YOUR TRUSTED SOURCE OF HEALTHCARE INFORMATION IN ASIA MALAYSIA JULY 2017

Highlights from
ASCO 2017 & ADA 2017

How to manage
vertebral compression
fractures
CONTENTS
MIMS DOCTOR - YOUR TRUSTED SOURCE OF HEALTHCARE INFORMATION IN ASIA CEO
Yasunobu Sakai

Senior Editor
Saras Ramiya

Associate Editor
Pank Jit Sin
JULY ISSUE
Contributing Editors
Malaysia Focus Christina Lau, Jackey Suen, Joseph Ro-
bles (Hong Kong), Dr. Joslyn Ngu, Rachel
6 Back pain in young people possibly due to AS Soon (Malaysia), Elvira Manzano, Audrey
Abella, Roshini Claire Anthony, Pearl Toh
(Singapore), Dr. Mel Beluan (Philippines)
8 Metabolism a promising biomarker of embryo viability
Designers
10 More screening awareness required to reduce thalassaemia Razli Rahman, Tina Ng, Peggy Tio, Sam
Shum

12 Gearing up for the 12th Liver Update Production

Raymond Choo
14 Burden of untreated hepatitis C to persist for decades Circulation Executive
Pauline Hoe
15 Dolutegravir relaunch improves accessibility, affordability Accounting Manager
Minty Kwan
16 Role of IP rights in pharmaceutical innovation, affordable access to healthcare
Advertising Coordinator
Raymond Choo

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Back pain in young people possibly due
to AS
L–R: Dr. Amir Azlan Zain, Nawfal Johnson, AS Fighter; Associate Professor Dr. Sargunan Sockalingam, Bernice Chan, franchise head for immunology
and dermatology, neuroscience of Novartis Malaysia.
SARAS RAMIYA
F
urther investigation of back
pain in the below 30 age group
may lead to early diagnosis of
ankylosing spondylitis (AS), says an
expert.
“Ankylosing spondylitis is a
chronic condition that causes back
pain because of inflammation of lig-
aments between the vertebra and
inflammation of the tendons and lig-
aments,” said Dr. Amir Azlan Zain,
consultant physician and rheuma-
tologist, at a media briefing on AS in
Kuala Lumpur.
The inflammatory back pain ex-
perienced by patients with AS is the
opposite of mechanical back pain. It
improves when they move and wors-
ens with rest. The early morning stiff-
ness usually lasts for hours. These
two symptoms are cardinal in inflam-
matory back pain. “Awareness of AS
MALAYSIA FOCUS
has to be not only amongst the mem-
bers of the public but also members
within the medical community as well
including family physicians, ortho-
paedic surgeons and professionals
who also evaluate people with back
pain on a regular basis,” said Amir.
AS is in a group of conditions
which is typified by long-term inflam-
mation. If the inflammation is left un-
checked, it can lead to progressive
stiffening of the areas involved. In the
case of the intervertebral ligaments, it
causes a stiffening of the spine. This
process is irreversible. [Spondylitis
Association of America. Available at:
www.spondylitis.org Accessed on
30 May]
Other comorbidities associated
with AS include cardiovascular com-
plications, osteoporosis, reduced
pulmonary function, chronic pain,
depression and gastrointestinal prob-
lems. Patients with AS are also at a
6
DOCTOR | JULY ISSUE
higher chance of dying compared
with the general population. [Arthri-
tis Rheum 2011;63:1182–1189, Ann
Rheum Dis 2011;70:1921–1925]
AS is an autoimmune disease
whereby the immune system has
been switched on via trigger and
the immune cells—mostly white
blood cells (WBC)—are activated
and produce inflammatory substanc-
es. These inflammatory substances
drive the inflammation in the spine
and cause the eventual stiffening of
the spine. The HLA-B27 is a genetic
marker found in most of the human
cells and 90% of people with AS have
it although it is a fairly common ge-
netic marker in general.
The prevalence of AS is much
higher in North America (3,190 per
million) and Europe (2,380 per mil-
lion) but there is a fair number in
Asia (1,670 per million). [Rheuma-
tology (Oxford) 2014;53:650–657]

AS affects young people and is di-
agnosed when patients are at the
most productive age in terms of work
productivity. [Curr Opin Rheumatol
2000;12:239–247] As a result, 30%
of patients with AS have to quit their
job because they are unable to sus-
tain the job in the long term. [Curr
Rheumatol Rep 2010;12(5):325–331]
Diagnosing AS is fairly straight-
forward and involves firstly, the rec-
ognition that back pain is inflamma-
tory and secondly, through specific
physical examination especially of the
spine. Tests for inflammation and
HLA-B27 are recognized as standard
tests for inflammatory back pain.
X-ray or magnetic resonance imaging
(MRI) changes are now important in
classification of AS, said Amir.
FA_Miaryl Tab_Mims Doctor_July 2017.pdf 1 6/7/2017 3:17:54 PM
MALAYSIA FOCUS
In terms of treatment, only
anti-inflammatory tablets and physio-
therapy were available until about 18
years ago. The emergence of tumour
necrosis factor (TNF) inhibitors—so-
called biologic medicines—have
changed the treatment landscape
for patients with AS. There are five
anti-TNF medicines that are licensed
for use in Malaysia, he said.
The newly available secukinum-
ab (Cosentyx®) targets a completely
novel pathway ie, IL-17A. Inflamma-
tory substances produced by WBC
include TNF and IL-17A. Blocking
these molecules has been effective in
controlling AS, said Amir.
Speaking on Arthritis Foundation,
Malaysia (AFM), its president Asso-
ciate Professor Dr. Sargunan Sock-
7
DOCTOR | JULY ISSUE
alingam, consultant rheumatologist,
University Malaya Specialist Centre,
said, “AFM was founded in 1994 and
an organization for people involved in
the care of arthritis patients and also
of people living with arthritis.”
AFM is a support group for peo-
ple with rheumatoid arthritis, psoriatic
arthritis, osteoarthritis and, more re-
cently, AS. AFM organizes fundrais-
ing activities in terms of public fo-
rums, support group platforms with
meetings and activities and weekly
exercise sessions. The Arthritis Fund,
which was established sometime in
1995, provides partial or full finan-
cial support for joint replacements
and plans to include biologics. AFM
held a fundraising run in May for the
Arthritis Fund. For further information
on AFM, go to www.afm.org.my

Metabolism a promising biomarker
of embryo viability
DR. JOSLYN NGU
M
etabolism plays an important
role in the development of an
embryo, particularly during
the pre-implantation period, and may
have a role to play in the selection of
embryos in in vitro fertilization (IVF),
says an expert.
According to a study, glucose up-
take by the embryo was shown to be
associated with pregnancy outcome.
The findings showed that glucose
consumption by embryos which re-
sulted in a pregnancy was higher on
day 4 and 5, compared to embryos
that failed to develop post-transfer.
[Hum Reprod 2011;26(8):1981–
1986] As such, glucose metabolism
in embryos may be useful as a fac-
tor in the selection of embryos for
transfer in IVF, said Professor David
K. Gardner, of the School of Biosci-
ences, University of Melbourne and
MALAYSIA FOCUS
scientific director of Melbourne IVF,
Australia.
In IVF, better identification and se-
lection of viable embryos for transfer
will lead to a reduction in the number
of embryos that need to be trans-
ferred and improve the efficiency of
single embryo transfer. This will play a
role in reducing the frequency of mul-
tiple gestations and increasing the
efficiency of IVF.
Conventionally, the embryo’s
morphology is used to determine
embryo selection. However, mor-
phology alone is not an accurate indi-
cator of the embryo’s physiology and
not indicative of its viability. In animal
studies, metabolism has been shown
to be a useful marker of viability after
transfer and the same may be true for
humans, said Gardner.
The embryo’s metabolism chang-
8
DOCTOR | JULY ISSUE
es to accommodate stage-specific
requirements during its development
and differentiation. If the changes did
not occur, development will be com-
promised. In day 1 to 3 of life, embry-
os utilize pyruvate, lactate and amino
acids to generate energy. In day 4,
embryos switch to a glucose-based
metabolism, he explained.
It is difficult to quantify the met-
abolic functions of an embryo in
cultures as it can be influenced by
factors such as oxygen concentra-
tion, gender and composition of the
culture medium. Continuous technol-
ogy advancements will enable future
research to further explore the link
between said factors and metabolic
functions, leading to the development
of metabolism algorithms for embryo
selection. Gardner was speaking at
the 7th Congress of the Asia Pacific
Initiative on Reproduction (ASPIRE
2017), held in Kuala Lumpur recently.
 MALAYSIA FOCUS

More screening awareness required to

reduce thalassaemia
RACHEL SOON

G
reater awareness of once-
in-a-lifetime screening for
thalassaemia among Malay-
sian adults is necessary to mitigate a
growing healthcare burden, accord-
ing to government statistics.

“In Malaysia, the estimated num-

ber of patients with thalassaemia in
2004 was 2,500. However, the num-
ber of patients reported to the Ma-
laysian Thalassaemia Registry has
climbed to 7,220 patients as of 8
May 2017,” said Dato’ Dr. Haji Azman
bin Abu Bakar, director of the MOH
Medical Development Division. “Out
of this number, an estimated 5,000
patients have a severe form requiring
regular blood transfusion, [known as]
transfusion dependent thalassaemia
(TDT).”
Speaking at a recent blood do-
nation drive in Petaling Jaya, Azman
clarified that the increase in patient
numbers were partly due to better
reporting and diagnosis confirma-
tion, as well as improved quality of
care and subsequent improved pa-
tient survival. However, he added
that an estimated 100 new cases of
thalassaemia would be added to the
registry each year based on current
growth rates, adding to the need for
increased blood collection efforts to
ensure sufficient nationwide supply.
According to Dr. Jameela Sathar,
consultant haematologist at Hospital
Ampang, the lifetime cost of provision
of medical care for a single patient
with TDT from birth to 40 years of
age can amount to over RM4 million
due the need for regular blood trans-
fusions, drugs, equipment and di-
agnostic procedures. With improve-
ments in healthcare, patients with
TDT in Malaysia are now expected to
survive beyond 40 years.
“Now that there are so many pa-
tients, we have to ask them to buy
their own syringes, because we don’t
have the budget. Syringes and saline
alone cost RM500 per month per per-
son,” said Jameela, speaking at the
same event. “Yet every week, I see
a new child referred to our [Hospital
Ampang] clinic with thalassaemia
major. More than [the currently pro-
jected] 100 patients per year, I would
say close to 800 are being born per
year… All their costs are paid for by
taxpayers’ money. But it is no fault of
the child.”
While individuals can carry a
thalassaemia gene asymptomatically,
children of two carriers have a 25%
risk of manifesting the disease, while
children of one carrier and a non-car-
rier have a 50% chance of carrying
the gene.
According to Jameela, an esti-
mated 1-in-10 Malaysians are carri-
ers, while across the globe more than
60% of carriers reside in Southeast
Asia.
“We don’t prevent two carriers
from getting married. But you have
to take responsibility for prenatal di-
agnosis and testing,” said Jameela. “I
have known of doctors who preach
and teach about thalassaemia, but
they have never asked their own chil-
dren to do screening. Why are we so
complacent? Because we think we
don’t have a family history of thalas-
saemia, (therefore) we are safe? Yet
I have seen couples—doctors, even;
one a carrier, and the other self-as-
sured of their lack of family history
of thalassaemia, have a child with
thalassaemia major.”
Jameela emphasized the impor-
tance of screening for adolescents,

10
DOCTOR | JULY ISSUE

young adults, partners planning to
have children, and pregnant mothers
especially so that prenatal diagnosis
can be offered and termination of
pregnancy suggested if necessary.
As part of the MOH’s national
thalassaemia programme, a nation-
wide targeted screening initiative for
students 16 years of age (Form 4)
was launched in November 2016.
Jameela and Azman also encour-
aged the public to take advantage of
voluntary screening services provid-
ed at public healthcare centres, the
list of which can be found at www.
mytalasemia.net.my/.
The hidden hereditary
link
Thalassaemia refers to a group of
autosomal recessive genetic blood
disorders which result in insufficient
haemoglobin production from birth.
Characteristic symptoms include
anaemia (comprising pale complex-
ion, fatigue, shortness of breath), re-
current fevers, spleen enlargement,
dark urine production and overall
stunted development.
Apart from bone marrow trans-
plantation—and only 25% of patients
have suitable sibling donors—no
known cure is available for the dis-
ease. Severe thalassaemias (eg, beta
thalassaemia major) require the pa-
tient to receive regular blood transfu-
sions to prolong life, but this brings
its own host of problems, Jameela
noted.
MALAYSIA FOCUS
“Transfusions are lifesaving for
thalassaemia, but with every trans-
fusion, iron buildup occurs,” said Ja-
meela. “One bag of blood contains
200 mg of iron. A young adult weigh-
ing 50 kg requires three bags of blood
transfused per month… by the end of
the year they have about 7 g of iron,
and the human body has no mecha-
nism for getting rid of this excess iron
[beyond] what we shed through our
skin, mucosa, and—in women—the
menstrual blood. Iron accumulation
in the pancreas can cause diabetes,
while accumulation in the thyroid can
cause hypothyroidism.”
Jameela added that even with
regular blood transfusions and iron
chelation therapy, some patients with
thalassaemia are unable to achieve
normal growth rates, often resulting
in additional psychosocial issues as
they attain school-going age.
“Those born with thalassaemia
live a life full of injections, tied to
the hospital,” said Jameela. “Every
3 weeks a blood transfusion, every
night parents who must make sure
they get their medication.”
Shortfalls in blood sup-
ply
According to the 2014 guidelines for
TDT management by the Thalassae-
mia International Federation, patients
with TDT require transfusions every 2
to 5 weeks, with each patient requir-
ing between 7.5 to 24 ml of blood per
kg of body weight.
11
DOCTOR | JULY ISSUE
“On average, 2,000 bags of
blood are needed every day in MOH
hospitals throughout the country… in
the Klang Valley alone, the National
Blood Center is required to provide
more than 500 bags a day to meet
MOH hospital requirements and
some supplies to the private hos-
pitals,” said Azman. “It is estimated
about 17% to 20% of the [national]
blood supply goes to TDT patients
annually.”
Azman added that in 2016,
693,982 bags of blood in total were
collected nationwide, amounting to
around 1,900 bags per day. Given
that regular blood donors can only
donate every 3 to 4 months a year,
concerted and continuous efforts are
needed to recruit new donors and re-
tain existing ones, he said.
“Overall, the total number of [Ma-
laysians] who become regular blood
donors is still low compared to other
developed countries,” said Azman.
“At the moment, our percentage
is about 2% [of the population] … I
hope we can attract more people to
donate and achieve 3% to 5%.”
Jameela encouraged more men
to donate blood, as women were
more likely to be iron deficient; in ad-
dition, women who had undergone
one or more pregnancies were more
likely to have foetal antigens which
could result in adverse reactions in
the patient recipient.

Gearing up for the 12th Liver Updates
PANK JIT SIN
L
iver Update is a series of inter-
national scientific meetings or-
ganized by the Malaysian Liver
Foundation. It is meant to keep our
healthcare professionals (HCPs) up-
dated on current developments and
new advances in the management
of liver diseases. Usually held around
mid to late July, the conference is a
must-go for hepatologists, GPs and
allied health professionals alike.
MIMS Doctor got in touch with
Tan Sri Dato’ Seri Dr Haji Mohd Is-
mail Merican, founder and president
of the Malaysian Liver Foundation,
to get his views about the upcoming
event. He said: “It is imperative that
our HCPs keep themselves updated
on current advances in the approach
and management of common liver
disorders found in this country so
that their patients will be given the
right information and advice.”
Mohd Ismail said patients are
nowadays actively searching for infor-
mation on the World Wide Web and
it is therefore imperative that HCPs
know more about liver diseases
than their patients. Also, information
on the internet may be misleading,
which requires a well-informed and
up-to-date HCP to put the patient
back on track. “This is in fact part
of continuing professional develop-
ment and is an important factor in the
practice of medicine, as information
is ever evolving, even as we speak,
and none of our HCPs should be left
behind clinging to outdated knowl-
edge.”
This year’s Liver Update has
been organized with great effort to
bring world renowned experts to
share their experiences and knowl-
edge with our HCPs. Recent devel-
opments pertaining to liver diseases
MALAYSIA FOCUS
have ignited both hope and
concern amongst health-
care professionals and pol-
icy makers. Mohd Ismail
said: “Now we have a real-
istic possibility of a cure for
patients with chronic hepa-
titis C, a major public health
problem globally.” Howev-
er, on the other end of the
spectrum, the increasing
incidence of non-alcoholic
fatty liver disease (NAFLD)
which is associated with
obesity, diabetes mellitus,
hyperlipidaemia, the meta-
bolic syndrome and lifestyle
diseases is a great concern
to all of us.
The event will see lec-
tures from local and overseas ‘su- • Dato Dr Christopher Lee
perstars’ in hepatology. Overseas • Professor Dato’ Dr Nor Shahidah
speakers include the following: Khairullah
• Professor Dr Edward Gane from • Professor Dato’ Dr Ravindran Je-
New Zealand gasothy
• Professor Dr Henry Chan from • Dato’ Dr Robert Ding
Hong Kong • Dato‘ Dr Nik Ritza Kosai Nik Mah-
• Dr Thomas Leung from Hong mud
Kong • Dr Tan Soek Siam
• Professor Dr Mohamad Rela • Dr Haniza Omar
from India • Dato’ Dr Mazlam Mohd Zawawi
• Dr Richard Guan from Singapore
• Dr Rohit Agarwal from Singapore When asked which particular
• Dr Chow Wan Cheng from Singa- sessions he deem as ‘must-attend’
pore sessions, Mohd Ismail said all ses-
• Professor Dr Laurentius Lesmana sions are important, it just depends
from Indonesia on the interest of the delegate. “If I
• Professor Dr Teerha Piratvisuth can make a suggestion, sessions
from Thailand on chronic hepatitis C and fatty liver
should be attractive to participants in
Meanwhile the local speakers list view of recent developments.”
comprises:
• Datuk (Mr) Harjit Singh- Malaysia The conference will be looking at
• Datuk Dr Ryan Ponnudurai more than 300 participants with more
• Mr Krishnan Raman slated to register on the spot. Spe-
• Datin Dr Sharmila Sachithanan- cialists, doctors and allied healthcare
dan professionals including pharmacists,
• Dr Manisekhar Subramaniam assistant medical officers and nurses
• Datuk Dr Shahnaz Murad should make their way to the event.
• Dr L. Sanker
12
DOCTOR | JULY ISSUE

Burden of untreated hepatitis C to persist
for decades
RACHEL SOON
D
espite declining incidence of
hepatitis C virus (HCV) infec-
tions in Malaysia, the impact
of existing untreated cases will con-
tinue to be felt for years to come,
says an expert.
“[Many] who were infected 30
to 60 years ago are now dying from
HCV-related cirrhosis and hepato-
cellular carcinoma (HCC),” said Da-
tuk Dr. Jayaram Menon, head of the
department of medicine at Queen
Elizabeth Hospital, Kota Kinaba-
lu. “In the absence of interventions,
HCV-related mortality and morbidity
will double over the next 15 years ...
the increasing number of deaths re-
flects the high incidence of hepatitis
C in the mid-20th century due to ex-
panded use of parenteral injections
and drug use.”
Jayaram noted that according
to estimates from the Global Burden
of Disease studies, worldwide mor-
tality from hepatitis C complications
increased from 333,000 in 1990
to 499,000 in 2010, followed by
704,000 in 2013. Current prevalence
of infection among Malaysians is es-
timated to be around 2.5%. [Lancet
Gastroenterol Hepatol 2017;2:52–
62]
Chronic HCV infections—which
produce detectable HCV RNA only
after 6 months post-infection—ac-
count for 75 to 80% of all cases of
HCV, and often prove challenging for
primary care physicians to diagnose
without blood tests. Common ear-
ly symptoms (if they manifest at all)
such as fatigue, muscle ache, and
nausea may be passed off as those
of a flu-like viral infection, or another
MALAYSIA FOCUS
inflammatory disorder.
Speaking at a recent MMA con-
ference in Kota Kinabalu, Jayaram
added that an estimated 30% of
individuals with chronic infection re-
tain normal liver enzyme function, al-
though silent damage to the liver may
yet be progressing.
“All patients with risk factors for
hepatitis C should have a serological
screening test for anti-hepatitis C an-
tibodies,” said Jayaram. “A positive
screening test should be followed by
a test for hepatitis C RNA to confirm
the diagnosis.”
Current recognized risk factors
for HCV infection include recipients
of blood transfusions prior to 1992 or
clotting factor concentrates prior to
1990; transfusions from donors later
found to be HCV+; organ transplants
before the 1990s; maternal HCV+;
current or past intravenous drug use;
invasive medical procedures done
prior to the 90s; haemodialysis; HIV
infection; healthcare workers, es-
pecially after needle/sharp injury or
exposure to HCV+ blood; high-risk
sexual behaviours; incarceration;
intravenous illicit drug use; and un-
regulated tattoos. [J Fam Pract
2017;66(3):136–144]
Considering treatment
options
Jayaram noted that at present, six
key HCV genotypes have been iden-
tified globally; while HCV-1 is the
most common on an international
scale, a recently published study of
HCV prevalence in the Asia-Pacific
region found that 62.3% of Malaysian
cases involved HCV-3, while 35.8%
involved HCV-1. The same study
also noted that overall prevalence
of infection in Malaysia was 2.5%.
14
DOCTOR | JULY ISSUE
[Lancet Gastroenterol Hepatol 2017;
2:52–62]
“Treatment with pegylated inter-
feron-α and ribavirin was the gold
standard up to 4 years ago, but that
is no longer the case,” said Jayaram.
“Genotype 1 only had a 40 to 50%
chance of treatment success with
PEG-IFN/RBV, while genotype 3 had
about 60 to 70%.”
At present, three classes ofdi-
rect-acting antivirals (DAAs) are avail-
able; most recommended DAA treat-
ment regimens span 8 to 24 weeks,
which Jayaram highlighted as an
improvement from PEG-IFN and rib-
avarin, which can involve up to 1 year
of treatment.
“Combinations of two or three
of these DAAs can cure HCV infec-
tion—with ‘cure’ defined as a sus-
tained virologic response (SVR) at 12
weeks post-treatment—in over 90%
of patients, including populations
that have been difficult to treat in the
past,” said Jayaram.
However, he noted that issues of
pricing remain a barrier to the wider
use of DAAs for treatment compared
to more cost-effective options such
as PEG-IFN/RBV. In addition, a re-
cently published Cochrane review
of 138 randomized clinical trials for
DAAs on the market found little long-
term evidence available to support
DAA impact on hepatitis C-related
morbidity or all-cause mortality (OR
3.72, 95% CI 0.53 to 26.18, P =
0.19, I² = 0%, 2,996 participants, 11
trials), and warned that all trials and
outcome results were at high risk
of bias. [Cochrane Database Syst
Rev 2017; doi:10.1002/14651858.
CD012143.pub2]

Dolutegravir relaunch improves
accessibility, affordability
PANK JIT SIN
D
olutegravir (Tivicay®), a HIV-1
integrase strand transfer in-
hibitor (INSTI) is now part of
the MOH medicine formulary.
The drug was recently relaunched
after being accepted into the medi-
cine formulary. Respondng to ques-
tions from MIMS Doctor, Steve
Yoong, associate marketing and
sales manager, HIV Business Unit,
GSK, said the drug will now feature
more prominently in the treatment of
HIV in Malaysia. Beyond better ac-
cessibility, a pricing restructure prac-
tice will also make it more affordable.
MALAYSIA FOCUS
Dolutegravir is indicated in the treat-
ment of HIV-1 in combinations with
other antiretroviral medications.
In the government setting, do-
lutegravir will be prescribed as a cat-
egory ‘A’ drug, meaning it can only
be prescribed by specialists in the
field of infectious disease. In the pri-
vate setting, there are no restrictions
on prescriber category or purchaser
ie., GP or specialist. However, this
is still a specialized medicine for HIV
treatment and will require prescription
and monitoring by a trained special-
ist. GPs will normally refer patients to
an infectious disease centre or ideally
together with an infectious disease
15
DOCTOR | JULY ISSUE
specialist to manage the patient.
While the initial launch was car-
ried out towards the end of 2014, the
drug grappled with accessibility and
affordability issues. With its accep-
tance into the government’s medicine
formulary, the drug should see wider
use among persons with HIV.
Dolutegravir is an integrase inhib-
itor. Integrase is required by the HIV
virus as part of its replication process.
By binding to the integrase and thus
blocking viral replication, dolutegravir
slows down the reproduction of HIV-
1 virus particles. However, it should
be used in combination with other
antiretroviral therapy.
 MALAYSIA FOCUS

Role of IP rights in pharmaceutical

innovation, affordable access to healthcare
DR. JOSLYN NGU

I
ntellectual Property (IP) rights play
a key role in strengthening the
pharmaceutical industry, which can
contribute to improving Malaysia’s
economy and general health out-
comes, experts say.

Speaking at the Improving Health

Innovation and Access to Medicines
seminar organized by the Institute
for Democracy and Economic Affairs
(IDEAS), the company’s director of
research, Ali Salman said in order to
spur the growth of innovation, strong
IP laws are necessary. He cited the
US as an example; a big percentage
of revenue for the most success-
ful US companies are derived from
ideas, concepts, brands, innovative
products and processes.

A patent is the most important

IP for a pharmaceutical company,
said Linda Wang, a lawyer with Zaid
Ibrahim & Co, which specializes in
IP rights. In agreement with Ali, she
said patents will encourage innova-
tion, and this has been shown in the
US where the generic industry expe-
rienced a 40% growth. A patent will
provide the company monopoly for a
set duration, and this will allow them
to cover the cost of research and de-
velopment.
There is a need for balance be-
tween providing incentives for re-
search and development against
access to medical innovations, said
Dr. Salmah Bahri, senior director of
the Pharmaceutical Services Office,
MOH. Among the challenges faced
by the healthcare system today is an
exponential rise in drug prices. The
increase in pricing is partly contrib-
uted by the power given to compa-
nies through patent rights, she said.
As the regulatory body in the coun-
try in charge of healthcare, several
steps can be taken by the MOH to
improve access to medicines. Ex-
amples include creating conducive
regulatory infrastructure, establish-
ing government-to-government rela-
tionships through mutual recognition
agreements and providing incentives
for the generics industry. A more
transparent patient access scheme
or management entry agreements
will be helpful for the local healthcare
system, said Salmah.
Also speaking at the forum, Chin
Keat Chyuan, country manager of
Johnson & Johnson Sdn Bhd and
president of the Pharmaceutical As-
sociation of Malaysia said IP rights
should be viewed as a system that
provides sustainable and win-win
framework for both the pharmaceu-
tical industry and regulators. He said
there are more than 240,000 on-go-
ing clinical trials at the moment and
this is an indication of growth in the
pharmaceutical industry. Strong IP
rights would not only encourage in-
vestment and innovation, but it will
also help to increase economic activ-
ity, he said.
Intellectual Property rights are
defined as ideas, inventions and cre-
ative expressions based on which
there is a public willingness to bestow
the status of property. [J Adv Pharm
Technol Res 2011;2(2):88–93] It is
the legal rights given to an inventor
or creator to protect his invention or
creation for a fixed duration. Among
the types of IP protection are patent,
copyright and trademark.

16
DOCTOR | JULY ISSUE
 COVER STORY

Is lower
better?
Blood
pressure
target:

PEARL TOH

A
chieving a systolic blood pres-
sure (SBP) below the currently
recommended targets signifi-
cantly decreases the risk of cardiovas-
cular disease (CVD) and death from
any cause, according to a network me-
ta-analysis of 42 randomized trials.
“[T]here were linear associations
between mean achieved SBP and risk
of CVD and mortality, with the lowest
risk at 120 to 124 mmHg,” said the re-
searchers. “Our findings do not support
the existence of a J-shaped association
between achieved SBP and the risk of
CVD and all-cause mortality.”
The researchers observed that the
higher the levels of achieved SBP, the
greater the risk for major CVD: in in-
dividuals who achieved a mean SBP
between 120–124 mmHg, the risk of
major CVD was 29% lower vs the 130–
134 mmHg group, 42% lower vs the
140–44 mmHg group, 54 percent low-

18
DOCTOR | JULY ISSUE

er vs the 150–154 mmHg group, and
64% lower vs the ≥160 mmHg group
(hazard ratio [HR], 0.71, 0.58, 0.46, and
0.36 for each increasing SBP stratum
respectively).
Similarly, individuals who achieved
an SBP of 120–124 mmHg were in-
creasingly less likely to die from any
cause compared with individuals
with progressively higher SBP: HRs
for all-cause mortality were 0.73 vs
the 130–134 mmHg group, 0.59 vs
the 140–44 mmHg group, 0.51 vs
the 150–154 mmHg group, and 0.47
vs the ≥160 mmHg group. [JAMA
Cardiol 2017;doi:10.1001/jamacar-
dio.2017.1421]
“The lowest risks for major CVD,
coronary heart disease, all-cause mor-
tality, and CVD mortality were at a mean
achieved SBP of 120–124 mmHg,
whereas the lowest risk for stroke
was at a mean achieved SBP of <120
mmHg,” the researchers observed.
“These findings support more in-
tensive SBP control among adults with
hypertension and suggest the need for
revising the current clinical guidelines
for management of hypertension,” they
contended.
Intensive treatment
remains controversial
“[The study provides] provocative evi-
dence that lower is better and likely so
in all cohorts with hypertension,” wrote
Drs Clyde Yancy and Robert Bonow
from the Feinberg School of Medicine,
Northwestern University in Chicago, Illi-
nois, US, in a separate editorial. “These
are nontrivial findings. We should not
ignore the potential for harm attribut-
ed to lowering blood pressure too ag-
gressively, particularly in the elderly, but
those harms have not yet emerged to
be more important than the benefits.”
[JAMA Cardiol 2017;doi:10.1001/ja-
macardio.2017]
“Recommendation for more ag-
gressive lowering below 120 mmHg
COVER STORY
remains controversial … There were
too few studies of treatment below 120
mmHg to comment on,” said Adjunct
Associate Professor Tan Ru San, a se-
nior consultant at the Department of
Cardiology at the National Heart Cen-
tre, Singapore, noting that there were
only three trials in the meta-analysis
with achieved SBP of <120 mmHg.
The network meta-analysis includ-
ed 42 randomized trials comprising
144,220 hypertensive participants
with diverse comorbidities (30 trials
with type 2 diabetes patients). They
were followed for an average of 3.6
years (range, 6 months to beyond 8
years) and categorized into 10 groups
of achieved SBP range, from <120 to
>160 mmHg.
The finding that intensive SBP low-
ering to 120–124 mmHg is associated
with the lowest risk for CVD and mor-
tality corroborates with the SPRINT
study, but contradicts with some stud-
ies which suggest a J-shaped relation-
ship between SBP and CV outcomes.
One such study is the pooled analysis
from ONTARGET and TRANSCEND tri-
als, which showed that achieved SBP
of 130 mmHg was associated with the
lowest risk for composite CV events
and all-cause mortality, while intensive
lowering to <120 mmHg was associat-
ed with increased risk of CV outcomes.
[Lancet 2017;389:2226–2237]
Commenting on the conflicting re-
sults, Tan said the J-shaped associa-
tion may not be conclusively confirmed
or refuted by the current network me-
ta-analysis, simply because there were
few data below this threshold.
“Another point to consider is that
the ONTARGET and TRANSCEND
populations comprised patients with
existing CVD, a higher-risk subgroup
compared to the JAMA study which
included hypertensive patients with a
broader range of risks. Thus, the in-
ferences may not [be] directly transfer-
able,” explained Tan.
19
DOCTOR | JULY ISSUE
Approaches to BP control
Several considerations to managing
hypertension, according to Yancy and
Bonow, include: confirm diagnosis with
multiple BP recordings, determine the
patient’s overall risk of CVD, and remain
aware of the risks of intensive treatment
and polypharmacy.
A target SBP of <130 mmHg might
be applicable to high-risk patients (eg,
diabetic with hypertension), while non-
pharmacological intervention should
be the first step for low-risk patients
who cannot tolerate antihypertensive
therapy, with a treatment goal of <150
mmHg (the lower the better), they sug-
gested.
“In addition, analysis of mean
achieved SBP does not guide treat-
ment decisions regarding diastolic BP,”
reminded researchers of the meta-anal-
ysis.
“Medicine is practised on a pa-
tient-level basis, and individualized
treatments based on a shared deci-
sion-making model should drive pa-
tient-level interventions; this is especial-
ly the case for those at higher risk for
CVD and for those who are most vul-
nerable,” said Yancy and Bonow.
A common risk of intensive SBP
management, postural hypotension,
can lead to falls and fractures especially
among the elderly, cautioned Tan.
“Whatever SBP target one choos-
es, the medications should be intro-
duced gradually with adequate moni-
toring,” he said.

77th Scientific Sessions of the American Diabetes Association (ADA) • June 9-13 • San Diego, California, US
Canagliflozin associated with fewer CV
events, higher amputation risk in CANVAS
ROSHINI CLAIRE ANTHONY
T
he sodium-glucose cotransport-
er 2 (SGLT2) inhibitor canagli-
flozin was associated with better
cardiovascular (CV) outcomes com-
pared with placebo in individuals with
type 2 diabetes (T2D) and high CV risk,
though it was also linked to an elevated
risk of amputation, according to find-
ings from the CANVAS* Program.
“The CANVAS Program met its pri-
mary objective of demonstrating [CV]
safety, and also showed efficacy of
canagliflozin for the prevention of CV
events,” said study investigator Pro-
fessor Bruce Neal from The George
Institute of Global Health, New South
Wales, Australia, who presented the
findings.
“The primary adverse effect that we
observed that was unanticipated was
amputations. There was an approx-
imate doubling of the risk of amputa-
tions in the participants treated with
canagliflozin compared to placebo and
about two-thirds of these were ampu-
tations of the toe or forefoot and about
one-third were amputations above the
level of the ankle,” he said.
Participants in the CANVAS Pro-
gram which comprised the CANVAS
and CANVAS-R** studies were 9,734
individuals with T2D (mean age 63.3
years, 35.8% female, mean diabetes
duration 13.5 years) from 667 centres
in 30 countries. About 66% of partic-
ipants had a history of CV disease.
Participants were randomized to daily
doses of canagliflozin (100 mg or 300
mg in the CANVAS study or 100 mg
with the option to increase to 300 mg
at week 13 in the CANVAS-R study) or
placebo and followed up for a mean of
CONFERENCE COVERAGE
188.2 weeks.
The incidence of the primary out-
come (composite of CV death, nonfatal
myocardial infarction, or nonfatal stroke)
was lower among patients on canagli-
flozin vs those on placebo (26.9 vs 31.5
participants per 1,000 patient-years,
hazard ratio [HR], 0.86, 95% confidence
interval [CI], 0.75–0.97; p<0.001 for
noninferiority and p=0.0158 for superi-
ority). [N Engl J Med 2017;doi:10.1056/
NEJMoa1611925]
Patients on canagliflozin also had
a lower incidence of hospitalization
for heart failure (HR, 0.67, 95% CI,
0.52–0.87) and CV death or hospital-
ization for heart failure (HR, 0.78, 95%
CI, 0.67–0.91) compared with those on Professor Bruce Neal
placebo.
would be 23 fewer deaths from CV
There was a 40 percent reduction in disease, nonfatal heart attacks, or non-
the composite of estimated glomerular fatal strokes, 17 fewer hospitalizations
filtration rate, end-stage renal disease, for heart failure, and 16 fewer serious
or renal-related death (5.5 vs 9.0 par- declines in renal function, but 15 more
ticipants per 1,000 patient-years, HR, amputations, said Neal.
0.60, 95 percent CI, 0.47–0.77), though
these findings were not significant. “These data suggest net overall
benefit of canagliflozin for most patients
While the incidence of serious ad- with type 2 diabetes and high CV risk,”
verse events was less frequent among he said, and recommended that physi-
patients on canagliflozin compared cians take into account the amputation
with placebo (104.3 vs 120.0 partic- risk when planning diabetes care for
ipants per 1,000 person-years, HR, their patients.
0.93, 95% CI, 0.87–1.00), patients on
canagliflozin had an elevated risk of
lower extremity amputations compared
with those on placebo (6.3 vs 3.4 par-
ticipants per 1,000 person-years, HR,
1.97, 95% CI, 1.41–2.75), 71 percent
of which involved the toe or metatarsal
and 29% above-ankle amputations.
* CANVAS: CANagliflozin cardioVascular
To estimate the risks vs benefits of Assessment Study
** CANVAS-R: Effects of canagliflozin on renal
canagliflozin, in an estimate of 1,000 endpoints in adult participants with type 2
patients treated for 5 years, there diabetes mellitus
20
DOCTOR | JULY ISSUE

77th Scientific Sessions of the American Diabetes Association (ADA) • June 9-13 • San Diego, California, US
Expert throws light on retinopathy complica-
tion seen in SUSTAIN-6
ELVIRA MANZANO
T
he higher rate of diabetic retinop-
athy seen in patients taking the
glucagon-like peptide 1 (GLP-1)
receptor agonist semaglutide vs place-
bo is likely a result of the rapid lowering
of HbA1c, a new analysis of data from
the SUSTAIN-6* trial suggests.
“Patients who had retinopathy
complications had a rapid and steep
decrease of approximately 2.5% in
HbA1c level,” said investigator Dr. Tina
Vilsbøll, clinical manager at the Steno
Diabetes Center in Copenhagen, Den-
mark. “Rapid improvement in glycae-
mic control is a risk factor for retinopa-
thy complications.”
Semaglutide cut the primary com-
posite outcome of cardiovascular (CV)
death, nonfatal MI, or nonfatal stroke
in SUSTAIN-6, an outcome that estab-
lished its noninferiority to placebo, with
a safety profile that was comparable to
other GLP-1 agonists for type 2 diabe-
tes (T2D). Rates of new or worsening
nephropathy were lower with sema-
glutide vs placebo. However, rates of
retinopathy complications (vitreous
CONFERENCE COVERAGE
haemorrhage, blindness, or conditions
requiring treatment with an intravitreal
agent or photocoagulation) were signifi-
cantly increased with semaglutide (haz-
ard ratio, [HR], 1.76; p=0.02). [N Engl J
Med 2016;375:1834–1844]
Further analysis of the data showed
that the 79 patients who had retinop-
athy had a longer duration of diabetes
(17.7 years vs 13.9 for the overall study
population) and higher mean HbA1c (9.4
vs 8.7% for the entire cohort). [ADA
2017, presentation 1-AC-SY09]
Almost 65% of patients who expe-
rienced retinopathy were taking insulin Dr. Tina Vilsbøll
compared with 58% of the total study
population. In addition, 83.5% of those dard care regimen.
in the retinopathy group had a history
of diabetic retinopathy at baseline, 29 Vilsbøll said the data at hand sug-
percent had a history of proliferative gest that compared with the full study
retinopathy, and 17.7% had a laser or population, patients with retinopa-
injection therapy for proliferative reti- thy complications had worse control
nopathy. of their HbA1c and are more likely to
have pre-existing retinopathy at base-
“When we split the patients into line. Considering that patients with
those without retinopathy at baseline the greater treatment effect in terms
and patients with retinopathy, patients of HbA1c were the ones most at risk,
who did not have any history of retinop- clinically this means clinicians should
athy [had] no signals with semaglutide exercise caution when using potent
—it was exactly the same as placebo,” glucose-lowering agents in this popu-
said Vilsbøll. lation.
Regulatory guidance mandates “When initiating a highly effective
the need to establish CV safety of treatment [such] as semaglutide, similar
novel diabetes therapies. SUSTAIN-6 guidance should be given in these vul-
was the second CV outcomes trial to nerable patients,” Vilsbøll concluded.
demonstrate positive results for a GLP-
1 agonist in T2D patients at high risk
of cardiovascular disease (CVD). The
trial was a randomized, double-blind,
placebo-controlled, parallel group tri-
al of 3,297 patients from 230 sites in
20 countries. Researchers compared
* SUSTAIN-6: Trial to Evaluate Cardiovascular and
semaglutide 0.5 mg or 1.0 mg once Other Long-term Outcomes With Semaglutide in
weekly vs placebo, on top of their stan- Subjects With Type 2 Diabetes
21
DOCTOR | JULY ISSUE

77th Scientific Sessions of the American Diabetes Association (ADA) • June 9-13 • San Diego, California, US
BCG vaccine may induce reversal of T1D
STEPHEN PADILLA
T
reatment with bacillus Calmette-
Guérin (BCG) appears to reverse
advanced type 1 diabetes (T1D)
in patients after repeat vaccination, ac-
cording to a phase II study.
“BCG may induce a permanent
increase in expression of genes that
restore the beneficial regulatory T cells
[Tregs] that prevent the immune system
from attacking the body’s own tissue,”
researchers said. “Increasing the po-
tency or numbers of [Tregs] is a goal of
many clinical trials.”
In the study, T1D patients treated
with BCG had statistically significant
increases in Treg numbers for 4 to 6
weeks following repeat BCG vaccina-
tion; a longer-lasting effect would be
optimal and might even steadily reverse
diabetic autoreactivity, according to
the researchers. [ADA 2017, abstract
1816]
“We and other global efforts have
known for some time that restoring
beneficial Treg cells might halt the ab-
normal self-reactivity in type 1 diabetes
and other autoimmune diseases, but
therapies to restore this immune bal-
ance have not achieved long-lasting re-
sults,” said Dr Denise Faustman, asso-
ciate professor of Medicine at Harvard
Medical School, director of the Massa-
chusetts General Hospital Immunobiol-
ogy Laboratory and principal investiga-
tor of the trial.
“The discovery that BCG restores
Tregs through epigenetics, a process
that modulates whether or not genes
are expressed, is exciting. This now
provides a better idea of how BCG vac-
cination appears to work by powerfully
modulating Treg induction and resetting
the immune system to halt the underly-
CONFERENCE COVERAGE
ing cause of the disease,” she added.
Faustman and her team investigat-
ed whether the effect of repeat BCG
vaccinations on Tregs could be per-
manent and driven by host epigenetic
modifications to Treg signature genes.
They profiled transcriptional start
site (TSS) clusters located within the
Treg-specific demethylation region in
T1D patients before and 8 weeks after
in vivo BCG dosing to assess the im-
pact of BCG on methylation at methyl-
ation sites on six Treg signature genes,
namely FoxP3, TNFRSF18, IL2RA,
IKZF2, IKZF4 and CTLA4.
Monitoring via CD4 T cells in blood
collected from BCG-treated T1D pa-
tients revealed that repeat BCG vac-
cinations reset the immune system by
consistent and rapid demethylation of
all six key Treg genes for enhanced
mRNA expression.
“This suggests that not only are
Treg cell numbers transiently elevated
after BCG vaccination, but also that
permanent epigenetic expression of
Treg genes that control Treg potency
is stably re-established by BCG treat-
ment,” researcher said. “BCG vaccina-
tion, like tuberculosis, powerfully mod-
ulates Treg induction.”
22
DOCTOR | JULY ISSUE
Known for its role in preventing
tuberculosis (TB), the BCG vaccine is
based on a harmless strain of bacte-
ria associated with the one that causes
TB. It is approved by the FDA for vac-
cination against TB and for the treat-
ment of bladder cancer. According to
researchers, there are currently several
studies investigating the potential of re-
peat BCG vaccinations to prevent and
reverse autoimmune diseases, includ-
ing T1D and multiple sclerosis.
“Repeat BCG vaccination appears
to permanently turn on signature Treg
genes, and the vaccine’s beneficial ef-
fect on host immune response recapit-
ulates decades of human co-evolution
with mycobacteria, a relationship that
has been lost with modern eating and
living habits,” said Faustman. “It is in-
credible that a safe and inexpensive
vaccine may be the key to stopping
these terrible diseases.”
An autoimmune disease, T1D is
characterized by the destruction of is-
lets by autoreactive T cells, which mis-
takenly attack islets as if they were an
infection. Tregs help prevent these mis-
guided attacks against tissues without
diminishing the entire immune system,
according to researchers.

77th Scientific Sessions of the American Diabetes Association (ADA) • June 9-13 • San Diego, California, US
Glucose self-monitoring of no help in
glycaemic control
ELVIRA MANZANO
G
lycaemic control is no better
in diabetic patients who moni-
tor their blood glucose than in
those who do not, the open label ran-
domized MONITOR trial has shown.
There were no significant differenc-
es in HbA1c levels or in health-related
quality of life (HRQoL) among patients
with noninsulin-treated type 2 diabe-
tes (T2D) who did self-monitoring of
their blood glucose (SMBG) compared
with those who did not at 1 year. Hy-
poglycaemia frequency, healthcare uti-
lization, and insulin initiation were also
comparable between groups. [JAMA
Intern Med 2017;doi:10.1001/jamaint-
ernmed.2017.1233]
“Even tailored feedback through
messaging did not provide any advan-
tage in glycaemic control,” said lead
investigator Dr. Laura Young from the
University of North Carolina at Chapel
Hill School of Medicine in North Caro-
lina, US. “These findings suggest that
glucose monitoring should not be a
routine in patients with noninsulin-treat-
ed T2D.”
The MONITOR trial included 450
adult patients (age >30 years) with
T2D (HbA1c 6.6 to 9.5%) who were not
treated with insulin and randomized to
SMBG once daily, SMBG once daily
with enhanced feedback, or no SMBG.
Neither type of self-monitoring showed
advantage over no self-monitoring
in terms of HbA1c reduction at 1 year
(SMBG with messaging vs no SMBG,
−0.09%; SMBG vs no SMBG, −0.05 %;
average over SMBG arms vs no SMBG,
−0.07%).
Of note, the coprimary endpoint of
CONFERENCE COVERAGE
HRQoL was also comparable between
mental and physical estimated adjust-
ed mean difference scores (SMBG
with messaging vs no SMBG, −0.83
points; SMBG vs no SMBG, −0.05
points; average over SMBG arms vs no
SMBG, −0.44 points for the physical
score whereas SMBG with messaging
vs no SMBG, −0.19 points; SMBG vs
no SMBG, 0.19 points; average over
SMBG arms vs no SMBG, 0 points for
the mental score).
Previous studies assessing the
efficacy of self-monitoring in diabet-
ic patients have shown contradictory
results. “Proponents of routine SMBG
postulate that testing promotes better
awareness of glucose levels, leading to
improvements in diet and lifestyle,” said
Young. “However, our findings showed
that SMBG does not help at all.”
Sensitivity analysis at 6 months
showed slight differences in mean
HbA1c levels between the intervention
and control groups (-0.33%; p=0.002).
However, improvements in glycaemic
control regressed back to baseline from
23
DOCTOR | JULY ISSUE
6 through 12 months.
Adverse events reported included
severe hypoglycaemia (1), hospitaliza-
tions (62), and deaths (2). However,
none was treatment-related.
“As the first large pragmatic US trial
of SMBG, our findings provide evidence
to guide patients and clinicians in mak-
ing important clinical decisions about
routine blood glucose monitoring,” said
Young. “[Both] should engage in a dia-
logue regarding SMBG … it should not
be routine for most patients with nonin-
sulin-treated T2D. The findings should
not also be extrapolated to patients
taking insulin,” she cautioned.
In an accompanying editorial, Drs.
Elaine Khoong of the University of
California, San Francisco, US and Jo-
seph Ross of Yale University School
of Medicine, New Haven, Connecti-
cut, US said the study supports the
“less is more” approach to glucose
monitoring considering that there are
no clear benefits accrued. [JAMA In-
tern Med 2017;doi:10.1001/jamaint-
ernmed.2017.1251]
 CONFERENCE COVERAGE
77th Scientific Sessions of the American Diabetes Association (ADA) • June 9-13 • San Diego, California, US

SGLT-2 inhibitors may lower HF, death rates

in T2D patients regardless of CVD status
AUDREY ABELLA

S
odium-glucose transporter-2
inhibitors (SGLT-2i) were associ-
ated with a significant reduction
in the rates of death and hospitaliza-
tion due to heart failure (HF) in patients
with type 2 diabetes (T2D) regardless
of pre-existing cardiovascular disease
(CVD), according to a new analysis of
the CVD-REAL* study.

“The benefits seen with [SGLT-2i]

are likely to be a class effect,” said Dr.
Matthew Cavender from the University
of North Carolina School of Medicine,
Chapel Hill, North Carolina, US. The as-
sociation remained consistent despite
the geographic variations relative to
the specific SGLT-2i used and the lack
of heterogeneity across participating
countries.
In this multinational (US, UK, Nor-
way, Sweden, and Denmark) study,
researchers evaluated 306,156 partic-
ipants with T2D who had undergone
SGLT-2i treatment. Of these, 13%
(n=39,293) had established CVD, and
950 new HF events were reported. HF
and death rates in patients with and
without prior CVD history were com-
pared against HF rates in new users
of SGLT-2i and other glucose-lowering
drugs (oGLD).
Compared with oGLD, SGLT-2i
was associated with decreased HF
rates in patients with and without pri-
or CVD (hazard ratio [HR], 0.69, 95%
confidence interval [CI], 0.59–0.80 and
HR, 0.45, 95% CI, 0.32–0.63, respec-
tively). [ADA 2017, abstract 377-OR]
Similar results were observed for
death with and without existing CVD
(HR, 0.47, 95% CI, 0.36–0.61 and HR,
Dr Matthew Cavender
0.54, 95% CI, 0.44–0.66, respectively)
with SGLT-2i vs oGLD use.
SGLT-2i use also resulted in de-
creased rates of death due to HF with
and without existing CVD (HR, 0.59,
95% CI, 0.52–0.67 and HR, 0.52, 95
%CI, 0.44–0.61, respectively) vs oGLD
use.
The findings suggest that the inci-
dence of HF in diabetic patients could
be reduced with SGLT-2i use, said
Cavender. “[Our] results go one step
further to show that SGLT-2 inhibition
may benefit all patients with diabetes,
regardless of whether they have known
[CVD].”
These findings were consistent
with the full results of the CVD-REAL
study, which showed a reduced risk of
death (HR, 0.49; p<0.001) and hospi-
talization for HF (HR, 0.61; p<0.001)
with SGLT-2i vs oGLD. [Circulation
2017;doi:10.1161/CIRCULATIONA-
HA.117.029190]
However, as SGLT-2i is a relatively
new class, longer follow-ups are war-
ranted to evaluate its effects over time,
noted the researchers.
Overall, this study has important
clinical implications and underlines the
need for new treatment alternatives for
T2D, considering that it is a major CVD
risk factor. [Lancet 2010;375:2215–
2222; Circulation 2008;117:2544–
2565] Together with other ongoing
randomized trials, the findings provide
further evidence regarding the potential
role of SGLT-2i in T2D management,
said Cavender. “[These data may] help
establish the real-world effectiveness of
treatments in a broad population of pa-
tients from clinical practice.”
* CVD-REAL: Comparative effectiveness of
cardiovascular outcomes

24
DOCTOR | JULY ISSUE
 CONFERENCE COVERAGE
77th Scientific Sessions of the American Diabetes Association (ADA) • June 9-13 • San Diego, California, US

REMOVAL: Metformin may slow

atherosclerosis progression in adults
with T1D
ROSHINI CLAIRE ANTHONY

A
dults with type 1 diabetes (T1D)
who were prescribed metformin
experience reductions in athero-
sclerosis progression and low density
lipoprotein-cholesterol (LDL-c), accord-
ing to results of the REMOVAL* study.
However, the impact of metformin on
glycaemic control in these patients is
limited.

“[We] were surprised to discov-

er a reduction in LDL cholesterol and
atherosclerosis progression with met-
formin treatment,” said lead investiga-
tor Professor John Petrie, of the Univer-
sity of Glasgow in Scotland, UK, who
presented the findings. “The results of
REMOVAL support wider prescribing of
metformin to help reduce heart disease
risk factors over a lifetime of [T1D], mir-
roring its current use in adults with type
2 diabetes,” he said.
The population of this multicentre,
multinational, double-blind trial was
428 adults aged ≥40 years with T1D
duration ≥5 years (mean age 55.5
years, 60% male, mean diabetes du-
ration 33.8 years, mean HbA1c 8.05%,
82% on statin therapy) and ≥3 specific
cardiovascular risk factors who were
randomized to receive oral metformin
(1,000 mg twice daily, n=219) or place-
bo (n=209) in addition to titrated insulin
for 3 years.
Compared with placebo, metformin
did not significantly reduce mean
common carotid artery intima-media
thickness (cIMT; a measure of ath-
erosclerosis progression, -0.005 mm
per year; p=0.167), though there ap-
peared to be a significant reduction
Prof John Petrie
in averaged maximal cIMT (-0.013
mm per year; p=0.0093). [ADA 2017,
session 3-CT-SY23, Lancet Diabetes
Endocrinol 2017;doi:10.1016/S2213-
8587(17)30194-8]
Over the three-year treatment pe-
riod, patients given metformin had
significant reductions in body weight
(-1.17 kg; p<0.0001) and LDL-c levels
(-0.13 mmol/L; p=0.0117) as well as an
increase in estimated glomerular filtra-
tion rate (eGFR; 4.0 mL/min/1.73 m2;
p<0.0001).
Metformin reduced HbA1c levels
over the three-year period (-0.13%;
p=0.006); however, this was accounted
for by a reduction at 3 months (-0.24%;
p<0.0001) and there was no difference
to HbA1c following this point.
“Since our study confirmed that
metformin only improved blood sugar
control in the very short term, guide-
lines in the US and UK should be up-
dated to reflect the lack of a sustained
effect of metformin on blood glucose
levels in adults with T1D,” said Petrie.
Treatment discontinuation was
more frequent in patients on metformin
compared with placebo (27 vs 12%;
p=0.0002), though this was primarily
driven by gastrointestinal adverse ef-
fects. The five and two deaths in patients
on metformin and placebo, respectively,
were not determined to be treatment-re-
lated. There was no difference in inci-
dence of hypoglycaemia between pa-
tients on metformin or placebo.
“Metformin is an inexpensive agent
that is widely used to reduce heart dis-
ease in type 2 diabetes so we hypoth-
esized that it might have similar effects
in [T1D],” said Petrie. “Unless a [CV]
outcomes trial is performed, clinicians
and adults with [T1D] will have to de-
cide whether to add in metformin with
insulin on the basis of the REMOVAL
trial results,” he said.
* REMOVAL: REducing with MetfOrmin Vascular
Adverse Lesions in type 1 diabetes

25
DOCTOR | JULY ISSUE
 CONFERENCE COVERAGE
77th Scientific Sessions of the American Diabetes Association (ADA) • June 9-13 • San Diego, California, US

DEVOTE: Degludec as safe as glargine for

the heart, with less severe hypoglycaemia
ROSHINI CLAIRE ANTHONY

I
nsulin degludec had comparable car-
diovascular safety and reduced the
risk of severe hypoglycaemia com-
pared with insulin glargine U100 in
patients with type 2 diabetes and high
cardiovascular risk, according to results
of the DEVOTE* study.

“[Complications] from cardiovas-

cular disease remain an unmet clinical
need for people with type 2 diabetes,”
said study investigator Dr. Steven Mar-
so, chief medical officer for HCA Mid-
west Health cardiovascular services,
Kansas City, Missouri, US, who pre-
sented the findings of the phase III,
multicentre (436 sites in 20 countries),
head-to-head trial.
“[Severe] hypoglycaemia is another
very relevant safety issue for both pro-
viders and patients, and it is a goal of
therapy to lower glucose values in a
safe and effective way to reduce micro-
vascular complications.”
“The [DEVOTE] trial demonstrated
that [insulin] degludec was as safe as
[insulin] glargine with respect to cardio-
vascular outcomes and safer with re-
spect to hypoglycaemia risk,” he said.
Dr Steven Marso
ceiving insulin at baseline and 85.2%
of patients had chronic kidney disease,
cardiovascular disease, or both.
Patients on insulin degludec did not
experience an increase in the incidence
of cardiovascular events (composite of
cardiovascular death, nonfatal myo-
cardial infarction, and nonfatal stroke)
compared with patients on insulin
glargine U100 (8.5 vs 9.3%, hazard ra-
tio [HR], 0.91, 95% confidence interval
[CI], 0.78–1.06; p<0.001 for noninferi-
ority). [ADA 2017, session 3-CT-SY22;
N Engl J Med 2017;doi:10.1056/NEJ-
Moa1615692]
“The findings of the DEVOTE study
are in line with previous clinical trials
comparing insulin degludec to insulin
glargine U100, so we are pleased to
be able to provide conclusive evidence
regarding the safety of insulin degludec
for patients with type 2 diabetes who
are at high risk of cardiovascular com-
plications,” said Marso.
* DEVOTE: A trial comparing cardiovascular safety
of insulin degludec vs insulin glargine in subjects
with T2D at high risk of cardiovascular events

Between October 2013 and No- Patients on insulin degludec also

vember 2014, 7,637 patients with type
2 diabetes and at high risk of major
adverse cardiovascular events (MACE;
mean age 65 years, mean diabetes du-
ration 16.4 years, mean HbA1c 8.4%)
were randomized to receive insulin
degludec (n=3,818) or insulin glargine
U100 (n=3,819) once daily between
dinner and bedtime in addition to stan-
dard-of-care therapy. Patients were fol-
lowed up for a median 2 years.
Almost 84% of patients were re-
Scan the
had a 40% reduction in the incidence
QR code for
of severe hypoglycaemia compared
full coverage
with patients on insulin glargine U100
of the ADA 2017
(4.9 vs 6.6%, rate ratio [RR], 0.60, 95%
meeting.
CI, 0.48–0.76; p<0.001 for superiority,
odds ratio, 0.73, 95% CI, 0.60–0.89;
p<0.001 for superiority), as well as a
53 percent reduction in the incidence
of severe nocturnal hypoglycaemia (1.0
vs 1.9%, RR, 0.47, 95% CI, 0.31–0.73;
p<0.001).

26
DOCTOR | JULY ISSUE
 CONFERENCE COVERAGE
2017 American Society of Clinical Oncology (ASCO) Annual Meeting • June 2-6 • Chicago, Illinois, US

High-dose vitamin D boosts PFS

in metastatic colorectal cancer
ELVIRA MANZANO

S
upplementation with high doses
of vitamin D slows down disease
progression in patients with col-
orectal cancer, the phase II SUNSHINE
trial has shown.

“Patients seemed to do better on

high-dose vitamin D. I am really excited
with the results as this is the first ran-
domized trial of vitamin D as a colorec-
tal cancer therapy,” said lead investiga-
tor Dr Kimmie Ng of the Dana Farber
Cancer Institute in Boston, Massachu-
setts, US. “Definitely, a phase III trial is
warranted.”

The primary endpoint of median

progression-free survival (PFS) was
longer in the high-dose group (13.3
months) vs the low-dose group (11.2
months).This translates into a differ-
ence of 2 months in PFS. Of note,
there was a 31 percent reduction in the
relative risk for disease progression in
the high-dose group (hazard ratio [HR],
0.69; p=0.04]. Disease control rate was
96% in the high-dose group vs 84% in
the low-dose group (p=0.05). [ASCO
2017, abstract 3506]
Patients in the high-dose group re-
ceived a loading dose of 8000 IU/day of
vitamin D3 orally for 2 weeks followed
by 4000 IU/day. Those in the low-dose
group received a standard vitamin D3
dose of 400 IU/day. Median follow-up
was 16.9 months in the high-dose
group and 17.9 months in the low-dose
group.
All had metastatic disease and
received standard treatment with
mFOLFOX6 (folinic acid [leucovorin],
fluorouracil, and oxaliplatin) plus beva-
cizumab. The number of chemotherapy
cycles were similar for both the high- The study raised a question about
dose and low-dose groups; primary the existing levels of vitamin D in pa-
tumour locations were comparable. tients included in the study. “It’s not
Both groups were compliant with their known if these patients were deficient
vitamin D regimen. by US standards,” Cercek said.
Of note, more patients in the high- A phase III trial in patients with met-
dose arm were able to undergo surgery astatic disease may shed light to the
after chemotherapy (11 vs 6), but this long-debated issue of vitamin D sup-
did not reach statistical significance. plementation in colorectal cancer, Cer-
cek concluded.
Most patients in the trial were from
New England, the others from the US.
Discussant Dr. Andrea Cercek, of the
Scan the
Memorial Sloan Kettering Cancer Cen-
QR code for
ter in New York City, US said geogra-
full coverage of
phy may have played a role. “In New
the ASCO 2017
England, there is a little less sunshine
meeting.
than other parts of America.”
Vitamin D3 is produced when the
skin is exposed to the sun. Vitamin
D3 then binds to a protein, which then
ships the vitamin to the liver. Other
sources of vitamin D3 are fatty fish or
fortified foods, and supplements.

27
DOCTOR | JULY ISSUE

Moderate alcohol intake ups risk
of hippocampal atrophy
STEPHEN PADILLA
A
lcohol intake, even in moder-
ation, is a risk factor for multi-
ple markers of abnormal brain
structure and cognitive function, includ-
ing hippocampal atrophy, a recent UK
study has found.
“We have found a previously un-
characterized dose-dependent asso-
ciation between alcohol consumption
… and hippocampal atrophy, as well as
impaired white matter microstructure,”
researchers said. “Additionally, higher
alcohol consumption predicted greater
decline in lexical fluency but not in se-
mantic fluency or word recall.”
Over the 30-year follow-up, higher
alcohol consumption showed a cor-
relation in a dose-dependent manner
with greater odds of hippocampal at-
rophy. Interestingly, even individuals
who drink moderately (14 to 21 units/
week) had a threefold chance of having
right-sided hippocampal atrophy (odds
ratio [OR], 3.4; 95 percent CI, 1.4 to
8.1; p=0.007), while those who drink
more than 30 units a week had the
highest risk compared with abstainers
(OR, 5.8; 1.8 to 18.6; p≤0.001). [BMJ
2017;357:j2353]
“The finding that alcohol consump-
tion in moderate quantities is associat-
ed with multiple markers of abnormal
brain structure and cognitive function
has important potential public health
implications for a large sector of the
population,” researchers said.
Light drinking (1 to <7 units/week)
showed no protective effect compared
to abstinence. In addition, higher alco-
hol consumption correlated with differ-
ences in corpus callosum microstruc-
ture and faster decline in lexical fluency,
but not with cross-sectional cognitive
NEWSBITES
performance or longitudinal changes in
semantic fluency or word recall.
“Our findings support the recent re-
duction in UK safe limits and call into
question the current US guidelines,
which suggest that up to 24.5 units a
week is safe for men, as we found in-
creased odds of hippocampal atrophy
at just 14 to 21 units a week, and we
found no support for a protective effect
of light consumption on brain struc-
ture,” researchers said.
“Alcohol might represent a mod-
ifiable risk factor for cognitive impair-
ment, and primary prevention interven-
tions targeted to later life could be too
late,” they added.
The results of this study strength-
en the view that the beneficial effects
of alcohol on health, if any, is probably
limited to low intakes of no more than
a unit a day, according to Dr. Killian A
Welch, consultant neuropsychiatrist at
the Robert Fergusson Unit, Royal Ed-
inburgh Hospital, UK. Nonetheless, this
level of consumption still carries risk rel-
ative to abstinence for such conditions
as breast cancer, and the evidence of
benefit is not strong enough to justi-
fy advising abstainers to drink. [BMJ
28
DOCTOR | JULY ISSUE
2017;357:j2645]
“We all use rationalizations to justify
persistence with behaviours not in our
long-term interest, Welch said. “With
publication of this paper, justification of
‘moderate’ drinking on the grounds of
brain health becomes a little harder.”
This observational cohort study
involving 550 men and women (mean
age 43.0 years at baseline) measured
weekly alcohol intake and cognitive
performance repeatedly from 1985
to 2015. At study endpoint (2012 to
2015), researchers conducted multi-
modal magnetic resonance imaging
(MRI). Of the participants, 23 were
excluded due to incomplete or poor
quality imaging data or gross structural
abnormality, or incomplete alcohol use,
sociodemographic, health or cognitive
data.
“Prospective studies of the effects
of alcohol use on the brain are few,
and replication of these findings in
other populations will be important,”
researchers said. “Investigations with
larger numbers are needed to clari-
fy whether there are graded risks be-
tween short vs long periods of higher
alcohol consumption.”

Statin-associated muscle symptoms likely
a nocebo effect
PEARL TOH
P
atients are more likely to report
muscle-related adverse effects
(AEs) when they know they are on
statins, but not when they have no idea
whether they are given statin or place-
bo in a blinded trial, the ASCOT-LLA*
study found, suggesting that clinicians
should be aware of potential nocebo
effects when prescribing statins.
“These results will help assure both
physicians and patients that most AEs
associated with statins are not causally
related to use of the drug and should
help counter the AE on public health of
exaggerated claims about statin-relat-
ed side-effects,” said the researchers.
During the blinded randomized
phase of the study, there was no ex-
cess of muscle-related AEs among
atorvastatin-treated patients vs the
placebo group (incidence rate, 2.03 vs
2.0%, hazard ratio [HR], 1.03; p=0.72).
[Lancet 2017;doi:10.1016/ S0140-
6736(17)31075-9]
However, the same patients report-
ed a significantly higher rate of mus-
cle-related AEs when they were aware
that they were treated with atorvastatin
compared with nonusers of atorvas-
tatin during the open-label extension
phase of the study (incidence rate, 1.26
vs 1.00%, HR, 1.41; p=0.006).
“These analyses illustrate the so-
called nocebo effect, with an excess
rate of muscle-related AE reports only
when patients and their doctors were
aware that statin therapy was being
used and not when its use was blind-
ed,” explained the researchers.
The trial included 10,180 hyperten-
sive patients (aged 40–79 years) who
had fasting total cholesterol of ≤6.5
NEWSBITES
mmol/L and not treated with a statin
or fibrate, ≥3 other cardiovascular risk
factors but no history of myocardial in-
farction and not undergoing treatment
for angina. During the double-blind ran-
domized phase, the participants were
assigned to either atorvastatin 10 mg
daily (n=5,101) or placebo (n=5,079)
and followed up for a median of 2.3
years. All the patients were then offered
atorvastatin in the open-label extension
phase, of which 6,409 chose atorvas-
tatin and 3,490 preferred not to take
the drug.
Besides muscle-related AEs, erec-
tile dysfunction also occurred at sim-
ilar rates in the statin and placebo
groups during the blinded phase (1.86
vs 2.14%, HR, 0.88; p=0.13). Sleep
disturbance rate was significantly low-
er with statin than with placebo (1.00
vs 1.46%, HR, 0.69; p=0.0005), while
cognitive impairment occurred too rare-
ly to be reliably assessed statistically
30
DOCTOR | JULY ISSUE
(0.20 vs 0.22%, HR, 0.94; p=0.81).
All the other reported AEs were not
significantly different between the two
groups, except for renal and urinary
AEs, which were more common among
patients taking atorvastatin than place-
bo (1.87 vs 1.51%, HR, 1.23; p=0.002).
In the open-label phase, no signif-
icant differences were seen between
statin users and nonusers for the oth-
er AEs except for blood and lymphatic
system disorders (0.88 vs 0.64%, HR,
1.40; p=0.03) and musculoskeletal and
connective tissue disorders (8.69 vs
7.45%, HR, 1.17; p=0.001).
Due to widespread claims about
the side effects of statins, particular-
ly muscle pain and weakness, which
were mainly based on observational
studies, the researchers noted that “up
to one fifth of patients … at high risk of
major vascular events with established
cardiovascular disease [stopped] their
statin therapy.”
“Clinicians should be fully informed
about potential nocebo effects, includ-
ing patients’ previous knowledge or
perceptions of statin therapy, and dis-
cuss the evidence for [statin-associated
muscle symptoms] with patients,” ad-
vised Drs Juan Pedro-Botet and Juan
Rubiés-Prat of Universitat Autònoma de
Barcelona, Barcelona, Spain, in a sep-
arate commentary, as they noted that
poor understanding of warnings about
the side effects related to statins can lead
to poor adherence or discontinuation of
treatment. [Lancet 2017;doi:10.1016/
S0140-6736(17)31163-7]
* ASCOT-LLA: Anglo-Scandinavian Cardiac
Outcomes Trial—Lipid-Lowering Arm

Metformin tied to lower coronary calcium
in prediabetes
PEARL TOH
L
ong-term metformin was associ-
ated with a significantly lower cor-
onary artery calcium (CAC) than
placebo or lifestyle modification in men,
but not in women, with prediabetes,
according to data from the DPP* and
DPPOS** cohort.
“[The study suggests that] met-
formin treatment … within a few years
before or after diabetes development
… may have reduced early stages of
plaque development in men,” said the
researchers.
The DPP randomized 2,061 partic-
ipants (aged ≥25 years, body mass in-
dex ≥24 kg/m2) with prediabetes to one
of three arms: metformin 850 mg twice
daily, an intensive lifestyle modification
programme, or placebo twice daily.
After treatment has been unmasked
at the end of DPP, 2,029 (regardless
of diabetes status) joined the DPPOS
which offered maintenance group life-
style sessions to all participants quar-
terly, of which the original lifestyle group
in DPP received supplementary group
programmes twice a year and the met-
formin group continued with the drug.
CAC—a marker of subclinical cor-
onary atherosclerosis—was 41% less
severe among men who continued with
metformin at 14 years after DPP study
than those randomized to the placebo
group in the original study (mean CAC
severity, 39.5 vs 66.9 arbitrary unit [AU];
p=0.04 after adjusting for age). [Circu-
lation 2017;doi:10.1161/CIRCULATIO-
NAHA.116.025483]
Similarly, mean CAC severity was
lower among men in the metformin vs
the lifestyle groups (39.5 vs 58.3 AU),
although the difference was not sta-
tistically significant in the age-adjusted
NEWSBITES
analysis.
There were also fewer men with
CAC>0 in the metformin group than the
placebo group (75 percent vs 84 per-
cent; p=0.02) and the lifestyle group (75
vs 85%; p<0.05).
However, the beneficial effects
of metformin on CAC were not seen
among women.
“CAC severity was considerably
lower in women than in men in our
study, making it more difficult to identify
an effect of metformin in women,” ob-
served the researchers. They also be-
lieved that premenopause might have
contributed to the absence of met-
formin effect in women since athero-
genesis progresses more slowly in pre-
menopausal women, which made up
36 percent of the women in the study.
Stratifying the analysis by age
showed that CAC severity (3.0 vs 17.6
AU; p<0.05) and CAC>0 (40 vs 71%;
p<0.05) were both significantly low-
er with metformin than with placebo
among men in the age group of 25–44
years. Similar trends toward lower CAC
severity and prevalence among men
taking metformin were seen in the old-
er age groups, although these did not
reach statistical significance.
According to the authors, the ob-
31
DOCTOR | JULY ISSUE
servation that metformin effect on CAC
was most evident in younger men aged
25–44 years “who would be expected
to have atherosclerotic lesions earlier
in their development than among old-
er men… [implies] that the effect of
metformin involves smaller and more
recently calcifying plaques, rather than
well-established lesions.”
Besides age, differences in CAC
severity (but not CAC>0) between the
treatment groups were also observed
regardless of race/ethnic subgroups,
statin use and diabetes status, which
according to the authors, suggest that
“the effect of metformin on CAC in men
does not depend on diabetes preven-
tion.”
Since participants weighing >350
lbs were excluded from the analyses
because CAC could not be accurately
quantified in these individuals, the re-
searchers cautioned against generaliz-
ing the results to the entire population
with prediabetes.
“Whether these findings translate
into beneficial effects on CVD events
will require ongoing follow-up,” said the
researchers.
* DPP: Diabetes Prevention Program
** DPPOS: DPP and its Outcome Study
 NEWSBITES

Does painless rectal bleeding indicate presence

of colonic polyp in children?
JAIRIA DELA CRUZ

O
nly one-in-five children with
painless rectal bleeding, the
most common symptom of
rectal polyps, presents with a fleshy
growth on the lining of the rectum at
endoscopy, a study finds.

In a cohort of 401 children (medi-

an age 10 years) who underwent either
flexible sigmoidoscopy (n=21) or colo-
noscopy (n=380) to investigate rectal
bleeding, polyps were identified in 46,
among whom 42 had painless rectal
bleeding and four did not. Of the pa-
tients with painless rectal bleeding, 24
did not show any other sign or symp-
tom. [Arch Dis Child 2017;doi:10.1136/
archdischild-2016-311245]

Overall, 123 patients presented with

painless rectal bleeding alone, yielding
a polyp detection rate of 19.5 % for the
symptom. A notable 28% increase in
the detection rate was observed when
both rectal bleeding and mucous per
rectum were present, although only 25
patients had this clinical history.
A common reason for referral to
secondary or tertiary care, rectal bleed-
ing in children could be a source of
great anxiety for both the patient and
parents. While it has been suggested
that most cases are attributed to ae-
tiologies that have little morbidity, the
literature is rather limited on findings
and outcomes. [Afr J Paediatr Surg
2012;9:169–171]
“Thus, primary, secondary, and ter-
tiary physicians require better evidence
in order to manage parent’s expecta-
tions appropriately,” said study authors
Drs. Ian Sugarman and Alison Morag
Campbell, of the Leeds General Infir-
mary in UK.
“It is often stated that if a patient
presents with ‘painless rectal bleed-
ing’ then a rectal polyp is the probable
diagnosis,” Sugarman and Campbell
noted.
The finding that painless rectal
bleeding alone is the most common
presenting symptom of a rectal polyp,
being present in 57% of patients di-
agnosed with polyps at endoscopy in
the study, “confirms that endoscopic
investigation is warranted in those pre-
senting with painless rectal bleeding.”
However, a specific diagnosis is of-
ten not established in the absence of a
polyp in patients who do not show no
other sign or symptom except for rectal
bleeding, they said.
They also pointed out that the in-
crease in polyp detection rate seen in
cases where both rectal bleeding and
mucous are present is a “useful infor-
mation to impart to families and sup-
ports investigation with colonoscopy
for these symptoms.”
Nearly all colorectal tumours in
children present as polyps, which by
definition is an elevation on a muco-
sal surface. Such polyps may remain
asymptomatic, with an estimated inci-
dence of 1 to 2% of the childhood pop-
ulation. While usually of benign nature,
colorectal polyps in children potentially
develop adenomatous features or turn
into cancer in a small minority. [Gözte-
pe Tıp Dergisi 2012;27:1–5]
The polyps, which commonly ap-
pear in the left colon, can be removed
using rigid rectosigmoidoscopy. How-
ever, the value of routine colonoscopic
evaluation has been increasingly em-
phasized to detect the more proximally
located or multiple polyps. [Med Princ
Pract 2009;18:53–56; J Pediatr Surg
2005;40:1920–1922]

32
DOCTOR | JULY ISSUE

Cerebral small vessel disease common in Asians
TRISTAN MANALAC
T
he prevalence of cerebral small
vessel disease (SVD) is high in
Asian populations, particularly
in the elderly, a new population-based
study reveals. Moreover, SVD is cor-
related with poorer cognitive function
and may be caused by environmental,
cultural, and genetic risk factors.
“In this study, the prevalence of
confluent [white matter hyperintensity
(WMH)] was 36.6%, lacunes 24.6%,
and microbleeds 26.9% in a multi-eth-
nic Asian population. The most im-
portant risk factors for [SVD] were in-
creasing age and hypertension,” the
researchers wrote.
A total of 1,797 participants (mean
age 70.1 years; 57% female) were re-
cruited from three studies in Asian
countries: the epidemiology of demen-
tia in Singapore (EDIS) study, the risk
index for subclinical brain lesions in
Hong Kong (RISK), and the oligomer-
ic beta-amyloid detection by multimer
detection system in Alzheimer’s disease
(OBAMA) in Korea.
Cognitive function was assessed
using modified versions of the mini
mental status examination (MMSE)
and Montreal cognitive assessment
(MoCA) tests. Neuroimaging across the
three studies was performed using a
3T scanner. Markers of SVD included
WMH, cerebral microbleeds, and la-
cunes.
The most common vascular risk
factor was hypertension, with an inci-
dence rate of 67.9% in the entire co-
hort. This was followed by hyperlipidae-
mia (48.8%), diabetes (29.4%), and a
history of smoking (23.1%). The median
MMSA and MoCA scores were 26 and
22, respectively. [J Neurol Neurosurg
Psychiatry 2017;doi:10.1136/jnnp-
2016-315324]
NEWSBITES
The prevalence of lacunes in the
entire cohort was 24.6%. For conflu-
ent WMHs and cerebral microbleeds,
the prevalence was 36.6 and 26.9%,
respectively. In the entire cohort, 45.2
percent (n=619) had only one SVD
marker, while 30.2 (n=324) and 12.2
(n=104) percent had two and three
markers, respectively.
Of the three Asian countries, Hong
Kong had the highest incidence of la-
cunes (p<0.001). On the other hand,
those in Singapore showed signifi-
cantly higher rates of vascular risk fac-
tors (p<0.001), cerebral microbleeds
(p<0.001) and confluent WMHs
(p<0.001). Cognitive impairment and
the proportion of higher severity of SVD
markers were also significantly greater
in Singapore.
Age was determined to be a strong
risk factor for the severity of SVD mark-
ers. While individuals in the 65 to 69
age group, for instance, had increased
risks of one marker (odds ratio [OR],
1.41; 95% CI, 1.02 to 1.94; p=0.04),
the risk was greater in those in the ≥75
age group (OR, 2.38; 1.64 to 3.45;
p<0.001).
Moreover, while the OR in the 65
to 69 group jumped from 1.41 for one
marker to 6.16 (1.39 to 27.1; p=0.016)
for three markers, the increase was
much greater in the ≥75 age group,
jumping from 2.38 for one marker to
27.24 (6.30 to 117.8; p<0.001) for
34
DOCTOR | JULY ISSUE
three markers.
Hypertension was also associated
with higher risks of one (OR, 1.43; 1.16
to 1.92; p=0.002), two (OR, 2.58; 1.81
to 3.68; p<0.001) and three (OR, 3.34;
1.67 to 6.69; p=0.001) SVD markers.
Increasing severity of SVD markers
was also associated with poorer cog-
nitive performance. For instance, the
presence of three markers was associ-
ated with worse MMSE (p<0.001) and
MoCA (p<0.001) outcomes.
Despite differences in methodology,
sample characteristics and definitions,
all of which make comparisons be-
tween other studies difficult, the current
findings generally echo the literature
on the differences in SVD prevalence
across different ethnicities.
Among the possible explanation for
this variation include differences in the
burden of risk factors such as hyper-
tension, diabetes and hyperlipidaemia,
the authors noted. The timing of the on-
set of these risk factors may also differ
between ethnic groups and thus may
affect the prevalence of SVD.
“[O]ther potential risk factors such
as exposure to various intrinsic (eg,
inflammation, total cholesterol) and en-
vironmental/lifestyle (eg, nutrition, head
trauma, reduced levels of exercise) fac-
tors may also explain such ethnic differ-
ences,” they added.
 NEWSBITES

ECT effective for youth mental disorders

and treatment-resistant depression
DR. JOSEPH DELANO FULE ROBLES

R
esults of recent studies present-
ed at the American Psychiatric
Association 2017 Annual Meet-
ing showed that electroconvulsive ther-
apy (ECT) is effective for treatment of
depression, psychosis, and self-harm
among patients aged 16 to 25 years
and those with severe long-lasting de-
pression refractory to treatment.

In a study that included 188 pa-

tients (about 50% female) aged 16 to
25 years (mean age, 21 years) recruit-
ed from May 2011 to August 2016 at a
single centre, there were significant im-
provements in outcomes (depression,
interpersonal relationships, self-harm,
and emotional lability; p<0.001) and
psychotic symptoms (p=0.004) after
five ECT treatments. [Benson NM, et al,
APA Annual Meeting 2017]

Diagnoses of patients in the study
included depressive disorder (61.7%)
and psychotic disorder (16.5%). Around
60% of the patients screened positive
for substance use disorder based on
AUDIT-C, a single-item screening tool
derived from the Drug Abuse Screening
Test (DAST)-10.
The researchers also found signifi-
cantly greater improvements in patients
with co-existent substance use disor-
der vs those who tested negative for
substance use (depression, p=0.008;
interpersonal relationships, p=0.037;
emotional lability, p=0.042)
In the study, BASIS-24 (Behaviour
and Symptom Identification Scale-24)
was used to assess outcomes based
on six domains, namely depression/
functioning, interpersonal relationships,
psychosis, emotional lability, self-harm,
and substance abuse.
“The study, however, is not a ran-
domized trial. A lot more research is
needed in this very unstudied popula-
tion,” commented Dr. Nicole Benson ,of
the Massachusetts General Hospital–
McLean Hospital, Boston, Massachu-
setts, US, one of the study authors who
presented the results at the meeting.
ECT has been shown to be effica-
cious and safe for treatment of depres-
sive and psychotic disorders in adults,
but studies in the younger population
are still lacking.
Another study presented at the
meeting showed the efficacy of ECT in
patients with severe depression refrac-
tory to conventional treatment.
In this study of 54 patients (female,
61 percent; mean age, 59.1 years) hos-
pitalized in 2005–2015 for bipolar dis-
order (74 percent) or major depressive
disorder (26 percent), bitemporal ECT
twice per week was associated with an
overall response rate of 92 percent and
a remission rate of 44 percent. [Del-
monte D, et al, APA Annual Meeting
2017]
Relapse rates during the follow-up
period were 5.5% in the first month, 3.7
% within the third month, 16.6% within
the sixth month and 14.8% within 12
months.
Around 60% of the patients exhib-
ited improved well-being at the end of
the follow-up period.
ECT involves a brief electrical stim-
ulation of the brain while the patient
is under anaesthesia. The treatment
is administered by a team of medical
professionals including a psychiatrist,
an anaesthesiologist, and a nurse or
a physician assistant. [https://www.
psychiatry.org/patients-families/
ect]

35
DOCTOR | JULY ISSUE

Antibiotics tied to increased risk of abortion
ELAINE SOLIVEN
T
he use of antibiotics such as
quinolones, tetracyclines, met-
ronidazole, sulfonamides, and
macrolides (excluding erythromycin)
may increase the risk of spontaneous
abortion in early pregnancy, according
to a recent study.
“Our findings may be of use to pol-
icy-makers to update guidelines for the
treatment of infections during pregnan-
cy,” said the researchers.
The researchers gathered data
from the Quebec Pregnancy Cohort
and conducted a nested case-con-
trol study involving 95,722 pregnant
women, of which 8,702 had sponta-
neous abortion (defined as pregnancy
termination at <20 weeks of gestation
[cases]) and 87,020 were matched
controls. [CMAJ 2017;doi:10.1503/
cmaj.161020]
Among all the participants, 12,446
were exposed to antibiotics during ear-
NEWSBITES
ly pregnancy (mean gestational age,
14.1 weeks). Penicillins were the most
commonly used antibiotics (n=6,073),
followed by macrolides (n=1,789),
quinolones (n=689), cephalosporins
(n=682), metronidazole (n=344), tet-
racyclines (n=315), and sulfonamides
(n=169).
Compared with no antibiotic use,
the risk of spontaneous abortion
was increased with the use of quino-
lones (adjusted odds ratio [adjOR],
2.72, 95% confidence interval [CI],
2.27–3.27), tetracyclines (adjOR, 2.59,
95%CI, 1.97–3.41), metronidazole (ad-
jOR, 1.70, 95% CI, 1.27–2.26), and
sulfonamides (adjOR, 2.01, 95% CI,
1.36–2.97) after adjusting for potential
confounders.
The risk of spontaneous abortion
also increased with the use of mac-
rolides such as clarithromycin (adjOR,
2.35, 95% CI, 1.90–2.91) and azith-
romycin (adjOR, 1.65, 95% CI, 1.34–
2.02), and this was consistent with a
previous study revealing an association
36
DOCTOR | JUNE ISSUE
between clarithromycin use in early
pregnancy and the risk of spontaneous
abortion. [PLoS One 2013;8:e53327]
A subgroup analysis on pregnant
women who had urinary tract infection
showed that the use of quinolone was
also associated with an increased risk
of spontaneous abortion compared
with the use of penicillin (adjOR, 8.73,
95%t CI, 3.08–24.77).
Given the overlapping indications of
penicillins or cephalosporins with other
antibiotics, confounding by indication
was considered a potential limitation,
said the researchers.
“Many classes of antibiotics were
associated with increased risk of spon-
taneous abortion ... [However,] we in-
cluded only pregnant women who were
insured by the province’s Prescription
Drug Insurance programme. Therefore,
our results may not be generalizable
to those with private drug insurance,”
they added.
 NEWSBITES

Fewer dysmenorrhoea days with extended

combo regimen
AUDREY ABELLA

A
flexible extended regimen of
ethinylestradiol plus drospire-
none decreased the number of
days with dysmenorrhoea compared
with the standard 28-day cyclic regi-
men of ethinylestradiol plus drospire-
none, according to a Japanese study.

Of the 216 women (mean age 29.7

years) included in this multicentre,
open-label study, 212 were included
in the full set analysis and randomized
to receive ethinylestradiol 20 μg plus
drospirenone 3 mg in a flexible regimen
(n=105, one tablet/day for 24–120 days
followed by a 4-day tablet-free interval)
or a standard 28-day regimen (n=107,
one tablet/day for 24 days followed by
4 days of placebo tablets for six cycles).

Participants either had primary dys-
menorrhoea (n=148, most common
form with unknown aetiology) or sec-
ondary dysmenorrhoea (n=64, asso-
ciated with pelvic pathologies such as
endometriosis or uterine fibroids, and
occurs mostly in older women).
Compared with participants in the
standard group, women in the flexi-
ble extended group had fewer days
with dysmenorrhoea over the 140-day
evaluation period (mean -3.4 days,
95% confidence interval [CI], -6.5 to
-0.3; p=0.03). [Int J Womens Health
2017;9:295–305]
In the subgroup analysis, the num-
ber of days with dysmenor­rhoea was
also fewer in the flexible extended vs
standard group (11.0 vs 14.3 days for
women with primary dysmenorrhoea
and 13.8 vs 17.8 days for those with
secondary dysmenorrhoea).
Genital haemorrhage, headache,
nasophar­
yngitis, and increased plas-
minogen levels were the most common
treatment-emergent adverse events in
both the flexible extended and standard
groups.
Overall, the findings suggest that
at an annual rate, the number of days
with dysmenorrhoea is estimated to be
31 days shorter in the flexible extended
group vs 40 days shorter in the stan-
dard group. “[This suggests] that the
number of days with [dysmenorrhoea]
is 9 days shorter per year in the flexible
extended group than in the 28-day cy-
cle group,” said the researchers.
There was also a significant reduc-
tion in the need for analgesics in the
flexible extended vs standard group
(mean -2.6 days, 95% CI, -5.2 to 0.1).
Due to the pain severity associat-
ed with dysmenorrhoea, about 52% of
Japanese women reported medication
use for pain management, while approx-
imately 28% reported absenteeism. [Int
J Gynaecol Obstet 2008;100:13-17;
Soc Sci Med 1989;29:163–169]
“[R]educing the number of days
with [dysmenorrhoea] even by 1 day
can substantially alleviate the burden …
on both patients and society,” said the
researchers.
The ethi­nylestradiol+drospirenone
combination has a well-characterized
safety profile as an oral contraceptive,
with previous evidence revealing its ef-
ficacy in reducing the severity of symp-
toms associated with dysmenorrhoea.
[Aust Fam Physician 2016;45:59–64;
Contraception 2014;89:253–263; Con-
traception 2016;93:378–385; Obstet
Gynecol 2010;77:977–988]
The findings were not generalizable
to the full study population as a major-
ity of the participants had primary dys-
menorrhoea, noted the researchers,
who called for further trials in women
with secondary dysmenorrhoea.

38
DOCTOR | JULY ISSUE

Low fracture incidence, continued BMD increase
with 10-year denosumab treatment
ROSHINI ANTHONY CLAIRE
P
ostmenopausal women with os-
teoporosis had a low incidence
of fracture and a continuous in-
crease in bone mineral density (BMD)
after 7 to 10 years of denosumab
treatment, according to results of the
open-label, 7-year extension of the
phase III FREEDOM* trial.
“These findings suggest a con-
tinued favourable balance between
benefit and risk through 10 years of
treatment with denosumab,” said the
researchers. “Fracture rates remained
consistently low throughout the study,
similar to rates observed in the active
treatment group during FREEDOM and
lower than in a virtual long-term place-
bo cohort. Our results support the skel-
etal safety of long-term treatment with
denosumab,” they said. [Lancet Dia-
betes Endocrinol 2017;doi:10.1016/
S2213-8587(17)30138-9]
Participants in the 3-year FREE-
DOM trial were 7,808 postmenopausal
women aged 60 to 90 years with os-
teoporosis who were randomized to
receive subcutaneous denosumab (60
mg) or placebo every 6 months for 3
years.
Women who completed the trial
without treatment discontinuation or
missing more than one dose of inves-
tigational drug were enrolled in the ex-
tension trial where all participants were
given subcutaneous denosumab (60
mg) every 6 months and asked to take
calcium (≥1.0 g) and vitamin D (≥400
IU) daily.
A total of 2,626 women completed
the extension study (1,343 and 1,283
were given denosumab [long-term
group] and placebo [crossover group]
in the initial FREEDOM study, respec-
NEWSBITES
tively, mean age 80.8 years at exten-
sion end).
Over the extension period, five and
four subtrochanteric or diaphyseal fem-
oral fractures occurred in the long-term
and crossover groups, respectively,
with one in each group determined as
atypical.
The annual incidence of new ver-
tebral and nonvertebral fractures in the
long-term group was low (0.90–1.86%
and 0.84–2.55%, respectively) during
the extension period and comparable
to that of the initial FREEDOM trial,
while in the crossover group, incidence
of new fractures was comparable to
that in the first 7 years of denosumab
treatment in the long-term group.
BMD increased over time in both
the long-term and crossover groups
(increase of 21.7 and 16.5% at the lum-
bar spine, 9.2 and 7.4% at total hip, 9.0
and 7.1% at femoral neck, and 2.7 and
2.3% at the one-third radius; p<0.05 for
all, based on FREEDOM and extension
baseline, respectively).
“Closing of the remodelling space
and increases in secondary mineraliza-
tion of bone matrix”, “modelling-based
bone formation”, and “reductions in cor-
tical porosity” were among the potential
mechanisms behind the improvement
in BMD, said the researchers.
Over the 10-year treatment period,
yearly incidence of adverse events re-
duced from 165.3 to 95.9 per 100 par-
ticipant-years among all individuals on
denosumab, while the incidence of se-
rious adverse events ranged from 11.5
to 14.4 per 100 participant-years.
Incidence of osteonecrosis of the
jaw was comparable between groups
(seven and six in the long-term and
39
DOCTOR | JULY ISSUE
crossover groups, respectively). Aside
from one patient who discontinued the
study (long-term group) and one who
withdrew consent (crossover group), all
other cases were resolved. None of the
participants developed neutralizing an-
tibodies to denosumab.
However, the prescribing informa-
tion for denosumab was revised to sug-
gest a possible increase in incidence of
osteonecrosis of the jaw with longer
exposure, said the researchers.
“Given the need for long-term treat-
ment in many people with osteoporo-
sis, this evidence that the safety pro-
file of denosumab remains stable over
many years in an ageing population is
important,” said Professor Juliet Comp-
ston from the University of Cambridge,
UK, in a commentary. [Lancet Diabetes
Endocrinol 2017;doi:10.1016/S2213-
8587(17)30178-X]
“The results of our study support
the use of denosumab as primary
long-term therapy in patients with post-
menopausal osteoporosis similar to our
study population. [However], routine
interruption of treatment is not recom-
mended,” said the researchers.
“[Cessation] of denosumab is fol-
lowed by rapid bone loss and an in-
crease in the rate of vertebral fractures;
therefore, if treatment is discontinued,
patients should be switched to an alter-
native therapy,” cautioned Compston.
* FREEDOM extension: Extension study to evaluate
the long term safety and efficacy of denosumab
in the treatment of osteoporosis
 NEWSBITES

High BMI an independent risk factor for ESRD

ROSHINI ANTHONY CLAIRE

A
n increase in body mass index
(BMI) is independently associat-
ed with an elevated risk of devel-
oping end-stage renal disease (ESRD),
according to a Singapore study.

“We found a positive linear asso-

ciation between BMI and the risk of
developing ESRD. The risk increase
began at BMI levels that are generally
considered to be normal or lean,” said
the researchers.

“[The] BMI-ESRD risk association

was only present in individuals who had
no history of diabetes, hypertension,
stroke, and chronic heart disease at
baseline, which minimized the potential
confounding effect of these pre-existing
conditions on the BMI-ESRD associa-
tion,” they said.

Researchers compared data of

52,777 patients aged 45 to 74 years
in the Singapore Chinese Health Study
(SCHS) with that of the Singapore Re-
nal Registry. Over the mean 15.5-year
follow-up period, 827 incident ESRD
cases were identified, of which underly-
ing cause was determined for 822 cas-
es as diabetes (60.4%), renal vascular
disease (16.6%), and other causes (23
percent) including glomerulonephritis
(15.4%) and polycystic disease (2.2%).
Mean baseline BMI was 23.1 kg/m2
and 7.7% of the study population was
underweight (BMI <18.5 kg/m2).
After adjusting for demographic,
lifestyle, and dietary factors, compared
with normal BMI (18.5 to <23 kg/m2),
increasing BMI was associated with
an increased risk for developing ESRD
(hazard ratio [HR], 0.54 for BMI <18.5
kg/m2, HR, 1.40 for BMI 23 to <27.5
kg/m2, and HR, 2.13 for BMI ≥27.5 kg/
m2; ptrend<0.0001). The dose-depen-
dent association was attenuated upon
adjusting for patient-reported history
of diabetes, hypertension, stroke, or
coronary heart disease (ptrend=0.079).
[Kidney Int 2017;doi:10.1016/j.
kint.2017.03.019]
Researchers then categorized pa-
tients with no history of stroke, cor-
onary heart disease, hypertension,
and diabetes at baseline into ten BMI
groups. Analysis showed that the risk
of developing ESRD increased with in-
creasing BMI (HR, 1.06 in the 18– <20
kg/m2 to HR, 2.84 in the ≥27 kg/m2
group; ptrend<0.0001 compared with
BMI <18 kg/m2). There was no asso-
ciation between increasing BMI and
ESRD risk in individuals who had any of
the comorbidities at baseline.
“BMI is a dose-dependent risk fac-
tor for the development of ESRD ...
[and] a modifiable risk factor in a gen-
erally healthy population to reduce the
development of ESRD,” said the re-
searchers.
While the mechanism behind the
association is undetermined, previous
research has suggested that increased
BMI could be linked to glomerular hy-
perfiltration and hyperfusion, which in
turn are linked to an increase in mi-
croalbuminuria, proteinuria, and focal
segmented glomerularsclerosis. An-
other study pointed to a possible hor-
monal mechanism. [Diabetes Metab
Syndr Obes 2014;7:347–355; Contrib
Nephrol 2006;151:175-183]
The researchers acknowledged that
the lack of information on hip-waist ratio
or blood lipid levels meant that the po-
tential role played by other components
of metabolic disease on the BMI-ESRD
association could not be determined.
They also cautioned against determin-
ing causality due to the observational
nature of the study.

40
DOCTOR | JULY ISSUE
ASIAN PACIFIC
DIGESTIVE WEEK
23 – 26 SEP TEMBER 20 1 7
H O N G KO N G

W W W. A P D W 2 0 1 7. O R G

THE FUTURE IN DIGESTIVE DISEASES

Pre-registration Deadline: 31 August 2017

NAMED LECTURESHIPS

JGHF Marshall & Warren Lectureship WGO Distinguished Global Lectureship

Professor Khean-lee Goh (Kuala Lumpur) Professor Joseph Sung (Hong Kong)
Professor of Medicine, Mok Hing Yiu Professor of Medicine,
University of Malaya President and Vice Chancellor,
The Chinese University of Hong Kong

JGHF Okuda Lectureship IDD Forum Joseph Sung Lectureship

Professor Ching-lung Lai (Hong Kong) Professor Andrew Chan (Boston)
Chair of Medicine and Hepatology, Chief, Clinical and Translational Epidemiology Unit,
The University of Hong Kong Massachusetts General Hospital

JGHF Emerging Leaders Lectureship IDD Forum Tzu-leung Ho Lectureship

Professor Grace Wong (Hong Kong) Adjunct Professor Edward Gane (Auckland)
Professor, Department of Medicine & Therapeutics, Faculty of Medical and Health Sciences,
The Chinese University of Hong Kong The University of Auckland

JGHF Emerging Leaders Lectureship

Dr. Norihisa Ishimura (Shimane)
Associate Professor,
Department of Gastroenterology and Hepatology,
Shimane University School of Medicine
APDW 2017 SECRETARIAT
MIMS (Hong Kong) Limited
Comprehensive speaker list and programme details are 27/F., OTB Building, 160 Gloucester Road, Wanchai, Hong Kong
available on website Tel: (852) 2155 8557 Fax: (852) 2559 6910 Email: info@apdw2017.org
*All listed details are subject to change without prior notice
 CLINICAL INSIGHTS | DEVICE
Robotic PCI safe, feasible via
radial, femoral access
PEARL TOH
R
obotic-assisted percutane-
ous coronary intervention (PCI)
showed high clinical and tech-
nical success rates across multiple
sites in patients with lesions, according
to data from the PRECISION* registry
presented at the Society for Cardiovas-
cular Angiography and Interventions
(SCAI) 2017 Scientific Sessions held in
New Orleans, Louisiana, US.
“This is the first time we are demon-
strating that the robotic system can be
used, with either a radial or femoral ap-
proach, with high clinical and technical
success in multiple sites with multiple
operators,” said lead author Dr. Ehtish-
am Mahmud, director of the Sulpizio
Cardiovascular Center at the University
of California, San Diego School of Med-
icine in La Jolla, California, US.
The multicentre PRECISION reg-
istry (16 US sites) included data from
754 robotic PCI procedures performed
on 949 lesions using the first FDA-ap-
proved robotic system for PCI, CorPath
200. Two-thirds of the procedures were
conducted using transradial access
(n=452) and the remaining cases with a
transfemoral approach (n=298).
”
Clinical success—as determined by
“This is the first time procedural success (residual stenosis
of <30% and TIMI 3 flow) without any
we are demonstrating major adverse cardiovascular event
that the robotic (MACE; comprising cardiac death,
system can be used, myocardial infarction, or urgent need for
with either a radial target vessel revascularization)—was
reported in 99% of transradial and 95%
or femoral approach, of transfemoral procedures (p=0.0012).
with high clinical and
technical success In addition, technical success—
in multiple sites with which refers to clinical success without
manual assistance—was also high with
multiple operators” both the transradial and transfemoral
approaches (88.6 vs 82.4%; p=0.017).
42
DOCTOR | JULY ISSUE
“In unadjusted analysis, it appears that
there may be slightly better outcomes
with the radial approach,” observed
Mahmud.
“[However], after conducting a pro-
pensity score matched analysis, no dif-
ferences were observed between the
two approaches. Although, there was
a slightly superior clinical success with
radial access, it was likely the result of
patient selection,” he added, noting that
several baseline demographic and an-
giographic characteristics were signifi-
cantly different between the two groups
of patients. In general, patients in the
transfemoral group were older (mean
age, 68.9 vs 65.1 years; p<0.001) and
had lower BMIs (mean, 29.1 vs 31.1;
p<0.001) with a higher prevalence of di-
abetes (49.8 vs 32.2%; p<0.001) than
the transradial group.
They were also more likely to have
more complex lesion, as assessed by
the ACC/AHA lesion classification (le-
sion type C, 44.3 vs 27.7%) compared
with patients undergoing transradial
robotic PCI. There were 18 serious ad-
verse events in total, with 1.99% occur-
ring in the transradial group vs 3.02%
in the transfemoral group (p=0.47), of
which six were MACE in the transfemo-
ral group. All were adjudicated to be not
related to the robotic system.
The CorPath 200 allows coronary
guidewires and stents to be remotely
controlled for PCI patients. The newer
CorPath GRX system, which enables
robotic control of the guide catheter,
would be expected to further reduce
the rates of manual assistance or con-
version, according to Mahmud.
* PRECISION: Post-market CorPath Registry on the
CorPath 200 System in percutaneous coronary

Dr Benjamin Tow
Vertebral compression
fractures can lead
to serious pain and
disability that can
significantly affect
quality of life and
activities of daily living.
It comes with significant
economic drawbacks
due to the high risk
of refracture and
rehospitalization.
MIMS Doctor spoke
with Dr. Benjamin Tow,
orthopaedic surgeon
at the Orthopaedic and
Spine Clinic at Mount
Elizabeth Medical
Centre, Singapore,
on how GPs can best
manage this preventable
condition.
CLINICAL INSIGHTS | IN PRACTICE
Managing vertebral
compression fractures
in primary care
V
ertebral compression fractures,
or fragility fractures, are preva-
lent in the elderly and character-
ized by severe back pain. If left untreat-
ed, this condition may result in loss of
height, deformity, immobility, increased
number of bed days, and reduced
pulmonary function, which can further
lead to low self-esteem and even de-
pression.
Osteoporosis is a significant factor
in the aetiology of fragility fractures. To-
gether with menopause and increased
age, the weakened bone structure due
to the gradual loss of minerals in oste-
oporosis increases an individual’s frac-
ture risk.
Other contributing factors are phys-
ical inactivity and sedentary lifestyle as
these impair neuromuscular function
(gait, balance, and muscle strength),
prolonged corticosteroid use, and low
body weight/weight loss. Long-term
use of proton pump inhibitors (PPIs)
may also increase the risk of osteo-
porosis-related fractures because PPI
decreases calcium absorption, subse-
quently leading to a lower bone mass.
Diagnosing vertebral
compression fractures
The back pain could range from mini-
mal pain with normal activities (eg, sit-
ting, lying at rest) to excruciating pain
even with slight movements (eg, get-
ting up from a chair). Such mechanical
pain with light motion signals a defect
in the spine, which signifies that it is
unable to support the patient’s load.
The compromised support eventu-
ally leads to serious pain and immobil-
ity and may further progress to spinal
cord and nerve compression with pa-
ralysis.
43
DOCTOR | JULY ISSUE
Underdiagnosis of fragility fractures
is a primary concern. Evidence shows
that majority of high-risk individuals are
neither diagnosed nor treated, with
only about one-third seeking medical
attention, and other cases are being
left unrecognized during a routine tho-
racolumbar radiographic assessment.
An X-ray of the spine is mandato-
ry to assess the presence and severity
of the fracture. However, fracture age
might not be accurately evaluated as
X-rays are unable to detect microscop-
ic bone cracks.
A magnetic resonance imaging
(MRI) scan is therefore recommended
for diagnosing fracture age and occult
fractures missed by X-rays. This can
also better distinguish the presence
of spinal cord compression and risk
of paralysis, as well as rule out other
conditions such as tumours and/or in-
fections.
Bone mineral density (BMD) test
is an important tool that can assess
the degree of osteoporosis and risk
of developing a fragility fracture. Addi-
tionally, the FRAX tool may be able to
estimate the likelihood of sustaining a
fragility fracture.
The pain associated with vertebral
compression fractures is far worse than
the usual arthritic aches and pains.
However, in other cases, the pain may
not be severe enough to warrant at-
tention and might be misconstrued as
arthritic back pain.
It is therefore important to acknowl-
edge the onset and severity of pain,
and take note of the patient’s history
of fragility fractures and other recent
injuries that may have contributed to
 CLINICAL INSIGHTS | IN PRACTICE
Image courtesy of Orthopaedic and Spine Clinic Pte Ltd
Supplementation should be aug-
mented by bone strengthening agents
such as bisphosphonates and deno-
sumab to inhibit bone resorption, and
strontium and teriparatide to stimulate
bone formation.
For pain management, nonsteroi-
dal anti-inflammatory drugs and acet-
aminophen are most commonly used.
However, given the risk of gastrointes-
tinal bleeding and motility with these
medications, these must be used with
caution. Muscle relaxants and narcotic
pain medications may be prescribed
for a short term only given their addic-
tive properties.
Poor medication compliance is a
major treatment problem, as some
patients discontinue their medications
within the first year of treatment. GPs
should therefore highlight potential
problems associated with noncompli-
ance.
MRI scan showing compression fracture of the
L1 vertebra. Back braces can provide external
support, while physiotherapeutic mo-
the condition to help GPs during the dalities may aid in pain control and
assessment. The patient’s frame, med- mobility.
ication history, particularly steroid use
(eg, prednisolone, dexamethasone), Failed conservative management
and habits such as cigarette smoking and severe pain or neurologic deficits
and alcoholism should also be noted. (eg, lower limb numbness or weak-
ness) might require surgical interven-
With fracture being the clinical out- tion such as vertebroplasty or balloon
come of osteoporosis, it is important kyphoplasty to restore lost vertebral
to identify individuals with high-fracture body height, stabilize the bone, and
risk rather than those with osteoporo- free the spinal cord from compression.
sis. Early identification and accurate This usually results in immediate pain
assessment may substantially reduce relief and mobility. However, outcomes
the burden of osteoporosis, as well as and complications associated with
the risk of initial fracture. surgical measures must be thoroughly
evaluated against any existing comor-
Treating vertebral bidity.
compression fractures
Initial treatment should address the Proper nutrition is also an essen-
underlying cause which, in most cas- tial factor in a successful rehabilitation
es, is osteoporosis. Daily intake of cal- programme for fragility fractures. Evi-
cium (1000 mg) and vitamin D (2000 dence shows that fruit and vegetable
IU) supplements is advised, particularly intake positively affects bone density
for elderly patients, to improve calcium in adults, while increased dietary pro-
absorption, bone mineral density, and teins potentially reduces age-related
lower extremity muscle performance. bone loss. Additionally, physical activity
44
DOCTOR | JULY ISSUE
through exercise training is highly rec-
ommended especially in the elderly to
help strengthen the back muscles and
improve balance.
Conclusion
Vertebral compression fractures are
often missed due to the absence of
pain at rest and normal X-ray results.
Pain with activities and posture chang-
es signify mechanical bone failure and
could be the initial sign of osteoporo-
sis. An MRI scan of the thoracolumbar
spine is warranted if patients present
with such symptoms. Alternatively,
GPs may refer the patient to an ortho-
paedic specialist for a more compre-
hensive assessment.
While most vertebral compression
fractures can heal without surgical in-
tervention, managing both the pain
and osteoporosis is a key approach
especially in the elderly population. De-
creasing risk factors and a change in
lifestyle (eg, physical activity, smoking
and alcohol cessation) may also help
to reduce the rate of bone loss and
prevent recurrence.
Online Resources:
• Fracture Risk Assessment Tool
www.shef.ac.uk/FRAX/index.aspx
• International Osteoporosis Foundation
www.iofbonehealth.org/facts-statistics
• American Association of Neurological Surgeons
www.aans.org
Scan the
QR code to
view more of
MIMS clinical
news
 Singapore Prevention & Cardiac
Rehabilitation Symposium 2017

FRIDAY – SATURDAY
20 – 21 OCTOBER 2017
8:00AM – 5:00PM
OBJEC TIVE
NOVOTEL SINGAPORE The SPCRS 2017 aims to provide the latest information and connect them
CLARKE QUAY under an overarching theme, Advances in Cardiac Rehabilitation for
Improved Health. The conference will feature a series of prominent
international and national speakers, and serve as a platform to promote
knowledge exchange, networking and drive strategic alliances for
collaborative research.

WHO SHOULD AT TEND

Cardiologists | General Physicians | Allied Health Professionals
Researchers | Healthcare Students | Senior Management
Featuring For foreign delegates, please visit Singapore Immigration and Checkpoint Authority’s website
(www.ica.gov.sg), if you are uncertain about entry visa requirement for Singapore.
Keynote Speaker
Professor Hugo Saner MD, FESC TOPIC HIGHLIGHTS
Professor of Medicine, University of Bern
Director of Cardiovascular Prevention and
• Impact of E-Health on Cardiac Rehabilitation
Rehabilitation, Swiss Cardiovascular Centre • Importance of Psychosocial Management in Cardiac Rehabilitation
Bern University Hospital, Switzerland
• Barriers to Cardiac Rehabilitation and How to Overcome Them
Other International Speakers • Standing or Sitting at Work – A Revolution in the Office
• How Current and New Pharmacotherapy Affect Cardiac Rehabilitation
Professor David Thompson
Director of the Centre for the Heart and Mind
Mary Mackillop Institute for Health Research
Australia C ALL FOR ABSTR AC TS
Professor Nizal Sarrafzadegan You are cordially invited to submit scientific abstracts for inclusion in
Director of Isfahan Cardiovascular Research Institute
Isfahan University of Medical Sciences
the scientific programme of the SPCRS 2017. The abstract submission
Iran deadline is Friday, 25 August 2017.
Professor John Buckley We are accepting abstracts in the following categories: Telehealth/IT in
Professor of Applied Exercise Science in Health
University Centre Shrewsbury Cardiac Rehabilitation | Policy and Strategy | Nursing and Allied
United Kingdom
Health | Exercise Prescription
All abstracts must be submitted in English language and sent electronically
via the SPCRS website: www.spcrs.sg
For further information, please contact:
Congress Secretariat: MIMS Pte Ltd
Phone: +65 6290 7532
Email: enquiry@spcrs.sg Organised By:
Website: www.spcrs.sg
 CLINICAL INSIGHTS | INDUSTRY UPDATE

Optimizing the management

of stable CAD and HF
Coronary artery disease (CAD) is the leading cause of
death worldwide and is expected to remain so for the
foreseeable future due to both the ageing population and the
Prof Peter Collins increasing prevalence of risk factors such as hypertension,
dyslipidaemia, and diabetes. CAD is also the primary risk
factor in the development of heart failure (HF). At the 2nd Asia
Pacific CardioConnect Meeting in Hong Kong sponsored
by Menarini, a group of international and regional experts
discussed current strategies for managing stable CAD and
HF and highlighted areas where patient outcomes may be
improved.

Stable CAD: Importance of Professor Claudio Borghi from the

Prof Giuseppe Mancia risk stratification
“The natural history of athero-
sclerosis tells us that there is a window
of opportunity during which we can
intervene to prevent CAD-related
adverse events,” said Dr Choo Gim
Hooi from the Cardiac Vascular Sentral
Kuala Lumpur (CVSKL), Malaysia.
“Although largely silent, stable CAD is
not entirely benign. We need to risk-
stratify our patients because we need
to know who is at the highest risk for an
Prof Carolyn Lam event and mortality so we can provide
aggressive intervention.”
There is overwhelming evidence
that hypertension, dyslipidaemia,
and glucose intolerance significantly
increase the risk of cardiovascular (CV)
events. Hypertension, in particular,
affects approximately 30–40 percent
of the adult population. However,
most patients with stable CAD have
Dr Choo Gim Hooi overlapping risk factors, which increase
their CV risk. Professor Giuseppe
Mancia from the University of Milano-
Bicocca in Milan, Italy, noted that
“patients who have hypertension,
dyslipidaemia, and glucose intolerance
are at very high risk, but evidence from
randomized controlled trials clearly
shows that treating each of these risk
factors has a protective effect.”
University of Bologna, Italy, cautioned
that “management of hypertension
is very important for improving CV
outcomes, but is not sufficient to
reduce the overall CV burden because
of the problem of residual CV risk.”
Organ damage is one important cause
of residual CV risk and is linked to
abnormalities in central blood pressure
(BP), which can be used to determine
the haemodynamic performance of a
patient. It may also have a role as a CV
risk factor, particularly in the young and
elderly populations. “Increased central
BP and pulse wave velocity have been
shown to increase the relative risk of
major CV complications and may be
associated with a worse prognosis,”
said Borghi.
The importance of low-density
lipoprotein (LDL) cholesterol levels
in reducing CV risk was noted by
Associate Professor Yiu Kai Hang
from the University of Hong Kong,
China. He also highlighted new risk
factors linked to an increased risk
of myocardial infarction, including
circulating microRNAs, nonsteroidal
anti-inflammatory drugs, and chronic
inflammatory diseases such as systemic
lupus erythematosus, rheumatoid
arthritis, and psoriasis.

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 CLINICAL INSIGHTS | INDUSTRY UPDATE
Pharmacological
management of stable CAD
“There is some discordance be-
tween the level of evidence and rec-
ommendations made for the treat-
ment of stable CAD in international
guidelines,” noted Professor Peter
Collins from Imperial College and the
Royal Brompton Hospital, London,
UK.
Beta-blockers and calcium channel
blockers are recommended for first-line
therapy (class IA evidence in the ESC
guidelines). However, US guidelines rate
the level of evidence for these therapies
as class IB. The rating for ranolazine, a
novel anti-angina therapy that inhibits
the ischaemia-induced sodium influx
that occurs in cardiac myocytes, also
differs (IIaA in the US guidelines and
IIaB in the ESC guidelines).
“The US guidelines are probably
correct,” said Collins. “Ranolazine, for
example, is the only novel anti-angina
therapy recommended for clinical use in
the US in the past 20 years. Uniquely, it
does not have any significant effects on
heart rate or BP and is a highly effective
second-line and add-on therapy.”
The esteemed international faculty comprises 22 European and Asian key opinion leaders.
Ranolazine has signifi cant an-
tianginal actions in a clinical trial da-
tabase of almost 10, 000 subjects. It
is an effective antianginal when com-
pared to placebo and in addition to
standard antianginal therapy such
as beta-blockers, calcium channel
blockers, and nitrates. It also has a
signifi cant antianginal action in di-
abetic subjects and in patients with
acute coronary syndromes. It has
also been shown to improve diabet-
ic control by reducing HbA1c and has
antiarrythmic properties, reducing
atrial fi brillation and supraventricular
and ventricular tachyarrythmias.
Professor Jong-Won Ha from the
Yonsei University College of Medicine,
Seoul, South Korea, emphasized the
importance of distinguishing between
older and newer-generation beta-
blockers when treating hypertension.
“Older generation beta-blockers
such as atenolol have been shown
to be inferior to angiotensin receptor
blockers [ARBs] for uncomplicated
hypertension, suggesting that they are
no longer suitable for first-line therapy,”
he said. “However, third-generation
vasodilating beta-blockers such as
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DOCTOR | JULY
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nebivolol have a favourable effect on
endothelial function and show much
promise.”
Central BP elevation can also be
successfully treated with vasodilatory
beta-blockers. Dr Antonia Anna Lukito
of Pelita Harapan University, Tangerang,
Indonesia, reviewed study data showing
that nebivolol, which modulates nitric
oxide release, effectively reduces
central BP and aortic stiffness without
any of the limitations associated with
traditional beta-blockers. Nebivolol
also has favourable effects on lipids
and glucose control in patients with
hypertension.
Revascularization
“Revascularization procedures
should only be considered for
patients who have symptoms that
are not satisfactorily controlled with
optimal medical therapy,” said Collins.
He reported data from the Clinical
Outcomes Utilizing Revascularization
and Aggressive Drug Evaluation
(COURAGE) trial, which indicated that
coronary interventions had a neutral
effect on patient outcomes. [N Engl J
Med 2007;356:1503-1516]
 CLINICAL INSIGHTS | INDUSTRY UPDATE

Group Captain Krisada Sastravaha, bypass grafting (CABG) or PCI. [Lancet
Bhumibol Adulyadej Hospital, Thailand, 2013;381:629-638] Although the
agreed that revascularization is researchers found fewer adverse events
not suitable for most patients with following CABG, outcomes were similar
stable CAD. However, he noted between the two interventions when
that in the NUCLEAR substudy of patients had a SYNTAX score <22.
the COURAGE trial, percutaneous “CABG remains the standard of care
coronary intervention (PCI) was found for patients with complex, multivessel
to improve outcomes in patients with disease but in less complex cases, such
significant ischaemia. [J Nucl Cardiol as patients who have left main disease
2006;13:685] “PCI is a mechanical with low or intermediate SYNTAX
revascularization procedure aimed scores or triple vessel disease with a
at relieving acute ischaemia. Optimal low SYNTAX score, PCI is a reasonable
medical therapy is clearly the best alternative treatment,” said Dr Kai Hang
first-line option for most patients with Yiu from the University of Hong Kong
stable CAD, but medical therapy is and the Queen Mary Hospital, Hong
insufficient in certain patients, such as Kong.
those with left ventricular dysfunction,”
he said. Optimal medical therapy
after revascularization
The type of intervention selected Optimal medical therapy (OMT)
also requires careful targeting. In the is defined as a combination therapy
Synergy Between Percutaneous Co- with at least one antiplatelet drug,
ronary Intervention with TAXUS and such as aspirin (or thienopyridine
Cardiac Surgery (SYNTAX) trial, clinical after PCI), and a beta-blocker, statin,
outcomes were compared among and angiotensin converting enzyme
patients with complex CAD randomized (ACE) inhibitor or ARB. The regimen
to revascularization with coronary artery is aggressive and is used to prevent
future CV events, not for ischaemic
control.
“There is compelling evidence
that optimal medical therapy reduces
postrevascularization mortality rates
and should be initiated in all patients
following revascularization unless
there are any contraindications,” said
Collins. Analyses of the 5-year clinical
outcomes from the SYNTAX trial have
shown that postrevascularization
OMT signifi cantly reduces the risk
of death (hazard ratio [HR], 0.64,
95 percent confi dence interval [CI],
0.48–0.85; p=0.002) (Figure 1) as
well as the composite endpoint of
death, myocardial infarction (MI),
and stroke (HR, 0.73, 95 percent
CI, 0.58–0.92; p=0.007) (Figure 2).
[Lancet 2013;381:629-638]
“However, changes in clinical
practice have been modest despite
the publication of such findings and
further work is required to determine
how best to incorporate OMT into
interventional strategies and to improve

Figure 1. Optimal medical therapy significantly reduces postrevascularization mortality risk

Drug Group Death HR (95% CI) P-value

Aspirin Overall 0.29 (0.22, 0.39) <0.001

CABG 0.22 (0.15, 0.33) <0.001
PCI 0.37 (0.23, 0.59) <0.001
Any antiplatelet Overall 0.20 (0.15, 0.27) <0.001
CABG 0.16 (0.11, 0.24) <0.001
PCI 0.25 (0.15, 0.41) <0.001
Statin Overall 0.31 (0.24, 0.41) <0.001
CABG 0.21 (0.14, 0.31) <0.001
PCI 0.43 (0.29, 0.64) <0.001
ACE I/ARB Overall 0.70 (0.54, 0.91) 0.010
CABG 0.70 (0.47, 1.05) 0.091
PCI 0.69 (0.48, 0.99) 0.041
Beta-blocker Overall 0.47 (0.36, 0.62) <0.001
CABG 0.46 (0.30, 0.70) <0.001
PCI 0.48 (0.33, 0.70) <0.001
OMT Overall 0.65 (0.49, 0.86) 0.002
CABG 0.54 (0.35, 0.84) 0.008
PCI 0.70 (0.49, 1.01) 0.049
0.1 0.2 0.5 1 2 5 10
Favours using drug Favours omitting drug
ACE-I = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker;
CABG = coronary artery bypass grafting; OMT = optimal medical therapy; PCI = percutaneous coronary intervention

Adapted from Circulation 2015;131:1269–1277

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 CLINICAL INSIGHTS | INDUSTRY UPDATE

the translation of clinical evidence into the importance of viewing HF-PEF cite concerns regarding possible
practice,” concluded Collins. as a real HF and not a collection angioedema and cognitive adverse
of comorbidities. Although there events. The use of beta-blockers in
Management of HF is at present no specific treatment HF patients with atrial fibrillation is also
“China is facing an epidemic of for HF-PEF that improves survival, controversial given that they do not
HF, and the prevalence is only likely LCZ696 was shown in the phase II seem to significantly reduce mortality
to increase given that a significant PARAMOUNT trial to significantly risk in this population.
proportion of the population is classified reduce N-terminal pro-B-type natriuretic
as high risk,” said Dr Jiefu Yang, peptide (NT-proBNP) levels after 12 Future directions
Beijing Hospital, China. Hypertension weeks compared with valsartan. Professor Panos Vardas from the
and CAD are the leading causes of HF [Lancet 2012;380:1387-1395] HF-PEF Heraklion University Hospital, Greece,
in the region, and diuretics, digitalis, and is now thought to result from systemic highlighted promising developments
nitrates the primary therapies. However, endothelial activation and inflammation, expected to impact CV medicine
the use of digitalis is declining and and drugs such as LCZ696, an in the next two decades. PCSK9
that of beta-blockers, ACE inhibitors, angiotensin receptor neprilysin inhibitor, inhibitors, monoclonal antibodies,
ARBs, and aldosterone antagonists may be beneficial by addressing this and novel antithrombotic and anti-
are increasing. The number of patients endothelial dysfunction. A phase III arrhythmic drugs are all expected
reaching the target doses of these agents PARAGON trial of LCZ696 is currently to alter medical therapy, while
remains quite low and they are more underway. Professor Imran Zainal technological advances are expected
frequently used for HF-reduced ejection Abidin from the University of Malaya, to lead to the miniaturization of
fraction (REF) rather than HF-preserved Kuala Lumpur, Malaysia noted that pacemakers, the advent of leadless
ejection fraction (PEF) patients. there is currently some controversy and batteryless devices, increased
regarding whether or not LCZ696 use of multisensors, high-quality
Professor Carolyn Lam, National should be recommended as first-line imaging, and increasing use of
Heart Centre, Singapore, noted therapy. Those advocating caution regenerative biology.

Figure 2. Optimal medical therapy significantly reduces the risk of the composite endpoint of death, MI, and stroke
following revascularization
Drug Group Death/MI/CVA HR (95% CI) P-value

Aspirin Overall 0.39 (0.29, 0.52) <0.001

CABG 0.32 (0.22, 0.47) <0.001
PCI 0.45 (0.29, 0.69) <0.001
Any antiplatelet Overall 0.33 (0.25, 0.43) <0.001
CABG 0.27 (0.19, 0.38) <0.001
PCI 0.35 (0.21, 0.58) <0.001
Statin Overall 0.41 (0.32, 0.52) <0.001
CABG 0.32 (0.23, 0.45) <0.001
PCI 0.51 (0.36, 0.72) <0.001
ACE I/ARB Overall 0.77 (0.62, 0.96) 0.024
CABG 0.78 (0.56, 1.09) 0.152
PCI 0.77 (0.57, 1.04) 0.078
Beta-blocker Overall 0.62 (0.49, 0.78) <0.001
CABG 0.57 (0.40, 0.81) 0.002
PCI 0.66 (0.48, 0.91) 0.010
OMT Overall 0.77 (0.61, 0.97) 0.020
CABG 0.72 (0.50, 1.03) 0.072
PCI 0.77 (0.58, 1.03) 0.084
0.1 0.2 0.5 1 2 5 10
Favours using drug Favours omitting drug
ACE-I = angiotensin converting enzyme inhibitor; ARB= angiotensin receptor blocker;
CABG = coronary artery bypass grafting; CVA= cerebrovascular accident; OMT = optimal medical therapy; PCI = percutaneous coronary intervention

Adapted from Circulation 2015;131:1269–1277

49
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The Role of Modern Second-generation
Antihistamines in Allergic Rhinitis
Allergic rhinitis (AR) is a common global health problem that poses a significant impact on the
quality of life and productivity of affected patients. At the Ear, Nose and Throat (ENT) Summit
2017 held recently at Hilton Sentral, Kuala Lumpur, Malaysia, Associate Professor Dr Marysia
P Tiongco-Recto was invited by A. Menarini to deliver a lecture on the potential of modern
second-generation antihistamines, particularly bilastine (Bilaxten®) in the management of AR.
Associate Professor Dr Marysia
P Tiongco-Recto MD, FPPS, FPSAAI
Allergist and Immunologist, Section of Allergy and Immunology,
Department of Paediatrics, Asian Hospital and Medical Centre,
Muntinlupa City, Philippines
Allergic rhinitis: The burden of disease
AR is an immunoglobulin E (IgE)-mediated inflammation
of the nasal mucosa which is accompanied by one or more
symptoms such as, nasal congestion, rhinorrhoea, sneezing,
itching and post-nasal drip.1 With a global prevalence of 10–
30%, AR poses significant socio-economic implications due
to the financial burden associated with treatment costs as well
as the adverse effects on the patients’ routine function and
quality of life.2,3 The interaction between the constantly evolving
environment and our genetics is thought to play a significant
epigenetic role in the development and growing prevalence of
allergic diseases such as AR, said Assoc Prof Tiongco-Recto.
Managing allergic rhinitis
The management of AR follows a four-pronged approach,
comprising, allergen avoidance, pharmacotherapy, patient
education and immunotherapy.4 The Allergic Rhinitis and its
Impact on Asthma (ARIA) guidelines serves as the benchmark
referral guide for healthcare professionals managing AR,
providing evidence-based revisions on diagnostic methods
as well as treatment approaches and strategies. Based on
the ARIA guidelines, antihistamines, leukotriene-receptor
antagonists and intranasal steroids are the first-line therapies
for patients with AR.4
Oral or nasal nonsedative H1-antihistamines are the
recommended pharmacotherapy to alleviate the symptoms and
discomfort associated with the acute phase reaction of AR.2,3
According to Assoc Prof Tiongco-Recto, first-generation H1-
antihistamine are not recommended mainly due to its adverse
effects such as, somnolence, sedation, dry mouth, palpitation
in certain patients, urinary retention in the elderly, weight
gain and effects on the QTc interval of the heart’s electrical
cycle. Second-generation oral H1-antihistamines, in particular,
are recommended by the ARIA guidelines for use in patients
with mild intermittent, moderate-to-severe intermittent, mild
persistent and moderate-to-severe persistent AR due to their
nonsedative properties and higher anti-inflammatory effect.4
Sponsored Symposium Highlights
Bilastine has proven efficacy in the
treatment of allergic rhinitis
Bilastine is a second-generation oral H1-antihistamine that
is clinically proven to alleviate the symptoms of AR, allergic
rhinoconjunctivitis and urticaria.5,6 Bilastine exhibits in vitro
anti-inflammatory activity by binding to H1-receptors on mast
cells, thus inhibiting the release of inflammatory mediators.7
The potency of bilastine is reflected by its high selectivity and
high affinity towards the H1-receptor, which was demonstrated
in vitro, to be 5-fold and 3-fold greater than fexofenadine and
cetirizine respectively.8
In pivotal, double-blind, randomized, placebo-controlled phase
III studies, bilastine 20 mg was shown to significantly reduce
the nasal symptom score (NSS) (ie, congestion, rhinorrhoea,
itching and sneezing) and non-nasal symptom score (NNSS)
(ie, itching/burning eyes, tearing eyes, reddened eyes and
itching ears/palate) of seasonal AR compared with placebo
(p<0.001).9,10 Bilastine also demonstrated comparable efficacy
to desloratadine 5 mg and cetirizine 10 mg (p<0.001).9,10
Bilastine exhibited rapid onset of action in the Vienna
Challenge Chamber (VCC) study, whereby bilastine
20 mg was efficacious in alleviating allergen-induced nasal
and ocular symptoms within 1 hour of allergen exposure,
which was demonstrated through the reduction of NSS
(Figure 1A).11 Furthermore, bilastine 20 mg exhibited long
duration of action beyond 24 hours of allergen exposure, which
was comparable to the duration of action of cetirizine but
longer than fexofenadine (Figure 1B).11
Bilastine has a good safety profile
In general, bilastine is well tolerated and has a good safety
profile. In terms of long-term safety, bilastine was shown to be
well tolerated over a treatment period of 1 year.12,13 Bilastine
confers good central nervous system (CNS) safety due to its
limited passage through the blood-brain barrier.14 Furthermore,
positron emission tomography investigations indicated that
bilastine has minimal H1-receptor occupancy in the brain.15 The
limitation of bilastine across the blood-brain barrier coupled
with its minimal H1-receptor brain occupancy contributes to
its nonsedative effects and overall CNS safety. Safety studies
also concluded that bilastine does not potentiate the effects of
CNS depressants such as alcohol and lorazepam.14
 this study further accentuates the nonsedative effect of
Figure 1. Bilastine reduced the total NSS within 1 hour bilastine whereby it does not impact psychomotor and driving
(A) with persistent activity beyond 24 hours (B)11 performance. Bilastine is associated with good cardiac safety,
Treatment
whereby a multiple-dose, triple-dummy, crossover study
(A) 10 concluded that bilastine did not cause any significant change
9 Day 1 experiment on the QTc interval of healthy subjects at therapeutic and
8 supratherapeutic doses.12,17
7
6 * Figure 2. Bilastine exhibited no effects towards driving
Total NSS

5 performance even at twice its recommended dose15

4 Placebo 25
Bilastine 20 mg
**
3 24 Day 1
Cetirizine 10 mg
2 23 Day 8
Fexofenadine 120 mg *
1 22

SDLP (cm)
21
0
20
-2 -1 0 1 2 3 4
19
Allergen exposure time (hours)
18
17
(B) 10
Day 2 experiment 16
9
15
8 Placebo Bilastine Bilastine Hydroxyzine
20 mg 40 mg
7
° † Treatment
6
Total NSS

# *p<0.01 vs placebo; **p<0.001 vs placebo SDLP, standard deviation of lateral position

5
4 Placebo The pharmacokinetics of bilastine is particularly unique as it
3 Bilastine 20 mg is not significantly metabolized in the liver and kidney and is
Cetirizine 10 mg
2 Fexofenadine 120 mg
excreted unchanged.18 As such, bilastine does not require
1 dose adjustments in the elderly as well as patients with mild
0
renal and hepatic conditions.6,18 Bilastine is a substrate of the
22 23 24 25 26 organic anion transporter (OATP1A2) pump which translates
to its good absorption and slow clearance rates.6,19
Allergen exposure period, time (hours)
without treatment
*p<0.001 for bilastine, cetirizine and fexofenadine vs placebo #
p<0.001 for cetirizine vs fexofenadine Summary
p<0.001 for bilastine, cetirizine and fexofenadine vs placebo °p<0.0012 for bilastine vs fexofenadine
• Bilastine is a modern second-generation, nonsedative H1-
†

NSS, nasal symptom score

In a placebo-controlled, randomized, double-blind, four-way
crossover study that evaluated the driving performance of
subjects who received once-daily doses of bilastine (20 and
40 mg) for 8 consecutive days, the standard deviation of lateral
position (SDLP) demonstrated by bilastine was comparable
to that of placebo, even at twice the recommended dose.
Hydroxyzine, but not bilastine, significantly increased SDLP
on days 1 and 8 of treatment (Figure 2).16 The results of
antihistamine, clinically proven to alleviate the symptoms of
AR, allergic rhinoconjunctivitis and urticaria.
• Bilastine has a rapid onset of action within 1 hour and long
duration of action of at least 24 hours.
• Bilastine is generally well tolerated with good CNS and
cardiac safety profiles.
• Bilastine is suitable for the elderly and patients with renal
and hepatic conditions.
• Bilastine has rapid absorption and a longer half-life.

References: 1. Mello Junior JF. Braz J Otorhinolaryngol 2016;82:621–622. 2. Brozek JL, et al. J Allergy Clin Immunol 2010;126:466–476. 3. Okubo K, et al. Allergol Int
2017;66:97–105. 4. Bousquet J, et al. Allergy 2008;63:8–160. 5. Bousquet J, et al. Curr Med Res Opin 2012;28:131–139. 6. Bilaxten® (product information). Italy: A.
Menarini Manufacturing Logistics and Services; 2014. 7. Corcóstegui R, et al. Drugs R D 2005;6:371–384. 8. Sadaba B, et al. Ther Clin Risk Manag 2013;9:197–205.
9. Kuna P, et al. Clin Exp Allergy 2009;39:1338–1347. 10. Bachert C, et al. Allergy 2009;64:158–165. 11. Horak F, et al. Inflamm Res 2010;59:391–398. 12. Tyl B, et al.
J Clin Pharmacol 2012;52:893–903. 13. Bachert C, et al. Allergy 2010;65:1–13. 14. Church MK. Expert Opin Drug Saf 2011;10:779–793. 15. Farŕe M, et al. Br J Clin
Pharmacol 2014;78:970–980. 16. Conen S, et al. J Psychopharmacol 2011;25:1517–1523. 17. Sastre J, et al. Curr Med Res Opin 2012;28:121–130. 18. Lasseter KC, et
al. Clin Drug Investig 2013;33:665–673. 19. Kalliokoski A, et al. Br J Pharmacol 2009;158:693–705.

Sponsored as a service to the medical profession by

Editorial development by MIMS Medica. The opinions expressed in this publication

are not necessarily those of the editor, publisher or sponsor. Any liability or
obligation for loss or damage howsoever arising is hereby disclaimed. ©2017
MIMS Medica. All rights reserved. No part of this publication may be reproduced
by any process in any language without the written permission of the publisher.
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Drug and non-drug
approaches to managing
tension-type headache
At the recent launch of Nurofen® Express by
Reckitt Benckiser Malaysia, Ms Joyce McSwan
spoke on the importance of managing tension-
type headache (TTH), highlighting the roles of
drug and non-drug approaches in improving
treatment outcomes.
O
ften described as pain that is akin to a tight
band placed around the head, TTH is a form
of mild-to-moderate pain that occasionally
radiates down the neck.1 Globally, TTH accounts for
42% of the adult population with an active headache
disorder.2 In the United States, 9.2% of people who
experienced headaches during work were reported to
be associated with more than 50% reduction in work
productivity.3 In addition, the lost of work days due
to headaches was 40 days in a year, equivalent to 3
years in one’s working life (assuming one works from
ages 25–65).4
According to Ms McSwan, TTH can be divided into
episodic or chronic TTH. Episodic TTH occurs in
attack-like episodes that last no more than a few
hours but can persist for several days. On the other
hand, chronic TTH occurs for 15 or more days in a
month; and is also less common compared with
episodic TTH.1
Differentiating primary from secondary
headache disorders
TTH is a type of primary headache disorder. Primary
headaches are usually recurrent and are not
attributable to underlying organic diseases. The other
two common primary headache disorders are migraine
and cluster headache.5 Causative and exacerbating
factors of TTH include stress/tension, irregular meal
time, fatigue and lack of sleep.6
On the other hand, secondary headache disorders are
caused by underlying organic diseases, ranging from
sinusitis to subarachnoid hemorrhage.5
To differentiate TTH from secondary headache
disorders, healthcare professionals should look
out for “red flags” (Box) that might suggest
Sponsored Symposium Highlights
Joyce McSwan
Clinical Director, Consultant Pharmacist
Gold Coast Primary Health Network
Persistent Pain Program
Queensland, Australia
underlying organic diseases as the cause of the
headache. 5
Box. Red flags in the evaluation of acute
headaches in adults4
● Sudden onset of headache
● Headaches increasing in frequency and severity
● Headache with signs of systemic illnesses (fever,
stiff neck and rash)
● New-onset headache in high-risk patients
● Papilloedema
● Headache subsequent to head trauma
● Headache beginning after 50 years of age
TTH is mediated by both central and
peripheral pathways
Evidence suggests that TTH is associated with an
increased number of active trigger points in the
pericranial muscles, leading to increased myofascial
pain sensitivity.7 This increase in myofascial pain
sensitivity in TTH is thought to be due to peripheral
sensitization as well as central factors such as
sensitization of various neurons in the brain.7 In view
of this, Ms McSwan emphasized that nonsteroidal
anti-inflammatory drugs (NSAIDs) are favourable for
management of acute TTH as these agents target
both central and peripheral pathways of TTH.
Ibuprofen: A first-line treatment for TTH
with favourable side-effect profile
According to the European Federation of Neurology
Societies (EFNS), mild-to-moderate, episodic TTH
can be easily managed with simple analgesics
(paracetamol and aspirin) or NSAIDs. However,
 Sponsored Symposium Highlights

simple analgesics are usually ineffective in chronic Figure 2. The efficacy of ibuprofen is optimized in
TTH since their efficacy tend to decrease with fasted state12
increasing frequency of the headaches.8 Ms McSwan
suggested that a NSAID with good bioavailability 30

Mean plasma concentration (µg/mL)

and fast pain relief should be used to manage acute
TTH effectively. 25 Ibuprofen/fasted state
Ibuprofen/fed state
Paracetamol/fasted state
20 Paracetamol/fed state
Ibuprofen is endorsed by the International Headache
Society (IHS) as a first-line treatment of TTH since it has 15

a favourable side-effect profile.9 It is associated with a 10

low relative risk for gastrointestinal (GI) complications
compared with other NSAIDs (Figure 1).10 It is also 5
associated with effective pain relief, with treatment
0
success rate (defined as achieving at least 50% pain 0 2 4 6 8 10 12
Time (hours)
relief over 4–6 hours) of above 50% for fast-acting
formulations of ibuprofen 200 mg and 400 mg.11
suggested that ibuprofen may be taken without food
Figure 1. Ibuprofen is associated with lower for quick and effective pain relief over short term,
dose-related GI complications compared with provided that the patient has no contraindications.
other NSAIDs10
100
As with other NSAIDs, patients with a history of
Pooled relative risk log scale

hypersensitivity to aspirin or NSAIDs should consult

20.3 a pharmacist or doctor before taking ibuprofen.13
10 7.9
6.4
4.9
8.5 6.9 Similarly, patients with a current or history of stomach
4.2

1.9
3.9
2.0 2.3
3.2
2.5 2.9 3.2 ulcer, severe heart failure, severe liver disease or
1
1.4
who are taking low-dose aspirin as treatment for
cardiovascular disease should seek advice from a
healthcare professional prior to using ibuprofen.13
0.1
ro LD

c HD

co LD

D
HD

In fena D

In eta D

Na tac D

Na xen D
o LD

D
LD

xi HD

xic LD
HD
fe b H

fe b L

m cH

m in L

pr in H

to n H
Ce oxib

cl ac

Pi cam
Ib ofen

xib

ro n

am
Ce fen

Ibuprofen lysine (Nurofen® Express, Reckitt

Ke rofe
Ro oxi

Ke xe

Pi fe
c
Ro xi

n
co

o
o
e
c
r

pr
of

p
e

pr
up

le
up

le

ro
cl

to
do
Ib

do
Di

Di

NSAIDs
GI, gastrointestinal; HD, high dose; LD, low dose; NSAIDs, nonsteroidal anti-inflammatory drugs Benckiser): Relieves pain twice as fast
Ibuprofen lysine is an improved formulation of
A study was conducted to evalute the absorption ibuprofen and has been shown to absorb faster than
of ibuprofen and paracetamol given as a fixed-dose standard ibuprofen. In a study to compare the time
combination tablet in fed and fasted patients.12 It was to reach the maximum plasma concentration (Cmax) of
found that absorption for both drugs was delayed standard ibuprofen (TmaxRef) for various formulations
in fed patients compared with patients who fasted of ibuprofen, Sancak et al noted that ibuprofen lysine
(p>0.05 for ibuprofen and p<0.001 for paracetamol, can be absorbed up to 5.75 times faster than the
respectively) (Figure 2). In view of this, Ms McSwan standard ibuprofen (Table).14 Furthermore, 100% of

Table. Ibuprofen lysine has faster absorption and rapid onset of action14

Parameter Ibuprofen acid Ibuprofen lysine Ibuprofen liquid Ibuprofen sodium

(n=40) (n=38) (n=38) (n=38)

Cmax, mean (SD), [µg/mL] 29.1 (7.60) 42.3 (10.50) 39.6 (9.37) 37.8 (10.78)
Tmax, median, [min] 150 36 40 37
TCmaxRef, Ref to test GLSM 5.75 (4.53–7.29) 4.51 (3.62–5.64) 3.66 (2.71–4.95)
ratios (95% CI), [%]
Tlag, GM (95% CI), [min] 10.1 (8.7–11.5) 3.1 (2.8–3.4) 4.8 (4.3–5.4) 6.1 (5.5–6.7)
Subjects with Tlag ≤5 min 12 (0–23) 100 (100–100) 64 (48–80) 32 (17–48)
(95% CI), [%]
Cmax, maximum plasma concentration; CI, confidence interval; GLSM, geometric least squares mean; GM, geometric mean; Ref, reference; SD, standard
deviation; TCmaxRef, time to reach Cmax of ibuprofen acid; Tlag, time between drug administration and start of drug absorption; Tmax, time to maximum plasma
concentration

subjects in the ibuprofen lysine group achieved less
than 5 minutes onset of action (Tlag ≤5 minutes).14
Nurofen® Express should be consumed with water
for best result and to further enhance the benefits of
ibuprofen in fasted and fed states.
Non-drug approaches: Equally important
for management of TTH
Nonpharmacologic interventions play important
roles in the management of TTH.15 Active (relaxation
training, yoga) and passive (acupuncture, spinal
manipulative therapies, massage) modalities are
examples of nonpharmacologic therapies effective
in managing TTH. Although studies have shown that
pharmacologic intervention is typically more quick
and effective, over time, however, nonpharmacologic
intervention is equally as effective.15 Therefore, both
pharmacologic and nonpharmacologic therapies
are equally important and work synergistically in the
management of TTH.
Optimizing care in TTH: Tips for healthcare
professionals
TTH is often managed at primary care level by both
doctors and pharmacists. To enhance patient care, Ms
McSwan shared some useful tips on how healthcare
professionals can engage patients to educate them
on the importance of adhering to interventions and
modifying lifestyle.
► H Have a conversation with patients purchasing
analgesics
► E Elicit their motivation for using a certain type of
treatment
Early intervention reduces progression to
chronicity
For healthcare professional only
Sponsored as a service to the medical profession by
Reckitt Benckiser (Malaysia) Sdn Bhd
Level 5, Menara UAC, No. 12, Jalan PJU 7/5, Mutiara Damansara,
47800 Petaling Jaya, Selangor Darul Ehsan, Malaysia.
Tel: +603 7719 1000 Fax: +603 7719 1193
www.reckittbenckiser.com
Sponsored Symposium Highlights
► A Appropriate use of NSAIDs for those who can
take them
► D Duration of use is for no more than 3 days per
week to avoid medication-overuse headache
► S Symptoms that are red flagged that you should
be aware of or refer to the pharmacist
Self-care should be the preferable way to
manage in the long-term.
Summary
Even though TTH is regarded as a form of mild-
to-moderate pain, it has adverse impact on work
productivity, highlighting the need for effective
management of TTH. Ibuprofen is a first-line
treatment for TTH and the novel formulation
of ibuprofen lysine is associated with faster
absorption and rapid onset of action for effective
pain relief. To achieve maximal and effective
treatment outcomes, it is important for healthcare
professionals to consider using both drug and
non-drug approaches in managing TTH.
References: 1. World Health Organization. Atlas of Headache Disorders
and Resources in the World 2011. Geneva, Switzerland: World Health
Organization; 2011. WHO Press 2011. 2. Stovner LJ, et al. Cephalalgia
2007;27:193–210. 3. Schwartz BS, et al. J Occup Environ Med 1997;39:320–
327. 4. Ho K-H, Ong BK-C. Cephalalgia 2003;23:6–13. 5. Spierings EL, et
al. Headache 2001;41:554–558. 6. Clinch CR, Hébert FE. Am Fam Physician
2001;63:685–693. 7. Bendtsen L, Jensen R. Neurol Clin 2009;27:525–535.
8. Bendtsen L, et al. Eur J Neurol 2010;17:1318–1325. 9. Verhagen AP, et al. J
Fam Pract 2006;55:1064–1072. 10. Moore RA, et al. Cochrane Database Syst
Rev 2015;11:CD010794. 11. Castellsague J, et al. Drug Saf 2012;35:1127–
1146. 12. Tanner T, et al. BMC Clin Pharmacol 2010;10:10. 13. National
Health Service (NHS). Ibuprofen. Available at: http://www.nhs.uk/Conditions/
Painkillers-ibuprofen/Pages/Introduction.aspx. Accessed 4 May 2017.
14. Sancak O, et al. Tlag and TCmaxRef as predictors of rapid analgesic onset:
Comparison of soluble ibuprofen with standard ibuprofen formulations.
Presented at: 9th Congress of the European Pain Federation EFIC®; 2–5
September 2015; Vienna, Austria. Abstract 039. 15. Nicholson RA, et al. Curr
Treat Options Neurol 2011;13:28–40.
Editorial development by MIMS Medica. The opinions expressed in this publication are not
necessarily those of the editor, publisher or sponsor. Any liability or obligation for loss or
NRF/000640/A
damage howsoever arising is hereby disclaimed. ©2017 MIMS Medica. All rights reserved.
No part of this publication may be reproduced by any process in any language without
the written permission of the publisher. Enquiries: MIMS Medica Sdn Bhd (891450-U),
2nd Floor, West Wing, Quattro West, No. 4, Lorong Persiaran Barat, 46200 Petaling Jaya,
Selangor, Malaysia. Tel: (603) 7623 8000 Fax: (603) 7623 8188 Email: enquiry.my@mims.com
Website: www.mims.com MY-REC-066
 Sponsored Symposium Highlights

Calcium channel blockers in the

modern treatment of hypertension:
Are there differences?
Hypertension management has significantly evolved over the past decades. New treatment
strategies are constantly being developed to manage the condition. At a recent Abbott-sponsored
lunch symposium held during the 14th Annual Scientific Meeting of the Malaysian Society of
Hypertension in Kuala Lumpur, an expert from Italy provided some insights into the modern treatment
of hypertension, with particular interest in the use of calcium channel blockers (CCBs).

Professor Enrico Agabiti Rosei

President of the European Society of Hypertension
Director of Department of Clinical and Experimental Sciences
Clinica Medica – University of Brescia, Italy

H
ypertension (blood pressure [BP] ≥140/90
mmHg) is one of the leading causes of death
worldwide.1 At present, about 1.5 billion of the
adult population suffer from hypertension, and this
number is projected to increase in the coming years,
emphasized Professor Agabiti Rosei. Studies have
shown that BP levels are strongly correlated to the
relative risks of stroke, heart failure, coronary heart
disease (CHD) and renal disease.2,3
Investigations of the cause of hypertension are typically
inconclusive as most parameters would be, on average,
normal (eg, sympathetic activity, plasma renin activity).
There is only one parameter that is consistently
abnormal, ie, increased peripheral resistance.4 The
increased peripheral resistance is generally due to
structural remodelling of small resistance vessels
(consisting of the small arteries and arterioles) that
can also lead to a reduction in blood flow at maximal
vasodilatation. The structural alteration in the vascular
wall of small arteries may have a strong prognostic
significance in patients with hypertension, particularly
on the risk of cardiovascular events.5 Therefore, the
correction of small artery remodelling should be a goal
of antihypertensive therapy. Evidence have shown
that different classes of antihypertensive agents (ie,
CCBs, angiotensin-converting enzyme inhibitors,
angiotensin receptor blockers, beta-blockers,
diuretics and direct renin inhibitors) have different
effects on reversing abnormal vascular structure in
patients with hypertension with beta-blockers and
diuretics being less effective in this respect.5
It is noteworthy that the overall reduction of BP is
key in reducing the rate of premature morbidity and
mortality in the general hypertensive population.
The role of CCBs in hypertension
management
CCBs are medications that inhibit the movement
of calcium ions into cardiac and vascular smooth
muscle cells via calcium channels. 6 The main
effect of CCBs is vasodilation, which decreases
peripheral resistance. The three major classes
of CCBs – dihydropyridines (eg, lercanidipine),
phenylalkylamines and benzothiazepines – have
a similar mechanism of action, but they differ in
selectivity and reactivity at tissue sites.6 For instance,
dihydropyridines predominantly affect vascular
smooth muscle cells.
Based on a meta-analysis of 10 randomized controlled
trials in which active treatment was based on a CCB
(dihydropyridine), a –6/–3.4 mmHg systolic BP/
diastolic BP difference between CCB therapy and
placebo was accompanied by a significant relative
risk reduction of all outcomes, including CHD and
heart failure (Table).7
The 2013 guidelines on hypertension of the European
Society of Hypertension (ESH) and the European
Society of Cardiology (ESC) recommend the use
of CCBs in hypertension associated with several
clinical conditions, ie, left ventricular hypertrophy,
 Sponsored Symposium Highlights

Table. Relative and absolute risk reduction of various outcomes in BP lowering by CCBs trials in
hypertensive patients with no or minimal baseline therapy7

Events (n/patients) Absolute risk

Difference reduction
Trials Outcome risk SBP/DBP P 1,000 pts/5 years NNT 5 years
Outcome (n) (% in 5 years) (mmHg) Treated Controls RR (95% CI) RR (95% CI) (Heterogen) (95% CI) (95% CI)

Sensitivity analysis

Stroke 4 7.8 -6.5/-3.7 306/9532 466/9348 0.63 (0.53–0.76) 0.25 -26 (-31, -17) 39 (32,58)

CHD 3 2.9 -6.3/-3.5 113/8492 151/8308 0.74 (0.58–0.94) 0.26 -7 (-11, -2) 143 (94, 579)

HF 3 1.9 -6.3/-3.5 59/8492 84/8308 0.68 (0.49–0.95) 0.77 -5 (-7, -1) 194 (135,1091)

Stroke + 3 10.3 -6.3/-3.5 382/8492 528/8308 0.71 (0.62–0.81) 0.36 -27(-34, -18) 37 (29, 55)
CHD

Stroke + 3 12.3 -6.3/-3.5 463/8492 612/8308 0.74 (0.66–0.83) 0.64 -29 (-37, -20) 34 (27,51)
CHD + HF

CV death 3 4.6 -6.3/-3.5 162/8492 221/8308 0.71 (0.58–0.87) 0.87 -12 (-16, -6) 84 (62,176)

All-cause 4 7.7 -6.5/-3.7 344/9532 432/9348 0.77 (0.67–0.89) 0.68 -16 (-23, -8) 61 (144,123)
death

0.3 0.6 1.0 1.3

CCB better Control better

BP: blood pressure; CCBs: calcium channel blockers; CHD: coronary heart disease; CI: confidence interval; CV: cardiovascular; DBP; diastolic blood pressure; HF: heart failure; n: number; NNT: number
(and 95% CI) of patients needed to treat for 5 years to prevent one event; pts: patients; P (Heterogen): P for the heterogeneity test χ2Q; RR: Mantel–Haenszel risk ratios; SBP: systolic blood pressure.

asymptomatic atherosclerosis, angina pectoris, ► It does not cause significant reflex tachycardia or
atrial fibrillation for ventricular rate control, other signs of sympathetic activation in the long
peripheral artery disease and isolated systolic term when given at therapeutic doses.16
hypertension. 8 Additionally, findings from the
► At a dose of 10 mg, it has a significant and durable
Valsartan Antihypertensive Long-Term Use Evaluation
antihypertensive effect over 24 hours.17
(VALUE) and Avoiding Cardiovascular Events
through Combination Therapy in Patients Living ► It helps in the regression of left ventricular
with Systolic Hypertension (ACCOMPLISH) studies hypertrophy in patients with hypertension.18
showed that CCBs may be recommended as part ► It displays a particular activity on small-sized
of the first-line regimen for hypertensive patients at intraparenchymal brain arteries and this might
high cardiovascular risk.9,10 CCBs have also been represent an interesting property for the treatment
found to reduce carotid intima-media thickening – of hypertensive brain damage with concomitant
a mechanism that might confer protection against ischaemia.19
stroke.11
Various comparative studies between lercanidipine
Clinical efficacy of lercanidipine and other dihydropyridines have been conducted. In a
(Zanidip®) double-blind, crossover study, lercanidipine was found
to be as effective as amlodipine (24-hour efficacy) in
Lercanidipine is a third-generation lipophilic
lowering systolic and diastolic BP in patients with mild-
dihydropyridine CCB with a long half-life.12 It is
to-moderate essential hypertension (Figure 1).20 Both
characterized by a high vasoselectivity and a
prolonged interaction with L-type calcium channel in agents are known to exhibit consistent BP control;
human cardiovascular tissue.13 The following are the however, lercanidipine is associated with a better
main clinical benefits of lercanidipine: tolerability profile and lesser vasodilation-related
adverse reactions (eg, peripheral oedema, swelling,
► It consistently decreases matrix metalloproteinase-9 flushing and headache) than amlodipine, either used
activity and reduces oxidative stress in patients as a single agent or as initial therapy combined with
with hypertension.14 other classes of antihypertensive agents.21.22
► It improves flow-mediated dilatation in brachial
arteries in patients with coronary vasospasm, and Besides providing effective BP control, lercanidipine
this process is accompanied by an improvement of also exerts favourable effects on the renal vasculature,
chest pain and stress-induced ischaemic changes.15 thus conferring renal protection in patients with
 Figure 1. Consistency of BP control (24-hour Figure 2. Preservation of small-sized renal
efficacy) between lercanidipine and amlodipine20 artery lumen by llercanidipine in spontaneously
hypertensive rats24
Placebo
Amlodipine 10 mg
Systolic Lercanidipine 20 mg
160 Normal rat SHR
Blood Pressure (mmHg)

140

120
Diastolic
100
SHR + SHR +
Lercanidipine Manidipine
80

60
9 am 12 3 pm 6 pm 9 pm 12 3 am 6 am
noon midnight
Time of day L: lumen; M: media; A: adventitia; SHR: spontaneously hypertensive rats

hypertension.23 A preclinical study by Sabbatini et al
showed that lercanidipine administration prevented
wall thickening and luminal narrowing in small-sized
arteries and glomerular arterioles (Figure 2). 24,25
Moreover, lercanidipine exerted antiproteinuric effects
to a greater extent than other calcium antagonists,
by inducing vasodilatation of glomerular afferent and
efferent arterioles in patients with hypertension.26
Findings from the REnal Disease: LErcanidipine
Valuable Effect on urine protein Losses (RED LEVEL)
study also showed that lercanidipine provides
long-term renoprotective effects in patients with
hypertension, a benefit not seen with the use of
amlodipine.27
Take-home message
Lercanidipine is a third-generation dihydropyridine
CCB with high lipophilicity and high vascular
selectivity, which confers a gradual and prolonged
antihypertensive effect throughout 24 hours. It has a
good tolerability profile and provides renoprotective
effects in patients with hypertension.
References: 1. American Heart Association. What is High Blood
Pressure? Available at: https://www.heart.org/idc/groups/heart-public/@
wcm/@hcm/documents/downloadable/ucm_300310.pdf. Accessed 7
April 2017. 2. Thomopoulos C, et al. J Hypertens 2014;32:2285–2295.
3. World Health Organization. A Global Brief on Hypertension.Available
at:http://ish-world.com/downloads/pdf/global_brief_hypertension.pdf.
Accessed 7 April 2017. 4. Mulvany MJ. News Physiol Sci 2002;17:105–
109. 5. Agabiti-Rosei E, et al. J Hypertens 2009;27:1107–1114. 6. Parmley
WW. Clin Cardiol 1992;15:235–242. 7. Thomopoulos C, et al. J Hypertens
2015;33:195–211. 8. Mancia G, et al. J Hypertens 2013;31:1281–1357.
9. Julius S, et al. Lancet 2004;363:2022–2231. 10. Weber MA, et al. Blood
Press 2007;16:13–19. 11. Wang JG, et al. Stroke 2006;37:1933–1940.
12. Borghi C. Vasc Health Risk Manag 2005;1:173–182. 13. Brixius K,
et al. Clin Exp Pharmacol Physiol 2005;32:708–713. 14. Martinez ML, et
al. J Cardiovasc Pharmacol 2006;47:117–122. 15. Janaviciene S, et al.
Seminars in Cardiology 2005;11:15–23. 16. Grassi G, et al. Hypertension
2003;41:558–562. 17. Omboni S, Zanchetti A. J Hypertens 1998;16:1831–
1838. 18. Fogari R, et al. J Hypertens 2000;18:s65. 19. Sabbatini M, et
al. Mech Ageing Dev 2001;122:795–809. 20. De Giorgio L, et al. Current
Therapeutic Research 1999;60:511–520. 21. Zanchetti A. Clin Cardiol
2003;26:II17–II20. 22. Barrios V, et al. Int J Clin Pract 2008;62:723–728.
23. Burnier M. Curr Med Res Opin 2013;29:1727–1735. 24. Sabbatini M,
et al. J Cardiovasc Pharmacol 2000;39:39–48. 25. Rosenthal T, et al. J
Cardiovasc Pharmacol Ther 2007;12:145–152. 26. Robles NR, et al.
Renal Failure 2010;32:192–197. 27. Robles NR, et al. Curr Med Res Opin
2016;32:29–34.

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