YOUR MOST TRUSTED SOURCE OF HEALTHCARE INFORMATION IN ASIA INDONESIA AUGUST 2020

Highlights from AHS,

ADA & EULAR 2020

Managing HFMD
in primary care
CONTENTS
MIMS DOCTOR - YOUR MOST TRUSTED SOURCE OF HEALTHCARE INFORMATION IN ASIA Managing Editor
Elvira Manzano

Contributing Editors
Roshini Claire Anthony,
Pearl Toh, Stephen Padilla,
Jairia dela Cruz, Elaine Soliven,
Audrey Abella, Christina Lau,
AUGUST ISSUE Dr Margaret Shi, Natalia Reoutova

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Cover Story
4 Global race for COVID-19 vaccine gains momentum Production
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10 Galcanezumab may CONQUER treatment-resistant migraine Circulation Executive
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33 Secukinumab gets FDA nod for nr-axSpA

34 Tanezumab reduces pain intensity, improves daily function in patients

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 COVER STORY

ELVIRA MANZANO no history of COVID-19 from 5 UK hospitals. They received

either the ChAdOx1 nCoV-19 vaccine (n=543) or the menin-

T
he global race for a COVID-19 vaccine moves at an
unprecedented speed, buoyed by public pressure and
geopolitical crosscurrents that were punctuated by
deaths and infections around the world.
Seven vaccine candidates already entered human clinical
testing. Nearly 70 more are in the pipeline.
One of the frontrunners, ChAdOx1 nCoV-19, a vaccine
the University of Oxford, UK is developing with AstraZeneca,
showed promising preliminary results in the phase 1/2 clinical
trial.
ChAdOx1 nCoV-19, also known as AZD1222 vaccine,
was demonstrated to be safe, with only a few side effects,
and induced strong immune responses. It provoked a T-cell
response peaking at 14 days post-vaccination, and an an-
tibody response within 28 days. [Lancet 2020;doi:10.1016/
S0140-6736(20)31604-4]
gitis vaccine as a control (n=534).
ChAdOx1 nCoV-19 showed an acceptable safety and
tolerability profile, with headache and fatigue as the most
commonly reported reactions. There were no serious adverse
events related to ChAdOx1 nCoV-19.
The results were “encouraging and an important mile-
stone” in the search for a COVID-19 vaccine, said Dr Andrew
Pollard, lead investigator and professor of paediatric infection
and immunity, University of Oxford.
ChAdOx1 nCoV-19 is made from a weakened version of
adenovirus, a common cold virus that causes infections in
chimpanzees. The virus was genetically modified to code for
the SARS-CoV-2 virus spike protein.

The vaccine was tested vs a meningococcal conjugate

vaccine in 1,077 healthy adults (age 18–55 years) who had

4
DOCTOR | AUGUST ISSUE
 COVER STORY
Too early to tell
Dr Sarah Gilbert, professor of vaccinology, University of
Oxford and one of the investigators of the ChAdOx1 nCoV-
19 study, said the results, while encouraging, should not be
trumpeted too soon.
“It is too early to tell … the difficulty is that we don’t know
how strong the immune response needs to be,” she said. “We
can’t tell, just by looking at immune responses, whether this
vaccine is going to protect people or not.”
The only way to find out is to do phase III trials and “wait
for people to be infected to know if the vaccine can work,” she
added.
The team is now advancing to phase III trials, enrolling
30,000 patients. The speed at which the vaccine has made
through the testing process is quite impressive. What usually
takes years, has only taken months. If successful, Oxford’s
programme would leapfrog all other COVID-19 vaccines in
development.
5
DOCTOR | AUGUST ISSUE
“Yet, for any vaccine to be useful, we not only need larger
studies in [places where] COVID-19 is still at a high rate. We
need to be reasonably sure that the protection lasts for a con-
siderable time,” commented Professor Stephen Evans from the
London School of Hygiene and Tropical Medicine, London, UK,
who is unaffiliated with the study. “The trial should also include
people older than 55 years.”
mRNA vaccine candidates
Meanwhile, preliminary results from an ongoing German
phase I/II trial of an mRNA vaccine, BNT162b1, by Pfizer and
BioNTech, support the positive findings from the US trial.
BNT162b1, targeting the RBD* SARS-CoV-2, produced neu-
tralizing antibody responses in humans beyond the levels ob-
served in convalescent sera at low doses. [medRXiv; doi:https://
doi.org/10.1101/2020.06.30.20142570]
Other big players, US-based biotech company Moderna and
the US National Institute of Allergy and Infectious Diseases (NI-
AID), are also capitalizing on the newer messenger RNA tech-
nology to develop a COVID-19 vaccine.
Early data on the first 45 healthy adults (age 18–55 years)
enrolled in Seattle and Emory University sites in Atlanta, US, who
were vaccinated twice, at 28 days apart, with the mRNA-1273
COVID-19 vaccine (25 μg, 100 μg, or 250 μg dose), showed
that the vaccine induced anti–SARS-CoV-2 immune responses.
There were no trial-limiting safety concerns identified. [N Engl J
Med 2020;doi:10.1056/NEJMoa2022483]
In a related commentary, Dr Penny Heaton of the Bill & Me-
linda Gates Medical Research Institute in Cambridge, Massa-
chusetts, US, said the world has born witness to the compres-
sion of the typical 3–9 years of vaccine work into 6 months. [N
Engl J Med 2020;doi:10.1056/NEJMe2025111]
While the data look promising, she cautioned that much work
remains to be done, partly because the 250-μg dose was linked
to severe systemic side effects without increasing efficacy be-
yond the 100-μg dose. “It is prudent to evaluate doses of 100 μg
and lower to define the regimen that provides the most appro-
priate benefit–risk profile for this vaccine,” she said. A planned
phase 3 trial of the mRNA SARS-CoV-2 vaccine is imminent.
Experts do not anticipate full approval of a vaccine before
early 2021. But if it does arrive, do we have enough? Any vac-
cine will have to be distributed globally to stamp out the pandem-
ic of human disaster wherein rich countries restart their econo-
mies whereas people from poor countries are left to die.
Any future COVID-19 vaccine is precious and should be uni-
versally accessible. With reports from ELAINE SOLIVEN
*RBD: receptor-binding domain

Ad5-vectored
COVID-19 vaccine
gets a boost with new data
PEARL TOH
A
midst the global race for pro-
tection against COVID-19, the
Ad5*-vectored COVID-19 (Ad5-
nCoV) vaccine gets a boost with the
release of encouraging data from the
phase II trial, which provide further evi-
dence supporting the safety and immu-
nogenicity of this vaccine.
The novel Ad5-nCoV vaccine has
been shown to be safe, well-tolerated,
and induce rapid immune response
against SARS-CoV-2 in healthy adults
in the phase I trial. Specific T-cell re-
sponse against SARS-CoV-2 was seen
as early as 14 days after a single vac-
cine shot, while humoral immune re-
sponse peaked at 28 days.
“These results represent an import-
ant milestone. The trial demonstrates
that a single dose of the new Ad5-nCoV
vaccine produces virus-specific anti-
bodies and T cells in 14 days, making
it a potential candidate for further in-
vestigation,” said principal investigator
COVER STORY
Professor Chen Wei from the Beijing In-
stitute of Biotechnology, Beijing, China.
Unlike the phase I trial, the phase II
trial enrolled a more diverse population
(without the age cap) – thus expanding
the population to individuals 55 years
and older.
“Since elderly individuals face a
high risk of serious illness and death as-
sociated with COVID-19 infection, they
are an important target population for a
COVID-19 vaccine,” Chen said.
Nonetheless, the researchers were
cautiously optimistic on what the data
mean for a working vaccine against
SARS-CoV-2. “These results should
be interpreted cautiously. The challeng-
es in the development of a COVID-19
vaccine are unprecedented, and the
ability to trigger these immune respons-
es does not necessarily indicate that
6
DOCTOR | AUGUST ISSUE
the vaccine will protect humans from
COVID-19,” he cautioned.
Promising data from phase I
Ad5-nCoV vaccine, the first
COVID-19 vaccine to enter a phase I
trial, consists of an Ad5 vector carrying
the genetic code of the SARS-CoV-2
spike glycoprotein.
The phase I trial is a dose-esca-
lation study to determine the suitable
doses for further investigation among
three doses tested: high dose (5x1010
viral particles; n=36), middle dose
(1x10¹¹ viral particles; n=36), and low
dose (1.5x10¹¹ viral particles; n=36).
Participants were 108 healthy adult vol-
unteers aged 18–60 years (mean age
36.3 years, 51 percent male). [Lancet
2020;395:1845-1854]
Regardless of the dosage used, the
vaccine was able to trigger both arms
of the immune system: the humoral
immunity, which entails the produc-
tion of neutralising antibodies, and the
cell-mediated immunity involving T cell
response. Humoral immunity targets
circulating virus in the blood and lym-
phatic system, while T cells directly at-
tack infected cells.

Immune responses were seen in
most participants at the 14-day peak for
T-cell response (83.3 percent, 97.2 per-
cent, and 97.2 percent for low, medium,
and high dose, respectively) and the
28-day peak for humoral response (97
percent, 94 percent, and 100 percent,
respectively).
However, the high-dose vaccine
was also associated with a greater inci-
dence of severe adverse reactions such
as severe fever, fatigue, dyspnoea,
muscle pain, and joint pain. Hence, the
low- and middle-dose were chosen for
further evaluation in the phase II study.
Consistent findings in phase II
The double-blind phase II trial in-
volved 508 participants randomized
2:1:1 to receive a high-dose (1x10¹¹
viral particles) or a low-dose vaccine
(5x1010 viral particles) or placebo.
Also included among the participants
were 65 seniors (13 percent) aged ≥55
years. [Lancet 2020;doi:10.1016/S0140-
6736(20)31605-6]
Consistent with the phase I data,
both doses of vaccine induced an im-
mune response (antibody or T cell-me-
diated responses) in the majority of
participants at 28 days post-vaccination
(95 percent and 91 percent in the high-
and low-dose groups, respectively).
Specifically, neutralising antibody
response to live SARS-CoV-2 was de-
tected in 59 percent and 47 percent of
participants receiving the high and low
dose, respectively – with geometric
mean titres (GMTs) of 19.5 and 18.3, re-
spectively. Binding antibody response,
on the other hand, was shown in 96 per-
cent and 97 percent of participants and
peaked at 656.5 ELISA units and 571
ELISA units, respectively.
COVER STORY
For T cell-mediated immunity, 90
percent and 88 percent of participants in
the high- and low-dose groups showed
positive responses as measured by IF-
Nγ-ELISpot — with a median of 11 and
10 spot-forming cells per 1×1010 periph-
eral blood mononuclear cells, respec-
tively, at day 28.
“A single injection of the Ad5-vec-
tored COVID-19 vaccine … induced
comparable specific immune respons-
es to the spike glycoprotein at day 28,
with no significant differences noted
between the two [doses],” Chen and
co-authors reported.
Common adverse reactions
post-vaccination included fever, fatigue,
and pain at injection site, but were
mostly mild to moderate.
Insights on older people
“Compared with the younger pop-
ulation, we found older people have a
significantly lower immune response,
but higher tolerability, to the [vaccine],”
said Chen.
As the researchers observed, older
age – in addition to pre-existing immu-
nity to the Ad5 vector (a vector also car-
ried by the common cold virus) – could
stifle the immune responses to vacci-
nation. The reverse was observed with
regard to tolerability, in which incidence
of fever was associated with younger
age and low pre-existing immunity to
the Ad5 vector.
These findings are in line with the
expectation that older people are more
likely to have prior exposure to Ad5, the
researchers explained.
“It is possible that an additional dose
may be needed to induce a stronger im-
mune response in the elderly population,
and further research [in phase IIb trial]
is underway to evaluate this,” said Chen.
7
DOCTOR | AUGUST ISSUE
The road ahead
“[The results] augur well for phase III
trials … [and] the safety signals … are
reassuring,” commented Drs Naor Bar-
Zeev and William J Moss from Johns Hop-
kins Bloomberg School of Public Health,
Baltimore, Maryland, US, in a linked
commentary. [Lancet 2020;doi:10.1016/
S0140-6736(20)31611-1]
“But when things are urgent, we
must proceed cautiously. The success
of COVID-19 vaccines hinges on com-
munity trust in vaccine sciences,” they
wrote.
Whether the specific immune re-
sponse elicited confers an effective
protection against infection is not yet
known based on the early-phase re-
sults, noted Chen and co-authors.
Also, questions remained regarding
the durability of immune response, the
type of immune response required to
drive protection, or whether immunoge-
nicity differs by patient characteristics
such as age, sex, or ethnicity.
“Our results suggest a single-dose
immunization at 5×1010 viral particles
is an appropriate regimen for healthy
adults,” and this, according to the re-
searchers, will be further investigated in
the phase III trial.
*Ad5: non-replicating adenovirus type-5

Singapore
joins the race
ROSHINI CLAIRE ANTHONY
C
ollaborations with international
vaccine groups and companies
have helped Singapore land a
spot in the global race for a COVID-19
vaccine.
One such vaccine will be the result
of combining the STARR Technology™
from US-based Arcturus Therapeutics
and a platform developed at Duke-NUS
Medical School (Duke-NUS). The STARR
Technology™ platform is a combination
of self-replicating RNA and a nanoparti-
cle non-viral delivery system known as
LUNAR®. This combination results in
protein production in the body. STARR
Technology™ also has superior immune
response and sustained protein expres-
sion which allows for a vaccine response
at a much lower dose than that achieved
with traditional mRNA vaccines. [https://
www.duke-nus.edu.sg/about/media/
media-releases/media-releases/arc-
turus-dukenus-covid-19-vaccine-using-
starr-technology, accessed 22 July 2020]
“We have observed STARR Technol-
ogy™ in preclinical models to be effec-
tive at extraordinarily low doses – greater
than 30-fold more efficient than tradition-
al mRNA. If successful, Arcturus could
develop a vaccine capable of vaccinat-
ing millions of people for a fraction of the
cost of traditional mRNA vaccines,” said
Joseph Payne, President & CEO of Arc-
turus Therapeutics.
COVER STORY
“There is a tremendous urgency to
develop an effective prevention for the
current coronavirus crisis. The Duke-
NUS and Arcturus partnership could ex-
pedite a solution to this urgent need as
we utilize STARR Technology™ to bring
a vaccine candidate for clinical testing
in the shortest time possible,” said Pro-
fessor Ooi Eng Eong, Deputy Director of
the Emerging Infectious Diseases pro-
gramme at Duke-NUS.
“Duke-NUS has been on the front
lines in the fight against COVID-19,
developing the first serological tests
for COVID-19 and was among the first
groups to isolate and culture the virus.
The partnership with Arcturus Ther-
apeutics combines complementary
strengths as we work together to fight
this global outbreak,” added Professor
Thomas M. Coffman, Dean of Duke-
NUS Medical School.
On 21 July 2020, the Singapore
Health Sciences Authority (HSA) cleared
the way to initiate human trials of this
vaccine candidate (LUNAR-COV19).
The safety, tolerability, and extent and
duration of humoral and cellular im-
mune response of several different
doses of the LUNAR-COV19 vaccine
8
DOCTOR | AUGUST ISSUE
will be assessed in up to 108 healthy
adults (including older adults). [https://
www.duke-nus.edu.sg/about/media/
media-releases/media-releases/arc-
turus-therapeutics-duke-nus-clinical-tri-
als-for-covid-19-vaccine-candidate-ap-
proved-to-proceed, accessed 23 July
2020]
“Preclinical studies on LU-
NAR-COV19 have shown very prom-
ising findings, including the possibility
that a single dose of this vaccine may
be sufficient to trigger robust and dura-
ble immune responses against SARS-
CoV-2. We are very eager to start the
first-in-human clinical trial here in Sin-
gapore and advance LUNAR-COV19
on its journey to becoming a potential
commercial vaccine,” stated Ooi.
“Based on our preclinical data, we
believe that our self-replicating mR-
NA-based approach may produce high
rates of seroconversion and robust
T-cell induction with a potential single
administration, at very low doses. The
LUNAR-COV19 profile is meaningful-
ly differentiated and may facilitate the
mass vaccine campaigns necessary to
target hundreds of millions of individuals
globally,” added Payne.
 COVER STORY

backbone from the influenza virus. Esco

Another collaboration to develop
a COVID-19 vaccine is between Esco
Aster, a local contract development and
manufacturing organization, and US-
based biotechnology company Vivaldi
Biosciences. [https://www.edb.gov.sg/
en/news-and-events/insights/innova-
tion/singapore-researchers-in-global-
search-for-covid-19-vaccines.html, ac-
cessed 22 July 2020]
This vaccine will combine antigens
from the SARS-CoV-2 virus and a protein
Aster is in the process of identifying the
correct antigen sequence and increas-
ing production of the protein backbone,
while Vivaldi Biosciences is working on
the process to connect the two com-
ponents. [https://www.straitstimes.com/
singapore/health/team-developing-vac-
cine-that-can-tackle-virus-mutations-as-
well, accessed 22 July 2020]
In the case of SARS-CoV-2 virus mu-
tation, substituting the antigens of the
current virus with that of the mutated
strain, will enable a new vaccine to be
produced within weeks.
A site for vaccine trials
Another way Singapore is playing a
part in the global vaccine search is by
volunteering to be a vaccine trial site.
This is evident in the partnership between
Duke-NUS and the Norway-based Coa-
lition for Epidemic Preparedness Innova-
tions (CEPI).
“If any vaccine is ready for human
trials, the doctor-scientist team across
SingHealth and Duke-NUS is experi-
enced in similar type of trials … we’re
trying to convince CEPI to select Sin-
gapore as one of the trial sites,” noted
Professor Wang Linfa, Director of the
Duke-NUS Emerging Infectious Diseas-
es Programme. [https://news.nus.edu.
sg/research/nus-scientists-work-covid-
19-vaccine-trial-and-rapid-test-kits, ac-
cessed 22 July 2020]
In this trial, healthy volunteers will be
vaccinated, and the potential immune
protection conferred by the vaccine and
vaccine side effects will be monitored.
Singapore has also registered as a
trial site for the Solidarity vaccine trial
which is spearheaded by the World
Health Organization. [https://www.moh.
gov.sg/news-highlights/details/collabo-
ration-with-global-scientific-communi-
ty-for-covid-19-vaccine/, accessed 23
July 2020]

9
DOCTOR | AUGUST ISSUE

Galcanezumab may CONQUER
treatment-resistant migraine
AUDREY ABELLA
T
he monoclonal antibody galca-
nezumab may offer benefits for
treatment-resistant* episodic or
chronic migraine, according to post hoc
results of the CONQUER trial presented
at AHS 2020.
“This population is of particular interest
due to evidence of decreased quality of
life (QoL) and increased economic burden
among people with migraine that is inad-
equately managed,” said the researchers.
The double-blind phase of this phase
III study randomized 462 adults (mean age
46 years, 86 percent female) 1:1 to receive
monthly galcanezumab 120 mg (240 mg
loading dose) or placebo for 3 months. Of
these, 197 had ≥1 pain disorder.
Early onset
Weekly migraine days (MDs) dropped
with galcanezumab vs placebo as early
as week 1 (least-squares mean [LSM]
change from baseline, –1.10 vs –0.19;
p≤0.001), reflecting the drug’s early
onset of efficacy. The effect remained
significant until week 4 (p<0.05). [AHS
2020, ePoster 831274]
Compared with placebo, galcane-
zumab use also led to significant reduc-
AHS 2020
tions in MDs at months 1, 2, and 3 (LSM
change from baseline, –4.02 vs –0.70,
–3.97 vs –1.06, and –4.42 vs –1.30, re-
spectively; p<0.0001 for all).
Fewer galcanezumab vs place-
bo recipients had a migraine on day 1
(p<0.05) of treatment and on each day
at week 1 (p<0.001), and more galcane-
zumab recipients achieved ≥50-percent
response at weeks 1–4 and months 1–3
(p≤0.0001 for all).
“Many patients who use current pre-
ventive therapies are unable to achieve
early onset of efficacy or experience dif-
ficulty tolerating their medicine. [Hence,]
more than half … discontinue its use within
6 months of treatment,” said the research-
ers. [Headache 2011;51:1336-1345; Pain
Pract 2012;12:541-549] The findings pro-
vide insight on the potential of galcane-
zumab to address this issue, they noted.
Prior treatment failure
Monthly MDs also dropped with gal-
canezumab vs placebo among those
who discontinued topiramate, amitrip-
tyline, valproic acid, and onabotulinum-
toxinA (p<0.0001), as well as propranolol
(p<0.01), due to lack of efficacy. A simi-
lar effect in favour of galcanezumab was
seen among those who stopped topi-
ramate and amitriptyline due to safety/
10
DOCTOR | AUGUST ISSUE
June 13-16
tolerability issues (p<0.01 for both). [AHS
2020, ePoster 831301]
These imply that those who had
failed other commonly prescribed mi-
graine-preventive drugs may benefit from
galcanezumab, noted the researchers.
Concomitant pain
disorders
Galcanezumab also trumped pla-
cebo in this cohort of patients with
comorbid pain issues, as seen by the
overall reduction in monthly MDs (LSM
difference vs placebo, –2.2) and the
percentages of participants achieving
50-percent (31 percent vs 14 percent)
and 100-percent response rates (3 per-
cent vs 0 percent; p≤0.001 for all). [AHS
2020, poster session]
“Patients with migraine frequently re-
port comorbid pain conditions, [the most
common being] back pain, osteoarthritis,
and neck pain … [These results suggest
that] galcanezumab [was] superior …
to placebo for the [prevention] of treat-
ment-resistant migraine even in patients
with ≥1 concomitant pain disorder,” they
said.
*Documented failure of 2–4 standard migraine preven-
tive medication categories in the past 10 years due to
inadequate efficacy or safety
**MSQ-RFR: Migraine-Specific Quality of Life – Role
Function-Restrictive

American Headache Society (AHS) 2020 Virtual Annual Scientific Meeting • June 13-16
Migraine in midlife
tied to increased
risk of dementia
PEARL TOH
H
aving migraine during midlife
appears to be associated with
a higher risk of developing de-
mentia in later life, according to a large
population-based longitudinal Danish
study presented at AHS 2020, indicat-
ing that migraine may be a risk factor
for dementia.
“The study highlights
the importance
of monitoring severe
migraine to prevent
dementia”
During a median follow-up of 6.9
years on 62,578 participants in the na-
tional registry, 207 individuals with hos-
pital-based migraine diagnosis during
midlife (age 31–58 years) eventually had
dementia. [AHS 2020, 1st Jul session]
Compared with controls without mi-
graine, cases diagnosed with migraine
in midlife were 50 percent more likely to
have dementia after age 60 (hazard ratio
[HR], 1.50, 95 percent confidence inter-
val [CI], 1.28–1.76).
In particular, individuals who had mi-
graine with aura had more than twofold
higher rates of dementia in later life than
CONFERENCE COVERAGE
those without a history of migraine (HR,
2.11, 95 percent CI, 1.48–3.00).
Dementia was also more common
among individuals who had a history of
migraine without aura compared with
those who were never diagnosed with
migraine during midlife by 19 percent
(HR, 1.19, 95 CI, 0.84–1.70), although
the difference between groups was not
statistically significant.
Also, frequent hospital contacts
among patients with migraine were pre-
dictive of a higher risk of dementia in
later life.
“These results support the hypoth-
esis that migraine is a midlife risk factor
for dementia in later life … especially
for patients with migraine with aura,”
concluded Dr Sabrina Islamoska from
the University of Copenhagen in Co-
penhgen, Denmark, who presented the
study during the virtual session.
In the population-based cohort
study, Islamoska and colleagues ex-
tracted data of individuals born be-
tween 1935–1956 and who were aged
60 years before 2017 from the Danish
national registry. Individuals diagnosed
with migraine in the hospital (cases) be-
fore turning 59 years (n=18,135) were
matched in a 1:5 ratio based on sex
and birthdate with individuals without
migraine history (control; n=1,378,346).
A total of 62,578 eligible participants
11
DOCTOR | AUGUST ISSUE
were included in the analyses.
“[Our data] emphasize the need for
studies on migraine-dementia patho-
physiology, particularly in migraine with
aura and … studies on potential demen-
tia prevention by proper prophylactic
treatment of migraine,” said Islamoska.
“The study also highlights the impor-
tance of monitoring severe migraine to
prevent dementia.”
There are several potential pathways
which could mediate the association
between migraine and dementia risk,
explained Islamoska on the plausible
underlying mechanisms. Risk factors
associated with migraine — such as al-
lostatic load, metabolic, cerebrovascu-
lar, or cardiovascular diseases, and be-
havioural factors — can lead to changes
in brain networks, lesions, brain atrophy,
and neurodegeneration. All these, she
said, can increase the risk of dementia
in the long run.
As the study only assessed migraine
cases diagnosed in the hospital while
most migraine cases in Denmark are
treated in the primary care setting, the
number of migraine cases might have
been underestimated, which Islamoska
noted, presents a limitation to the study.
She also said her team was currently
studying whether there is an association
between migraine medications and the
risk of dementia in later life.

American Headache Society (AHS) 2020 Virtual Annual Scientific Meeting • June 13-16
Low incidence of CV events with lasmiditan
for migraine
ROSHINI CLAIRE ANTHONY
C
ardiovascular (CV) event inci-
dence was low among patients
taking lasmiditan for migraine,
according to an interim analysis of the
phase III GLADIATOR* study presented
at AHS 2020.
The open-label GLADIATOR trial
included individuals with migraine who
had received lasmiditan 50, 100, or 200
mg, or placebo, in the double-blind, sin-
gle-attack, phase III SPARTAN or SA-
MURAI** trials. They were re-random-
ized 1:1 to receive lasmiditan 100 or
200 mg, either as a single dose (within
4 hours of pain onset) or if required, two
doses (2–24 hour interval; n=1,978).
Eighty-one percent of SPARTAN and
SAMURAI participants had CV risk fac-
tors. A total of 19,058 migraine attacks
were treated over a median 288 days in
GLADIATOR.
Overall, CV adverse event (AE) rate
was low during all three time periods
assessed (treatment-emergent [TE]:
<48 hours post-dose; intermediate: 48
hours–1 week post-dose; remote: >1
week post-dose). Eight palpitation in-
cidents occurred during the TE period
(80.4 per 1,000 patient-years) and one
in the remote period. There were two
incidents each of increased heart rate
in the TE and remote periods, and two
incidents each of decreased heart rate
and dyspnoea, both in the TE period.
There were three, two, and six inci-
dents of increased blood pressure in the
TE, intermediate, and remote periods,
respectively, and three, nine, and 12 in-
cidents of hypertension (34.6 and 15.4
per 1,000 patient-years in the latter two).
“Lasmiditan, a selective serotonin
(5-HT) 1F receptor agonist, lacks the
vasoconstrictive activity of other acute
CONFERENCE COVERAGE
migraine treatments,” noted the re-
searchers. In this analysis, vasocon-
striction-related CV events (eg, angina)
were rare, with none occurring in the TE
period.
Dose-dependent
outcomes
A separate analysis examined the ef-
fect of increasing or decreasing lasmid-
itan dose in GLADIATOR from SPAR-
TAN/SAMURAI.
Two hours after the first lasmiditan
dose in GLADIATOR, taken after the first
migraine attack, more patients who re-
ceived a higher dose than in SPARTAN/
SAMURAI were pain-free. In contrast, a
decrease in dose in GLADIATOR com-
pared with SPARTAN/SAMURAI led to a
lower percentage of patients who were
pain-free. For example, 30 percent of
patients who received lasmiditan 100
mg in SPARTAN/SAMURAI were pain-
free after 2 hours; this increased to 36
percent among those who received 200
mg in GLADIATOR.
TEAE incidence – occurring within
48 hours of the first dose for the first
migraine attack – tended to increase
with an increased dose. For example,
12
DOCTOR | AUGUST ISSUE
TEAE incidence was 15 percent in pa-
tients who received lasmiditan 50 mg
in SPARTAN/SAMURAI and 22 percent
upon increase to 100 mg in GLADIA-
TOR and increased from 17 to 22 per-
cent when dose increased from 50 to
200 mg. Likewise, a decrease in dose in
GLADIATOR led to a decrease in TEAEs
(from 29 to 18 percent when dose was
reduced from 200 to 100 mg). TEAE
incidence did not differ when the dose
was increased from 100 to 200 mg.
“[T]he study was designed to evalu-
ate the safety and efficacy of lasmiditan
for the intermittent, acute treatment of
migraine attacks for up to 1 year [and]
to help provide insights for clinicians in
choosing the most appropriate dose for
patients,” said the researchers.
“Increasing the dose may result in
improvement in efficacy (pain freedom
at 2 hours) and an increase in AE report-
ing,” they noted.
*GLADIATOR: An open-label, long-term, safety study
of lasmiditan for the acute treatment of migraine
**SPARTAN: Three doses of lasmiditan (50 mg, 100
mg and 200 mg) compared to placebo in the acute
treatment of migraine; SAMURAI: Lasmiditan com-
pared to placebo in the acute treatment of migraine

American Headache Society (AHS) 2020 Virtual Annual Scientific Meeting • June 13-16
Fremanezumab: Sustained benefits across the
board for refractory migraine
PEARL TOH
A
fter treatment with fremanezum-
ab, a difficult-to-treat patient pop-
ulation with treatment-resistant
episodic or chronic migraine saw sus-
tained benefits across a broad range of
measures, according to multiple analy-
ses of the FOCUS study released at AHS
2020.
Improvements seen included reduc-
tions in migraine frequency, symptoms,
and headache-related disability, as well
as better quality of life during the open-la-
bel treatment phase.
The phase IIIb FOCUS study com-
prised two phases: a double-blind phase
and an open-label extension phase, both
lasting for 12 weeks. During the dou-
ble-blind phase, patients with episodic
or chronic migraine who failed two to
four classes of prior migraine preven-
tive therapies were randomized 1:1:1 to
receive subcutaneous fremanezumab
675 mg quarterly, 225 mg monthly*, or
matching placebo monthly. This was fol-
lowed by the open-label phase whereby
all patients received fremanezumab 225
mg monthly for 3 months. A total of 772
patients who completed the open-label
extension phase were included in the
analyses.
Migraine frequency,
symptoms
At the end of the open-label phase,
all patients continued to have fewer
migraine episodes from baseline, with
slightly more patients who previous-
ly received fremanezumab in the dou-
ble-blind phase achieving ≥50 percent
reduction in monthly average migraine
days compared with those originally on
placebo (45 percent and 46 percent vs
38 percent for fremanezumab quarterly
and monthly vs placebo, respectively).
[AHS 2020, 1st Jul session]
CONFERENCE COVERAGE
The proportions of patients achieving
≥75 percent reduction in migraine days
were similar among the three groups (15
percent and 20 percent vs 16 percent).
“[The responses were] clinically
meaningful … regardless of whether
patients had received fremanezumab or
placebo in the double-blind period,” ob-
served the researchers.
In terms of migraine-related symp-
toms, more patients who received fre-
manezumab in the double-blind period
saw greater reductions in nausea or
vomiting during the open-label phase
compared with those initially assigned to
placebo (change from baseline in month-
ly average days, -3.1 and -3.0 vs -2.3,
respectively).
Other related symptoms such as
photophobia and phonophobia were
also less frequent with initial assignment
to fremanezumab than placebo in the
double-blind period (change from base-
line in monthly average days, -3.4 and
-4.0 vs -3.2, respectively).
For headache-related disability, sub-
stantial improvements were seen in all
patients during the open-label phase
regardless of their initial treatment in the
13
DOCTOR | AUGUST ISSUE
double-blind period. Score reductions in
Migraine Disability Assessment (MIDAS)
were generally comparable across groups
(-29.9 and -33.9 vs -27.3, respectively).
When assessed using the Headache
Impact Test (HIT-6), improvements were
slightly greater in patients initially receiv-
ing fremanezumab vs placebo (mean,
-8.4 and -8.3 vs -7.6, respectively).
Quality of life measures
There were also sustained improve-
ments in quality of life with fremanezum-
ab throughout the open-label period, as
measured on the MSQoL**.
Health status, assessed using the
EQ-5D-5L***, also improved at the end
of the open-label phase, regardless of
the initial treatment assigned during the
double-blind period (mean change from
baseline, 8.0 and 7.3 vs 6.6, respectively).
“Open-label administration of fre-
manezumab maintained improvements
in health-related quality of life, as mea-
sured by both disease-specific and gen-
eral quality of life questionnaires,” the
researchers pointed out.
*loading dose of 675 mg in the first month for chronic
migraine
**MSQoL: Migraine-specific quality of life
***EQ-5D-5L: EuroQoL-5 Dimension-5 Level

American Headache Society (AHS) 2020 Virtual Annual Scientific Meeting • June 13-16
OnabotulinumtoxinA effectively controls
chronic migraine
AUDREY ABELLA
L
ong-term use of onabotulinumtox-
inA led to reductions in monthly
headache days (MHDs) in adults
with chronic migraine (CM), according
to post hoc analyses of the COMPEL*
study presented at AHS 2020.
“Frequent migraine attacks limit
work and leisure activities, affect so-
cioeconomic status, and impair quality
of life,” said the researchers. [Cepha-
lalgia 2015;35:563-578; Cephalalgia
2011;31:301-315] Studies have attest-
ed the clinical efficacy and tolerability
of onabotulinumtoxinA in this setting.
[Headache 2010;50:921-936; J Head-
ache Pain 2017;18:75]
COMPEL evaluated 716 adults with
CM (mean age 43 years, 85 percent
female) receiving onabotulinumtoxinA
155 U every 12 weeks for 108 weeks.
Of these, 52 percent completed the
trial. Mean baseline MHDs and monthly
moderate/severe HDs were 22 and 18
days, respectively.
Responder rates
At week(W) 108, 62 percent re-
ported that their mean MHDs were re-
duced by half, which was higher than
the W24 percentage of 40 percent. Im-
provements were also observed among
those reporting ≥25, ≥75, and 100-per-
cent reduction in mean MHDs. “[These
reflect the] consistent and progressive
reductions in headache day responder
rates [with onabotulinumtoxinA],” said
the researchers. [AHS 2020, poster
session]
This trend was also observed
among those who completed all treat-
ment cycles. The percentage of partic-
ipants whose MHDs were reduced by
half increased from 47 percent at W24
to 62 percent at W108.
CONFERENCE COVERAGE
The fraction of W24 responders sus-
taining ≥25, ≥50, and ≥75-percent MHD
reduction through W108 were 85, 76,
and 61 percent, respectively. These data
suggest that most achieved a sustained
response throughout the study duration,
noted the researchers.
Less than 5 percent of participants
ceased treatment due to treatment-re-
lated adverse events, the most common
being neck pain, followed by eyelid pto-
sis and musculoskeletal stiffness.
Treatment-controlled CM
In another subanalysis, those who
achieved treatment-controlled** CM
(tcCM) following onabotulinumtoxinA use
increased over time (from 56 percent
at W24 to 74 percent by W108). [AHS
2020, poster session]
At W108, mean MHD was 5.8, which
according to the researchers, was far
below the <15 MHD criteria. The 7.8
MHD at W24 was already a far cry from
the tcCM definition criteria, reflecting the
efficacy of the study drug early on, they
noted.
Moderate/severe MHDs substantially
dropped (mean change, –12.1; p<0.001),
while a majority met the ≥50-percent re-
sponder rate at W108 (83 percent).
14
DOCTOR | AUGUST ISSUE
These data were mirrored among
those with sustained*** tcCM (50 per-
cent of participants with MHD data
across all timepoints) by W108 (mean
MHDs, 4.5; mean change in moderate/
severe MHDs, –11.9; p<0.001; and per-
centage of participants with ≥50-per-
cent reduction in MHDs, 89 percent).
“[These data show that] a high pro-
portion of individuals achieved tcCM
and/or sustained tcCM throughout the
2-year study. A reduction in MHDs to
<15 is clinically meaningful, as support-
ed by the high and increasing ≥50-per-
cent responder rates and the large re-
ductions in moderate/severe MHDs in
these individuals,” said the researchers.
Although nearly half discontinued
treatment (which may have influenced
the upsurge in responder rates), the
collective results support the long-term
benefits of onabotulinumtoxinA in this
setting, they said. Further exploration
is warranted to ascertain the effects of
onabotulinumtoxinA in CM.
*COMPEL: Chronic migraine OnabotulinuMtoxinA
Prolonged Efficacy open-Label study
**<15 MHDs at a given timepoint (ie, W21–24 or 57–60
or 105–108)
***<15 MHDs at all timepoints (ie, W21–24 and 57–60
and 105–108)

American Headache Society (AHS) 2020 Virtual Annual Scientific Meeting • June 13-16
LIBERTY: Erenumab shows
sustained efficacy in refractory
episodic migraine over 2 years
PEARL TOH
T
he CGRP* receptor blocker ere-
numab shows sustained efficacy in
reducing migraine frequency over
2 years in a difficult-to-treat patient pop-
ulation with episodic migraine who had
failed 2–4 prior preventive treatments,
an interim analysis of the LIBERTY**
open-label extension study shows.
The phase III LIBERTY trial com-
prised two phases: a double-blind
phase, whereby patients were random-
ized 1:1 to once-monthly subcutaneous
erenumab 140 mg or placebo for 12
weeks, followed by an open-label phase
in which all patients who completed the
double-blind phase received erenumab
for 3 years. Participants were 246 pa-
tients with episodic migraine (4–14 mi-
graine days/month) who had previously
failed 2–4 preventive treatments. [AHS
2020, 1st Jul session]
Primary analysis for the double-blind
phase has been reported previously,
showing that erenumab was effective in
this patient population compared with
placebo. The current 2-year interim re-
sults represent an analysis of erenum-
ab efficacy at week 112 of the 3-year
open-label treatment phase.
“The efficacy of erenumab was
sustained throughout 2 years of treat-
ment with erenumab 140 mg in a diffi-
cult-to-treat patient population,” the re-
searchers reported.
Changes in mean monthly migraine
days (MMD) from baseline were sustained
through 2 years during the open-label
phase: -3.7 days at 1 year and -4.2 days
at 2 years, compared with a baseline of
9.2 days in the double-blind phase.
CONFERENCE COVERAGE
Specifically, the proportion of patients
who achieved ≥50 percent reductions
in MMD with erenumab remained sta-
ble (57.2 percent) through the 2nd year
of open-label treatment, similar to what
was observed during the first year.
Similarly, the ≥75 percent and ≥100
percent responder rates were also sus-
tained over 2 years, at 30.6 percent and
16.2 percent, respectively, across all
treatment groups.
The improvements were seen in the
overall patient population during the
open-label phase, regardless of whether
the patients were previously assigned to
erenumab or placebo in the double-blind
phase.
In addition, improvements in func-
tional outcomes from baseline were con-
sistent at week 112 during open-label
treatment, as indicated by the Headache
Impact Test (HIT-6; mean changes, -9.5)
total score and Migraine Physical Func-
tion Impact Diary (MPFID; mean changes,
-4.5 for physical impairment and -5.4 for
everyday activities domains, respectively).
“Erenumab was well tolerated and no
new safety signals were detected over
the extended treatment period,” the re-
searchers noted.
15
DOCTOR | AUGUST ISSUE
During the open-label phase, approx-
imately 86.3 percent of the overall patient
population experienced adverse events
(AEs). Specifically, 82.2 percent occurred
in patients continuing erenumab (ie, ini-
tially assigned to erenumab during the
double-blind phase) and 90.2 percent
in those initiating erenumab during the-
open-label treatment (ie, previously on
placebo).
After adjusting for exposure, the in-
cidence rate of AEs was 198.0 per 100
patient-years in the overall population.
The exposure-adjusted rate for serious
AEs was 6.3 per 100 patient-years. AEs
leading to discontinuation occurred in
nine patients (3.8 percent). There were
no deaths reported.
The most common AEs during the
open-label treatment were nasophar-
yngitis (33.9 per 100 patient-years),
followed by influenza (10.3 per 100 pa-
tient-years) and back pain (6.6 per 100
patient-years).
“The 3-year open-label phase of the
LIBERTY study is ongoing,” stated the
researchers.
*CGRP: Calcitonin gene-related peptide
**LIBERTY: A study evaluating the effectiveness of
AMG 334 injection in preventing migraines in adults
having failed other therapies
 ADA 2020
June 12-16
Does spacing pregnancies help women
with gestational diabetes?
ELVIRA MANZANO
W
omen with a history of ges-
tational diabetes were 50
percent more likely to have
a short interval between pregnancies
compared to women without the condi-
tion, suggests a new study.
“The proportion of short interpreg-
nancy intervals – 18 months or short-
er spacing between a live birth and
the beginning of the next pregnancy
– was higher in women with a history
of gestational diabetes vs those with-
out, and this reached statistical signif-
icance [56.4 percent vs 43.6 percent;
p<0.001],” reported lead researcher Dr
Ronald Anguzu from the Medical Col-
lege of Wisconsin, Milwaukee, Wiscon-
sin, US at ADA 2020. [ADA 2020, ab-
stract 192-OR]
Anguzu said intervals of 18 months
or less between pregnancies are linked
to adverse outcomes which included
spontaneous abortion, preterm birth,
and low birth weight.
Intervening to prolong these inter-
vals might provide an opportunity for
pre-conception counselling, in addition
to screening and management of type 2
diabetes (T2D), he proposed.
Problem with undiagnosed
diabetes
Anguzu said promoting education
and strategies for birth spacing in this
high-risk group is crucial given that con-
ception in the setting of undiagnosed
and uncontrolled diabetes carries signifi-
cant health risks to both the mother and
her baby.
Although gestational diabetes is usu-
ally temporary and goes away after the
baby is born, Dr Mary Loeken, chair of
the ADA Scientific Sessions Planning
Subcommittee on Pregnancy and Re-
productive Health, and associate profes-
sor at Harvard Medical School, Boston,
Massachusetts, US, said most women
who had gestational diabetes are at high
risk of progressing to T2D.
“Entering pregnancy with T2D poses
increased risks for the mother and the
foetus, including the possibility of con-
genital malformations,” she warned.
“Hence, counselling these women to
space their pregnancies may improve
their health and that of their foetus in
subsequent pregnancies.”
Maternal age, BMI:
Is there a link?
Anguzu looked at data from 28,000
women aged 18–44 years from the US
16
DOCTOR | JULY ISSUE
National Survey on Family Growth Data
Sets from 2011–2017 and found a histo-
ry of gestational diabetes in 9.9 percent
of the participants.
These women had a higher mean
maternal age vs those without a histo-
ry of gestational diabetes (36.3 vs 34.3
years; p<0.001). Mean BMI in those with
gestational diabetes was also greater vs
those without a history ((31.3 kg/m2 vs
27.9 kg/m2).
The odds ratio of having short inter-
pregnancy intervals if the women had
a history of gestational diabetes was
1.43 (95 percent confidence interval [CI],
1.22–1.66) vs those without gestational
diabetes.
The association remained strong
despite adjusting for confounding fac-
tors such as maternal age, BMI, race/
ethnicity, marital status, education, family
income, contraception use, and history
of sexually transmitted infections (ad-
justed odds ratio, 1.49, 95 percent CI,
1.26–1.76).
“The implication is that perinatal
complications may be reduced by low-
ering the number of short interpregnancy
intervals in this population through effec-
tive contraception,” concluded Anguzu.

American Diabetes Association (ADA 2020) Virtual 80th Scientific Sessions • June 12-16
Icosapent ethyl may REDUCE CV risk
in diabetes
ROSHINI CLAIRE ANTHONY
I
cosapent ethyl may reduce the risk of
cardiovascular (CV) events in patients
with diabetes mellitus (DM) taking statins,
according to findings of the REDUCE-IT
DIABETES presented at ADA 2020.
“Statin-treated patients with DM are
at high CV risk,” said Professor Deepak
Bhatt from Brigham and Women’s Hos-
pital and Harvard Medical School, Bos-
ton, Massachusetts, US.
“[Results of this analysis showed
that] icosapent ethyl at 4 g/day provides
robust CV benefits in statin-treated pa-
tients with DM, with large relative and
absolute risk reductions in both first and
total CV events,” he said.
In the REDUCE-IT* trial, 8,179 sta-
tin-treated patients aged ≥45 years with
either established CV disease (CVD) or
DM plus other risk factors were random-
ized to receive icosapent ethyl (4 g/day)
or placebo in addition to their statins.
Previous results showed that icos-
apent ethyl reduced the composite of CV
death, nonfatal myocardial infarction (MI),
nonfatal stroke, coronary revasculariza-
tion, or unstable angina compared with
placebo (primary endpoint; hazard ratio
[HR], 0.75) as well as the composite of
CV death, nonfatal MI, or nonfatal stroke
(secondary endpoint; HR, 0.74; p<0.001
for both). [N Engl J Med 2019;380:11-22]
Of the total population, 58.5 per-
cent had DM (n=4,787; median age 64
years, 36.1 percent female, 87.6 percent
Caucasian, median HbA1c 7.0 percent).
About 50 percent had established CVD,
and 63.2 percent were on moderate in-
tensity statins. Ninety-one percent of pa-
tients were on antidiabetes medications,
with 49.5 percent on ≥2 medications.
[ADA 2020, abstract 4-LB]
CONFERENCE COVERAGE
Consistent with the overall results, time
to first and recurrent incidence of the pri-
mary composite endpoint was significant-
ly reduced in icosapent ethyl vs placebo
recipients (38.9 percent vs 51.6 percent;
relative risk [RR], 0.77, 95 percent confi-
dence interval [CI], 0.66–0.88; p=0.0003).
First and recurrent incidence of the
secondary endpoint was also reduced
with icosapent ethyl vs placebo (21.2 per-
cent vs 30.1 percent; RR, 0.71, 95 per-
cent CI, 0.60–0.84; p=0.00005).
There was a significant 24 percent
reduction in first and subsequent primary
endpoint events, accounting for 234 fewer
CV events, with icosapent ethyl vs place-
bo (RR, 0.76, 95 percent CI, 0.65–0.88;
p=0.0003).
The reduction with icosapent ethyl
vs placebo was most evident in patients
with established CVD and diabetes
(58.0 percent vs 82.0 percent; RR, 0.70;
p<0.00009) compared with those with di-
abetes and other risk factors but without
established CVD (22.1 percent vs 25.4
percent; RR, 0.88; p=0.35) and those with
established CVD but without diabetes
(31.5 percent vs 53.3 percent; RR, 0.59;
p=0.000000007).
“Patients with and without DM showed
substantial benefits, but patients with DM
17
DOCTOR | AUGUST ISSUE
had 1.5-fold greater rates of the primary
endpoint in the placebo group, and a 7
percent absolute risk reduction in first and
a 12.7 percent reduction in total events
(both p<0.001) with icosapent ethyl,” said
the authors.
Safety profiles were consistent with
the main study. Atrial fibrillation/flutter oc-
curred more frequently in icosapent ethyl
than placebo recipients (3.5 percent vs
2.2. percent; p=0.01), as did bleeding
(13.1 percent vs 10.9 percent; p=0.02),
though serious bleeding did not signifi-
cantly differ between groups (3.2 percent
vs 2.5 percent; p=0.19).
“The reductions were consistent and
robust across the prespecified hierarchy of
endpoints, among patients with diabetes
with or without CVD, as well as for those
with established CVD and no diabetes at
baseline,” noted Bhatt and colleagues.
However, the study was not powered for
subgroup analysis, nor was the presence
of diabetes in established CVD a stratifica-
tion factor, they said.
“[Regardless,] these data highlight the
substantial impact of icosapent ethyl on
the underlying atherothrombotic burden
in the at-risk REDUCE-IT population, in
those with [and] without DM,” they said.
*REDUCE-IT: Reduction of Cardiovascular Events with
Icosapent Ethyl–Intervention Trial

American Diabetes Association (ADA 2020) Virtual 80th Scientific Sessions • June 12-16
Dorzagliatin
SEEDs good
outcomes in T2D
AUDREY ABELLA
T
he novel dual-acting glucokinase
activator (GKA) dorzagliatin pro-
vides good glycaemic control and
has a favourable safety profile in Chinese
patients with type 2 diabetes (T2D), the
phase III SEED* study has shown.
Given the central role of GK in glucose
homeostasis and the significant reduction
in GK expression among individuals with
T2D, the findings “bring the reality a step
further in developing a novel T2D drug
with a GKA mechanism of action,” said
Dr Li Chen from Hua Medicine in Shang-
hai, China, who presented the findings at
ADA 2020.
SEED was conducted in 40 sites
across China, comprising 463 treat-
ment-naïve adults with T2D (mean age
53 years, 65 percent male). Participants
initially received placebo in the 4-week
run-in phase and were then randomized
2:1 to receive dorzagliatin 75 mg BID or
placebo for 24 weeks in the double-blind
phase. Open-label treatment with dor-
zagliatin ensued thereafter for an addi-
tional 28 weeks. [ADA 2020, abstract
182-OR]
At week 24, the reduction in baseline
HbA1c was greater with dorzagliatin vs
placebo (least-squares [LS] mean, –1.07
percent vs –0.50 percent; p<0.0001),
which reflects the study drug’s efficacy in
terms of blood glucose control, noted Li.
CONFERENCE COVERAGE
The secondary efficacy endpoints
were also met as reflected by the mean
reduction in 2-hour post-prandial plas-
ma glucose from baseline (LS mean,
–2.83 vs –0.50 mmol/L; p<0.001), as
well as the significant improvement in β-
cell function (HOMA2-β**) with dorzagli-
atin vs placebo at week 24 (LS mean,
2.56 vs –0.72; p<0.05).
There were also good HbA1c re-
sponse (HbA1c <7 percent; 45 percent
vs 22 percent) and homeostasis control
rates (HbA1c <7 percent without hypo-
glycaemia; 45 percent vs 22 percent;
p<0.0001 for both) with dorzagliatin vs
placebo at week 24.
Each study visit reflected a signifi-
cantly reduced HbA1c from baseline
with dorzagliatin vs placebo (p<0.001),
noted Li.
Time to reach first HbA1c response
was also significantly shorter with dor-
zagliatin vs placebo (p<0.001). “Pa-
tients with baseline HbA1c of ≤8 percent
reached the HbA1c <7 percent target at
week 4.7, [reflecting the] fast onset of
action [of dorzagliatin],” said Li.
Dorzagliatin was well-tolerated and
had a favourable safety profile, with
<1 percent of participants experienc-
ing hypoglycaemia over 24 weeks.
The incidence of adverse events (AE)
was similar between groups, majori-
ty of which were mild in severity. No
18
DOCTOR | AUGUST ISSUE
deaths, drug-related serious AEs, or
severe hypoglycaemia were reported
with dorzagliatin.
Good from the get-go
“Our earlier study … demonstrat-
ed that dorzagliatin can repair glucose
sensor function and restore glucose ho-
meostasis in T2D patients,” explained
Li. This study also showed that dor-
zagliatin has excellent pharmacokinet-
ic/pharmacodynamic properties, high-
lighting a dose range between 50 and
100 mg BID as beneficial for improving
β-cell function, he added.
“[Our] proof-of-mechanism [and
phase II studies] validated the 75-mg
dose [as] the minimum therapeutic ef-
fective dose [for achieving] good gly-
caemic control and improving insulin
sensitivity and β-cell function … [T]his
served as the basis for selecting the
75-mg BID dose in [SEED, which is] the
first successful phase III trial for a GKA,”
said Li.
“Overall, [the current findings show
that] dorzagliatin had a favourable effect
on glycaemic control and a good safety
profile over 24 weeks … [Our] results
support [dorzagliatin] 75 mg BID as a
monotherapy for drug-naïve T2D pa-
tients in China,” he added.
*SEED: Safety and Efficacy Evaluation of Dorzagliatin
**HOMA2-β: HOmeostasis Model Assessment of
Beta-cell function

American Diabetes Association (ADA 2020) Virtual 80th Scientific Sessions • June 12-16
Prepregnancy
plant-based diet
may cut GDM risk
PEARL TOH
W
omen who follow a healthy
plant-based diet before preg-
nancy have a lower risk of
developing gestational diabetes melli-
tus (GDM), suggests a large, prospec-
tive cohort study presented at the ADA
2020 annual meeting.
“GDM is linked to adverse perina-
tal outcomes and increased long-term
cardio-metabolic disease risk,” said
presenting author Dr Frank Qian from
the Harvard T.H. Chan School of Public
Health in Boston, Massachusetts, US.
“[Therefore, it is] crucial to identify novel
modifiable factors for the prevention of
GDM.”
The study built on the known asso-
ciation between plant-based diets and a
lower risk of type 2 diabetes (T2D) and
cardiovascular disease (CVD). Based on
these findings, the 2015-2020 Dietary
Guidelines for Americans also recom-
mended a healthy vegetarian diet to
prevent cardio-metabolic diseases, ac-
cording to Qian.
“Due to other contributing risk fac-
tors for GDM, whether the beneficial as-
sociations of plant-based diets with T2D
can be extended to GDM is not known,”
he added.
For the prospective analysis,
14,926 women (aged 25–44 years)
CONFERENCE COVERAGE
with 20,707 eligible singleton pregnan-
cies in the Nurses’ Health Study II were
assessed using a food frequency ques-
tionnaire every 4 years. Dietary intake
of three categories of foods was scored
as index points: healthful plant-based
diet (eg, fruits, vegetables, and whole
grains), unhealthful plant-based diet
(eg, refined grains and fruit juice), and
animal-based foods (eg, eggs, dairy,
and meat). [ADA 2020, abstract 189-
OR]
A total of 846 incident GDM were
reported among the women over 10
years of follow-up.
Based on the overall plant-based
diet index (PDI), women in the highest
intake quintile of plant-based diets be-
fore pregnancy had a 19 percent lower
risk of GDM than the comparator group
in the lowest intake quintile (adjust-
ed relative risk [RR], 0.81, 95 percent
confidence interval [CI], 0.65–1.01),
with incremental risk reduction from the
lowest to the highest intake quintiles
(p=0.03 for trend).
Similarly, the healthful diet PDI
(hPDI) showed an inverse association
between healthful plant-based diet and
GDM: the higher the intake, the lower
the risk of GDM (RR, 0.78, 95 percent
CI, 0.62–0.99 for quintile 5 vs quintile 1;
p=0.04 for trend).
19
DOCTOR | AUGUST ISSUE
Although the associations were at-
tenuated after adjusting for prepregnan-
cy BMI, they remained significant, Qian
noted.
“We estimated that prepregnancy
BMI mediated 61.3 percent of the as-
sociation between PDI and GDM, and
44.4 percent of the association between
hPDI and GDM,” he reported.
Also, the associations persisted
across subgroups regardless of age,
parity, family history of diabetes, phys-
ical activity, and BMI before pregnancy.
“Our study suggests that prepreg-
nancy adherence to plant-based diets,
particularly healthful plant-based diet,
may be associated with a lower risk
of GDM,” Qian concluded. “These as-
sociations were substantially mediated
through prepregnancy BMI.”
“Future studies are needed to ad-
dress whether the associations be-
tween prepregnancy plant-based diets
and GDM risk are causal,” he said.
Qian also suggested further research
to examine the role of dietary habits
during pregnancy itself and whether
prepregnancy plant-based diets may
influence offspring health and any po-
tential adverse effects, such as nutrient
deficiencies.

American Diabetes Association (ADA 2020) Virtual 80th Scientific Sessions • June 12-16
Insulin detemir use not
tied to adverse pregnancy
outcomes
ELAINE SOLIVEN
T
he use of insulin detemir among
women with pre-existing diabe-
tes was not associated with an
increased risk of negative pregnancy
outcomes, such as major congenital
malformations and perinatal or neonatal
deaths, compared with other basal in-
sulins, according to the EVOLVE* study.
This prospective, noninterventional
study involved 1,457 pregnant women
(mean age 31 years, mean BMI 26
kg/m2, mean HbA1c 7.1 percent) with
pre-existing type 1 or type 2 diabetes
who were recruited from 92 sites in 17
countries. Participants were using either
insulin detemir (n=727) or other basal in-
sulins (n=730), primarily insulin glargine,
for 4 weeks prior to and following con-
ception. Baseline characteristics were
comparable between the treatment
groups. [ADA 2020, abstract 172-LB]
Compared with those on other
basal insulins, there were fewer cases
CONFERENCE COVERAGE
of liveborns with major congenital mal-
formations at or after delivery among
women using insulin detemir (15 vs 17).
There were also fewer perinatal deaths
from 22 weeks of gestation to 7 days
after birth among women using insulin
detemir compared with those on other
basal insulins (6 vs 13).
There was only one neonatal death
reported in the insulin detemir group,
while none occurred in the other basal
insulin group.
Overall, the rate of the composite of
no major congenital malformations and
perinatal or neonatal deaths was higher
among women treated with insulin de-
temir compared with other basal insulins
(97.0 percent vs 95.5 percent; adjusted
risk difference, -0.003, 95 percent con-
fidence interval, -0.03 to 0.03).
“Women with pre-existing diabetes
are at increased risk for severe pregnan-
cy complications. [However,] there are
limited data available on the effect of the
20
DOCTOR | AUGUST ISSUE
basal insulin analogue, insulin detemir,
on congenital malformation and peri-
natal death,” said lead author Dr Elis-
abeth Mathiesen from the Department
of Endocrinology, Center for Pregnant
Women with Diabetes at Copenhagen
University Hospital, Rigshospitalet, in
Copenhagen, Denmark.
Mathiesen pointed out that the
major strength of this study is that it
was based on real-world data with a
large sample size and included many
nationalities.
“In summary, our study found that
in pregnant women with pre-existing
diabetes, insulin detemir was not as-
sociated with an excess risk of major
congenital malformation and perinatal
or neonatal death compared with other
basal insulins,” Mathiesen concluded.
*EVOLVE: An international non-interventional cohort
study to evaluate the safety of treatment with insulin
detemir in pregnant women with diabetes mellitus

American Diabetes Association (ADA 2020) Virtual 80th Scientific Sessions • June 12-16
EMPRISE reinforces CV benefits
of empagliflozin
ELVIRA MANZANO
T
he efficacy and cardiovascular
(CV) safety of the SGLT2* inhibitor
empagliflozin vs DPP-4** inhibi-
tors and GLP-1*** receptor agonists in
real-world patients were demonstrated
in two interim analyses of the EMPRISE+
study presented at ADA 2020.
Over 5 years, EMPRISE will collect
real-world evidence that is beyond the
scope of cardiovascular outcomes tri-
als (CVOTs). EMPRISE investigators
will specifically assess whether the CV
effectiveness of empagliflozin seen in
EMPA-REG OUTCOME, the first CVOT
to demonstrate cardioprotection, can
be confirmed in routine clinical practice
with a broader patient cohort.
CV outcomes in older
adults
In one of the analyses, empaglifloz-
in reduced the risk of hospitalization for
heart failure (HHF), both as a primary di-
agnosis at discharge (HHF-specific) and
as diagnosis of any sort at discharge
(HHF-broad), vs DPP-IV inhibitors (haz-
ard ratio [HR] for HHF-specific, 0.43,
95 percent confidence interval [CI],
0.3–0.63; HR for HHF-broad, 0.57, 95
percent CI, 0.47–0.69). [ADA 2020, ab-
stract 133-LB]
Empagliflozin also reduced the risk
for major adverse cardiovascular events
(MACE; HR, 0.63, 95 percent CI, 0.5–
0.79) vs DPP-IV inhibitors.
Compared with GLP-1 receptor ag-
onists, empagliflozin reduced the risk
for HHF (HR for HHF-specific, 0.67,
95 percent CI, 0.50–0.91; HR for HHF-
broad, 0.83; 95 percent CI, 0.71–0.96)
but conferred similar risk for MACE (HR,
1.02; 95 percent CI, 0.85-1.23).
For this analysis, researchers as-
CONFERENCE COVERAGE
sessed data from the Medicare data-
base between 2014 and 2017. The
aim was to identify propensity score-
matched patients who were 66 years of
age with type 2 diabetes (T2D) and ini-
tiated on either empagliflozin, a DPP-4
inhibitor, or a GLP-1 receptor agonist.
“Results for the individual compo-
nents of MACE were consistent and ro-
bust to competing risks,” said principal
author Dr Elisabetta Patorno, assistant
professor of medicine at Harvard Med-
ical School and associate epidemiolo-
gist, Division of Pharmacoepidemiology
and Pharmacoeconomics, Brigham and
Women’s Hospital both in Boston, Mas-
sachusetts, US.
“These findings, addressing the
comparative effectiveness of empagli-
flozin in routine care patients with mean
age of 72 years, complement available
information from randomized controlled
trials.”
Empagliflozin in routine
care patients
For the second interim analysis look-
ing at figures from Medicare and two US
commercial claims datasets from 2014
to 2017, empagliflozin reduced the risk
for HF hospitalization (HR for HHF-spe-
cific, 0.46, 95 percent CI, 0.3-0.73;
HR for HHF-broad, 0.63, 95 percent
21
DOCTOR | AUGUST ISSUE
CI, 0.51-0.77) and all-cause mortality
(HR, 0.52, 95 percent CI, 0.36-0.76)
compared with DPP-IV inhibitors. [ADA
2020, abstract 134-LB]
There was no significant difference
in risk for MI or stroke (HR, 0.89, 95 per-
cent CI, 0.73-1.09).
In terms of the safety outcomes,
empagliflozin conferred a decreased
risk for acute kidney injury (HR, 0.64, 95
percent CI, 0.53-0.77), increased risk
for hospitalization for diabetic ketoaci-
dosis (HR, 1.56, 95 percent CI, 1-2.44),
and similar risk for lower-limb amputa-
tions (HR, 0.97, 95 percent CI, 0.67-
1.42), and bone fractures (HR,1.21,
95 percent CI, 0.81-1.81) over a mean
follow-up of 178 days compared with
DPP-IV inhibitors.
Patients were at least 18 years of
age with T2D and who were initiating
either empagliflozin or a DPP-IV inhib-
itor. Effectiveness outcomes included
HF hospitalization (defined as discharge
diagnosis in the primary or any position),
a composite of MI and stroke, and all-
cause mortality. Safety outcomes in-
cluded lower limb amputations, bone
fractures, diabetic ketoacidosis, and
acute kidney injury.
“In routine care, empagliflozin had
an effectiveness profile consistent with
randomized controlled trial findings and
safety outcomes in line with document-
ed information,” the researchers said.
The findings also provide additional
context to the CVOT-generated insights
into CV protection with empagliflozin.
*SGLT2: sodium-glucose cotransporter
**DPP-4: dipeptidyl peptidase-4
***GLP-1: glucagon-like peptide-1
EMPRISE: EMPagliflozin compaRative effectIveness
+
and SafEty

American Diabetes Association (ADA 2020) Virtual 80th Scientific Sessions • June 12-16
Use of sensor-based glucose
monitoring system may reduce DKA
ROSHINI CLAIRE ANTHONY
U
se of the FreeStyle Libre glucose
monitoring system almost halved
the rates of hospitalization due to
diabetic ketoacidosis (DKA), according
to results of the retrospective RELIEF*
study presented at ADA 2020.
“This was a dramatic reduction in ke-
toacidosis-related hospitalization rates
among patients with both type 1 and
type 2 diabetes [T1D and T2D] – espe-
cially among people who previously had
very low self-monitoring of blood glu-
cose (SMBG),” said lead author Profes-
sor Ronan Roussel from Hôpital Bichat
and Université de Paris, Paris, France.
“[The results] support the use of
intermittently scanned continuous glu-
cose monitoring systems like the Free-
Style Libre for individuals who are at risk
for diabetes-related complications such
as DKA,” he added.
“Intermittently scanned
continuous glucose
monitoring may have
significant implications
for patient-centred
clinical care”
Using the French SNDS nationwide
reimbursement claims database, the
researchers identified patients with T1D
(n=33,203) or T2D (n=40,955) on insulin
therapy who initiated the FreeStyle Libre
system between August and December
2017. They compared DKA rates 1 year
prior and after the first FreeStyle Libre
sensor claim. SMBG in the 1 year prior
to FreeStyle Libre use was assessed by
the mean number of SMBG strips reim-
bursed per day.
CONFERENCE COVERAGE
In patients with T1D, there was a 52
percent reduced rate of annual hospital-
ization due to DKA (not including coma)
in the 1 year after vs 1 year before use of
the FreeStyle Libre system (5.46 vs 2.59
per 100 patient-years). [ADA 2020, ab-
stract 68-OR]
In patients with T2D, DKA-related
hospitalization was reduced by 47 per-
cent in the 1 year after vs 1 year before
initiating the FreeStyle Libre system (1.70
vs 0.90 per 100 patient-years).
The greatest reduction in DKA hos-
pitalization rates was noted in patients
who did not use SMBG in the year prior
to using the FreeStyle system (0 strips/
day; T1D: 8.31 vs 3.31 per 100 pa-
tient-years [60 percent reduction]; T2D:
2.51 vs 1.23 per 100 patient-years [51
percent reduction]).
Similar results were noted in patients
with regular use of SMBG in the year prior
(≥5 strips/day; T1D: 5.55 vs 2.26 per
100 patient-years [59 percent reduction];
T2D: 1.88 vs 0.90 per 100 patient-years
[52 percent reduction]).
Reduction in DKA hospitalization 1
year after vs before FreeStyle initiation
22
DOCTOR | AUGUST ISSUE
was also noted regardless of insulin type
(from 2.58 percent to 1.8 percent in pa-
tients treated with continuous subcuta-
neous insulin infusion and from 2.89 per-
cent to 1.32 percent in patients treated
with multiple daily insulin injections).
According to Roussel, use of the
FreeStyle Libre system may have en-
abled the detection and management
of persistent hyperglycaemia and sub-
sequent prevention of DKA. However, it
is possible that patients also improved
their self-care after initiating use of this
system, he noted.
“Although preventing ketoacido-
sis has traditionally relied on intensive
SMBG, there is growing literature that
shows this has not helped reduce the
overall incidence of DKA. The positive
results of this study demonstrate that in-
termittently scanned continuous glucose
monitoring may have significant implica-
tions for patient-centred clinical care,” he
went on.
“[G]iven the increased burden of ke-
toacidosis on healthcare utilization and
expenditure, it may have a positive im-
pact on long-term economic health out-
comes,” he pointed out.

American Diabetes Association (ADA 2020) Virtual 80th Scientific Sessions • June 12-16
Next-gen automated insulin pump trumps
current tech for glycaemic control in T1D
PEARL TOH
T
he next-generation automated in-
sulin delivery (AID) system signifi-
cantly improved daytime glycaemic
control without increasing hypoglycaemia
over the current 670G hybrid closed-loop
system on the market in young patients
with type 1 diabetes (T1D), according to
the FLAIR* trial presented at ADA 2020.
Despite the use of daily insulin in-
jections or insulin pumps and continu-
ous glucose monitoring (CGM), young
patients with T1D often face difficulty
achieving optimal glycaemic control —
which is necessary for preventing diabe-
tes complications, pointed out present-
ing author Dr Richard Bergenstal of the
International Diabetes Center at Park
Nicollet in Minneapolis, Minnesota, US.
While AID system has been effective
in improving time in range (TIR), espe-
cially overnight, there are still barriers
to overcome, said Bergenstal, citing
daytime hyperglycaemia and glycaemic
control in the young T1D population (age
14–29 years) as prime target in the cur-
rent study. [ADA 2020, 12th Jun session]
“This age group has traditionally
been the most difficult group in which to
optimize glucose management and the
FLAIR study shows that individuals using
any type of therapy, even insulin injec-
tions without a pump or CGM system,
can benefit from the next-generation ad-
vanced hybrid closed-loop [AHCL] AID
therapy,” he highlighted.
Compared with the 670G (the hy-
brid closed-loop system that is currently
available), the AHCL system was supe-
rior in reducing daytime hyperglycaemia
with a 3 percentage-point difference
between the two systems (p<0.001 for
superiority).
Importantly, this was achieved
CONFERENCE COVERAGE
without an increase in hypoglycaemia
(difference between treatments, -0.06
percentage points; p<0.001 for nonin-
feriority), reported Bergenstal.
The AHCL system also led to almost
threefold increase from baseline in the
proportion of patients achieving the in-
ternational consensus target of >70
percent TIR compared with a twofold
increase with the 670G system. The TIR
over 24 hours (ie, 70–180 mg/dL) rose
to 67 percent with AHCL vs 63 percent
with 670G, compared with 57 percent
at baseline.
In addition, the average HbA1c levels
dropped to 7.4 percent when patients
were using the AHCL system compared
with 7.6 percent when on 670G, from a
baseline level of 7.9 percent.
“Both systems were safe in terms of
severe hypoglycaemia and diabetic ke-
toacidosis,” said Bergenstal.
The multinational cross-over study
enrolled 113 young patients (age 14–29
years) with T1D. After a run-in period,
they were randomized 1:1 to use the
AHCL or the 670G system for 12 weeks,
before crossing over to the other arm for
another 12 weeks.
23
DOCTOR | AUGUST ISSUE
A significant step forward
The components of an AID system
comprised an insulin pump connected
to a continuous glucose monitor, plus
an automated algorithm for insulin dos-
ing, explained Bergenstal.
Unlike the 670G system, one added
feature of the AHCL system is having
automatic correction boluses. It also
does not have auto exit from the HCL
mode when blood glucose exceeds a
certain level for a certain duration — a
conventional safety feature which ex-
perts said can interfere with tight control
of blood sugar.
In the study, AHCL exited out of au-
tomode much less often (by threefold)
than 670G. User satisfaction survey
also showed that patients preferred the
AHCL over the 670G system.
“There is still room for further im-
provement in glycaemic control in this
population of patients with T1D, but
AHCL represents a significant step for-
ward for adolescents or young adults
who have a hard time managing their
glucose levels,” Bergenstal stated.
*FLAIR: Fuzzy Logic Automated Insulin Regulation

American Diabetes Association (ADA 2020) Virtual 80th Scientific Sessions • June 12-16
Bexagliflozin exhibits favourable glycaemic,
weight, BP control in T2D patients
AUDREY ABELLA
T
he highly selective SGLT2 inhib-
itor bexagliflozin demonstrated
significant efficacy and safety in
controlling hyperglycaemia, weight, and
blood pressure (BP) in patients with type
2 diabetes (T2D) who were at high risk of
cardiovascular (CV) events, results of the
BEST* trial have shown.
“BEST met its primary and second-
ary efficacy endpoints,” said Dr John Mc-
Murray from the University of Glasgow in
Scotland, who presented the findings at
the ADA 2020 virtual meeting.
At the prespecified analysis at week
24, mean HbA1c reduction was sig-
nificantly greater with bexagliflozin vs
placebo (least squares mean [LSM]
change, –0.85 percent vs –0.37 percent;
p<0.0001). This was observed within 6
weeks and sustained up to the 3-year
follow up mark. [ADA 2020, abstract 32-
OR]
Bexagliflozin demonstrated effective
glycaemic control despite the higher
number of placebo recipients receiv-
ing rescue glucose-lowering therapy**
(19.6 percent vs 7.1 percent), noted
McMurray.
Sustained efficacy
Bexagliflozin also bested placebo
in terms of HbA1c reduction at week 24
in participants on insulin (LSM change,
–0.84 percent vs –0.32 percent) and
weight loss at week 48 among those
with baseline BMI of ≥25 kg/m2 (LSM
change, –3.03 vs –0.38 kg; p<0.0001 for
both). The weight loss with bexagliflozin
was also apparent within 6 weeks and
continued to drop significantly over time.
There was also a rapid reduction in
systolic BP at week 24 among partici-
pants with baseline systolic BP ≥140 mm
CONFERENCE COVERAGE
Hg (LSM change, –9.83 vs –6.87 mm
Hg; p=0.012). As with other endpoints,
this was observed as early as 6 weeks
and persisted throughout the follow-up
period, generating a significant overall
treatment effect (p<0.0001).
Exploratory, safety
endpoints
The risk of first heart failure (HF) hos-
pitalization (hazard ratio [HR], 0.63) and
the composite of CV death or HF hos-
pitalization (HR, 0.73) were also lower
with bexagliflozin vs placebo. “Despite
the smaller number of events … the ef-
fect size is as large as those seen in other
SGLT2 inhibitor trials,” said McMurray.
The proportion of adverse events
(AEs) leading to treatment withdrawal
was 8 percent in each arm. In terms of
specific AEs of interest, genital mycotic
infections were significantly higher with
bexagliflozin vs placebo (9.5 percent
3 percent; p<0.0001). However, the
fraction of patients who discontinued
bexagliflozin due to such infections was
only 1.2 percent.
Another notable finding was the very
low percentage of participants with seri-
ous hypoglycaemia in both bexagliflozin
and placebo arms (0.9 percent vs 1.4
percent) despite the high overall inci-
24
DOCTOR | AUGUST ISSUE
dence of hypoglycaemia (42 percent vs
44 percent).
In terms of CV safety, bexaglifloz-
in-treated patients were less likely to
experience MACE*** (HR, 0.79) and
MACE+# events (HR, 0.77; pnoninferiori-
ty
<0.0001 for both) vs placebo recipients.
A total of 1,700 high-risk patients (70
percent male, mean age 64 years, mean
BMI 32.6 kg/m2, mean HbA1c 8.32 per-
cent) were randomized 2:1 to receive
bexagliflozin 20 mg QD or placebo. Of
these, 63 percent had a history of ath-
erosclerotic vascular disease, 14 percent
had a history of HF, while the remaining
23 percent had ≥2 CV risk factors. More-
over, ~20 percent had kidney disease
(eGFR <60 mL/min/1/73 m2). Median fol-
low up was 123 weeks.
“[Taken together,] in high-risk T2D
patients, bexagliflozin effectively reduced
HbA1c, was well-tolerated with an AE pro-
file similar to other SGLT2 inhibitors, was
associated with a low rate of treatment
discontinuation, and had a good overall
safety profile,” concluded McMurray.
*BEST: Bexagliflozin Efficacy and Safety Trial
**Biguanides (77 percent), sulfonylureas (40 percent),
insulin (53 percent)
***MACE: CV death, MI, and stroke
MACE+: MACE plus unstable angina
#

American Diabetes Association (ADA 2020) Virtual 80th Scientific Sessions • June 12-16
Reduction in new-onset T2D:
Another benefit of dapagliflozin
ROSHINI CLAIRE ANTHONY
D
apagliflozin reduced the incidence
of new-onset type 2 diabetes
(T2D) in patients with heart failure
and reduced ejection fraction (HFrEF),
according to a prespecified exploratory
analysis of the DAPA-HF* trial.
“While the major role of dapaglifloz-
in is to reduce cardiovascular (CV) mor-
tality and worsening of HF, decreasing
incident diabetes could be considered
an additional benefit,” said study author
Professor Silvio E. Inzucchi from the Yale
University School of Medicine and Yale
Diabetes Center, New Haven, Connecti-
cut, US, who presented the findings at
ADA 2020.
“In this very high-risk population, the
safety profile of dapagliflozin was excel-
lent, the treatment well-tolerated with low
discontinuation rates,” he added.
Of the 4,744 patients with HFrEF
(NYHA class II–IV and LVEF** ≤40 per-
cent) enrolled in the DAPA-HF trial, 55
percent (n=2,605) were without T2D at
baseline (mean age 66.2 years, 75.7 per-
cent male, mean BMI 27.2 kg/m2, mean
HbA1c 5.8 percent). They were random-
ized to receive once-daily doses of da-
pagliflozin (10 mg) or placebo. Median
follow-up was 18.2 months.
A total of 157 patients (6.0 percent)
developed T2D, 95.5 percent of whom
(n=150) had pre-diabetes at baseline
(HbA1c 5.7–6.4 percent).
There was a 32 percent significant
reduction in the incidence of new-onset
T2D, defined as HbA1c ≥6.5 percent at
two consecutive assessments or initi-
ation of glucose-lowering medication,
among those assigned to dapagliflozin
vs placebo (4.9 percent vs 7.1 percent;
hazard ratio [HR], 0.68, 95 percent con-
CONFERENCE COVERAGE
fidence interval, 0.50–0.94; p=0.019).
[ADA 2020, abstract 271-OR]
Compared with those who did not
develop T2D, those who did had a high-
er baseline HbA1c (mean 6.2 vs 5.7;
p<0.001), higher BMI (mean 28.5 vs 27.1
kg/m2; p=0.003), and lower estimated
glomerular filtration rate (eGFR; mean
61.5 vs 68.2 mL/min/1.73 m2; p<0.001),
with a greater proportion with eGFR <60
mL/min/1.73 m2 (48.4 percent vs 35.5
percent; p=0.001).
The effects of dapagliflozin in reduc-
ing new-onset T2D appeared greater
among patients aged ≤65 vs those >65
years (HR, 0.44 and 0.89, respectively;
p=0.04) or with below vs above median
NT-proBNP levels (HR, 0.42 and 1.02;
p=0.01).
Exploratory analysis suggested an
increased risk of all-cause mortality (HR,
1.70; p=0.035) and CV death (HR, 1.77;
p=0.035) with new-onset T2D vs non-di-
abetics.
Inzucchi noted that the findings only
applied to patients with HFrEF, and that
the lack of oral glucose tolerance testing
or fasting plasma glucose assessments
were limitations. “We will need to do
25
DOCTOR | AUGUST ISSUE
more studies to see if this effect extends
to patients without HFrEF and to evalu-
ate how durable the benefit might be and
how long diabetes prevention persists
after the discontinuation of therapy.”
“DAPA-HF was the first trial to show
the effectiveness of an SGLT2*** inhibitor
[dapagliflozin] in terms of improving clini-
cal outcomes in patients with HFrEF with
or without T2D,” pointed out Inzucchi.
This was previously demonstrated with
a reduction in a composite of CV death
and worsening HF with dapagliflozin vs
placebo (HR, 0.74; p=00001), a result
consistent regardless of whether pa-
tients did or did not have T2D (HR, 0.75
and 0.73, respectively). [N Engl J Med
2019;38:1995-2008]
“DAPA-HF is [also] the first trial to
demonstrate a “diabetes prevention” ef-
fect from an SGLT2 inhibitor,” he added.
He noted that the minimal reduction in
HbA1c with dapagliflozin in those without
diabetes at baseline “may dispel con-
cerns about merely masking the devel-
opment of T2D.”
*DAPA-HF: Dapagliflozin and Prevention of Adverse
Outcomes in Heart Failure
**NYHA: New York Heart Association; LVEF: Left ven-
tricular ejection fraction
***SGLT2: Sodium-glucose co-transporter-2

American Diabetes Association (ADA 2020) Virtual 80th Scientific Sessions • June 12-16
Ipragliflozin shows benefits for T2D patients
with NAFLD
AUDREY ABELLA
L
ong-term use of the sodium-glu-
cose cotransporter (SGLT) 2 inhib-
itor ipragliflozin improves obesity,
glycaemic control, and hepatic outcomes
in patients with type 2 diabetes (T2D)
who developed nonalcoholic fatty liver
disease (NAFLD), a study shows.
“Given the global increase in diabetes
and NAFLD, the effects of SGLT2 inhibi-
tors on hepatic outcomes and glycaemic
control are of interest,” said Dr Hirokazu
Takahashi from the Saga University in
Japan, who presented the findings at the
ADA 2020 virtual congress.
The ADA/EASD* consensus was re-
cently amended to give priority to SGLT2
inhibitors for the management of T2D
patients at high risk of cardiovascular
disease, heart failure, chronic kidney
disease, and obesity. [Diabetes Care
2020;43:487-493]
“[Our study shows that] ipragliflozin
reduces body weight and HbA1c in [T2D
patients] with NAFLD, and improves
pathologic liver fibrosis, liver function
tests, and serum fibrosis markers,” said
Takahashi.
Fifty-five patients with diabetes/pre-
diabetes (HbA1c >6 percent) and biop-
sy-proven NAFLD were randomized 1:1
to receive oral ipragliflozin 50 mg daily,
or antidiabetic agents other than SGLT2
inhibitors, pioglitazone, or GLP-1 ana-
logues (control arm). Participants in the
control arm were also instructed to alter
their lifestyle to include diet and exercise.
[ADA 2020, abstract 31-OR]
Obesity, glycaemic control
At week 72, mean body weight sig-
nificantly dropped with ipragliflozin vs
control (–3.2 vs –0.4 kg/m2; p<0.05).
Mean reduction in visceral fat area was
CONFERENCE COVERAGE
greater with ipragliflozin from week 12–
72, noted Takahashi.
Compared with control, ipraglifloz-
in led to significant reductions in HbA1c
at week 48 (–0.46 percent vs –0.09
percent) and fasting plasma glucose at
week 12 (p<0.05 for both).
These findings underscore the fa-
vourable effects of ipragliflozin on glycae-
mic control and obesity in this setting,
noted Takahashi.
Hepatic outcomes
Improvements in liver function tests
were also significant with ipragliflozin
vs control at week 48 (p<0.05 for AST/
ALT/GGT**). Type IV collagen 7s, a liver
fibrosis marker, was also reduced with
ipragliflozin at week 24 (p<0.05), which
was sustained until week 72. Despite the
substantial drop in type IV collagen 7s in
the control arm at week 48 (p<0.05), this
increased by week 72.
More ipragliflozin vs control recipients
improved in terms of hepatocyte balloon-
ing and fibrosis scores, be it in the overall
cohort (52 percent vs 24 percent [balloon-
ing] and 57 percent vs 16 percent [fibrosis])
or in the subgroup wherein individuals with
baseline scores of 0 were excluded (100
percent vs 46 percent and 71 percent vs
22 percent, respectively; p<0.05 for all).
26
DOCTOR | AUGUST ISSUE
The changes in liver fibrosis scores
are remarkable, noted Takahashi, as “liver
fibrosis is the most significant pathologic
finding associated with overall mortality.
Mortality rates increase with increasing
severity of liver fibrosis.” [Hepatology
2017;65:1557-1565] Moreover, this find-
ing is more remarkable as it relates to
mortality in other hepatic conditions such
as liver failure, hepatocellular carcinoma,
and liver transplants, he added.
NASH*** resolution rates were high-
er with ipragliflozin vs control at week
72 (67 percent vs 27 percent). Among
non-NASH patients at baseline, those on
ipragliflozin continued to have no NASH
until week 72, whereas 33 percent in the
control arm went on to develop NASH.
Safe alternative
Apart from one severe adverse event
(AE) in each arm (grade 3 gastric cancer
[ipragliflozin] and grade 2 asymptomatic
coronary stenosis [control]), both arms
had low-grade AEs. This reflects the
safety of ipragliflozin, further boosting its
potential as a therapeutic option in this
setting, said Takahashi.
*ADA/EASD: American Diabetes Association/European
Association for the Study of Diabetes
**AST/ALT/GGT: Aspartate aminotransferase/alanine
aminotransferase/gamma-glutamyl transferase
***NASH: Nonalcoholic steatohepatitis
EULAR 2020
June 3 - August 31
Novel JAK1 inhibitor on par with adalimumab
in RA over 52 weeks
PEARL TOH
T
he investigational JAK1* inhibitor
filgotinib was noninferior to adali-
mumab in reducing disease activ-
ity in patients with moderate-to-severe
rheumatoid arthritis (RA) who had inad-
equate response to methotrexate (MTX-
IR), according to the FINCH 1 study pre-
sented at EULAR 2020.
Moreover, the improvements were
sustained through 52 weeks.
In the global, phase III, double-blind
FINCH 1 study, 1,755 patients (81.8 per-
cent female, mean age 53 years, mean
disease duration 7.8 years) with active
RA and MTX-IR were randomized in a
3:3:2:3 ratio to receive oral filgotinib 200
mg (n=475) or 100 mg (n=480) once daily,
subcutaneous adalimumab 40 mg Q2W
(n=325), or a matching placebo (n=475),
on a background of stable methotrexate,
up to 52 weeks. After 24 weeks, patients
in the placebo arm were rerandomized
1:1 to filgotinib 200 mg or 100 mg.
Disease activity
At week 12, significantly more pa-
tients in the filgotinib arms achieved low
disease activity, defined as DAS28(CRP)**
score of ≤3.2, compared with the place-
bo arm (49.7 percent and 38.8 percent vs
23.4 percent for filgotinib 200 mg and 100
mg vs placebo, respectively; p<0.001).
[EULAR 2020, abstract THU0198]
When compared with adalimumab,
high-dose filgotinib (200 mg) met the cri-
teria of noninferiority for low disease ac-
tivity at 12 weeks (49.7 percent vs 43.4
percent; p<0.001 for noninferiority).
For clinical remission at 12 weeks
(defined as DAS(CRP) <2.6), high-dose
filgotinib was superior to adalimumab
(33.9 percent vs 23.7 percent; p<0.01
for superiority) while low-dose filgotinib
was noninferior to adalimumab (23.8
percent vs 23.7 percent; p<0.001 for
noninferiority).
Clinical response
There were also significantly more
filgotinib-treated patients who achieved
ACR20*** response — defined as a ≥20
percent reduction in swollen and tender
joint counts — compared with those on
placebo (76.6 percent and 69.8 percent
vs 49.9 percent; p<0.001).
Similarly, responder rates for ACR50
(47.2 percent and 36.3 percent vs 19.8
percent; p<0.001) and ACR75 (26.3 per-
cent and 18.5 percent vs 6.7 percent;
p<0.001) were significantly higher with fil-
gotinib 200 mg and 100 mg than placebo.
In the adalimumab arm, responder
rates for ACR20, ACR50, and ACR75
were 70.8 percent, 35.1 percent, and
14.2 percent, respectively — compara-
ble to those seen in the filgotinib arms.
Sustained benefits
“Through week 52, both doses of fil-
gotinib showed sustained efficacy based
on clinical and patient-reported outcomes
… in RA patients with MTX-IR, with faster
onset and numerically greater efficacy for
filgotinib 200 mg than 100 mg,” reported
27
DOCTOR | JULY ISSUE
lead author Dr Bernard Combe from the
University of Montpellier, France.
Efficacy of both filgotinib doses were
comparable to adalimumab through
52 weeks. Remission rates based on
DAS28(CRP) <2.6 at week 52 were 54
percent, 43 percent, and 46 percent for
filgotinib 200 mg, 100 mg, and adalim-
umab, respectively.
Furthermore, the higher filgotinib dose
(200 mg) was significantly better than
adalimumab in improving remission based
on CDAI+ ≤2.8 and DAS(CRP) <2.6 (nom-
inal p=0.028 and p=0.024, respectively).
“Both doses of filgotinib were well
tolerated with no new safety signals
through week 52,” Combe noted. “Ve-
nous thromboembolism rates were low
and occurred in all treatment groups.”
Herpes zoster infection occurred in
all groups, with a numeric increase with
filgotinib 200 mg dosing vs adalimumab
after week 24.
As there is currently no specific rec-
ommendation for biologics or JAK inhibi-
tor following methotrexate failure, Combe
said treatment decision is based on dis-
cretion of clinicians. He also added that
filgotinib can be combined with metho-
trexate, or used as a monotherapy.
*JAK1: Janus kinase 1
**DAS28(CRP): Disease Activity Score 28-joint count C
reactive protein
***ACR20: American College of Rheumatology criteria
for 20 percent improvement in RA disease activity
+
CDAI: Clinical Disease Activity Index

European E-Congress of Rheumatology 2020 (EULAR 2020) • June 3-August 31
Netakimab improves treatment outcomes in PsA
AUDREY ABELLA
T
he anti-interleukin 17A antibody
netakimab reduces disease activ-
ity and skin manifestations in pa-
tients with active psoriatic arthritis (PsA),
consequently improving patient-reported
outcomes (PROs), analyses of the phase
III PATERA trial have shown.
A total of 194 participants with inade-
quate response to conventional synthet-
ic DMARDs* or a tumour necrosis factor
inhibitor were randomized 1:1 to receive
subcutaneous netakimab 120 mg or pla-
cebo. Placebo recipients who did not
meet ACR20 by week 16 (n=84) were
switched to netakimab 120 mg. Week
24 results are reported.
Better responses
Compared with placebo, more ne-
takimab recipients achieved ACR20/50**
responses (82/70 percent vs 9/6 per-
cent), Psoriatic Arthritis Response Cri-
teria (87 percent vs 29 percent), and
minimal disease activity (42 percent vs 1
percent; p<0.0001 for all), as well as re-
mission as per Disease Activity Index for
PsA (36 percent vs 13 percent; p=0.003)
[EULAR 2020, abstract OP0226]
The rates of grade 3/4 treatment-re-
lated adverse events (TRAEs) were low
in both netakimab and placebo arms (1
percent vs 2 percent), and most were
mild-to-moderate in severity. There were
no serious TRAEs reported.
“[These findings suggest that] ne-
takimab is well-tolerated [and] provided
sustained improvements in the signs
and symptoms of active PsA through 24
weeks of therapy,” said the researchers.
Improved skin
manifestations
A greater fraction of netakimab
vs placebo recipients also achieved
PASI75/90/100*** responses (83/68/49
percent vs 11/7/7 percent; p<0.0001 for
CONFERENCE COVERAGE
all). [EULAR 2020, abstract AB0791]
In terms of percentage change in
PASI total score from baseline, the sub-
stantial difference between netakimab
vs placebo was evident at week 4 (–61
percent vs –9 percent), which remained
significant until week 24 (–88 percent vs
–4 percent; p<0.0001 for both).
“[These data imply that] netakimab
resulted in significant improvements
in skin manifestations in PsA patients,
[with nearly] half achieving complete skin
clearance,” said the researchers.
Better PROs
Quality of life (QoL) improvements
also favoured netakimab over placebo,
as shown by the improvements in QoL
domains such as mobility (81 percent
vs 47 percent), self-care (57 percent vs
28 percent), usual activities (62 percent
vs 38 percent), and pain/discomfort (74
percent vs 38 percent) with the former
vs the latter. [EULAR 2020, abstract
AB0792]
Netakimab use also led to greater
changes in HAQ-DI# (mean, –0.6 vs –0.1)
and Dermatology QoL Index (mean,
–11.4 vs –1.8; p<0.0001 for both), as
28
DOCTOR | AUGUST ISSUE
well as better Work Productivity and Ac-
tivity Impairment responses (mean, –22
percent vs –1 percent [presenteeism],
–19 percent vs –0.6 percent [overall work
impairment], and –26 percent vs –5 per-
cent [activity impairment]) compared with
placebo.
Axial disease
In a subset of patients with axial dis-
ease (n=104), netakimab vs placebo led
to greater reductions in mean BASDAI##
(–3 vs –0.19) and ASDAS-CRP### scores
(–2 vs –0.11; p<0.0001 for both), as well
as spinal (–2 vs –0.16) and nocturnal
pain (–2 vs –0.20). [EULAR 2020, ab-
stract FRI0346]
These data support the efficacy of
netakimab even in the presence of axial
involvement, which may heighten the im-
paired treatment outcomes and QoL in
this setting, said the researchers.
*DMARDs: Disease-modifying antirheumatic drugs
**ACR20/50: 20/50-percent improvement in American
College of Rheumatology criteria
***PASI75/90/100: 75/90/100-percent improvement in
Psoriasis Area and Severity Index score
HAQ-DI: Health Assessment Questionnaire–Disability
#
Index
##
BASDAI: Bath Ankylosing Spondylitis Disease Activity
Index
###
ASDAS-CRP: Ankylosing Spondylitis Disease Activity
Score with C-reactive protein

European E-Congress of Rheumatology 2020 (EULAR 2020) • June 3-August 31
SELECT-PsA-1 upadacitinib benefits
in psoriatic arthritis
ROSHINI CLAIRE ANTHONY
U
padacitinib may be a suitable
treatment for patients with active
psoriatic arthritis (PsA) who have
insufficient response to non-biologic
disease-modifying anti-rheumatic drugs
(non-bDMARDs), according to results of
the phase III SELECT-PsA-1* trial pre-
sented at EULAR 2020.
“In this … population, treatment with
upadacitinib 15/30 mg demonstrated im-
provement in musculoskeletal symptoms,
psoriasis, physical function, pain, and
fatigue, and inhibited radiographic pro-
gression,” noted first author Professor Iain
McInnes from the University of Glasgow
Institute of Infection, Immunity & Inflam-
mation, Glasgow, UK, and co-authors.
Participants were 1,704 patients with
active PsA (≥3 swollen and ≥3 tender
joints; mean age 50.8 years, 53.2 per-
cent female, mean duration of PsA 6.1
years) with inadequate response or intol-
erant to ≤2 non-bDMARDs. They were
randomized 1:1:1:1 to receive upadaci-
tinib (15 or 30 mg once daily), adalimum-
ab (40 mg every other week), or placebo.
At week 12, more upadacitinib than
placebo recipients achieved ACR20**
response (70.6 and 78.5 percent for up-
adacitinib 15 and 30 mg, respectively, vs
36.2 percent for placebo; p<0.001 for
both). Upadacitinib 30 mg also demon-
strated superiority compared with adali-
mumab (65.0 percent; p<0.001). [EULAR
2020, abstract LB0001]
Reductions from baseline in HAQ-
DI*** scores at week 12 were greater
among upadacitinib 15/30 mg (-0.42/-
0.47) compared with placebo (-0.14;
p<0.001) or adalimumab (-0.34; p<0.05
and p<0.001 vs upadacitinib 15 or 30
mg, respectively). FACIT-F*** scores were
also improved with upadacitinib 15/30
CONFERENCE COVERAGE
mg vs placebo (6.3/7.1 vs 2.8; p<0.001
for both), as were SF-36 PCS*** scores
(7.9/8.9 vs 3.2; p<0.001 for both).
At week 12, greater reductions in
patient assessed pain scores were ob-
served with upadacitinib 15/30 mg (-
2.3/-2.7) vs placebo (-0.9; p<0.001 for
both) or adalimumab (-2.3; p<0.001 vs
upadacitinib 30 mg).
More patients on upadacitinib 15
“Treatment with
upadacitinib 15/30
mg demonstrated
improvement in
musculoskeletal
symptoms, psoriasis,
physical function, pain,
and fatigue”
and 30 mg achieved PASI75# at week
16 (62.6 and 62.4 percent, respectively)
vs placebo (21.3 percent; p<0.001 for
both) and minimal disease activity (MDA)
at week 24 (36.6 percent and 45.4 per-
cent vs 12.3 percent [placebo]; p<0.001
for both or vs adalimumab [33.3 percent;
p<0.001 vs upadacitinib 30 mg]).
At week 24, more patients on upad-
acitinib 15 or 30 mg experienced resolu-
tion of enthesitis (53.7 and 57.7 percent,
respectively) compared with placebo
(32.4 percent; p<0.001 for both) or adali-
mumab (47.2 percent; p<0.05 for both),
or resolution of dactylitis (76.5 and 79.5
percent, respectively) vs placebo (39.7
percent; p<0.001 for both).
Serious adverse events (AEs) at week
24 were more frequent with upadacitinib
30 mg (6.1 percent), but comparable
among upadacitinib 15 mg, adalimumab,
and placebo recipients (3.3, 3.7, and 3.1
29
DOCTOR | AUGUST ISSUE
percent, respectively). This was mirrored
with rates of serious infection (1.2, 2.6,
0.7, and 0.9 percent of upadacitinib 15
and 30 mg, adalimumab, and placebo
recipients, respectively). Herpes zoster
occurred in three, four, and five placebo,
upadacitinib 15 mg, and upadacitinib 30
mg recipients, respectively.
No major adverse cardiovascular
events were reported with upadacitinib.
Malignancies occurred in one patient
each on placebo and upadacitinib 15
mg, and three each on upadacitinib 30
mg and adalimumab. One patient each
on placebo and upadacitinib 30 mg and
two on adalimumab experienced venous
thromboembolism. There was one death
in the placebo group.
No new safety signals emerged com-
pared with that of upadacitinib in RA
treatment, noted the authors.
Upadacitinib is approved for the
treatment of RA, but SELECT-PsA-1 re-
searchers sought to examine its efficacy
in PsA. “These data are encouraging and
add to the growing body of evidence that
upadacitinib has the potential to improve
outcomes for people living with PsA,”
said McInnes. [https://news.abbvie.com/
news/press-releases/rinvoq-upadaci-
tinib-meets-primary-and-key-second-
ary-endpoints-in-phase-3-study-in-pso-
riatic-arthritis.htm, accessed 1 July 2020]
*SELECT-PsA-1: A study comparing upadacitinib (ABT-
494) to placebo and to adalimumab in participants
with psoriatic arthritis who have an inadequate re-
sponse to at least one non-biologic disease modifying
anti-rheumatic drug
**≥20 percent improvement from baseline in tender
joint count, swollen joint count, and ≥3 of the 5
remaining American College of Rheumatology (ACR)
core set measures: patient’s assessment of pain, pa-
tient’s global assessment of disease activity, physi-
cian’s global assessment of disease activity, HAQ-DI,
and high-sensitivity C-reactive protein (hsCRP)
***HAQ-DI: Health Assessment Questionnaire-Disabili-
ty Index; FACIT-F: Functional Assessment of Chron-
ic Illness Therapy – Fatigue; SF-36 PCS: Short Form
Health Survey – Physical Component Summary
#
PASI75: 75 percent improvement in the Psoriasis Area
Severity Index

European E-Congress of Rheumatology 2020 (EULAR 2020) • June 3-August 31
Olokizumab excels in RA uncontrolled on MTX
PEARL TOH
T
he investigational interleukin (IL)-6
inhibitor olokizumab is effective in
improving symptoms and phys-
ical function of patients with moder-
ate-to-severe rheumatoid arthritis (RA)
who are inadequately controlled on
methotrexate (MTX), according to the
CREDO-1 study presented at EULAR
2020.
At week 12, the primary outcome
of ACR20* response was achieved by
significantly more patients treated with
olokizumab than placebo (63.6 per-
cent and 70.4 percent vs 25.9 percent
for olokizumab 64 mg Q2W and Q4W
vs placebo, respectively; p<0.0001 for
both). [EULAR 2020, abstract OP0021]
Also, more patients in both the oloki-
zumab arms attained low disease activi-
ty at week 12 (defined as DAS28** <3.2)
compared with the placebo arm (33.6
percent and 38.7 percent vs 3.5 per-
cent, respectively; p<0.0001 for both).
“Efficacy was achieved for all classi-
cal endpoints at weeks 12 and 24 and
over time,” reported Dr Rumen Stoilov
of University Hospital St. Ivan Rilski in
Sofia, Bulgaria.
At week 24, ACR50 responder rates
were also significantly greater with both
olokizumab regimens than with placebo
(42.7 percent and 48.6 percent vs 7.7
percent; p<0.0001 for both). Similarly,
ACR70 response rates were higher in
olokizumab-treated patients than those
on placebo (19.6 percent and 22.5 per-
cent vs 2.1 percent, respectively).
In addition, physical function mea-
sured on the HAQ-DI*** showed greater
improvements from baseline in both the
olokizumab arms vs the placebo arm at
week 12 (least-squares mean change,
-0.54 and -0.56 vs -0.20, respectively;
p<0.0001 for both).
CONFERENCE COVERAGE
“Both regimens of olokizumab were
significantly better than placebo in all
primary and secondary endpoints,”
Stoilov said. “Improvements in efficacy
outcomes became evident after 4 to 8
weeks from olokizumab initiation and
were maintained throughout the 24-
week period.”
The double-blind, multicentre,
phase III study involved 428 patients
(mean age 52.3 years, 82.7 percent fe-
male) with moderately to severely active
RA despite MTX treatment. They were
randomized 1:1:1 to receive subcuta-
neous olokizumab 64 mg Q2W or Q4W
or placebo for 24 weeks. From week
14 onwards, rescue medications were
allowed for nonresponders. After week
24, participants were eligible to enter an
open-label extension study.
Overall, treatment-emergent ad-
verse events (TEAEs) occurred in 58.0
percent, 57.0 percent, and 43.7 percent
of patients receiving olokizumab Q2W,
Q4W, and placebo, respectively. Se-
rious AEs were seen in 5.6 percent of
patients in both olokizumab arms com-
pared with 2.8 percent in the placebo
30
DOCTOR | AUGUST ISSUE
arm. There were no serious events of
thromboembolism, herpes zoster, or
gastrointestinal perforation.
Decreases in blood neutrophils oc-
curred predominantly in the olokizum-
ab arms (mean change from baseline,
-2.15 and -1.93 vs -0.19, respectively).
Elevations in total cholesterol levels and
liver enzymes were also seen with oloki-
zumab treatment.
According to Stoilov, “Safety profile
was consistent with phase II data and
with other agents with similar mecha-
nism of action.”
“There were no discernible differenc-
es between the two regimens of oloki-
zumab in efficacy or safety outcomes,”
he added.
*ACR20: American College of Rheumatology 20
percent improvement response
**DAS28: Disease Activity Score-28 for Rheumatoid
Arthritis
***HAQ-DI: Health Assessment Questionnaire Dis-
ability Index

European E-Congress of Rheumatology 2020 (EULAR 2020) • June 3-August 31
TNFi use in RA tied to reduced VTE risk
ROSHINI CLAIRE ANTHONY
P
atients with rheumatoid arthritis
(RA) treated with tumour necro-
sis factor (TNF) inhibitors may
have a reduced risk of venous throm-
boembolism (VTE) compared with those
treated with conventional synthetic dis-
ease-modifying antirheumatic drugs
(csDMARDs), according to an observa-
tional study presented at EULAR 2020.
“By treatment with TNF inhibitors, the
risk of major VTE events is reduced by al-
most half in comparison to csDMARDs,”
said lead author Dr Martin Schäfer from
the German Rheumatism Research Cen-
ter, Berlin, Germany.
“The risk of major VTE
events is reduced by
almost half”
The results were based on data from
the RABBIT* register in Germany which
tracks the disease course and biologic
treatment of >17,000 patients with RA.
The study involved 11,094 patients who
initiated a DMARD following insufficient
response to a csDMARD. In this co-
hort, 3,500 were receiving csDMARDs
(mean age 58.8 years, 73.6 percent fe-
male), 2,534 were receiving other biolog-
ic DMARDs (bDMARDs; mean age 58.1
years, 76.3 percent female), and 5,060
were receiving TNF inhibitors (mean age
56.5 years, 73.8 percent female). Mean
RA duration was 6.2, 11.9, and 9.4 years
in csDMARD, other bDMARD, and TNF
inhibitor users, respectively.
Baseline C-reactive protein (CRP)
levels were higher in patients on other
bDMARDs (mean, 12.4 mg/L) or TNF
inhibitors (mean, 11.6 mg/L) compared
with csDMARDs (mean, 8.8 mg/L). Car-
diovascular disease prevalence was also
higher in patients on other bDMARDs
CONFERENCE COVERAGE
or TNF inhibitors compared with csD-
MARDs (heart failure: 3.7, 2.2, and 1.0
percent, respectively; coronary artery
disease: 7.2, 6.4, and 5.6 percent, re-
spectively). bDMARD and TNF inhibitor
recipients also had a higher incidence of
osteoporosis than csDMARDs recipients
(20.9, 15.2, and 11.4 percent, respec-
tively), and were more likely to be receiv-
ing glucocorticoids (80.4, 78.1, and 73.3
percent, respectively). [EULAR 2020, ab-
stract OP0012]
VTE events occurred in 1.1 percent
of csDMARD or TNF inhibitor recipients
and in 0.9 percent of patients on other
bDMARDs. VTE risk was almost halved
among TNF inhibitor compared with
csDMARDs recipients (hazard ratio [HR],
0.53, 95 percent confidence interval [CI],
0.33–0.86). There was also a trend toward
reduced VTE risk among other bDMARD
compared with csDMARD recipients (HR,
0.66, 95 percent CI, 0.40–1.09).
Factors influencing a greater risk
of VTE were older age at baseline (≥65
years; HR, 2.96, 95 percent CI, 1.94–
4.52) and higher CRP levels (≥5 mg/L;
HR, 2.09, 95 percent CI, 1.39–3.14),
with an almost three- and twofold risk,
respectively. In contrast, better physical
31
DOCTOR | AUGUST ISSUE
function reduced VTE risk (HR, 0.85, 95
percent CI, 0.78–0.92 per 10 percentage
point increase in full physical capacity).
Previous research has shown that
VTE risk is increased in patients with RA.
[Ann Rheum Dis 2014;73:1774-1780] “In
the case of autoimmune diseases such
as RA, the immune system turns against
the body and causes inflammation in a
number of places. Inflammation may
have a disruptive effect on coagulation,”
pointed out EULAR president Profes-
sor Iain McInnes from the University of
Glasgow, Scotland, UK, who was not
affiliated with the study.
“For patients with an increased risk
of thrombosis, alternative treatment with
TNF inhibitors, and possibly other biolog-
ic drugs, should be considered instead
of standard csDMARD treatment,” noted
co-author Dr Anja Strangfeld, also from
the German Rheumatism Research Cen-
ter. “Reducing the inflammatory activity
is also an important factor to reduce the
risk of VTE,” she added.
*RABBIT: Rheumatoide Arthritis: Beobachtung der
Biologika-Therapie

European E-Congress of Rheumatology 2020 (EULAR 2020) • June 3-August 31
TULIP trials support clinical benefit of
anifrolumab in SLE
AUDREY ABELLA
T
he type I interferon receptor anti-
body anifrolumab reduced disease
activity and flares in patients with
moderate-to-severe active systemic lu-
pus erythematosus (SLE), results of the
TULIP-1 and TULIP-2 trials have shown.
The cohort comprised 726 SLE pa-
tients from TULIP-1 (n=364) and TULIP-
2 (n=362) who were receiving standard
treatment. Participants were randomized
1:1 to receive intravenous anifrolumab
300 mg Q4W or placebo for 48 weeks.
Primary endpoints were evaluated at
week(W)52.
Sustained benefit
In TULIP-1, more anifrolumab vs pla-
cebo recipients were classified as having
BICLA* responses at W4 (23 percent vs
18 percent), W8 (34 percent vs 23 per-
cent), and W12 (36 percent vs 28 per-
cent). A similar trend favouring anifrolum-
ab was also seen in TULIP-2 (27 percent
vs 21 percent [W4], 35 percent vs 21 per-
cent [W8], and 43 percent vs 32 percent
[W12]). [EULAR 2020, abstract OP0003]
By W52, overall BICLA responses in
favour of anifrolumab vs placebo were
sustained in both TULIP-1 and TULIP-2
(46 percent vs 30 percent and 48 per-
cent vs 32 percent, respectively).
Time to onset of BICLA responses
sustained from onset through W52 also
favoured anifrolumab over placebo in
both TULIP-1 and TULIP-2 (hazard ratios
[HRs], 1.93 and 1.55, respectively).
“[These show that] a greater pro-
portion of patients achieved BICLA re-
sponses … from onset through W52
with anifrolumab vs placebo … [The find-
ings] support the sustainability of clinical
benefit derived from anifrolumab [in this
setting],” said the researchers.
CONFERENCE COVERAGE
Uniform responses
In TULIP-1, between-group differ-
ences in BICLA responses favouring
anifrolumab over placebo were similar
across the subgroups of SLEDAI-2K**
scores at screening (17 percent for both
<10 and ≥10 points) and oral corticoste-
roid use (16 percent [<10 mg/day] vs 18
percent [≥10 mg/day]). [EULAR 2020,
abstract OP0049]
A similar trend was observed in
TULIP-2 (15 percent vs 17 percent [<10
vs ≥10 points in SLEDAI-2K scores] and
20 percent vs 12 percent [<10 vs ≥10
mg daily oral corticosteroid use]).
Between-group differences in BICLA
response rates also favoured anifrolum-
ab over placebo regardless of Type I
IFNGS*** tests, be it among those with
high (19 percent [TULIP-1] and 17 per-
cent [TULIP-2]) or low IFNGS (8 percent
and 11 percent, respectively).
“Other subgroups# showed similar
uniformity of response … The uniformity
of robust BICLA response rates across
prespecified subgroups in both trials [re-
flects the] consistent clinical benefit of
anifrolumab irrespective of patient base-
line characteristics,” said the research-
ers. However, caution is warranted in in-
terpreting the findings in view of the small
32
DOCTOR | AUGUST ISSUE
samples, they pointed out.
Flare drops
Flare-free rates were numerically
higher with anifrolumab vs placebo in
both TULIP-1 and TULIP-2 (64 percent
vs 56 percent and 69 percent vs 58 per-
cent, respectively). [EULAR 2020, ab-
stract SAT0174]
Compared with placebo, anifrolumab
also led to reductions in time to first flare
(HRs, 0.76 and 0.65 for TULIP-1 and
TULIP-2, respectively) and BILAG-based
annualized flare rates (adjusted rate ratio,
0.83 and 0.67, respectively).
Apart from the reduced disease
activity, these results suggest that an-
ifrolumab reduced the incidence of
new or worsened flares, boosting its
clinical benefit in this patient subgroup,
said the researchers. The pooled data
also reinforce the favourable results of
each trial, they noted. [N Engl J Med
2020;382:211-221; Lancet Rheumatol
2019;1:e208-e219]
*BICLA: British Isles lupus assessment group
(BILAG)-based Composite Lupus Assessment, a vali-
dated composite global disease measure registering
partial and complete improvements within organ
systems.
**SLEDAI-2K: SLE Disease Activity Index 2000
***IFNGS: Interferon gene signature
#
Age, sex, age at onset, body mass index, race, ethnic-
ity, antidrug antibody status
 CONFERENCE COVERAGE
European E-Congress of Rheumatology 2020 (EULAR 2020) • June 3-August 31

Secukinumab gets FDA nod for nr-axSpA

ELVIRA MANZANO

T
he US FDA has given secukinum-
ab the greenlight for the treatment
of active non-radiographic axial
spondyloarthritis (nr-axSpA), following
its success in the phase III PREVENT
trial, the largest ever for a biologic in
nr-axSpa.

The nr-axSpA approval is the fourth

indication for secukinumab, a fully
human mAb* that selectively inhibits
IL-17A. The drug is also approved for
moderate-to-severe plaque psoriasis,
psoriatic arthritis, and ankylosing spon-
dylitis.

Secukinumab was demonstrated

to be superior to placebo in ASAS40**
outcomes after 52 weeks of therapy in
the PREVENT trial of 555 adults with
active nr-axSpA (onset before age 45,
spinal pain ≥40/100 on a visual analog
scale, and ≥4 on Bath Ankylosing Spon- Efficacy was noted as early as week Other tell-tale signs
dylitis Disease Activity Index). Patients 16 in patients treated with secukinumab of nr-axSpA
were biologic-naïve or had inadequate (with or without a loading dose) every 4 A few signs that could differentiate
response/were intolerant to tumour weeks. The safety outcomes were con- nr-axSpA from other types of backpain
necrosis factor (TNF) inhibitor. [EULAR sistent with previous secukinumab stud- depends on when the pain occurs, how
2020, abstract OP0106] ies, and there were no new safety signals. long it lasts, and what makes it feel better.

nr-axSpA patients treated with sub-
cutaneous injection of secukinumab
150 mg had a significant and clinically
meaningful reduction in disease activity
vs placebo (41.5 percent vs 29.2 per-
cent; p<0.05), as measured by a 40 per-
cent improvement in ASAS40 at week
16 that continued through week 52.
Statistically significant improve-
ments in the secondary endpoints of
pain, disease burden, and health-relat-
ed quality of life were also demonstrated
in the trial.
Efficacy evident at
16 weeks
PREVENT had two independent anal-
ysis plans – week 16 for the EU and week
52 for the US regulatory requirements.
The EU earlier approved secukinum-
ab for nr-axSpA in May. It is the third
agent greenlighted by the FDA for nr-ax-
SpA; the first two are certolizumab and
ixekizumab.
“The approval of secukinumab brings
a new therapeutic option for people liv-
ing with nr-axSpA,” said Dr Atul Deodhar,
medical director of Rheumatology Clin-
ics, Oregon Health & Science University,
Portland, Oregon, US, who is PREVENT
trial investigator.
The disease is characterized by
chronic inflammatory back pain with no
visible damage seen on pelvic/sacroiliac
(SI) X-rays, but with an elevated C-reac-
tive protein (CRP) or abnormal MRI SI
imaging.
Timing of pain can be at night or in
the morning. Morning stiffness makes it
difficult to get out of bed or get moving.
Pain however feels better when moving
around.
Symptoms often present in late ad-
olescence or early adulthood. Enthesi-
tis, an inflammation of the entheses
(where tendons or ligaments insert into
the bone), may set nr-AxSpA apart from
other types of arthritis. Fingers or toes
may swell up and some patients may
even experience uveitis (inflammation of
the uvea or the middle layer of the eye).
*mAb:monolonal antibody
**ASAS40: improvement of 40 percent in Assessment
of Spondyloarthritis International Society response
criteria

33
DOCTOR | AUGUST ISSUE

European E-Congress of Rheumatology 2020 (EULAR 2020) • June 3-August 31
Tanezumab
reduces pain
intensity, improves
daily function in
patients with chronic
low back pain
ELAINE SOLIVEN
T
reatment with tanezumab, a
monoclonal antibody against nerve
growth factor, significantly reduces
pain intensity and improves daily function
in patients with chronic low back pain,
according to a phase III trial presented at
EULAR 2020.
The trial included patients with chron-
ic low back pain who were randomly
assigned to receive placebo (n=409;
mean age 49.0 years), subcutaneous
tanezumab 5 mg (n=407; mean age
48.7 years) or 10 mg (n=407; mean age
49.1 years) every 8 weeks, or oral tra-
madol prolonged-release 100–300 mg/
day (n=602; mean age 48.4 years). Brief
Pain Inventory-short form (BPI-sf) scores
were used to assess the severity of pain
and impact on daily function at week 16.
[EULAR 2020, abstract OP0090]
At baseline, mean BPI-sf average
pain scores were 7.00 and 6.88 for the
tanezumab 5 and 10 mg groups, respec-
tively, and 6.95 and 6.97 for the placebo
and tramadol groups, respectively.
CONFERENCE COVERAGE
At week 16, patients who received
tanezumab 5 or 10 mg had significant
improvements from baseline in BPI-
sf scores for average pain compared
with those who received placebo (least
squares [LS] mean difference, -0.37;
p=0.04 for 5 mg or -0.46; p≤0.01 for
10 mg).
Patients treated with tanezumab 5 or
10 mg also reported significant improve-
ments in worst pain (LS mean difference,
-0.52 and -0.54, respectively; p≤0.01 for
both) and pain interference index scores
(LS mean difference, -0.41; p=0.03 and
-0.58; p≤0.01) at week 16 compared
with placebo.
Greater improvements were also
seen across all BPI-sf domains of daily
function with tanezumab 10 mg com-
pared with placebo or tramadol. These
included general activity (-3.35 vs -2.70
or -2.89; p<0.05), walking ability (-3.15
vs -2.55 or -2.68; p<0.05), sleep (-3.44
vs -2.92 or -3.00; p<0.05), and normal
work (-3.33 vs -2.64 or -2.87; p<0.05).
34
DOCTOR | AUGUST ISSUE
Patients treated with tanezumab 5
mg also demonstrated significant im-
provements vs placebo in general activity
(-3.20 vs -2.70; p<0.05), sleep (-3.88 vs
-2.92; p<0.05), and normal work (-3.15
vs -2.64; p<0.05).
The researchers found no statisti-
cally significant differences between the
tramadol and placebo treatment groups
with regard to any BPI-sf domains of
daily function.
According to study investigator Dr
Serge Perrot from Paris Descartes Uni-
versity in Paris, France, patients in this
study “had no, or minimal, clinical and
radiographic evidence of osteoarthritis in
the knees, hips, and shoulders.”
“[These findings showed that,] after
16 weeks, [treatment with] tanezumab 5
or 10 mg led to significant improvements
in worst pain, average pain, and overall
pain interference index compared with
placebo in patients with chronic low back
pain,” he said.
 FOCUS ON ATTR-CM

Tafamidis emerges
as first approved
treatment for ATTR-CM
ROSHINI CLAIRE ANTHONY NYHA** class (I or II vs III), and tafa-
Adjunct Associate

T
reatment with tafamidis led
to a reduction in all-cause
mortality and cardiovascu-
lar (CV)-related hospitalizations
among patients with transthyre-
tin amyloid cardiomyopathy (AT-
TR-CM), according to the phase III
ATTR-ACT* trial.
The international study popu-
lation comprised 441 individuals
aged 18–90 years (median age 75
years) with ATTR-CM. They were
randomized 2:1:2 to receive ta-
famidis 80 mg, tafamidis 20 mg
(n=264 in the pooled population),
or placebo (n=177) once daily for
30 months. Twenty-four percent of
the patients had pathogenic muta-
tions in the transthyretin gene TTR
(ATTRm), with Val122Ile, Thr60Ala,
and Ile68Leu the most common
mutations.
In a pooled analysis of both ta-
famidis doses, all-cause mortality
was significantly lower among tafa-
midis dose (80 vs 20 mg).
Professor Tan Ru San
However, patients with baseline
NYHA class III had a higher rate of Senior Consultant
CV-related hospitalization with ta- Department of Cardiology
famidis vs placebo potentially due National Heart Centre Singapore
to extended survival during more
severe disease. “[This underscores]
the importance of early diagnosis
and treatment of this fatal, progres-
sive disease, which can be difficult
to diagnose,” the authors said.
Tafamidis recipients also experi-
enced improved functional capacity
compared with placebo recipients,
as demonstrated by a reduced de-
cline in distance walked in six-min-
ute walk test between baseline and
30 months (75.68 m; p<0.001),
and improved quality of life as per
a reduced decline in Kansas City
KOL perspective
Cardiomyopathy Questionnaire–
Overall Summary (KCCQ-OS) score
(13.65; p<0.001). The role
of tafamidis
Adverse event (AE) incidence
was similar between tafamidis and

in treating
midis compared with placebo recip- placebo, with no apparent differ-
ients (29.5 percent vs 42.9 percent; ence between tafamidis doses.
hazard ratio, 0.70, 95 percent con-

fidence interval [CI], 0.51–0.96). [N
Engl J Med 2018;379:1007-1016]
CV-related hospitalization was
also reduced among tafamidis vs
placebo recipients (0.48 vs 0.70
per year; relative risk ratio, 0.68, 95
percent CI, 0.56–0.81).
The greater reduction in all-
cause mortality occured at approx-
imately 18 months post-treatment.
The mortality and hospitalization
findings favouring tafamidis were
also consistent regardless of TTR
status (ATTRm or wild-type ATTR),
“ATTR-ACT showed that tafa-
midis is superior to placebo in re-
ducing the combination of all-cause
mortality and CV-related hospital-
izations,” said the authors. “These
findings indicate that tafamidis is an
effective therapy for ATTR-CM.”
“Given the progressive nature
of the disease and the mechanism
through which tafamidis reduces
amyloidogenesis – by specifically
stabilizing transthyretin tetramers –
the drug is expected to have great-
er benefit when administered early
in the disease course,” they added.
ATTR-CM
Evidence on the prevalence
of ATTR-CM in Singapore and
Southeast Asia is scarce and
mainly acquired through case
studies. The condition is probably
underdiagnosed, and screening
is insufficient. MIMS Doctor did
a one-on-one interview with Prof
Tan on the role of the new agent
tafamidis in adult patients with
wild-type or hereditary ATTR-CM.

35
DOCTOR | AUGUST ISSUE

How common is
hereditary vs
wild-type ATTR-CM?
Wild-type ATTR-CM is more
common than hereditary
ATTR-CM. In Asia, data on
ATTR-CM is primarily from
Japan where a retrospective
analysis of 23 million adults
hospitalized in 2010–2018
showed a prevalence of
3–5 per million patients for
hereditary ATTR-CM and
150–190 per million for wild-
type ATTR-CM. [Cardiol
Ther 2019;8:297-316] How-
ever, the true prevalence of
wild-type ATTR-CM may be
higher. In autopsy studies,
about a quarter of hearts
of persons aged ≥80 years
contained wild-type TTR fi-
brils, regardless of the pres-
ence of symptoms. [Ann Med
2008;40:232-239]
How is ATTR-CM
monitored in
asymptomatic
patients?
Physicians need to be watch-
ful for early manifestations
of ATTR-CM which include
orthopaedic presentations
such as bilateral carpal tun-
nel syndrome, biceps tendon
rupture, and lumbar stenosis.
There is no specific serolog-
ical biomarker for ATTR-CM.
However, among patients
with heart failure (HF), dis-
proportionately high N-termi-
nal (NT)-pro hormone BNP
(NT-proBNP) levels coupled
with raised highly sensitive
cardiac troponin, which sug-
gests a certain degree of
myocardial damage or injury,
could signal ATTR-CM.
*ATTR-ACT: The Transthyretin Amyloidosis
Cardiomyopathy Clinical Trial
**NYHA: New York Heart Association
FOCUS ON ATTR-CM
How important is early detection and treatment of ATTR-CM?
In the past, prognosis of ATTR-CM was dire,
rendering timing of diagnosis immaterial. The
introduction of specific anti-amyloid pharma-
cological treatment, which can reduce and
even reverse amyloid deposition in the heart
muscles, could lead to improved survival and
quality of life.
Ideally, all patients with ATTR-CM should
undergo genetic testing, regardless of AT-
Prior to tafamidis approval, how was ATTR-CM managed?
Most patients with ATTR-CM are managed
symptomatically, primarily with diuretics to
encourage fluid output and reduce systemic
fluid overload. Guideline-recommended op-
timal medical therapy for HF does not apply
to ATTR-CM and should be used with cau-
tion, if at all. If beta blockers are used, the
possibility of conduction problems needs to
be considered, and the potential use of pro-
phylactic pacing may have to be instituted.
As abnormal ATTR is manufactured in the
liver, liver transplant is a treatment option. It
What is the benefit of tafamidis?
Past oral management strategies have not
been very effective. Tafamidis is the first and
only approved treatment for ATTR-CM. It
has been assessed in a phase III trial (AT-
TR-ACT), where it demonstrated reduced
all-cause mortality and CV-related hospital-
ization in patients with ATTR-CM who had
prior hospitalization for HF.
Tafamidis can be used at all stages of AT-
TR-CM, from early in the disease course or
Are there contraindications to prescribing tafamidis?
There are no major contraindications to us-
ing tafamidis. The ATTR-ACT study showed
no serious safety signals with tafamidis com-
pared with placebo. Urinary tract infections
and diarrhoea were more common in the
latter group. The drug is predominantly ex-
creted in the liver, and there is no dose ad-
justment required in patients with abnormal
36
DOCTOR | AUGUST ISSUE
TR-CM type. Hereditary ATTR-CM is an
autosomal dominant disease and its mani-
festation is age-dependent. Detecting the
mutation would enable screening of family
members and guide treatment choice. For
instance, patients with the Val30Met muta-
tion of the transthyretin gene have a good
prognosis following liver transplant. Early
treatment could also avert many ATTR-CM
complications.
is effective in doubling the median survival
in certain patients, especially those with Val-
30Met ATTR-CM. Unfortunately, this is not
feasible for many patients due to age restric-
tion, cost, and lack of access. Liver transplant
may not cure ATTR-CM, nor does it guaran-
tee removal of TTR from myocardial tissue.
Among patients with Val30Met ATTR-CM
who present with severe heart disease, their
heart condition may potentially deteriorate af-
ter liver transplant. In these cases, patients
may need to undergo the high-risk option of
heart and liver transplants.
as an alternative to liver transplant. It can
also be used prior to or after liver transplant.
For example, tafamidis could be a substi-
tute for heart transplant after liver transplant
in patients with mild-to-moderate cardiac
dysfunction. Mechanistically, tafamidis helps
stabilize the tetrameric transthyretin protein
and ameliorate the deposition of abnormal
amyloid fibrils in organs. As such, it is very
plausible that early initiation of tafamidis may
help prevent pathological changes.
kidney function. This is important as patients
with kidney amyloid deposition may have re-
nal impairment. While women of reproduc-
tive age are not the primary group affected
by ATTR-CM, caution is however advised
when prescribing tafamidis in this group,
with concurrent advice for pregnancy plan-
ning and contraception warranted.

Cetirizine an attractive alternative
to diphenhydramine for hives
JAIRIA DELA CRUZ
C
etirizine drip for treating acute
urticaria or hives is as effective
as intravenous (IV) diphenhydr-
amine, with the added benefits of less
sedation, fewer adverse events, shorter
treatment time, and lower rates of revisit
to treatment centre, according to the re-
sults of a phase III study.
“Acute urticaria typically responds to
pharmacotherapy, with antihistamines
being the first-line treatment. The paren-
teral route of administration is often pre-
ferred to provide rapid onset of action,”
the investigators said. [J Allergy Clin Im-
munol 2014;133:1270-1277; Am Fam
Physician 2017;95:717-724]
“Overall, these
clinical trial data
have applicability in
emergency medicine as
well as other settings”
IV diphenhydramine has been a treat-
ment standard, but like other first-gener-
ation antihistamines, the drug is known
to have sedating effects that can cause
significant driving impairment compara-
ble to or greater than that of alcohol in-
toxication (blood alcohol level of 0.1 per-
cent), leading to recommendations that
patients not drive after treatment, they
pointed out. [Hum Psychopharmacol
2016;31:167-177; Ann Allergy Asthma
Immunol 2004;92:294-303]
In the current trial, 262 acute urticaria
patients (mean age, 39 years; 63 per-
cent female) who presented to emergen-
cy departments (EDs) and urgent care
centres requiring an IV treatment were
randomized to receive either the sec-
ond-generation antihistamine cetirizine
10 mg (n=127) or the first-generation
diphenhydramine 50 mg (n=135).
NEWSBITES
Cetirizine-treated patients experi-
enced less sedation than those who
received diphenhydramine. The corre-
sponding mean patient-rated sedation
scores (from 0 indicating not drowsy at
all to 3 being extremely drowsy) were
0.2 vs 0.7 (p=0.003) in the first hour
following treatment, 0.1 vs 0.5 (p=0.03)
at the 2-hour assessment, and 0.1 vs
0.5 (p=0.04) at discharge. The same
pattern of changes was observed
among older patients (age ≥65 years).
[Ann Emerg Med 2020;doi:10.1016/j.
annemergmed.2020.05.025]
Cetirizine was also associated with
fewer adverse events (AEs; 3.9 percent
vs 13.3 percent). Of the 31 AEs, only
seven occurred with the drug. Dizziness
and nausea were the most common
AEs, and all were documented in the di-
phenhydramine arm (4.4 percent and 3.0
percent, respectively).
“The safety and tolerability of ceti-
rizine have been well established during
the past 30 years,” the investigators
noted, adding that its IV and oral formu-
lations have similar safety profiles. [Drugs
2004;64:523-561]
In terms of efficacy, the 2-hour pruri-
tus score change from baseline with ceti-
rizine was noninferior to that with diphen-
37
DOCTOR | AUGUST ISSUE
hydramine (–1.6 vs –1.5, respectively, 95
percent confidence interval, –0.1 to 0.3;
p=0.35). This held true in subgroups of
patients defined by age (<65 and ≥65
years).
The number of “effectively treated”
patients according to physician assess-
ment was higher in the cetirizine arm
(p=0.02), and more patients required
rescue drug use in the diphenhydramine
arm (p=0.016). The most common res-
cue medication was corticosteroids in
both groups.
Cetirizine was also associated with
shorter time spent in treatment centre
(1.7 vs 2.1 hours; p=0.005) and fewer
instances of returning to the centre (5.5
percent vs 14.1 percent; p=0.02).
“Overall, these clinical trial data have
applicability in emergency medicine as
well as other settings, including emerg-
ing models of care in which safety and
sedation will be of paramount impor-
tance,” the investigators said.
“Although economic outcomes were
not captured in the current clinical trial,
the observed reductions [in] time spent
in ED, ED readmission rate, and rescue
medication use with IV cetirizine may
confer cost savings,” they added.

Cardiac CT doubling as bone density scan
for osteoporosis?
PEARL TOH
V
ery low thoracic bone mineral
density (BMD) measured on car-
diac CT scan is predictive of a
higher fracture risk, especially osteopo-
rosis-related fracture — thus highlighting
the potential utility of cardiac CT for op-
portunistic BMD screening.
“Many osteoporotic fractures occur
in individuals who have never been
screened,” wrote Professor Miriam Bre-
della of Harvard Medical School, Bos-
ton, Massachusetts, US, in a linked
editorial. [Radiology 2020;doi:10.1148/
radiol.2020202374]
“The prevalence of
chest CT imaging
provides a unique
opportunity for
opportunistic BMD
testing”
“Effective anti-osteoporotic treat-
ment exists and so, identifying individ-
uals with greater fracture rate who may
benefit from such treatment is imper-
ative,” said lead author Dr Josephine
Therkildsen from Herning Hospital, Hos-
pital Unit West in Herning, Denmark.
“The prevalence of chest CT imag-
ing provides a unique opportunity for
opportunistic BMD testing,” Therkildsen
and co-authors pointed out. “Routine
cardiac CT can be used to help mea-
sure thoracic BMD to identify individuals
who have low BMD and a greater frac-
ture rate.”
As cardiac CT also images the tho-
racic vertebrae (in addition to the heart),
this can be exploited for measurement
of spine BMD.
NEWSBITES
The prospective cohort study in-
volved 1,487 consecutive participants
who were referred for cardiac CT to
assess ischaemic heart disease. During
a median follow-up of 3.1 years, 80
participants (5.3 percent) had an inci-
dent fracture. Among the 80 incident
fractures, 31 were osteoporosis relat-
ed. [Radiology 2020;doi:10.1148/radi-
ol.2020192706]
The risk of any fracture was signifi-
cantly higher in participants with very
low BMD on cardiac CT (<80 mg/cm3)
compared with those with a normal
BMD (>120 mg/cm3; hazard ratio [HR],
2.6; p=0.002).
In particular, very low BMD was as-
sociated with a substantially elevated
risk of any osteoporosis-related fracture
vs normal BMD (HR, 8.1; p=0.001).
The associations with very low BMD
remained for any fracture (HR, 2.1; 95
percent confidence interval [CI], 1.1–
4.2) and any osteoporosis-related frac-
ture (HR, 4.0; 95 percent CI, 1.1–14.6)
after adjustment for age and sex.
While current guidelines recommend
using DEXA* as a diagnostic test for os-
teoporosis, a previous study has shown
that quantitative CT better predicts ver-
38
DOCTOR | AUGUST ISSUE
tebral fractures than DEXA scan, the
authors noted. [Bone 2016;92:100-106]
“Our results represent a step toward
appraisal and recognition of the clinical
utility of opportunistic BMD screening
from cardiac CT,” said Therkildsen and
co-authors.
According to Therkildsen, it is rela-
tively easy to add BMD testing to cardi-
ac CT as it does not require additional
time and radiation exposure to the pa-
tient. BMD measurements are possible
using existing CT images as long as
there are continuous scanner stability,
systematic imaging acquisition, plus a
suitable calibration system.
“We believe that opportunistic BMD
testing using routine CT scans can be
done with little change to normal clinical
practice and with the benefit of identi-
fying individuals with a greater fracture
rate,” said Therkildsen.
Future studies will help determine
the optimal thresholds for treatment
based on quantitative CT measure-
ments of thoracic spine BMD, the re-
searchers suggested.
*DEXA: Dual-energy X-ray absorptiometry

Positive anti-HBc tied to cirrhosis,
HCC in NAFLD patients
STEPHEN PADILLA
A
recent study involving Chinese
patients with nonalcoholic fatty
liver disease (NAFLD) suggests
that positive antihepatitis B core anti-
body (anti-HBc) is linked to cirrhosis and
possibly hepatocellular carcinoma (HCC)
and cirrhotic complications.
“In this large cohort of patients with
biopsy-proven NAFLD, we show that
positive anti-HBc was associated with
cirrhosis independent of age and meta-
bolic factors,” the researchers said. “Pa-
tients with positive anti-HBc also had a
higher incidence of liver-related events.”
Overall, 489 patients with biop-
sy-proven NAFLD and 69 with NA-
FLD-related or cryptogenic HCC were in-
cluded in this multicentre study. Anti-HBc
was used to detect the previous hepatitis
B virus (HBV) infection.
“Patients with positive
anti-HBc also had a
higher incidence of
liver-related events”
Positive anti-HBc correlated with
lower steatosis grade but higher fibrosis
stage in the biopsy cohort. Of the pa-
tients, 18.8 percent with positive and 7.5
percent with negative anti-HBc had cir-
rhosis, respectively (p<0.001). The signif-
icant association between anti-HBc and
cirrhosis persisted even after adjusting
for age and metabolic factors (adjusted
odds ratio, 2.232, 95 percent confidence
interval, 1.202–4.147). [Am J Gastroen-
terol 2020;115:867-875]
Furthermore, positive anti-HBc was
associated with a higher incidence of
HCC or cirrhotic complications (6.5 per-
cent vs 2.2 percent; p=0.039) over a
mean follow-up of 6.2 years. In addition,
NEWSBITES
positive anti-HBc was present in 73.9
percent of patients with NAFLD-related
or cryptogenic HCC. On the other hand,
no association was found between an-
tihepatitis B surface antibody and histo-
logical severity.
Several studies have also reported an
association between positive anti-HBc
and HCC in patients with chronic hepa-
titis C. [Gastroenterology 2004;126:102-
110; J Hepatol 2013;59:696-700; J Clin
Microbiol 2002;40:4068-4071; Hepa-
tology 2011;54:434-442; Intervirology
2008;51:352-361; Scand J Gastroenter-
ol 2008;43:849-856]
“Although all of our patients had neg-
ative serum HBV DNA, a few reasons
may explain the association between an-
ti-HBc positivity and HCC,” the research-
ers said.
“First, in all chronic liver diseases, the
clinical outcome is determined not only
by the current but also past disease ac-
tivity. Patients with active hepatitis in the
past could still accumulate more liver
injury with increased risk of HCC,” they
explained.
Second, those with positive anti-HBc
often present with detectable HBV DNA
or covalently closed circular DNA in the
39
DOCTOR | AUGUST ISSUE
liver, even with negative serum HBV
DNA. In addition, HBV DNA integration
into the host genome occurs frequently
in chronic HBV patients, persisting even
after HB surface antigen seroclearance,
according to the researchers. [Hepatolo-
gy 2011;54:829-836]
“HBV DNA integration is one of the
recognized mechanisms for HCC de-
velopment,” they added. [J Hepatol
2016;64:S84-101]
Of note, patients with positive an-
ti-HBc had lower body weight and body
mass index, higher high-density lipo-
protein cholesterol, and a trend toward
lower triglycerides, suggesting that the
metabolic factors were the main drivers
of liver disease in those with negative an-
ti-HBc, while both metabolic factors and
previous HBV infection were responsible
for liver injury in patients with positive an-
ti-HBc, according to the researchers.
Additionally, “[b]ecause NAFLD-re-
lated HCC may develop in noncirrhotic
patients, future studies should define
the role of anti-HBc in selecting non-
cirrhotic patients with NAFLD for HCC
surveillance,” they noted. [Clin Gastro-
enterol Hepatol 2011;9:428-433; Clin
Gastroenterol Hepatol 2016;14:124-
131.e1]

Add-on curcuminoid complex a promising
treatment option for knee OA
AUDREY ABELLA
A
dding curcuminoid complex (CC)*
to diclofenac led to greater im-
provements in pain and functional
capacity, with better tolerability in indi-
viduals with knee osteoarthritis (OA), an
Indian study has shown, highlighting the
potential of add-on CC as an alternative
approach when managing knee OA.
Despite the variety of nonopioid anal-
gesics** available for knee OA treatment,
there remains a need for more effective
and safer alternatives owing to the risks***
tied to long-term use of nonopioid anal-
gesics. [Arthritis Res Ther 2008;10:R85]
Given the reported analgesic, an-
ti-inflammatory, and gastroprotective
properties tied to curcumin and/or its
derivatives, the team sought to evaluate
its effects in 140 adults with knee OA.
Participants were randomized 1:1 to re-
ceive diclofenac 50 mg BID either alone
(diclofenac arm) or in combination with
CC 500 mg BID (CC arm) for 4 weeks.
[Medicine 2020;99:e19723]
From baseline to day 14, the CC arm
outshone the diclofenac arm in terms
of improvements in KOOS# subscales
(mean change, 25.18 vs 20.53 [pain] and
24.54 vs 17.23 [quality of life]). The sig-
nificant between-group differences were
mirrored at day 28 (mean change, 41.45
vs 37.23 and 41.20 vs 30.35, respective-
ly; p<0.001 for all).
Pain intensity was also significantly
reduced at day 14 (3.73 vs 1.38) and day
28 (4.58 vs 2.20; p<0.001 for both) in the
CC vs the diclofenac arm.
“Every patient in [the CC arm] had
>50 percent reduction in Visual Ana-
logue Scale score from baseline levels
compared to only 67 patients in the di-
clofenac arm … [This] clearly shows
the significant analgesic property of [the
combo regimen],” said the researchers.
NEWSBITES
The rate of rescue analgesic use was
lower in the CC vs the diclofenac arm (3
percent vs 17 percent; p<0.005), as was
H2 blocker use (6 percent vs 28 percent;
p<0.001). The former depicts the more
stable pain control with CC-diclofenac,
while the latter underpins the anti-ulcer
potential of CC, they noted.
Apart from the ability of CC to poten-
tiate the analgesic effect of NSAIDs, its
gastroprotective and anti-ulcer effects
may also aid in reducing the adverse
gastrointestinal effects of NSAIDs, they
added.
The incidence of adverse events –
which were mostly mild and transient
– was also significantly lower in the CC
vs the diclofenac arm (13 percent vs 38
percent; p<0.001). The greater fraction
of patients favouring CC-diclofenac
over diclofenac alone (30 percent vs 17
percent) reflects the better acceptability
profile of the combo regimen, noted the
researchers.
Synergistic effect
A major drawback of curcumin is
its poor pharmacokinetic/pharmaco-
dynamic properties, which may curtail
its therapeutic efficacy. [J Med Chem
2017;60:1620-1637; Int J Cancer
2010;126:1771-1775] Combining cur-
cuminoids with essential turmeric oil and
turmerones may enhance its bioavailabil-
ity which, according to the researchers,
40
DOCTOR | AUGUST ISSUE
may have been responsible for the bene-
fits of CC seen in the study.
“[Our findings suggest a] synergistic
effect between CC and diclofenac …
[Both] curcumin and NSAIDs … inhibit
COX-2 by different mechanisms – cur-
cumin downregulates COX-2 mRNA and
protein levels, while NSAID inhibits COX
enzyme activity directly by binding to its
active site,” they said. “[D]ue to its high
bioavailability, [CC may be given] along
with diclofenac … if monotherapy is in-
adequate.”
The favourable effects of add-on CC
appear to meet the primary goals of knee
OA therapy, which focus on pain relief and
physical function improvement, as well
as slowing the progression of underlying
structural damage, said the researchers.
However, the short study duration,
lack of placebo arm, and use of sub-
jective pain measurements are potential
limitations, they pointed out. Longer trials
are thus warranted to ascertain the long-
term efficacy and safety of the combo
regimen. Its effects in the different stages
of knee OA should also be explored in
future trials, they added.
*Curcumin, demethoxycurcumin, bisdemethoxycur-
cumin, and volatile oils from turmeric rhizome
**Acetaminophen, NSAIDs, COX-2 inhibitors
***Gastrointestinal bleeding, hypertension, congestive
heart failure, renal insufficiency
#
KOOS: Knee injury and OA Outcome Score

Vegan, vegetarian diets may increase
susceptibility to depression
JAIRIA DELA CRUZ
F
ollowing vegan and vegetarian di-
ets, which offer plenty of what is
good for health, has a downside:
it could increase the risks of depres-
sion and anxiety, particularly in younger
adults, according to a new study.
The finding may be explained by a
reverse causal relationship, whereby
individuals with psychosocial disorders
are more keen to follow both diets to
improve their mental health, according
to the investigators.
“Other possible explanations from
the literature include nutrient deficien-
cies common in vegan diets (eg, certain
amino acids, long-chain omega-3 fatty
acids, vitamins B6 and B12, zinc, cre-
atine, and even cholesterol) that could
accelerate or worsen pre-existing men-
tal conditions. All these deficiencies
have been linked to a higher risk of men-
tal health disorders,” they added. [Am J
Clin Nutr 2009;89:1627S-1633S; Indian
J Psychiatry 2008;50:77-82; Psychoth-
er Psychosom 2004;73:340-343]
The investigators performed a me-
ta-analysis of 13 studies evaluating the
effect of vegetarian (lacto-ovovegetari-
an, ovo-vegetarian, or lacto-vegetarian)
or vegan diets on mental or cognitive
outcomes in 17,809 adults in total.
Most studies were of medium quality.
Pooled data showed that relative
to an omnivorous diet, vegan and veg-
etarian diets were associated with an
elevated risk of depression (odds ratio
[OR], 2.142, 95 percent confidence
interval [CI], 1.105–4.148; I2, 65.4 per-
cent; p=0.089) but lower levels of anx-
iety (mean difference [MD], −0.847, 95
percent CI, −1.677 to −0.018; I2, 92.08
percent; p=0.001). There was no effect
seen on stress and memory impair-
ment. [Nutr Rev 2020;doi:10.1093/nu-
trit/nuaa030]
NEWSBITES
Clear age-dependent patterns
emerged in subgroup analyses, such
that vegans and vegetarians aged <26
years were at higher risk of the following
mental health outcomes than younger
omnivores: depression (MD, 1.739, 95
percent CI, 0.758–2.719), anxiety (MD,
0.901, 95 percent CI, 0.143–1.658),
and stress (MD, 1.033, 95 percent CI,
0.478–1.587).
“[The above finding] might reflect the
greater vulnerability of young people to
nutritional deficiencies, since their brain
and personality are still developing,” the
investigators noted.
Vegetarians and lacto-ovovegetari-
ans were described in the current study
as those who abstained from eating
meat, fish, and seafood but not milk
and dairy products from their diet. Veg-
ans, on the other hand, were those who
excluded any kind of animal product
from their diet.
“The necessary intakes of protein,
fat, carbohydrate, vitamins, and min-
erals within vegetarian and vegan diets
for optimal health is still under investiga-
tion. [Individuals who follow such diets]
may require supplementation, as some
41
DOCTOR | AUGUST ISSUE
nutrients may not be adequately avail-
able from plant sources,” according to
the investigators.
“Some supplements (eg, vitamin
B12, zinc, and creatine) to improve
short-term memory and intelligence/
reasoning may help in very restricted
diets. Otherwise, a well-chosen plant-
based diet provides all the necessary
protein, fats, carbohydrates, vitamins,
and minerals for optimal health,” they
said.
While the meta-analysis highlights
the potential for negative mental health
outcomes in individuals who adopt a
vegetarian/vegan diet, the considerable
heterogeneity among the included stud-
ies prevents definitive conclusions from
being drawn, the investigators pointed
out. “A major flaw in current literature
on this topic is the lack of adjustment
for confounders.”
“More studies on the effects of
vegan or vegetarian diets on mental
health, especially cognitive outcomes,
with overall better quality, are need-
ed before clear positive or negative
associations can be confirmed,” they
added.
 RESEARCH REVIEW

Synthetic Mindful
antibody neutralizes hypnotherapy may be
coronavirus good stress buster

C
ombining hypnotherapy with mindfulness training has a
positive effect on stress, a study has shown.

Mindfulness is an ancient mental technique used to manage

stress and anxiety. Hypnosis, like mindfulness, also involves fo-
cusing attention, but includes mental imagery, relaxation, and
suggestions for symptom reduction, said study author Dr Gary
Elkins from Baylor University, Waco, Texas, US.

Elkins and team analysed the effects of mindful hypnother-

apy in 42 participants who self-reported high stress levels. Half
of the participants took part in eight weekly, 1-hour hypnosis
interventions that incorporated hypnotic and mindfulness strat-
egies. The remaining half served as controls.

Patients who took part in mindful hypnotherapy reported

N
a significant reduction in perceived distress and an increase in
ew research in mouse model suggests that a synthetic mindfulness.
antibody could be effective at fighting the new coronavi-
rus SARS-CoV-2 that is responsible for COVID-19. “Combining mindfulness and hypnotherapy in a single ses-
sion is a novel intervention that may be equal to or better than
Researchers from the US did this by designing a decoy existing treatments ... This could be a valuable option for treat-
ACE2 that can neutralize the virus before it can attach to the ing anxiety and reducing stress, said Elkins.”
ACE2 on the cells and cause infections.
Oledzki, N et al. Mindful Hypnotherapy to Reduce Stress and Increase Mindfulness:
A Randomized Controlled Pilot Study. Int J Clin Exp Hypn 2020;68:151-166.
ACE2, in a soluble form, has been used by scientists pre-
viously. It is safe in humans, but generally does not stay in the
body for long. Hence, it cannot reach the lining of the lungs in
time, which is crucial for treating respiratory infections.

To overcome this limitation, the team attached ACE2 to the

end of an antibody to increase its stability and half-life. Four dif-
ferent antibodies were created, each with a different mutation.

All antibodies worked against SARS-CoV-2, but MDR504

was particularly effective. The virus bound more tightly to
MDR504 than it does to the human ACE2, suggesting that the
antibody could effectively outcompete the ACE2 expressed on
bodily cells, thus preventing the virus from infecting them.

The researchers said MDR504 could be used by healthcare

professionals for pre- or post-exposure prophylaxis or treat-
ment of COVID-19 and in patients who are ineligible to receive
a vaccine for health reasons.

Iwanaga, N. et al. Novel ACE2-IgG1 fusions with improved activity against SARS-
CoV2. bioRXIV 2020; doi:https://doi.org/10.1101/2020.06.15.152157.

42
DOCTOR | AUGUST ISSUE
 CLINICAL INSIGHTS | DEVICE
Fitness trackers may help gauge
lockdown adherence
TRISTAN MANALAC
U
sing data from wearable activity
tracking devices may be useful
for determining adherence to
home confinement and control mea-
sures put in place to combat the coro-
navirus disease 2019 (COVID-19) pan-
demic, according to a recent study.
“Objective, real-time measures to
assess population adherence to con-
finement are essential to adapt policies
and control measures accordingly,” re-
searchers said. “In the context of the
COVID-19 pandemic, activity trackers
provide a valuable data set that ob-
jectively document the time course of
adherence to home confinement world-
wide in response to the outbreak.”
Data from over 740,000 individuals
wearing fitness trackers were accessed
in the current study. Before COVID-19,
the mean number of daily steps followed
a consistent pattern across all countries
sampled, showing a reproducible drop
in counts during weekends. [J Med In-
ternet Res 2020;22:e19787]
After governments imposed varying
levels of quarantines in response to the
pandemic, noticeable changes in step
counts were observed.
For instance, in countries where to-
tal lockdowns were put in place, step
counts decreased greatly, changing
by 25 percent to 54 percent. In those
“Aggregate analysis of with partial lockdown measures, the
activity tracker data, researchers noted no significant clinical
impact on the wearers’ physical activity,
with the potential for
relative to prepandemic levels. Patterns
daily updates, can of movement in the partial-quarantine
inform governments countries mirrored that in territories
and stakeholders on without restriction orders.
adherence to home
Partial lockdowns were defined as
confinement policies” “social distancing measures such as
school closures, bar and restaurant
closures, and cancellation of public
43
DOCTOR | AUGUST ISSUE
meetings but without strict home con-
finement.”
The researchers also pointed out
that in France and Spain, the track-
ing devices logged a steady decline in
physical activity even in the days lead-
ing up to the official commitment to a
quarantine. More recently, however,
the activity trackers started detecting
upticks in movement, potentially indi-
cating slipping compliance to restriction
orders.
The researchers also highlighted
that the detected changes in activi-
ty level were all statistically significant.
This may be partly due to the large vol-
ume of data used, and the uniformity
with which the trends in step counts
changed. Importantly, this suggests
utility in terms of monitoring general ad-
herence to lockdown measures.
“In fully locked-down countries, with
the exception of Ireland, the number of
steps decreased below the maximum
on weekends; this shows overall good
compliance with lockdown rules,” they
added.
The countries sampled for the cur-
rent study were chosen based on their
quarantine rules and the availability of
data from activity trackers. This device
came in the form of a wristwatch with an
embedded accelerometer for counting
steps. All wearers were informed that
their anonymized data could be col-
lected and used for research purposes,
and written consent was collected.
“Aggregate analysis of activity
tracker data, with the potential for daily
updates, can inform governments and
stakeholders on adherence to home
confinement policies as well as their
efficacy without violating citizens’ priva-
cy,” the researchers said.
 CLINICAL INSIGHTS | DEVICE
Circumcision device makes the cut
in paediatric procedures
JAIRIA DELA CRUZ
A
modified disposable circumcision
suture device (DCSD) facilitates
simpler and faster procedure in
children, with a relatively lower complica-
tion rate and better cosmetic results com-
pared with the conventional dorsal slit
technique, according to a recent study.
Traditional methods, such as for-
ceps-guided, dorsal slit, and sleeve re-
section, are considered the gold standard
in most male circumcision programmes.
[Photomed Laser Surg 2013;31:422-
427; Int J Surg 2017;43:17-25; Urology
2015;85:799-804]
“However, [such] procedures are
time-consuming and have some draw-
backs, including bleeding, wound infec-
tion, pain, and unsatisfactory cosmetic
results. In order to overcome these prob-
lems, many newer devices … have been
developed,” the investigators said.
The study assessed the surgical out-
comes and complications of a modified
circumcision using the DCSD (n=144)
against those of a conventional dorsal
slit procedure (n=140) in boys aged 7–16
years. There was no difference in patient
age or indications between the groups
(p>0.05).
Compared with the conventional
method, the use of the DCSD led to a sig-
nificantly shorter operation time (mean,
7.4 vs 21.3 minutes; p<0.001) and less
blood loss (mean, 2.6 vs 5.6 ml; p<0.001).
Intraoperative and postoperative pain
scores were also lower with the DCSD
“Circumcision (p<0.001). [Urology 2020;doi:10.1016/j.
using the modified urology.2020.06.018]
DCSD represents an
attractive alternative Patients in the device vs the conven-
tional group had faster incision healing
to the conventional time (mean, 12.2 vs 14.2 days; p<0.001)
technique for children” and higher satisfaction rate of penile cos-
metic appearance (99.3 percent vs 92.8
percent; p<0.01).
44
DOCTOR | AUGUST ISSUE
In terms of safety, the DCSD outdid
the dorsal slit method and was being
associated with a significantly lower
complication rate (4.3 percent vs 12.3
percent; p<0.05) and less frequent oc-
currences of severe oedema (0.7 per-
cent vs 5.8 percent; p<0.05). There
were no between-group differences
in the rates of bleeding, infection, and
wound dehiscence.
The investigators combined the ad-
vantages of traditional dorsal slit method
and the DCSD technique. They marked
the inner foreskin layer incision at 0.5–1.0
cm proximal to the coronal sulcus before
removing the prepuce via DCSD.
“In [that] way, the DCSD made an
even and symmetrical incision and avoid-
ed too much or too little skin removed,
keeping the lengths of the edges on
the inner and outer skin of the prepuce
consistent, thereby improving the penile
cosmetic appearance,” they pointed out.
The investigators also emphasized
the importance of selecting an appropri-
ate DCSD size to prevent intraoperative
and postoperative complications. The
circumcision device used in the trial was
chosen based on the penis circumfer-
ence in the flaccid state, abiding by the
principle of “larger rather than smaller.”
“With increased experience, we have
observed [that] a slightly larger DCSD
maintains a certain tension of the fore-
skin and avoids poor incision alignment,
ensuring better aesthetic results post-
operatively. If the DCSD is too large, too
much foreskin will be removed,” they
stated.
In light of the findings, circumcision
using the modified DCSD represents an
attractive alternative to the conventional
technique for children, with the potential
to be used around the world, according
to the investigators.
 CLINICAL INSIGHTS | DEVICE
Aerosol containment devices may
increase exposure to COVID-19
TRISTAN MANALAC
N
ovel devices developed to pre-
vent aerosol exposure during
intubation of coronavirus dis-
ease 2019 (COVID-19) patients appear
to have no significant benefit to laryn-
goscopists, according to a new study.
On the contrary, the use of such devic-
es may increase exposure to the virus.
“[N]ovel devices intended to pro-
tect the laryngoscopist require objec-
tive testing to ensure they are fit for
purpose and do not result in increased
airborne particle exposure,” research-
ers said.
The study used an in situ simulation
model to evaluate the intubation tech-
nician’s degree of exposure to airborne
particle sizes 0.3–5.0 µm in size, com-
pared across five containment devic-
es: aerosol box, sealed box with and
without suction, vertical drapes, and
horizontal drapes. Seven healthy vol-
unteers (age >18 years; 4 were males)
participated in the study, along with a
volunteer laryngoscopist.
A one-way, Kruskal-Wallis analysis
of variance revealed that over a 5-min-
ute interval, there was a significant dif-
ference in the median airborne particle
counts across the six trial scenarios, in-
cluding the use of five containment de-
vices and a no-device control. [Anaes-
thesia 2020;doi:10.1111/anae.15188]
Post hoc comparisons were then
performed. Using the sealed box with
active suction led to a significant drop
in the counts of 0.3-, 0.5-, 1.0-, and
2.5-µm particles at all time periods
“Evidence for the after 30 seconds (p=0.003). No such
safety and efficacy effect was found for particles 5.0 µm.
In comparison, sealed boxes without
of these devices is suction only reduced the counts of
lacking” 2.5-µm particles vs no device use, and
only at the 300-second (p=0.004) and
360-second (p=0.007) time points.
45
DOCTOR | AUGUST ISSUE
Both the horizontal and vertical
drapes presented no significant benefit
or disadvantage to the no-device control
across all particle sizes and time points.
Notably, the use of the aerosol box led
to a significant spike in the median par-
ticle count at 300 seconds. This was re-
ported for particles with 1 µm (p=0.002),
2.5 µm (p=0.008), and 5.0 µm (p=0.002)
sizes. The researchers also noticed that
aerosolized particles escaped from the
arms of the aerosol box with every pa-
tient cough, leading to particle counts
that were consistently higher than in all
other devices tested.
“The race to generate sustainable
equipment to protect healthcare workers
during tracheal intubation procedures
in patients with suspected or proven
COVID-19, particularly in settings where
[personal protective equipment] supply is
limited, has flooded the scientific com-
munity and social media with a variety
of novel devices meant to contain po-
tentially infectious aerosols produced by
patients,” the researchers said.
“Evidence for the safety and efficacy
of these devices is lacking,” they added.
The present study has important lim-
itations. These include its small size, in
situ simulation design, and the observed
variability of particle sizes across the dif-
ferent devices. “This suggests that the
level of laryngoscopist exposure is un-
predictable and likely influenced by the
aerosol containment device set-up and
the volume, negative pressure generated
from suction, and frequency of patient
coughing.”
“Further large-scale studies are
needed to examine aerosol containment
devices in this context, as well as trache-
al extubation,” they said. “The use of any
aerosol containment device has been
eliminated from our intubation protocols
until safety can be properly established.”
 CLINICAL INSIGHTS | IN PRACTICE
Managing hand, foot, and
mouth disease in primary care
Introduction
HFMD is a common childhood vi-
ral disease caused by enteroviruses
that belong to the human enterovirus
Dr Chan Si Min A species of the family Picornaviridae,
most commonly Coxsackie virus type
A (CA) and Enterovirus 71 (EV71). En-
While generally a self-
teroviruses are small non-enveloped
limiting condition, positive stranded RNA viruses that are
hand, foot, and mouth composed of four structural proteins
disease (HFMD) can called VP1, VP2, VP3, and VP4. VP1 is
spread very quickly, the major capsid protein and molecular
particularly among typing of the gene encoding is used to
classify circulating strains.
children attending
childcare centres. Dr Enteroviruses are neurotropic viruses.
Chan Si Min, Head and EV71 directly infects the central nervous
Senior Consultant at the tissue and is associated with histologic
Division of Paediatric findings of severe inflammation in the hy-
Infectious Diseases, pothalamus, brainstem, spinal cord, and
cerebellar dentate nucleus. Pathogene-
National University
sis of virologic and host factors affecting
Hospital, Singapore, disease severity are not well understood.
talks to Roshini Claire
Anthony about the Among the Coxsackie viruses,
complications and CA10, CA6, and CA16 are the predomi-
management of HFMD. nant serotypes seen in Singapore.
Large outbreaks of HFMD have been
reported in Asia-Pacific countries in-
cluding Malaysia, Taiwan, Japan, Korea,
Australia, Brunei, Vietnam, Cambodia,
and mainland China. HFMD is endem-
ic in Singapore, with more than half of
the cases occurring in children young-
er than 5 years. According to a Ministry
of Health report in 2018, the incidence
rate of HFMD was >14,000 per 100,000
children aged 0–4 years.
Disease transmission
HFMD is transmitted through direct
contact with nasal discharge, saliva, re-
spiratory secretions, vesicular fluid, or
faeces from an infected person, or in-
direct contact with contaminated items.
Viral shedding can continue from the
upper respiratory tract for 2 weeks and
from the gut for 4–12 weeks.
46
DOCTOR | AUGUST ISSUE
HFMD transmission can occur rap-
idly in childcare centres and kinder-
gartens, with attack rates usually <10
percent but up to >40 percent in some
preschools. Clusters or outbreaks occur
regularly and may sometimes result in
school closure in order to halt transmis-
sion. Early diagnosis and appropriate in-
fection control measures help to reduce
transmission at home and in school.
The clinical burden of HFMD also has a
significant public health impact due to
school and work absence among par-
ents who require time off work for child-
care.
Diagnosing HFMD
Typically, symptomatic infections
manifest as brief fever, with rashes on
the hands and feet (HFMD), and/or
mouth ulcers (herpangina). Symptoms
usually resolve in 7–10 days. HFMD/
herpangina caused by EV71 can prog-
ress rapidly to neurological involvement
(aseptic meningitis, encephalitis, en-
cephalomyelitis, acute flaccid paralysis)
and autonomic dysfunction leading to
neurogenic pulmonary oedema, pulmo-
nary haemorrhage, and cardiopulmo-
nary failure. Symptoms include blood
pressure instability (hypertension or hy-
potension), cold sweats, hyperglycae-
mia, and frequent myoclonic jerks.
Poor oral intake in an otherwise well
child may be a sign of pharyngeal ul-
cers. GPs should have a high index of
suspicion for HFMD if a child presents
with a non-specific febrile illness and
there is recent history of contact with
other children who have HFMD such as
in a preschool cluster.
HFMD and herpangina are primarily
clinical diagnoses based on the typi-
cal features described. A nasopharyn-
geal or throat swab can be tested for
enterovirus polymerase chain reaction
(PCR) to confirm diagnosis. Enterovirus

PCR can also be tested in cerebrospinal
fluid samples for those with suspected
neurological infection, or in stool/rectal
swabs.
Although HFMD is usually a benign
self-limiting illness, it can sometimes
cause severe illness such as dehydra-
tion requiring hospital admission, and
rarely, neurological or cardiopulmonary
complications, or mortality. Children
with HFMD caused by the EV71 virus
can present with subtle clinical features
early in the illness course and deterio-
rate rapidly with a fulminant disease
course. Most survivors of EV71 cardio-
pulmonary failure have moderate-to-se-
vere neurological sequelae.
Children with signs of dehydration
or neurological involvement (eg, irritable
and excessive crying, lethargy, seizures)
should be evaluated in hospital as soon
as possible. Early recognition and time-
ly supportive intervention are needed to
reduce morbidity and mortality.
Diagnostic challenges
Mild infections may be asymptom-
atic, or manifest as mild febrile illness
or non-specific viral symptoms such
CLINICAL INSIGHTS | IN PRACTICE
as upper respiratory tract infection or
loose stools. Typical features of HFMD
and herpangina may also not be seen in
severe EV71 infections. A positive PCR
result in an asymptomatic child may
reflect gut carriage or post-infectious
shedding.
“HFMD can cause
severe illness such as
dehydration requiring
hospital admission”
Young children are difficult to ex-
amine, and ulcers at the back of throat
may not be easily visualized. Children
may also see the GP early in the illness
course when there is only fever or poor
feeding, and ulcers or rash may not be
apparent yet. Knowledge of specific ex-
posure such as at home or in a child-
care centre (cluster/outbreak) may help
to make a presumptive diagnosis.
Managing HFMD
There are two aspects to HFMD
management – symptomatic manage-
47
DOCTOR | AUGUST ISSUE
ment and infection control. Symptomat-
ic management involves managing fever
with antipyretics and improving hydra-
tion by encouraging oral fluid intake.
Children with painful oropharyngeal ul-
cers often prefer soft food, cold drinks,
or sucking on ice lollies made of frozen
rehydration solution. Infection control
measures and droplet precautions (eg,
frequent hand washing, no sharing of
utensils/towels, no kissing, cleaning
of toys and surfaces, and appropriate
cough etiquette including use of surgi-
cal masks in an older child) can prevent
transmission of HFMD to close contacts
at home and in school.
Conclusion
It is important for GPs to ask about
specific exposure to HFMD at home or
in school/childcare centres, and to have
a high level of suspicion if the child pres-
ents early with illness when clinical signs
and symptoms are still evolving. Parents
should be advised on what symptoms
to look out for, and when to return to
see the doctor. GPs should be vigilant
for children with poor oral intake leading
to dehydration, irritability, or other neu-
rological involvement as these children
should be evaluated in hospital.
 CALENDAR

AUGUST - SEPTEMBER SEPTEMBER SEPTEMBER

29-1
SATURDAY – TUESDAY
5-9
SATURDAY – WEDNESDAY
17-20
THURSDAY – SUNDAY

European Society of Cardiology European Respiratory Society Japan Society of Allergology

(ESC) Congress – The Digital (ERS) International Congress (JSA)/World Allergy Organization
Experience Virtual (WAO) Joint Congress
Tel: 33 4 92 94 76 00 Tel: 41 21 213 01 19 Location: Kyoto, Japan
Website: www.escardio.org/Congresses-&- Email: congress.registrations@ersnet.org Tel: 81 75 231 6357
Events/ESC-Congress?hit=home&urlorig=/ Website: www.erscongress.org Fax: 81 75 231 6354
vgn-ext-templating/ Email: jsawac2020@c-linkage.co.jp
Website: www.c-linkage.co.jp/jsawac2020/
information.html

SEPTEMBER SEPTEMBER OCTOBER

18-22
FRIDAY – TUESDAY
21-25
MONDAY – FRIDAY
9-12
FRIDAY – MONDAY

ESMO (European Society European Association for the Advances in Breast Cancer
for Medical Oncology) Virtual Study of Diabetes (EASD) – Research (AACRBCA)
Congress Virtual Meeting AI Location: San Diego, California, US
Tel: 41 0 91 973 19 63 Tel: 49 211 758 469 0 Tel: 215 440 9300
Fax: 41 0 91 973 19 18 Fax: 49 211 758 469 29 Email: aacr@aacr.org
Email: registration@esmo.org Email: secretariat@easd.org Website: www.aacr.org/meeting/breast-2020
Website: www.esmo.org/meetings/esmo- Website: www.easd.org/annual-meeting/
congress-2020 easd-2020.html

OCTOBER OCTOBER OCTOBER

14-17
WEDNESDAY – SATURDAY
14-18
WEDNESDAY – SUNDAY
15-17
THURSDAY – SATURDAY

18th Urological Association Transcatheter Cardiovascular International Master Course on

of Asia Congress Therapeutics (TCT) Connect Aging Science (IMCAS) Asia
Location: Seoul, South Korea Tel: 646 434 4500 Location: Bangkok, Thailand
Tel: 82 2 3452 7167 Email: registration@crf.org Email: contact@imcas.com
Fax: 82 2 521 8683 Website: www.crf.org/tct Website: www.imcas.com/en/attend/imcas-
Email: uaa2020@insession.co.kr asia-2020
Website: www.uaa2020.org

PENDING UPDATES

*In light of the evolving situation regarding COVID-19, kindly refer to the conference websites for updates.

48
DOCTOR | AUGUST ISSUE
 CALENDAR

OCTOBER OCTOBER - NOVEMBER OCTOBER - NOVEMBER

21-24
WEDNESDAY – SATURDAY
28-1
WEDNESDAY – SUNDAY
29-1
THURSDAY – SUNDAY

21st Congress of Asian Society 29th European Academy 25th ASEAN Federation
for Vascular Surgery (ASVS) of Dermatology and Venereology of Cardiology Congress (AFCC)
Location: Seoul, South Korea (EADV) Congress Website: themeetinglab.eventsair.com/
Tel: 82 2 3471 8555 Tel: 41 91 973 45 20 afcc-2020
Fax: 82 2 521 8683 Email: congress@eadv.org; registration@
Email: asvs2020@insession.co.kr eadvcongress.org
Website: www.asvs2020.org Website: www.eadvvienna2020.org

TO PROCEED WITH VIRTUAL

FORMAT; PENDING UPDATES POSTPONED TO NOV 2021

NOVEMBER NOVEMBER NOVEMBER

14-16
SATURDAY – MONDAY
14-17
SATURDAY – TUESDAY
19-21
THURSDAY – SATURDAY

American Heart Association 22nd Asia-Pacific League of 6th World Congress on

(AHA) Scientific Sessions Associations for Rheumatology Controversies in Breast Cancer
Location: Dallas, Texas, US Congress (APLAR) Location: Berlin, Germany
Tel: 1 800 242 8721; 1 214 570 5978 Location: Kyoto, Japan Tel: 972 72 279 0302
Website: www.professional.heart. Tel: 61 7 3858 5400⁠ Fax: 972 72 257 8799
org/professional/EducationMeetings/ Email: info@aplar2020.com Email: cobrca@congressmed.com
MeetingsLiveCME/ScientificSessions/ Website: aplar2020.com Website: www.cobrca.org
UCM_316900_Scientific-Sessions.jsp

NOVEMBER DECEMBER DECEMBER

20-22
FRIDAY – SUNDAY
5-8
SATURDAY – TUESDAY
8-12
TUESDAY – SATURDAY

ESMO Asia Congress 62nd American Society 43rd Annual San Antonio Breast
Location: Singapore of Hematology (ASH) Annual Cancer Symposium (SABCS)
Tel: 41 0 91 973 55 85
Meeting and Exposition Location: San Antonio, Texas, US
E-mail: asiacongress@esmo.org Tel: 210 450 1550
Location: San Diego, California, US
Website: www.esmo.org/meetings/esmo- Fax: 210 450 1560
Tel: 202 776 0544
asia-congress-2020 Email: sabcs@uthscsa.edu
Fax: 202 776 0545
Email: ashregistration@spargoinc.com Website: www.sabcs.org/2020-SABCS
Website: www.hematology.org/Annual-
Meeting
PENDING UPDATES

*In light of the evolving situation regarding COVID-19, kindly refer to the conference websites for updates.

49
DOCTOR | AUGUST ISSUE
 HUMOUR

“But seriously...” “Well, Mr. Rubaretzki, that wasn’t too bad!”

“Your necrotizing fasciitis is spreading even further. “Got the tests back.
I’m afraid they’ll have to cut off some more!” Nothing serious, just a severe case of goosebumps!”

“Sorry, we’re out of Ringer’s Lactate. “Did I pass the test?”

Why don’t you try the Normal Saline?”

50
DOCTOR | AUGUST ISSUE