Statins recommended for certain 8-year-olds

Medical Tribune September 2008 P1 & 7
David Brill

Cholesterol-lowering statins should be
considered for certain children as young
as 8, the American Academy of Pediatrics
has advised.
The new guidelines, which prompted a
heated debate in parts of the international
media, have been hailed as timely by a specialist
in Singapore.
Low-fat milk is also recommended for
certain infants between 1 and 2 years old.
Rising childhood obesity rates and the
associated health risks give the recommendations
a “new urgency,” the authors wrote.
[Pediatrics 2008 Jul;122(1):198-208]
Doctors should still work aggressively
on lifestyle change, diet and weight status
before resorting to medications, said lead
author Dr. Stephen Daniels.
He said that although long-term studies
on the safety of statins in children are lacking,
the short-term data suggest a similar
profile to that seen in adults.
“While there may be things that we
don’t know yet … I think that as the data
accumulates the sense is that these agents,
when they are used appropriately, can be
effective in lowering cholesterol and are
generally safe,” said Daniels, who is pediatrician-
in-chief at The Children’s Hospital
in Denver, Colorado.
The guidelines received a mixed response
in the US, with people questioning whether
statins should be used in such young patients.
Daniels said however that only a small
minority of children would be medicated,
and most of these would be likely to have
familial hypercholesterolemia.

“I think many of them got a bit confused
about what we were really recommending
… there seemed to be this sense
among some reporters that we were recommending
statins for a large number of
children,” he said.
The guidelines state that medication
can be considered for children whose LDL
cholesterol level remains above 190 mg/
dl despite dietary therapy. For those with
other cardiovascular risk factors the recommended
cut-off point is 160 mg/dl.
Dr. Fabian Yap, head of pediatric endocrinology
at KK Women’s and Children’s
Hospital in Singapore, said that he has
already prescribed statins in patients as
young as 8, but emphasized the need for
a clear indication and close monitoring for
potential side effects.
He said that the guidelines will give
pediatricians greater flexibility in managing
obese children with lipid disorders.
“I think that the recommendation is
timely because it gives due recognition to
the fact that atherosclerosis has its roots in
childhood and that hypercholesterolemia,
which is a key modifiable risk factor for
future cardiovascular disease, ought to be
tackled as early as possible,” said Yap.
“There is unequivocal evidence that
statin therapy is the single most effective
method of lowering LDL cholesterol levels
in children and adolescents. However,
long-term safety data is obviously lacking,
which is the main reason why statin therapy
in young children ought to be undertaken
after careful risk-benefit analysis,
preferably by specialist pediatricians in a
tertiary referral center.”
Two separate meta-analyses have concluded
that statin therapy appears to be
safe for children aged 8 to 18 with familial
heterozygous hypercholesterolemia,
although only 2 years of follow-up data
is presently available. [Arterioscler Thromb
Vasc Biol 2007 Aug;27(8):1803-10; Atherosclerosis
2007 Dec;195(2):339-47]
The previous guidelines set 10 years
of age as the cut-off point for cholesterollowering
medications but limited the recommendations
to bile acid sequestrants.
[Pediatrics 1998 Jan;101:141-7]

Prescribe fenofibrate to prevent diabetic retinopathy, doctors urged

Medical Tribune September 2008 P4
David Brill


Doctors should routinely
consider prescribing fenofibrate
alongside statins for
their diabetic patients, two leading
experts advised recently.
A large multinational trial,
published last year in The Lancet,
showed that fenofibrate significantly
reduced the chances of
needing laser treatment for retinopathy
among type 2 diabetics.
[370(9600):1687-97]
Yet awareness of the condition
and the protective effects of fenofibrate
is low according to Anthony
Keech, professor of medicine, cardiology
and epidemiology and
deputy director of the National
Health and Medical Research
Council Clinical Trials Centre at the
University of Sydney, Australia. He
was speaking at a press conference
recently held in Singapore.
“Doctors need to know that diabetic
eye disease is highly prevalent.
And secondly they need to be
aware of these findings – that one
can actually retard the progression
of the condition easily with a oncea-
day tablet,” he said.
The Fenofibrate Intervention
and Event Lowering in Diabetes
(FIELD) study randomized 9,795
patients at 63 sites to placebo or
fenofibrate (200 mg/day).
After an average of 5 years follow-
up, 238 patients (4.9 percent)
in the placebo group had undergone
laser surgery compared to
just 164 (3.4 percent) of those in the
fenofibrate group – corresponding
to a hazard ratio of 0.69 (P=0.0002).
The safety profile of the drug was
similar to that of placebo.
“These are really sensational
findings that caused a great deal
of excitement around the world,
particularly as this is something
that statins don’t seem to do,” said
Keech, who was principal investigator
for the FIELD study.
“I think that as people become
aware of these results … they will
form the view that really there’s
no reason why you wouldn’t want
everybody with diabetes to be on
this treatment. Certainly if I had
diabetes I’d be running to get it,”
he said.
Laser treatment is proven to be
a successful treatment for retinopathy
but can reduce the visual field
and cause other ocular side-effects.
Professor Wong Tien Yin, one of
Singapore’s top ophthalmologists,
called on primary care physicians
to do more to prevent the development
of diabetic retinopathy.
“This is a message that needs
to go out to GPs, polyclinics, cardiologists
and diabetologists – those
people that manage diabetes.
“When [patients] see me for laser
treatment it’s quite late already.
We want them to start sorting it out
early, and we want to avoid laser
treatment … you can’t wait until
you have problems before you
go and see an ophthalmologist,”
he said, adding that awareness of
fenofibrate among doctors in Singapore
is currently “not there.”
In general around a third of
diabetics will develop retinopathy
at some point said Wong, who is
an ophthalmology professor at the
National University of Singapore
and deputy director of the Singapore
Eye Research Institute.
A study of 3,000 Singaporean
diabetics carried out last year found
that 35 percent were affected, yet
80 percent of them had not seen an
eye doctor and were unaware that
they had the condition, he said.
As the prevalence of diabetes
continues to rise throughout Asia,
fenofibrate will become an important
addition to other interventions
in tackling the disease, he added.
Keech added that unlike some
other fibrates, fenofibrate is safe in
combination with statins, and that
he sees no downside to the treatment.
“I think that within a few years
time people will believe that every
patient with diabetes should be on
fenofibrate, or a similar treatment,
for its macro- and microvascular
benefits,” he concluded.

Tau targeting offers new hope for Alzheimer's

Medical Tribune September 2008 P5
David Brill


A promising new treatment
has been shown to halt the
progression of cognitive
decline in patients with mild and
moderate forms of Alzheimer’s
disease.
The drug, a modified form of
methylthioninium chloride, targets
the tau protein tangles that develop
in the disease, whereas other drug
development efforts have largely
focused on the amyloid beta pathology.
A phase II randomized trial
found that the therapy reduced the
rate of cognitive decline by 81 percent
compared to placebo, following
50 weeks of treatment.
Cognitive function in drugtreated
patients did not change significantly
over 84 weeks compared
with baseline.
“So far we [have] the first clinical
trial to show that targeting tau
tangles may have some effect on
cognitive decline in Alzheimer’s
patients. So this is a complete
paradigm shift to current thinking
on the cause and the treatment of
Alzheimer’s in the world today,”
said Dr. Seng Shay Way, managing
director of TauRX Therapeutics,
the Singapore-based company
that developed the drug.
“This is very exciting and it
shows a lot of promise and potential.
But most importantly, if
we manage to tackle this disease
it will actually help a lot of families
and Alzheimer’s patients,” he
said.
Seng estimates that the drug,
which is taken orally three times a
day, could be commercially available
by 2012, depending on the results
of an upcoming international
phase III trial.
The present trial involved 321
subjects in Singapore and the UK.
Cognitive function was assessed
using the Alzheimer’s Disease
Assessment Scale Cognitive Subscale.
Brain imaging at 25 weeks
showed that the treatment was
having the greatest effect in areas
with the highest density of tau
tangles. This validates the theory
that tangles are an important
cause of dementia in Alzheimer’s,
Seng said.
Methylthioninium chloride
has been used in the past to treat
methemoglobinemia and urinary
tract infections. The modified
version contained in the drug appears
to dissolve the filaments of
tau tangles, thereby preventing
aggregation of the protein without
affecting its normal function.
The trial was a joint venture
between TauRX and researchers
from the University of Aberdeen
in Scotland. The results were presented
at the recent 2008 International
Conference on Alzheimer’s
Disease in Chicago, US, and at a
press conference in Singapore.
TauRX has yet to decide
whether to publish the phase II
results in a journal, Seng said, but
added that the phase III results
will be published when they are
available.

Oncogene obsession blinding oncologists, expert says

Medical Tribune September 2008 P6
David Brill

Cancer research has been wearing
blinders for the past 30 years, according
to a world-renowned expert who
spoke recently at the National Cancer Centre
in Singapore.
By being “obsessed with oncogenes,” the
international research community has largely
overlooked simpler targets for drug development,
said Professor Mak Tak Wah, who
believes that disrupting the metabolic pathways
of cancer cells could be the answer.
A growing volume of research shows that
cancer cells need large amounts of glucose
and fatty acids to grow and survive. Halting
this supply, Mak says, could be a way to
starve these cells and cause them to run out
of fuel.
“You could argue that targeted therapies
– 30 years of development, tens of billions of
dollars gone into anti-cancer agents – have
been a success, but I would say that on the
street, people are saying that we’ve failed.
You could argue that it’s really been a miserable
failure,” he told Medical Tribune.
“For the last 30 years, we’ve been betting
on the same horse. Is it not time for us
to think, well, what’s the payback? Some
people argue that it’s been a fantastic success
given the complexity of the problem. I argue
no, there are clearly simpler ways.”
Mak rose to scientific fame in 1984 when
his laboratory announced the first cloning
of the human T-cell receptor gene. He has
since played an important role in developing
genetically-modified mice for use in
immunological research, published over
600 research papers and won a multitude of
prestigious awards.
Current approaches to drug development
have led to some successes, Mak said, noting
that imatinib mesylate and trastuzumab can
actually save lives in some patients. Many
other drugs, however, are widely sold for
billions of dollars yet can only prolong life
by a few months.
Mak recently co-founded a company
called Agios Pharmaceuticals, which seeks
to develop drugs that regulate cancer metabolism.
He is joined in the venture by two
like-minded US professors: Craig Thompson,
who is scientific director of the Abramson
Family Cancer Research Institute at
the University of Pennsylvania, and Lewis
Cantley, chief of the division of signal transduction
at Harvard Medical School.
“We’re looking at the problem differently,”
said Mak, himself a professor at the
University of Toronto, Canada, and director
of the Campbell Family Institute for Breast
Cancer Research.
“We want to reignite this concept. You
can’t eat breakfast all day – we’ve been eating
breakfast for 30 years. Don’t you think
it’s time to change?”
The metabolism concept advocated by
the three professors has already begun to
yield results: Cantley’s group published two
papers in Nature earlier this year, identifying
the enzyme pyruvate kinase M2 as playing
an important role in the rapid growth of tumor
cells. [2008 Mar 13;452:181-6; 2008 Mar
13;452:230-3]
Others are finally beginning to take note
of these ideas, said Mak, who has been invited
to organize a session on cancer metabolism
for next year’s meeting of the American
Association for Cancer Research.
“Some people are saying ‘well let’s keep
an open mind and listen to these people.
They may be crazy but what the heck,’” he
said.
“It’s a different way. But every time you
start a wave you still need to start with a ripple.
Let’s see,” he concluded.

Regional academy offers hope for kidney dialysis patients

Medical Tribune September 2008 P6
David Brill


A new academy has opened in China
which could improve the quality of
life for kidney dialysis patients throughout
the Asia Pacific region.
The multi-million dollar center will
train nephrologists and nurses in peritoneal
dialysis (PD) – a home-based therapy
that avoids the inconvenience associated
with conventional hemodialysis.
Applicants are invited from across the
region, with a view to educating their colleagues
and setting up new centers when
they return home.
The academy, called Baxter Scientia
Asia Pacific, is a joint project between Baxter
International Inc. and the Peking University
Third Hospital in Beijing, where it
is based. It opened in July, with the first
training course due to start on 12 October.
“Around 40 percent of all the global
PD patients are in [the] Asia Pacific so this
is a very critical treatment for the lives of
many people in the region,” said Mr. Gerald
Lema, Baxter’s corporate vice president
and president of the Asia Pacific division.
“Our hope with this Scientia academy is
that … we will be able to disseminate many
good treatments and train physicians from
around Asia Pacific so that their standards
of care improve. People on dialysis have a
long-term commitment to therapy because
it’s a lifelong disease, so making a difference
in those outcomes really improves patients’
lives,” he said.
Lema expects that the center will take
on 100 trainees in its first year and 200 in its
second. The exact costs of the center have
not been disclosed, but it will be “a multimillion
dollar commitment over the next
few years,” he said.
The academy will also provide training
in other areas such as the management of
chronic kidney disease and its complications.
Research programs are also available
from later this year, and clinical trials are
planned for the future.
PD is convenient for patients as it can
be performed at home, whereas conventional
hemodialysis typically requires three
trips a week to a specialist center with each
session lasting around 4 hours.
Patients typically take around a week
to learn the techniques for PD, Lema said,
adding that the costs of treatment vary but
are generally comparable to hemodialysis
and can sometimes be cheaper.
Four different courses are presently on
offer at the academy, taught in English and
Mandarin. The longest is a 3-month program
offering basic training and experience
in PD.
Applicants can be nominated by
their home hospital or university. Scholarship
funding is available for certain
cases.

Flu jab less effective against pneumonia in the elderly

Medical Tribune September 2008 SFV
David Brill


The influenza vaccine appears to be
less effective than previously thought
at preventing pneumonia among the
elderly.
Research published recently in The Lancet
found that US senior citizens who were
vaccinated were no less likely to get community-
acquired pneumonia during flu
season than those who were not. [2008 Aug
2;372(9636):398-405]
The findings prompted a leading infectious
diseases expert in Singapore to call for
more studies into the efficacy of the vaccine
and the causes of pneumonia – a common
complication of influenza.
The study was conducted at the Group
Health Center for Health Studies in Seattle,
US. Lead author Dr. Michael Jackson said
that for the time being doctors should continue
to encourage their older patients to
get the flu jab.
“We know it’s effective in younger,
healthy seniors. We don’t know how effective
it is in the older seniors and seniors that have
chronic medical problems but it’s a very low
risk vaccine with an extremely low rate of side
effects so even a small amount of protection,
if it’s there, is beneficial,” said Jackson,
who is presently an epidemiologist at the US
Centers for Disease Control and Prevention.
The study could have two different interpretations,
the authors wrote. It is currently
unclear whether the vaccine is ineffective
at preventing influenza infection among
people who are at risk of pneumonia, or
whether influenza infection is only responsible
for a small proportion of pneumonias
in this group.
“The controversy calls for additional
studies to assess vaccine effectiveness, improve
understanding about causes of pneumonia
in elderly individuals and the impact
on health secondary to influenza illness not
restricted to pneumonia,” said associate professor
Leo Yee Sin, clinical director of the
Communicable Disease Centre in Singapore.
She noted, however, that conducting
randomized control trials could be difficult
given the ethical problems associated with
not vaccinating certain people.
Leo added that current recommendations
for vaccine strategy are “under intense
review,” as mortality studies have failed to
show that influenza-related deaths actually
decrease as vaccine coverage increases.
The paper by Jackson et al. was a nested
case-control study involving 1,173 confirmed
cases of pneumonia and 2,346 controls,
selected from a population of immunocompetent
seniors aged 65 to 94, who were
enrolled in a health maintenance organization
in Washington state, US.
Observational studies had previously
found that the influenza vaccine reduced
the odds of being admitted for pneumonia,
but were typically based on the International
Classification of Disease codes that are
assigned to a patient’s visit. These studies
did not adjust for important health differences
between vaccinated and unvaccinated
participants and were therefore subject
to confounding.
As a result these studies have tended to
overestimate the efficacy of the vaccine, Jackson
said. His research addressed these issues
by reviewing medical records to identify
more detailed patient information, which
could then be taken into account in risk adjustment
models.
When applying a fully adjusted model
– controlling for smoking history, previous
pneumonia episodes and use of corticosteroids
and bronchodilators, among other
factors – the odds ratio for developing pneumonia
during influenza season was 0.92
among those who had been vaccinated (95
percent CI 0.77 – 1.10; P=0.35).

GERD presentation not always by the book

Medical Tribune September 2008 SFV
David Brill


Doctors should be more wary of atypical
presentations of gastro-esophageal reflux
disease (GERD), a Singapore specialist
advised recently.
Although the classical symptoms are easily
recognizable, some 10 percent of patients
will not fulfill the usual criteria for GERD,
said Dr. Lui Hock Foong, chairman of the
National Foundation for Digestive Diseases.
These patients may present with coldlike
symptoms such as a sore throat, hoarse
voice or rhinitis. A chronic cough, particularly
occurring at night, can also be a sign
of GERD, and is thought to result from the
irritation of cough receptors at the lower
end of the esophagus.
Alternatively patients may have atypical
chest pain, prompting the physician to
carry out cardiac testing. If these results
come back negative, Lui said, it is possible
that the symptoms would respond to GERD
treatment.
Lui, a consultant gastroenterologist at
Gleneagles Hospital, said that knowledge
of these issues among GPs was beginning to
increase following an active campaign by the
Gastroenterological Society of Singapore to
educate about the symptoms of the disease.
He was speaking at the country’s first national
GERD awareness day on 20th August.
The condition was traditionally thought
to result from Western diets but appears to
be increasingly common in Asia. In Singapore
the prevalence rose from 1.6 to 9.9 percent
between 1994 and 1999. [J Gastroenterol
Hepatol 2005 Jul;20:995-1001]
Doctors who are faced with a possible
case of GERD should first take the time to
rule out other conditions, Lui said. Once the
diagnosis is confirmed the physician should
assess the severity of the problem using investigations
such as endoscopy, and should
check for long-term complications such as
alterations to the esophageal lining which
can predispose patients towards cancer.
A survey announced on the same day
found that public awareness of GERD is
low, with 76 percent of those who had experienced
symptoms admitting that they
had not heard of the condition. Only 42 percent
had sought treatment in the past, and
a quarter of these had waited more than a
year before doing so.
Two hundred and four people aged 25 to
60 with a history of GERD symptoms took
part in the survey. The awareness campaign
also included the distribution of a “call to
action” postcard, listing six simple steps to
help patients discuss their symptoms with
their doctor.