with established
cardiovascular disease.
3. Reductions in albuminuria
have been reported in study
participants using the DPP-4
inhibitors saxagliptin and
sitagliptin. No significant effects
were seen on declining renal
function or the incidence of
renal failure.
4. DPP-4 inhibitors are
contraindicated in individuals
with a history of medullary
carcinoma of the thyroid.
Whether they have significant
effects on other cancers is
debatable.
Diabetes & Primary Care Australia Vol 2 No 3 2017 121

The new class war
“As a simple rule of
thumb, anytime it is
considered to stop
metformin, stopping
the SGLT2 inhibitor
may also be prudent.”
Competing interests
Merlin Thomas has received
honoraria for educational
symposia conducted on behalf
of AstraZeneca, BMS and the
Boehringer Ingelheim and Lilly
alliances, and MSD respectively,
manufacturers of sodium–glucose
cotransporter 2 and dipeptidyl
peptidase-4 inhibitors.
treatment or it appeared only a short time after
starting, which suggests a causal link to the drug
itself is unlikely. Trials of other SGLT2 inhibitors
have not observed any difference in the prevalence
of cancers, including those of the bladder (Lin and
Tseng, 2014). Additionally, there has been no excess
risk for any cancers reported for people who are
born without the SGLT2 protein (benign familial
glycosuria), despite persistent glycosuria throughout
life.
Question #7: ketoacidosis
Ketone bodies are fatty acid derivatives that are used
by many tissues when glucose availability is limited. It
is normal for a healthy human to increase production
of ketones during prolonged fasting. Apart from
during pregnancy, alcoholism and type 1 diabetes,
ketoacidosis does not occur due to the buffering
effects of bicarbonate. SGLT2 inhibitors trigger the
increased production of ketone bodies by the liver,
possibly to offset the glucose loss in the urine and,
as such, SGLT2 inhibitors have been associated with
diabetic ketoacidosis (DKA; FDA, 2015).
Most SGLT2-associated cases of DKA have
been when SGLT2 inhibitors have been continued
to be taken in stressful metabolic settings, like
prolonged starvation, after surgery, excess alcohol
intake or major inter-current illness. Inappropriate
and excessive reductions of insulin doses may also
induce excess ketone production. As a simple rule of
thumb, any time it is considered to stop metformin,
stopping the SGLT2 inhibitor may also be prudent.
For this reason, SGLT2 inhibitors should never be
used in people with type 1 diabetes, in which their
use is contraindicated.
Summary
SGLT2 inhibitors and DPP-4 inhibitors are both
second-line therapy options for type 2 diabetes.
It is important to consider the individual when
deciding what drug should be added to metformin.
No two individuals with type 2 diabetes are exactly
the same – what is best for one person may be
unthinkable for another. The balance of benefits
(“pluses”) and negatives (“minuses”) is vital to get
right (Figure 1).
n
Bolinder J, Ljunggren O, Kullberg J et al (2012) Effects of dapagliflozin on
body weight, total fat mass, and regional adipose tissue distribution
in patients with type 2 diabetes mellitus with inadequate glycemic
control on metformin. J Clin Endo Metab 97: 1020–31
Cornel JH, Bakris GL, Stevens SR et al (2016) Effect of sitagliptin on
kidney function and respective cardiovascular outcomes in type 2
diabetes: outcomes From TECOS. Diabetes Care 39: 2304–10
DeFronzo RA, Lewin A, Patel S et al (2015) Combination of
empagliflozin and linagliptin as second-line therapy in subjects with
type 2 diabetes inadequately controlled on metformin. Diabetes
Care 38: 384–93
DeVries JH, Rosenstock J (2017) DPP-4 inhibitor-related pancreatitis:
rare but real! Diabetes Care 40: 161–3
FDA (2015) FDA Drug Safety Communication: FDA warns that SGLT2
inhibitors for diabetes may result in a serious condition of too
much acid in the blood. FDA, Washington, DC, USA. Available at:
http://bit.ly/2slTTIF (accessed 19.05.17)
Goring S, Hawkins N, Wygant G et al (2014) Dapagliflozin compared
with other oral anti-diabetes treatments when added to metformin
monotherapy: a systematic review and network meta-analysis.
Diabetes Obes Metab 2014 16: 433–42
Johnsson KM, Ptaszynska A, Schmitz B et al (2013) Urinary tract
infections in patients with diabetes treated with dapagliflozin.
J Diabetes Complic 27: 473–8
Karagiannis T, Paschos P, Paletas K et al (2012) Dipeptidyl peptidase-4
inhibitors for treatment of type 2 diabetes mellitus in the clinical
setting: systematic review and meta-analysis. BMJ 344: e1369
Kawalec P, Mikrut A, Lopuch S (2014) The safety of dipeptidyl
peptidase-4 (DPP-4) inhibitors or sodium-glucose
cotransporter 2 (SGLT-2) inhibitors added to metformin background
therapy in patients with type 2 diabetes mellitus: a systematic review
and meta-analysis. Diabetes Metab Res Rev 30: 269–83
Kilov G, Yeung S, Thomas M et al (2013) SGLT2 inhibition with
dapagliflozin: A novel approach for the management of type 2
diabetes. Australian Family Physician 42: 706–10
Li L, Li S, Deng K et al (2016) Dipeptidyl peptidase-4 inhibitors and
risk of heart failure in type 2 diabetes: systematic review and metaanalysis
of randomised and observational studies. BMJ 352: i610
Lin HW, Tseng CH (2014) A review on the relationship between SGLT2
inhibitors and cancer. Intern J Endocrinol 2014: 719578
Liu SC, Tu YK, Chien MN, Chien KL (2012) Effect of antidiabetic agents
added to metformin on glycaemic control, hypoglycaemia and
weight change in patients with type 2 diabetes: a network metaanalysis.
Diabetes Obes Metab 14: 810–20
Mosenzon O, Leibowitz G, Bhatt DL et al (2017) Effect of saxagliptin on
renal outcomes in the SAVOR-TIMI 53 trial. Diabetes Care 40: 69–76
Neal B, Perkovic V, Mahaffey KM et al (2017) Canagliflozin and
cardiovascular and renal events in type 2 diabetes. N Engl J Med
12 June [Epub ahead of print]
Patil HR, Al Badarin FJ, Al Shami HA et al (2012) Meta-analysis of effect
of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2
diabetes mellitus. Am J Cardiol 110: 826–33
RACGP, Diabetes Australia (2014) General practice management of
type 2 diabetes – 2014–15. RACGP, Melbourne, Vic
Rosenstock J, Hansen L, Zee P et al (2014) Dual add-on therapy in
type 2 diabetes poorly controlled with metformin monotherapy:
a randomized double-blind trial of saxagliptin plus dapagliflozin
addition versus single addition of saxagliptin or dapagliflozin to
metformin. Diabetes Care 38: 376–83
Scirica BM, Bhatt DL, Braunwald E et al (2013) Saxagliptin and
cardiovascular outcomes in patients with type 2 diabetes mellitus.
N Engl J Med 369: 1317–26
Thomas MC, Paldanius PM, Ayyagari R et al (2016) Systematic literature
review of DPP-4 inhibitors in patients with type 2 diabetes mellitus
and renal impairment. Diabetes Ther 7: 439–54
Vangoitsenhoven R, Mathieu C, Van der Schueren B (2012) GLP1 and
cancer: friend or foe? Endocr Relat Cancer 19: F77–88
Vasilakou D, Karagiannis T, Athanasiadou E et al (2013) Sodium-glucose
cotransporter 2 inhibitors for type 2 diabetes: a systematic review
and meta-analysis. Ann Intern Med 159: 262–74
Wanner C, Inzucchi SE, Lachin JM et al (2016) Empagliflozin and
progression of kidney disease in type 2 diabetes. N Engl J Med 375:
323–34
Wilding JP (2014) The role of the kidneys in glucose homeostasis in
type 2 diabetes: clinical implications and therapeutic significance
through sodium glucose cotransporter 2 inhibitors. Metabolism 63:
1228–37
Zinman B, Lachin JM, Inzucchi SE (2016) Empagliflozin, cardiovascular
outcomes, and mortality in type 2 diabetes. New Engl J Med 374:
1094
122 Diabetes & Primary Care Australia Vol 2 No 3 2017

&
&
&
&&
&
&
&
&&
&
&
&
&&
&
&
&
!
The new class war
!
!
!
!
!!!!!
6!;!;?@!
!!!!!!!!!!!6!!%,:8-/*':'+D!
! !!!!!!!!!!!!!!!!!!!!!!3!%)-C.)! −
!!!!!!!!!!!!!!!!!!!!!3!2/(F-8/+'+'.!
−
same – what is best
!
!!
! !"#$%&'()'*'+,-& 7863&;& !!!!!!!!.//01&'()'*'+,-&
for one person may
!
! !
be unthinkable for
!!!!!!!!!!!!!!!!!!!!!!3!AB+-/!C-'(8!
−3 ?8/-+!E/':C-8
!
−
!
another.”
! !!!!!!!!!!!!!!!!!!!!!!3!%)-C.)! −
!!!!!!!!!!!!!!!!!!!!!3!2/(F-8/+'+'.!
−
"# $%&'(!%)(*+,!-.(-/*01+%-'0!12'('!.0!%)1!*/-2!1)!-2))0'!3'14''%!"#$%&!'()'*'+,-.!/(0!12234!
! !!
7863&;&
! '()'*'+,-.5!
!
! "# $%&'(!%)(*+,!-.(-/*01+%-'0!12'('!.0!%)1!*/-2!1)!-2))0'!3'14''%!"#$%&!'()'*'+,-.!/(0!12234!
!!!!!!!!!!!!!623'4)+&5,66&
!
'()'*'+,-.5!
b. !
!
!!!!!!!!!!!!!623'4)+&5,66&!
!!!!!!!!!!!!&
!
!!!!!!!!!!!!!!!!%,:8-/*':'+D!
+
"# $%&'(!%)(*+,!-.(-/*01+%-'0!12'('!.0!%)1!*/-2!1)!-2))0'!3'14''%!"#$%&!'()'*'+,-.!/(0!12234!
&
! '()'*'+,-.5! !3!AB+-/!C-'(8!
− !!!!!!!!!!!!&
!!!!!!!!!!!!!&
!
!!!!!!!!!!!!!!!!%,:8-/*':'+D!
+
! !!!!!!!!!!!!!!!!!!!!!!!!3!%)-C.)! −
!
&
! !!!!!!!!!!!!!623'4)+&5,66&
!!!!!!!!!!!!!!!!!!!!!3!?8/-+!E/':C-8!
−
!
!3!AB+-/!C-'(8!
−
7863&9& !!!!!!!!!!!!!&
!!!!!!!!!!!!!!!!!!!!!3!2/(F-8/+'+'.!
−
! !!!!!!!!!!!!!!!!!!!!!!!!3!%)-C.)! −
!!!!!!!!!!!!&
!
! !
!!!!!!!!!!!!!!!!!!!!!3!?8/-+!E/':C-8!
!!!!!!!!!!!!!!!!%,:8-/*':'+D!
+ −
!
& 7863&9& !!!!!!!!!!!!!!!!!!!!!3!2/(F-8/+'+'.!
−
! !
!
!
!3!AB+-/!C-'(8!
−
!!!!!!!!!!!!!&
! 5# !!!!!!!!!!!!!!!!!!!!!!!!3!%)-C.)!
6%!+!7)/%8'(!9'(0)%!4.12!0/3:)91.*+,!3,))&!8,/-)0'!*+%+8'*'%1!'+(,7!.%!12'.(!&.0'+0'!-)/(0';!
−
! .%!42)*!4'.821!,)00!.0!+!9(.)(.17;!+%&!3,+&&'(!&70!;?@!
+
!!!!!!!!!!&$,53-8*'5'+:&
+
!!!!!!!!!!!!!&
5# !!!!!!78'9)+!:,..!
6%!+!7)/%8'(!9'(0)%!4.12!0/3:)91.*+,!3,))&!8,/-)0'!*+%+8'*'%1!'+(,7!.%!12'.(!&.0'+0'!-)/(0';!
+
.//01&'()'*'+,-!
&
! ! .%!42)*!4'.821!,)00!.0!+!9(.)(.17;!+%&!3,+&&'(!&70!;?@!
+
)(.17;!+%&!3,+&&'(!&70!;?@!
+
7863&7&
−
!
!
!!!!!!!!!!!!!!!!!!!!!3!%)-C.)! −
!!!!!!!!!!!!!&
!!!!!!78'9)+!:,..!
+
.//01&'()'*'+,-!
!
! !!!!!!!!!!!!!!!!!!!!!3!;H1! −
!
−3!AB+-/!C-'(8!!
7863&7& !!!!!!!!!!!!3!?8/-+!E/':C-8!
−
! ! !!!!!!!!!!!!!!!!!!!!!3!%)-C.)!
!!!!!!!!!!!!!!!!!!!!!!3!2/(F-8/+'+'.!
!
!!!!!!!!!!!!
−
−
! Figure 1a. !!!!!!!!!!!!!!!!!!!!!3!;H1!
The main advantages − and negatives of SGLT2 and DPP-4 inhibitors. !
1b. In a younger person with sub-optimal blood glucose management early in their
!
! ! disease course, in whom weight loss is a priority, and bladder dysfunction and
−3!AB+-/!C-'(8!!
7863&7&
!
comorbidity are not limiting, then an SGLT2 inhibitor could be advantageous.
!!!!!!!!!!!!!!!!!!!!!3!%)-C.)! −
1c. In an older person, in whom weight loss is not a priority, and bladder dysfunction and
! comorbidity
!!!!!!!!!!!!!!!!!!!!!3!;H1!
are frequently
−
!
limiting, then good tolerability and easy efficacy of a DPP-4
inhibitor could be advantageous.
!
CHF=congestive heart failure; CKD=chronic kidney disease; CV=cardiovascular;
DPP-4=dipeptidyl peptidase-4; SGLT2=sodium–glucose cotransporter 2.
!
6!78'9)+!:,..!
!"#$%&'()'*'+,-!
!"#$%&'()'*'+,-!
!"#$%&'()'*'+,-!
!"#$%&'()'*'+,-!
!"#$%&'()'*'+,-!
!"#$%&'()'*'+,-!
.//01&'()'*'+,-!
.//01&'()'*'+,-!
.//01&'()'*'+,-!
Diabetes & Primary Care Australia Vol 2 No 3 2017 123

The PCDSA is a multidisciplinary society with the aim
of supporting primary health care professionals to deliver
high quality, clinically effective care in order to improve
the lives of people with diabetes.
The PCDSA will
Share best practice in delivering quality diabetes care.
Provide high-quality education tailored to health professional needs.
Promote and participate in high quality research in diabetes.
Disseminate up-to-date, evidence-based information to health
professionals.
Form partnerships and collaborate with other diabetes related,
high level professional organisations committed to the care of
people with diabetes.
Promote co-ordinated and timely interdisciplinary care.
Membership of the PCDSA is free and members get access to a quarterly
online journal and continuing professional development activities. Our first
annual conference will feature internationally and nationally regarded experts
in the field of diabetes.
To register, visit our website:
www.pcdsa.com.au