MARCH 2014

AHA rolls out stroke prevention guidelines for women

DRUG PROFILELinagliptin/metformin combination therapy for T2DM

NEWSAsthma gene profile distinct in Chinese individuals

RESEARCH REVIEWSSnus use not linked to neoplastic and oral conditions

IN PRACTICEManagement of osteoporosis: Diagnosis and treatment

MARCH 2014 2

AHA rolls out stroke prevention guidelines for womenELVIRA MANZANO

The American Heart Association (AHA) has

issued its first stroke prevention guidelines

for women based on risk factors unique to them.

Current guidelines for stroke prevention in

both men and women focus on controlling hy-

pertension, diabetes, quitting smoking, healthy

diet, and exercise. The new AHA guidance fo-

cuses on women-specific issues such as hy-

pertension during pregnancy, use of oral con-

traceptives, childbirth, menopause, hormonal

replacement and other risk factors more fre-

quently seen in women such as obesity and

metabolic syndrome, atrial fibrillation and mi-

graine with aura. [Stroke 2014; doi: 10.1161/01.

str.0000442009.06663.48]

“Those risk factors need to be recognized and

addressed,” said lead author Dr. Cheryl Bushnell

from the Wake Forest Baptist Medical Center in

Winston-Salem, North Carolina, US. “It is im-

portant to emphasize prevention and decrease

women’s risks early in their childbearing years.”

The new guidelines recommend that women

be screened for hypertension prior to taking oral

contraceptives as the combination raises stroke

risks. The risk increases in women aged 45-49

years and is even higher in those with migraine

with aura and among smokers, Bushnell said.

For women with a history of hypertension pri-

or to pregnancy, they should be considered for

low-dose aspirin (about 81mg) after the first tri-

mester and/or calcium supplement therapy any

time to reduce the risks of preeclampsia.

Preeclampsia doubles the risk of stroke later

in life and quadruples the risk of hypertension

after pregnancy, hence preeclampsia should be

recognized as a stroke risk factor well after preg-

nancy, said Bushnell.

Pregnant women with severely high blood

pressure (160/110 mmHg or higher) should be

treated with BP lowering medications but with

caution as some antihypertensives may be un-

safe during pregnancy. Expectant mothers with

moderately high BP (systolic pressure, 150-159

mmHg; diastolic pressure, 100-109 mmHg) may

be considered for treatment.

The guidelines also advise women >75 years

of age to be screened for atrial fibrillation as the

condition increases the risk of stroke.

As women live longer than men, they tend to

have a higher lifetime risk of stroke, Bushnell ex-

plained. Women also tend to do worse after a

stroke and are more likely to stay in long-term

nursing care, with worse quality of life.

A female-specific stroke risk score is therefore

warranted to reflect the risk of stroke in women

across the lifespan, as well as the clear gaps in

current risk scores, the authors concluded.

The US Association of Neurological Surgeons

and the Congress of Neurological Surgeons en-

dorsed the new guidelines.

MARCH 2014 3

Two doses of HPV vaccine may suffice for genital warts preventionRADHA CHITALE

Just two of the recommended three doses of

human papillomavirus virus (HPV) vaccine

may be enough to reduce the risk of condy-

loma (genital warts) infections and potentially

the risk of cervical cancer, a Swedish study has

shown.

Completing the three-dose HPV vaccine

series still conferred the most protection, but

an examination of data from national Swedish

population-based health data registers showed

that the difference in risk reduction between the

second and third doses was small, especially

among girls who received their first dose before

age 17. [JAMA 2014;311:597-603]

“The number of condyloma cases prevented

by three doses versus two doses was 59 cases

per 100,000 person years, which is a small dif-

ference,” said researchers from the Karolinska

Institutet in Stockholm, Sweden.

The researchers identified 20,383 new cases

of condyloma among a population of 1,045,165

females in Sweden aged 10 to 24 years, fol-

lowed up between 2006 and 2010. Of these new

cases, 322 occurred after at least one dose of

HPV vaccine.

Risk reduction was highest among females

who completed their vaccine course. However,

two doses of vaccine also conferred significant

protection.

For example, among girls aged 10-16, the in-

cidence rate ratio (IRR) for condyloma was 0.18

for those who completed the vaccine course,

0.29 for those who received two doses, and 0.31

for those who had only one dose (p<0.001 for

all), compared with those who did not receive

the vaccine.

These corresponded to an incidence rate

difference (IRD) of 459 cases of condyloma

per 100,000 person years for three doses, 400

cases per 100,000 person years for two doses,

and 384 cases per 100,000 person years for a

single dose (p<0.001 for all) compared with no

vaccine.

The IRR and IRD was consistently the least

different between two and three doses among

girls of any age, suggesting significant, if not the

most, risk reduction.

Accounting for the impact of varying vaccine

dose levels is important because “actual vacci-

nation programs include substantial numbers of

A study suggests that two doses of the vaccine may be sufficient.

MARCH 2014 4

women who do not complete the full vaccina-

tion schedules,” the researchers said.

HPV serotypes 6 and 11 cause about 90 per-

cent of condylomas, which are the first measur-

able endpoint for HPV infection and have an

incubation period between 1 and 6 months.

The females included in the study received the

quadrivalent HPV vaccine, which also protects

against serotypes 16 and 18, which are related

to cancer outcomes, including cervical cancer.

The researchers said further investigations

need to be done to determine if there is any

reduced risk of cervical cancer with fewer than

three doses of HPV vaccine. The current data

may have also underestimated the number of

condyloma cases since some patients can’t or

won’t seek medical care, nor did it account for

disease outcomes other than condyloma.

READ JPOG ANYTIME, ANYWHERE. Download the digital edition today at www.jpog.com

MARCH 2014 FORUM 5

Most recent data from UK point to substantial public health benefits of electronic cigarettes

While most anti-smoking organizations

continue to oppose electronic cigarettes

(e-cigarettes), warning of the hypothetical risks

of these products, new data from the UK sug-

gest that in real life, e-cigarettes are producing

substantial public health benefits.

Recent data (monthly tracking of key per-

formance indicators; e-cigarettes in England -

latest trends) from the Smoking Toolkit Study

(Cancer Research UK, UK Centre for Tobacco

Control Studies) reveal the following critical

points:

1. The use of e-cigarettes has increased dra-

matically, ever since the fourth quarter of

2011.

2. Precisely coincident with the rise in e-cig-

arette use in the UK has been a significant

increase in quit smoking attempts.

3. E-cigarettes have surpassed nicotine re-

placement therapy (NRT) and other drugs

as the most commonly used smoking ces-

sation method.

4. Overall motivation to quit has increased

Dr. Michael SiegelProfessor, Department of Community Health SciencesBoston University School of Public Health Boston, Massachusetts, US

since the dramatic rise in e-cigarette use.

5. The majority of dual users (e-cigarettes and

cigarettes) are using e-cigarettes every day,

and half are using at least two cartridges/

disposables per day.

6. Very few non-smokers or long-term ex-

smokers are using e-cigarettes.

Report STS140122 (Electronic cigarettes

in England - latest trends) draws the following

conclusions:

• The increase in e-cigarette use prevalence

MARCH 2014 FORUM 6

may have stalled;

• There is no evidence that e-cigarettes are

undermining motivation to quit or reduction

in smoking prevalence; and

• Use of e-cigarettes by never smokers or

long-term ex-smokers is extremely rare.

The rest of the storyBased on these most recent data from the

UK, it appears that there just is not evidence to

support the wild contentions that anti-smoking

groups, advocates, and health agencies like

the Centers for Disease Control (CDC) and

WHO are disseminating to the public. Contrary

to what Stan Glantz [Professor, Department of

Medicine, and Director, Center for Tobacco

Control Research and Education, University

of California San Francisco, US] is telling the

press, there simply is no evidence that the use

of e-cigarettes is undermining smoking cessa-

tion or impeding the decline in smoking preva-

lence. Nor is there evidence that e-cigarettes

are causing non-smokers or ex-smokers to

return to cigarette smoking. Moreover, there

is no evidence that dual use is decreasing

the motivation of smokers to quit or preclud-

ing these smokers from reaping any health

benefits.

In contrast, however, to the lack of evidence

that e-cigarettes are having any negative pub-

lic health effects, there is strong evidence

to suggest that these products are having a

substantial positive public health impact. In

particular, there is evidence that not only do

these products help many smokers quit smok-

ing, but more generally, they increase popu-

lation interest in smoking cessation, enhance

levels of motivation to quit smoking, and lead to

increased quit attempts among current smok-

ers.

The only bad news coming out of the actual

data is that the efforts of anti-smoking groups

and advocates appear to be working: they are

being successful in discouraging smokers from

trying to quit smoking using e-cigarettes. Ironi-

cally, the results of public health efforts have

been to impede smoking cessation, lower the

overall motivation of smokers to quit, and de-

creasing the number of quit attempts among

current smokers.

In other words, the anti-smoking movement

is violating the first principle of public health

practice by doing public health harm.

While it is difficult for me to have to criticize

anti-smoking groups because these are groups

with which I have had a career-long collegial

relationship, it appears that these groups are

substantially harming the health of the public

by impeding smoking cessation. Sadly, this

means that their efforts are going to result in a

significant amount of unnecessary disease and

death.

This is not the way public health is supposed

to be. But this is what happens when an absti-

nence-only mentality takes over in any area of

public health, whether it be nicotine addiction

or heroin addiction.

This article first appeared on Feb 10, 2014, on

the following website: http://tobaccoanalysis.

blogspot.sg/ and has been reprinted with per-

mission.

MARCH 2014 FORUM 7

About the author:Dr. Michael Siegel has 25 years of experience in the field of tobacco control. He previously spent

2 years working at the Office on Smoking and Health at CDC, where he conducted research

on second-hand smoke and cigarette advertising. He has published nearly 70 papers related

to tobacco. He testified in the landmark Engle lawsuit against the tobacco companies, which

resulted in an unprecedented US$145 billion verdict against the industry. He teaches social and

behavioral sciences, mass communication and public health, and public health advocacy in the

Masters of Public Health program at Boston University School of Public Health.

MARCH 2014 NEWS 8

Study highlights discrepancies in diabetes management in ethnic minoritiesJENNY NG

Physicians in Hong Kong should pay atten-

tion to the needs of diabetes patients from

ethnic minority groups, as a recent study high-

lighted discrepancies in comprehensive man-

agement of their condition compared with Chi-

nese patients.

The study, conducted by the Queen Eliza-

beth Hospital’s Department of Family Medicine,

is the first to assess diabetes control among

patients from ethnic minority groups in Hong

Kong. [Hong Kong Med J 2014, e-pub 30 Jan;

doi: 10.12809/hkmj134035]

Among 4,346 patients with type 2 diabetes

mellitus (T2DM) included in the study, those

from ethnic minority groups (including Nep-

alese, Indians, Filipinos, Pakistanis and Indo-

nesians) were significantly younger and more

obese than their Chinese counterparts.

In age- and sex-matched between-group

analyses, these South Asian patients were found

to have a higher incidence of hypertension (73.7

vs 66.3 percent; p=0.03), higher hemoglobin

A1c (HbA1c, 7.8 vs 7.5 percent; p=0.006) and

fasting blood glucose levels (8.1 vs 7.5 mmol/L;

p=0.02), higher diastolic blood pressure (78 vs

73 mm Hg; p<0.001), and lower levels of HDL-

cholesterol (1.19 vs 1.28 mmol/L; p=0.001) than

Chinese patients.

Within the group of ethnic minorities, re-

searchers found differences in measures of dis-

ease control that further highlighted the need for

more focused T2DM care.

For example, Pakistani patients showed

poorer glycemic control than patients of other

ethnicities (HbA1c, 8.4 percent), while Indo-

nesians had satisfactory control in general

(HbA1c, 6.8 percent). Pakastani patients were

also found to have much lower HDL-cholesterol

levels (1.04 mmol/L). Systolic blood pressure

was similar across the board, but Nepalese pa-

tients were found to have lower diastolic blood

pressure (84 mm Hg) than patients of other eth-

nicities. However, demographic differences be-

tween the ethnic groups prevented subgroup

comparisons.

The differences between Chinese and South

Asian patients may be due to multiple factors,

including genetics and the environment, noted

the researchers. South Asians have a four to

six fold higher risk for T2DM than other ethnic

MARCH 2014 NEWS 9

groups. The knowledge that these patients have

a preponderance of insulin resistance, obesity

and metabolic syndrome may help physicians

improve diabetes management.

Awareness that ethnic minorities may also be

at a socio-economic disadvantage, face greater

inequalities in accessing medical care, or face

limitations in differences of language, culture

and lifestyle, highlights the need for culturally

tailored healthcare interventions that include co-

ordinated efforts and integrated diabetes moni-

toring and surveillance programs, suggested

the researchers.

“Local doctors should therefore pay par-

ticular attention to the needs of different ethnic

groups and offer a flexible care package that re-

flects their physical, psychological, social, and

cultural needs and at the same time upholds

their autonomy, dignity, privacy, and personal

choice,” they concluded.

Acupuncture boosts memory in the elderlyCHRISTINA LAU

Older adults with mild cognitive impairment

(MCI) can benefit from improved memory

after 8 weeks of acupuncture treatment, a pilot

study suggests.

Seven individuals with MCI (age, 65-79

years) who participated in the first phase of

the study had improved memory and cognitive

function after receiving 24 acupuncture ses-

sions in the 8-week treatment program.

According to investigators from the Chinese

University of Hong Kong’s School of Chinese

Medicine and Department of Psychiatry, im-

provements were more significant in the par-

ticipants’ delayed recall.

The treatment, lasting 30 minutes per ses-

sion, was given to stimulate a specific set of

acupuncture points, including GV20 (Baihui),

GB20 (Fengchi), EX-HN1 (Sishenchong) and

KI3 (Taixi). Patients could receive the treatment

in a seated or prostrate position.

“In Chinese medicine, treatment of mem-

ory-related diseases focuses on regulation of

brain function and tonification of the kidney,”

explained Professor Albert Leung, Director of

MARCH 2014 NEWS 10

the School of Chinese Medicine. “Stimulation

of these acupuncture points can enhance cog-

nitive function.”

The pilot study, launched in August 2013,

aimed at ascertaining and quantifying the ef-

ficacy of acupuncture in MCI treatment. As-

sessments of cognitive function were carried

out at baseline, end of treatment, as well as 2

and 4 months post treatment, using widely rec-

ognized tools such as the Cantonese version

of the Mini-Mental State Examination and Al-

zheimer’s Disease Assessment Scale-cognitive

subscale (ADAS-cog).

With the promising initial results, the inves-

tigators are recruiting elderly individuals with

MCI to participate in the second phase of the

study. Interested parties can call 3943 1231,

6112 0106, or 2466 6591.

MCI: Facts and figures• MCI affects 8.5 percent of individuals aged 70 or above in Hong Kong.

• Ten to 15 percent of individuals with MCI eventually progress to develop dementia.

• The prevalence of MCI is expected to increase with the aging population. The elderly

population in Hong Kong is estimated to grow from 13 percent in 2011 to 30 percent in

2041.

MARCH 2014 NEWS 11

Asthma gene profile distinct in Chinese individualsJACKEY SUEN

Chinese individuals possess a distinct asth-

ma gene profile and haplotype structures

of asthma loci, as shown in recent research by

the Chinese University of Hong Kong.

Professor Gary Wong of the Department of

Pediatrics and colleagues conducted case-

control association and sequencing studies to

investigate the frequencies of asthma-related

single nucleotide polymorphisms (SNPs) in

Chinese, Caucasian and African populations.

[J Allergy Clin Immunol 2014;133:42-48]

Results showed substantial discrepancies in

the frequencies of asthma susceptibility SNPs

between Chinese and other populations. Near-

ly half of the studied SNPs showed differences

in minor allele frequencies of 0.2 or above be-

tween Chinese and Caucasians/Africans.

The researchers also sequenced 10 asthma

loci in 24 healthy Hong Kong children. Com-

pared with six other ethnic groups studied in

the 1,000 Genome Project, the Hong Kong

children had distinct haplotype structures (con-

structed from 224 common SNPs) at the 17q21

susceptibility locus.

The distinct asthma gene frequencies and

haplotype structures of asthma loci found in

this study may be used as tag SNPs for future

genetic association studies between popula-

tions, suggested the authors.

MARCH 2014 NEWS 12

Vitamin D supplementation lacks benefits, study suggestsCASSIE-ANNE LOW

The results of a new study suggest that vita-

min D supplementation provides little, if any,

health benefits.

A meta-analysis of 40 randomized controlled

trials found that vitamin D supplementation, with

or without calcium, did not alter rates of myo-

cardial infarction or ischemic heart disease,

stroke or cerebrovascular disease, cancer, total

bone fractures, or hip fractures by a pre-defined

risk reduction threshold of 15 percent or more.

[Lancet Diabetes Endocrinol 2014. http://dx.doi.org/10.1016/S2213-8587(13)70212-2]

“In view of our findings, there is little justifi-

cation for prescribing vitamin D supplements to

prevent [such outcomes],” wrote the study au-

thors, led by Dr. Mark Bolland of the University

of Auckland, New Zealand.

The authors also suggested that any further

trials similar in design to existing trials are un-

likely to alter these conclusions. “Investigators

and funding bodies should consider the prob-

able futility of undertaking similar trials of vitamin

D to investigate any of these endpoints,” they

said.

Previous observational studies have shown

that vitamin D deficiency is strongly associated

with poor health and even early death. Claims

that people can therefore benefit from vitamin

D supplementation have been lent strong sup-

port by several leading scholars in the field and

this has had a major impact on health practitio-

ners prescribing patterns. To illustrate this point,

US sales of vitamin D supplements increased

by more than 10 times from 2002 to 2011, from

US$42 million to $605 million.

In an accompanying editorial, Professor Karl

Michaëlsson from Uppsala University in Swe-

den, said that evidence now suggests that low

levels of vitamin D are a consequence, not a

cause of poor health, and he cited a report from

the US Institute of Medicine emphasizing that

both high and low concentrations of vitamin D

can lead to health risks in individuals. [J Clin En-docrinol Metab 2011;96:53-58]

“Without stringent indications – ie, supple-

menting those without true insufficiency – there

is a legitimate fear that vitamin D supplementa-

tion might actually cause net harm,” said Mi-

chaëlsson.

A large meta-analysis found that vitamin D supplementation had little, if any, health benefits.

MIMS Video Series features interviews with leading experts

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Dr John Foreyt Lifestyle approaches to manage weight loss in obese patients through exercise and dietary modifications

Professor Christophe de Block Risks associated with obesity and the benefits of early prevention

Dr David Sullivan Effective therapies for dyslipidemia when statins are insufficient and future treatments in development

Professor Brian Tomlinson Future therapies to treat familial hypercholes-terolemia and difficulties in measuring the prevalence of this disease in Asia

Professor Jonathan Shaw The importance of glucose control associated with cardiovascular risk and the safety of DPP4-I and GLP-1 treatments

Professor Helena Gylling The effective use of plant sterols and stanols in lowering LDL-cholesterol and how these products can be used to treat dyslipidemia

Treatment Updates on Diabetes and Lipid DisordersFind out what these experts have to say about upcoming treatments for diabetes and lipid disorders and the risks related to obesity

MARCH 2014 NEWS 14

Defer dialysis in ESRD: New guidelinesELVIRA MANZANO

New clinical practice guidelines from the Ca-

nadian Society of Nephrology recommend

deferred – over early – initiation of dialysis in pa-

tients with end-stage renal disease (ESRD).

With the deferred strategy, patients with an

estimated glomerular filtration rate (eGFR) of

<15 mL/min per 1.73 m2 need to be closely

monitored by a nephrologist. Dialysis is initiated

only when uremic symptoms (fluid overload,

refractory hyperkalemia or acidosis) emerge or

when the eGFR drops to ≤6 mL/min per 1.73m2.

[CMAJ 2014;186:112-117]

The updated recommendation was based on

a review of 23 studies, including the Initiating

Dialysis Early and Late (IDEAL) study, a large

clinical trial which showed that early dialysis did

not improve survival, quality of life, or hospital

admission rates in patients with chronic kidney

disease (CKD) compared with late or deferred

strategy. The findings start to reverse a trend to-

ward early initiation of dialysis.

There is a lack of compelling benefit for early

initiation of dialysis in CKD, said guideline chair

Professor Louise M. Moist from the Western

University in London, Ontario, Canada. Veering

away from the practice will avoid the burden and

inconvenience of an early start, which has been

associated with longer time on dialysis and

greater resource use, she added.

The new guideline covers adult patients (age

>18 years) with ESRD (stage 5 CKD) initiat-

ing chronic hemodialysis or peritoneal dialysis.

It does not consider the timing of pre-emptive

transplantation, dialysis for acute kidney injury,

pediatric patients, or those electing conserva-

tive management without dialysis.

The Canadian guidance does not recom-

mend earlier initiation of dialysis in higher-risk

subgroups, such as patients with diabetes. It

also dropped previous recommendations to ini-

tiate dialysis based only on a decline in nutrition-

al status (as measured by serum albumin, lean

body mass, etc). The recommendation differs

from that of the National Kidney Foundation’s

Kidney Disease Quality Outcomes Initiative

(KDOQI), which calls for nephrologists to eval-

uate the benefits, risks and disadvantages of

beginning kidney replacement therapy at eGFR

<15 mL/min and the Caring for Australians with

Renal Impairment (CARI) guidelines which rec-

ommend initiation of dialysis at eGFR <10 mL/

min or if uremic symptoms or signs of malnutri-

tion occur.

The guideline is intended not only for ne-

phrologists but for primary care physicians, oth-

er internal medicine subspecialties, and nursing

specialists caring for, referring, or co-managing

treatment for patients with CKD.

MARCH 2014 NEWS 15

Exercise, bodyweight influence future CVD risk in male teensRADHA CHITALE

Good health in the teenage years could sig-

nal whether or not someone will be at risk

of heart attack decades later.

An analysis of over 700,000 teenage males

revealed that high aerobic fitness reduced the

risk of myocardial infarction (MI) 30-40 years

later. However, as they aged, obesity seemed

to override the benefits of fitness as obese

men with high levels of fitness as teens were at

higher risk of MI than men who were not obese

and who were not aerobically fit when they were

younger. [European Heart Journal. doi:10.1093/

eurheartj/eht527]

was assessed with a cycling test and muscle

strength was determined by tests for knee ex-

tension, grip and elbow flexion. National health

registries helped them track MI events.

Over a median 34 years of follow-up, 7,575

MIs occurred in 620,089 men. The research-

ers adjusted the data for age, body mass index

(BMI), diseases, blood pressure, education and

other socioeconomic factors.

For each 15 percent increase in aerobic fit-

ness, the researchers found an associated 18

percent decreased risk of MI (HR 0.82).

The benefits of aerobic fitness were seen

across all strata of BMI, from underweight (BMI

less than 18.5 kg/m2) to normal weight (BMI be-

Good aerobic fitness and low BMI of teenage males were linked to lower rates of CVD in later years.“Our study suggests that it’s more

important not to be overweight or

obese than to be fit, but that it’s

even better to be both fit and a

normal weight,”

“Our study suggests that it’s more impor-

tant not to be overweight or obese than to be

fit, but that it’s even better to be both fit and a

normal weight,” said lead researcher Profes-

sor Peter Nordström, of Umeå University in

Sweden.

Nordström and colleagues examined health

records of 743,498 18-year-old Swedish men

between 1969 and 1984 when they were con-

scripted into military service. Aerobic fitness

MARCH 2014 NEWS 16

tween 18.5 and 25 kg/m2) and overweight (BMI

between 25-30 kg/m2, p<0.05 for all), except for

obese men (BMI more than 30 kg/m2). Muscle

strength did not appear to be strongly correlat-

ed with later risk of MI.

The researchers reported 271,005 (43.7 per-

cent) of the men were normal or lean whose

aerobic fitness was better than average, and

there were 2.176 MIs in this group, suggest-

ing that “regular cardiovascular training in late

adolescence is independently associated with

an about 35 percent reduced risk of early MI in

men.”

The data were limited to assessments of BMI

and fitness at the time of conscription. Smok-

ing, a critical cardiovascular disease (CVD) risk

factor, was not accounted for. Nordström also

noted that the data alone may not account for

those men who were genetically predisposed

for high fitness and low CVD risk. There are

also no data for women or older people in the

current study.

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MARCH 2014 IN PRACTICE 17

Management of osteoporosis: Diagnosis and treatment

Osteoporosis is a common problem. It is re-sponsible for 1.3 million fractures yearly, of

which half are vertebral fractures, a quarter hip fractures and another quarter wrist fractures.

Over 50 percent of women and 30 to 45 per-cent of men over the age of 50 have osteopenia, or osteoporosis. It is defined by systemic skeletal disease characterized by low bone mass and mi-croarchitectural deterioration of bone tissue, lead-ing to enhanced bone fragility and a consequent increase in fracture risk. The bone has a lower density and quality resulting in a higher fracture risk. WHO utilizes bone mineral density (BMD) as a surrogate marker with a T score <-2.5.

Dr. Eugene WongConsultant Orthopedic & Spine SurgeonAdjunct Assistant ProfessorPerdana University Graduate School of MedicineSerdang, Selangor Malaysia

Postmenopausal osteoporosis (type I)

• Caused by lack of estrogen• Causes parathyroid hormone (PTH) to

overstimulate osteoclasts. • Excessive loss of trabecular bone

Age-associated osteoporosis (type II)

• Bone loss due to increased bone turn-over

• Malabsorption • Mineral and vitamin deficiency

Table 1: Types of osteoporosis.

A. Non-pharmacologic

• Increasing age• Female gender• Family history of osteoporosis• Low body weight (BMI <18.5)• Caucasian (Northern European descent)

and Asian ethnicity• Late menarche• Nulliparity• Early menopause• Anorexia nervosa or bulimia• Low testosterone levels in men

B. Modifiable risk factors

• Diet – excessive consumption of caffeine and salt.

• Inadequate consumption of calcium and vitamin D.

• Sedentary lifestyle• Medical problems – anorexia, thyroid

problems, bowel diseases and rheuma-toid arthritis.

• Use of certain medications• Cigarette smoking• Excessive use of alcohol• Excessive exercise (resulting

in amenorrhea).

Table 2: Risk factors for osteoporosis.

MARCH 2014 IN PRACTICE 18

In osteoporosis, there is loss in total mineral-ized bone and disruption of the normal balance of bone breakdown and build up. There are imbal-ances in bone remodeling. There is a reduction in bone build up and accelerated bone breakdown during the postmenopausal period. Up to 5 per-cent of bone loss occurs every year during the first 5 years after menopause. Older women are at higher risk of fragility fracture compared with younger women with the same BMD. Other fac-tors to be considered in reducing fragility frac-tures include preventing falls and decreasing the risk of fracture by using hip protectors.

DiagnosisA fragility fracture is one that results from me-

chanical forces that would not ordinarily cause a fracture in a healthy young adult. A high suspi-cion of osteoporosis is warranted in any patient with a fracture caused by minimal trauma. Verte-bral fractures are associated with a loss of height caused by a progressive increase in the degree of kyphosis and lordotic curve flattening. The best predictor of fracture is a previous fracture.

Fractures can lead to decreased mobility and an additional risk of deep venous thrombosis and/or pulmonary embolism. Vertebral fractures can lead to severe chronic pain of neurogenic origin, which can be difficult to control.

The Osteoporosis Self-assessment Tool for Asians (COSTA) can be used to categorize a pa-tient clinically into low, medium and high risk. Pa-tients with medium or high risk are advised to un-dergo a dual energy x-ray absorptiometry (DEXA) scan. A DEXA scan measures bone density at the femoral neck, spine and distal radius. The frac-ture risk doubles for every standard deviation T-score decrease in BMD. Blood tests needed include a comprehensive metabolic panel, com-plete blood count, thyroid stimulating hormone

level and vitamin D levels. The Fracture Risk As-sessment Tool (FRAX) has been developed by the WHO to evaluate fracture risk of patients. It is based on individual patient models that integrate the risks associated with clinical risk factors as well as BMD at the femoral neck.

TreatmentTreatment can reduce fracture risk consider-

ably and aims to minimize fracture risk by achiev-ing ‘normal’ bone strength with a drug therapy that is safe, well-tolerated, easy to administer and cost effective. The management also in-cludes various non-pharmacological measures as listed in Table 4.

All fragility fractures are associated with mor-bidity. Patients will be unable to carry out nor-mal activities of daily living, walk independently

Idiopathic secondary

Nutritional:Lactose intolerance, vegetarian diet, low dietary calcium and excessive alcohol intakeLifestyle:Smoking and physical inactivityMedical:Type 1 diabetes, Cushing’s syndrome, chronic renal disease, inflammatory bowel disease, cystic fibrosis, hyperparathyroidism, hyperthyroidism, anorexia nervosa, celiac disease, idiopathic hypercalciuria and pre-mature ovarian failure.Medications:Glucocorticoid drugs, long-term lithium therapy, chemotherapy, anticonvulsants (phenytoin, phenobarbital, valproate and carbamazepine), long-term phosphate- binding antacid use, thyroid replacement drugs and methotrexate.

Table 3: Etiology of osteoporosis.

MARCH 2014 IN PRACTICE 19

and will suffer from permanent disability. There is a 20 percent risk of mortality 1 year after a hip fracture. Patients may suffer from depression due to altered body image, pain, loss of function and accelerated mortality due to complications. Therefore, prevention of secondary fractures

needs to be undertaken as the first occurrence of an osteoporotic fracture means patients are prone to subsequent fractures.

A. Non-pharmacologic

• Calcium intake 1.2 g/day• Vitamin D 800-1,000 IU daily• Maintain adequate body weight• Weight-bearing exercises• Safe and well-organized surrounding to

prevent falls• Avoid caffeine, alcohol and carbonated

drinks• Stop smoking• Treat visual disturbances• Patient education

B. Pharmacologic

Antiresorptive (anticatabolic)• Denosumab • Odanacatib • Lasofoxifene • Bazedoxifene • New delivery systems – oral salmon

calcitonin

Osteoanabolic (bone-forming)• Sclerostin inhibitor• Variations of PTH• Endogenous PTH stimulation – calcium

sensing receptor antagonist • New delivery systems – transdermal PTH

Antiresorptive and anabolic• Strontium ranelate

Table 4: Management of osteoporosis.

Figure 1: OSTA Score

Figure 2: Femur fracture

Figure 3: Osteoporotic fracture L3

MARCH 2014 DRUG PROFILE 20

Once considered a disease of the elderly, type 2 diabetes has now shifted down a

generation. Most people with diabetes are in the 40-59-year age group. Combination

therapies are commonly used since monotherapies fail to provide adequate glycemic

control. Combination oral agents can simplify the therapeutic regimen and improve

adherence. This report profiles a novel oral antihyperglycemic combination containing

linagliptin and metformin.

Linagliptin/metformin combination therapy for type 2 diabetes mellitus

EE LYN TAN, PHD

IntroductionDiabetes affects 382 million people world-

wide and caused 5.1 million deaths in 2013

alone. The International Diabetes Federation

(IDF) predicts that the number of people living

with diabetes will rise to 592 million by 2035.

[IDF Diabetes Atlas 2013]

As chronic hyperglycemia is associated with

an increased risk of diabetes-related complica-

tions, [Diabetes Care 2010;33:1090-1096; Dia-betes 2010;59:1244-1253; Lancet 1998;352:837-

853] prognosis in patients with diabetes is

MARCH 2014 DRUG PROFILE 21

strongly influenced by disease control.

Type 2 diabetes mellitus (T2DM accounts for

approximately 90 percent of patients with diabe-

tes. [http://www.who.int/mediacentre/factsheets/fs312/en/] The results of the United Kingdom

Prospective Diabetes Study (UKPDS) study un-

derscored the importance of glycemic control in

patients with T2DM. [Lancet 1998;352:837-53]

The goals of treatment are to eliminate symp-

toms and to prevent, or at least slow, the devel-

opment of both micro- and macrovascular com-

plications. [http://www.idf.org/webdata/docs/IDF%20GG]

The stepwise approach to the management

of T2DM usually involves lifestyle modification,

followed by the addition of oral hypoglycemic

monotherapy if glycated hemoglobin (HbA1c)

levels remain above the targets recommended

in guidelines. [Diabetes Care 2009;32:193-203]

Nevertheless, most patients do not achieve ad-

equate glycemic control with monotherapies,

[JAMA 2002;287:360-372] eventually necessi-

tating combination therapy.

Useful combination therapies comprise of in-

dividual agents that have complementary mech-

anisms of action. Ideally, the core pathophysi-

ologies of T2DM – insulin resistance and loss of

pancreatic beta-cell function – should be target-

ed. [Diabetes 2009;58:773-795]

Linagliptin/metformin therapy Mode of action

Linagliptin and metformin are two drugs with

complementary mechanisms of action for the

treatment of T2DM. [Trajenta Prescribing In-

formation] Linagliptin, a dipeptidyl peptidase-4

(DPP-4) inhibitor and metformin, a member of

the biguanide class, are both oral hypoglycemic

agents.

Linagliptin inhibits DPP-4, an enzyme in-

volved in the inactivation of the incretin hor-

mones glucagon-like peptide-1 (GLP-1) and

glucose-dependent insulinotropic polypeptide

(GIP). Both hormones are involved in the regula-

tion of glucose homeostasis. Incretins are con-

stantly secreted at low basal levels, but levels

peak following meals. GLP-1 and GIP increase

insulin biosynthesis and secretion from pancre-

atic beta-cells. GLP-1 also reduces glucagon

secretion. This causes a reduction in hepatic

glucose output. Linagliptin binds reversibly to

DPP-4, resulting in a sustained increase in in-

cretin levels. Linagliptin can cause a glucose-

dependent increase in insulin secretion and

decrease in glucagon secretion. This improves

glucose homeostasis.

Metformin is a biguanide that lowers both

basal and postprandial plasma glucose. It does

not stimulate insulin secretion, and therefore is

not associated with hypoglycemia. Metformin

acts via three mechanisms: inhibition of gluco-

neogenesis and glycogenolysis (thereby reduc-

ing hepatic glucose production), improvement

of peripheral glucose uptake and utilization

(thereby improving muscular insulin sensitivity),

and delay of intestinal glucose absorption. In-

dependent of its action on glycemia, metformin

also has favorable effects on lipid metabolism.

Clinical efficacy

A randomized, placebo-controlled, phase III

trial investigated the efficacy and safety of initial

MARCH 2014 DRUG PROFILE 22

combination therapy with linagliptin and metfor-

min in patients with inadequate glycemic control

compared with monotherapy. [Diabetes Obes Metab 2012;14:565-574] In this 24-week study,

researchers randomized 791 adults with inad-

equate glycemic control (HbA1c 7.5–11 percent)

to one of six treatment arms: two free combina-

tion therapy arms received linagliptin 2.5 mg

twice daily (bid) plus either 500 mg or 1,000 mg

metformin bid; four monotherapy arms received

either linagliptin 5 mg once daily, metformin 500

mg or 1,000 mg bid or placebo. [Diabetes Obes Metab 2012;14:565-574]

Severely hyperglycemic patients (HbA1c 11

percent) received open-label linagliptin 2.5

mg plus metformin 1,000 mg, both bid. Both

monotherapy arms demonstrated significant

changes in HbA1c values from baseline com-

pared with placebo. However, mean change

in HbA1c from baseline to week 24 was signifi-

cantly greater in the combination arms com-

pared with their respective metformin monother-

apy arms (p<0.0001). [Diabetes Obes Metab

2012;14:565-574]

Response to initial combination therapy was

greater in patients with high baseline HbA1c lev-

els (8.5–11 percent) compared with moderate

baseline HbA1c levels (7.5–<8.5 percent). Those

with severe hyperglycemia who received open-

label combination therapy experienced a mean

HbA1c reduction of 3.7 percent. [Diabetes Obes Metab 2012;14:565-574]

At the 2013 World Diabetes Congress held

in Melbourne, Australia, researchers presented

the results of an international multicenter phase

IV randomized, double blind study evaluating

linagliptin (5 mg) as monotherapy and in com-

bination with metformin (1,500 or 2,000 mg) in

treatment-naïve adults with newly diagnosed

(<12 months) uncontrolled T2DM. [Abstract

P-1104]

The study randomized 316 treatment-naïve

adults with a mean average plasma glucose

concentration (HbA1c) of 9.8 percent to receive

linagliptin 5 mg once daily (n=157) and the initial

combination of linagliptin 5 mg once daily plus

metformin twice daily (uptitrated to a maximum

dose of 2,000 mg daily; n=159) for 24 weeks.

This study demonstrated that while linagliptin

monotherapy and linagliptin/metformin initial

combination therapy conferred significant re-

ductions in HbA1c, the combination therapy was

statistically superior to monotherapy in terms of

HbA1c reduction. Sixty-one percent of patients

on the combination therapy of linagliptin/metfor-

min achieved the target HbA1c (<7 percent) at

week 24 (vs 39 percent for patients on linagliptin

monotherapy).

In this study, linagliptin/metformin combina-

tion treatment was associated with a low rate of

adverse reactions.

Adverse effects

Gastrointestinal disorders are most frequent-

ly reported in clinical trials. These usually occur

at the initiation of therapy and usually resolve

spontaneously. [Trajenta Duo Prescribing In-

formation] In the Haak study, the rates of diar-

rhea in patients taking the combination treat-

ment were found to be comparable with those

taking metformin alone. [Diabetes Obes Metab 2012;14:565-574]

MARCH 2014 DRUG PROFILE 23

Hypoglycemic episodes are also uncommon.

This adverse event occurs more often in patients

treated with linagliptin/metformin tablets com-

bined with sulfonylureas. [Trajenta Duo Prescrib-

ing Information] This combination therapy is not

associated with clinically significant changes in

body weight or waist circumference. Neither met-

formin nor linagliptin is associated with weight

gain. In the phase III trial described above, the

combination was found to be weight neutral. [Di-abetes Obes Metab 2012;14;565-574] Similarly,

body weight was stable with linagliptin and de-

creased in the combination arm (-1.3 kg between

group difference) in the phase IV study. [World Diabetes Congress 2013; Abstract P-1104]

Duo) are available in three dose combinations:

2.5 mg linagliptin/500 mg metformin, 2.5 mg

linagliptin/850 mg metformin, and 2.5 mg lina-

gliptin/1,000 mg metformin.

Doses should be individualized for each pa-

tient, up to a maximum of 5 mg linagliptin/2,000

mg metformin a day. In patients inadequately con-

trolled on the maximum tolerated dose of metfor-

min monotherapy, the usual starting dose is lina-

gliptin 2.5 mg twice daily (5 mg total daily dose)

plus the dose of metformin already being taken.

Patients well controlled with separate formu-

lations of both linagliptin and metformin should

start Trajenta Duo at the dose of linagliptin and

metformin already being taken. Patients inade-

quately controlled on dual combination therapy

with the maximum tolerated dose of metformin

and a sulfonylurea may be prescribed the start-

ing dose of linagliptin 2.5 mg twice daily (5 mg

total daily dose) and a dose of metformin similar

to the dose already being taken. When used in

combination with a sulfonylurea, a lower dose of

the sulfonylurea may be required to reduce the

risk of hypoglycemia. [Trajenta Duo Prescribing

Information]

Trajenta Duo is contraindicated in patients

with renal failure or dysfunction (CrCl <60 mL/

min) and those with hepatic impairment.

Place within guidelines

For patients with T2DM, management of

hyperglycemia is typically complex, and few

patients successfully achieve and maintain

recommended targets for HbA1c. Increasingly

combination therapy is recommended early in

the disease course, or even directly at diagnosis

“ Combination treatment with

linagliptin and metformin showed

superior efficacy compared with

monotherapy (using either agent ”

Pooled analysis of clinical trials demon-

strated that linagliptin was not associated with

increased rates of cancer and infections. [Dia-betes Obes Metab 2012;14:470-478] During

post-marketing surveillance, pancreatitis has

been associated with DPP-4 inhibitors, includ-

ing sitagliptin and saxagliptin. However, the in-

cidence of pancreatitis is low (<0.2 percent) in

patients receiving linagliptin therapy. [Diabetes Obes Metab 2012;14:470-478]

Dosing

The commercially available oral tablets

combining linagliptin with metformin (Trajenta

MARCH 2014 DRUG PROFILE 24

in patients with high HbA1c levels.

The ADA/EASD position statement pub-

lished in 2012 recommends a patient-centric

approach to diabetes management. [Diabetes Care 2012;35: 1364-1379] Glucose targets and

pharmacological treatments should be individu-

alized, with lifestyle modifications (diet, exercise

and education) forming the basis of any treat-

ment strategy.

If not contraindicated and tolerated, the ADA’s

Standards of Medical Care in Diabetes reaffirms

metformin as the preferred initial pharmacologi-

cal treatment of T2DM. [Diabetes Care 2013;36

(Suppl 1):S11-66] As diabetes is a chronic pro-

gressive disease, other antiglycemic agents

may be required to maintain glucose control.

When metformin fails to achieve or maintain gly-

cemic goals, another agent should be added.

[Diabetes Care 2013;36(Suppl 1):S11-66]

DPP-4 inhibitors (eg, linagliptin) and metfor-

min act in complementary ways. Combination

treatment with linagliptin and metformin showed

superior efficacy compared with monotherapy

(using either agent). Metformin and linagliptin

are weight-neutral agents, and may be preferred

in overweight and obese patients with diabetes.

It is well known that combination therapies can

improve adherence, and ultimately, patient out-

comes. As this combination therapy is generally

well tolerated, the oral combination therapy of

linagliptin plus metformin may be appropriate

for many T2DM patients.

MARCH 2014 RESEARCH REVIEWS 25

Gum chewing reduces hospital stay after laparoscopic colorectal cancer surgery

Hwang D Y et al. Effect of gum chewing on the recovery from

laparoscopic colorectal cancer surgery. Ann Coloproctol 2013;

29:248-251

“Sham feeding” patients who can poorly

tolerate food by initiating gum chewing

is a common method for reducing postopera-

tive ileus and stimulating intestinal motility. Gum

chewing has also recently been shown to sig-

nificantly shorten the length of hospital stay after

laparoscopic colorectal cancer surgery.

Researchers reviewed the medical records

of 132 patients who underwent laparoscopic

colorectal cancer surgery in Korea to compare

short-term clinical outcomes. Sixty-seven pa-

tients did not chew gum after surgery and 65

did. Gum chewing was initiated on the first post-

operative day and was continued three times a

day for 10 to 20 min at a time, until normal feed-

ing resumed.

No significant between-group difference was

observed in the first passage of gas, although it

was slightly earlier among those who chewed

gum. However, the length of hospital stay

was significantly shorter among patients who

chewed gum compared with those who did not

(6.7 days vs 7.3 days, p=0.018).

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MARCH 2014 RESEARCH REVIEWS 26

Snus use not linked to neoplastic and oral conditions

Swedish-type moist snuff (snus), which con-

sists of finely ground tobacco, salt, water,

humidifying and chemical buffering agents, and

food-grade flavorings, has been suggested as

a possibly safer alternative to smoking. A 2011

review found little evidence of serious adverse

effects associated with the use of snus, and its

author has now published an update to consider

findings from nine recent publications on snus

use and the incidence of neoplastic conditions,

oral conditions, and circulatory disease.

The report confirms that there is no evidence

of snus use being associated with cancers of the

oropharynx, esophagus, stomach, and lung, and

includes new observations that it is not linked to

colorectal cancer or acoustic neuroma. Reports

of an increased risk of pancreatic cancer are

further undermined, although a report of poorer

cancer survival in snus users is noted. There is no

evidence of snus use being associated with peri-

odontitis or dental caries despite the presence of

the characteristic ‘snuff-dipper’s’ lesion.

Although there is no evidence of snus use

being associated with the onset of myocardial

infarction, there is some evidence of reduced

survival among snus users.

The author commented that further studies

would be required to determine whether this is

a direct effect of snus use or the result of con-

founding by socioeconomic status or other fac-

tors. However, he noted that even if snus use

does have some adverse health effects, these

are clearly far less than those associated with

smoking.

Lee PN. Epidemiological evidence relating snus to health – an

updated review based on recent publications. Harm Reduction

Journal 2013;10:36.

MARCH 2014 RESEARCH REVIEWS 27

Abatacept vs adalimumab in RA: Two-year outcomes

The Abatacept versus Adalimumab Com-

parison in Biologic-Naive RA Subjects

with Background Methotrexate (AMPLE) trial

is a phase IIIb, 2-year, randomized, investiga-

tor-blinded study that was initiated to com-

pare the safety, efficacy, and radiographic

outcomes of subcutaneous abatacept and

adalimumab in combination with methotrex-

ate (MTX) in patients with rheumatoid arthri-

tis (RA). The present report summarizes the

2-year outcomes.

In the study, 646 biologic-naïve patients

with active RA and an inadequate response to

MTX were randomized to subcutaneous 125

mg abatacept weekly (n=318) or subcutane-

ous 40 mg adalimumab bi-weekly (n=328) in

combination with a stable dose of MTX.

A total of 79.2 percent of the abatacept re-

cipients and 74.7 percent of the adalimumab

recipients completed year 2 of the study. Com-

parable American College Rheumatology 20,

50, and 70 responses were observed at year

2 among the abatacept and adalimumab re-

cipients (59.7 percent, 44.7 percent, and 31.1

percent vs 60.1 percent, 46.6 percent, and

29.3 percent, respectively). Rates of adverse

events and serious adverse events were also

similar, but adalimumab recipients suffered

more serious infections (3.8 percent vs 5.8

percent). Overall, there were fewer discontinu-

ations in the abatacept group.

Schiff M et al. Head-to-head comparison of subcutaneous abatacept

versus adalimumab for rheumatoid arthritis: two-year efficacy and

safety findings from AMPLE trial. Ann Rheum Dis 2014;73:86-94

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MARCH 2014 RESEARCH REVIEWS 29

Risk factors linked to mortality in Taiwanese patients with methanol poisoning

Methanol poisoning is a serious public

health issue in Taiwan due to its use in

the production of illegal alcoholic beverages,

but very little is known about the risk factors and

outcomes of methanol poisoning in Asian pa-

tients. A recent study thus examined the predic-

tive potential of a number of clinical variables to

determine which, if any, were predictive of mor-

tality after methanol exposure.

The study assessed 32 patients admitted

to Chang Gung Memorial Hospital with acute

methanol poisoning between 2000 and 2008.

Most were middle-aged (46.1 ± 13.8 years),

male (87.5 percent), and habitual consumers

of alcohol (75 percent). All the poisonings were

from oral exposure except for one due to an

intentional injection of methanol (3.1 percent).

Symptoms of methanol poisoning began to ap-

pear after 9.3 ± 10.1 hours, and included renal

failure (59.4 percent), respiratory failure (50 per-

cent), hypothermia (50 percent), hypotension

(15.6 percent), and consciousness disturbance

(Glasgow coma scale [GCS] score 10.5 ± 5.4).

Most patients were treated with an ethanol an-

tidote (59.4 percent) and hemodialysis (58.1

percent). The remaining 41.6 percent of patients

did not meet the indications for ethanol therapy.

At the end of the analysis, six (18.8 percent)

patients were alive, 15 (46.9 percent) were

alive with chronic complications, and 11 (34.4

percent) had died. Multivariate Cox regres-

sion revealed that GCS score (odds ratio [OR]

0.816, 95% CI 0.682-0.976, p=0.026), hypo-

thermia (OR 168.686, 95% CI 2.685-10,595.977,

p=0.015), and serum creatinine level (OR 4.799,

95% CI 1.321-17.440, p=0.017) were significant

risk factors associated with mortality.

Lee C et al. Risk factors for mortality in Asian Taiwanese patients

with methanol poisoning. Therapeutics and Clinical Risk Manage-

ment 2014:10 61-67

MARCH 2014 RESEARCH REVIEWS 30

LUTS and BPH in Asian men

A systematic review of the epidemiology,

treatment, and pathophysiology of lower

urinary tract symptoms (LUTS) and benign pros-

tatic hyperplasia (BPH) with or without erectile

dysfunction (ED) was published recently. The re-

view was based on literature identified by Med-

line searches and focused to a certain extent on

Asian men as there is currently little information

available on ethnicity-based differences in these

conditions.

BPH was found to be relatively common,

occurring in approximately 42 percent of men

aged 51 to 60 years. In addition, approximate-

ly 90 percent of men aged 45 to 90 years were

found to experience LUTS, and the incidence

increased with age for almost all ethnicities.

The prevalence of LUTS was highest among

Hispanic men followed by Black, Caucasian,

and Asian men in that order. LUTS and BPH

were independently associated with ED; ap-

proximately 70 percent of men with either con-

dition also experienced ED, and the severity

of one condition was often correlated with that

of the other. Tadalafil, the phosphodiester-

ase-5 inhibitor, was the only treatment recom-

mended for co-existing BPH and ED. Tadalafil

5mg was reported to be both efficacious and

safe in Asian men with LUTS or BPH, and re-

portedly improved both these conditions and

co-existing ED. Incidence rates of LUTS/BPH,

co-existing ED, comorbid diseases, and risks

were comparable among Asian and non-Asian

men.

Park HJ et al. Urinary tract symptoms (LUTS) secondary to benign

prostatic hyperplasia (BPH) and LUTS/BPH with erectile dysfunc-

tion in Asian men: a systematic review focusing on tadalafil. World

J Mens Health 2013 December 31: 193-207

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MARCH 2014 CALENDAR 31

M A R C H

5th Congress of Asia Pacific Pediatric Cardiac Society (APPCS)6/3/2014 to 9/3/2014Location: New Delhi, IndiaInfo: APPCS SecretariatTel: (91) 11 2658 8116Fax: (91) 11 2658 8663E-Mail: appcs2014@gmail.comWebsite: www.appcs2014.org

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21st Regional Conference of Dermatology (RCD) 20149/4/2014 to 12/4/2014Location: Danang, VietnamInfo: Congress AdministrationTel: (603) 4023 4700Fax: (603) 4023 8100Email: secretariat@asianderm.orgWebsite: http://asianderm.org/21rcd/index.htm

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MARCH 2014 HUMOR 32

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M A N A G I N G E D I T O R

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S E N I O R E D I T O R

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C O N T R I B U T I N G E D I T O R S

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P H I L I P P I N E S

Kims Pagsuyuin, Rowena Belgica, Cor-Marie Bacdayan, Cliford Patrick Tel: (632) 886 0333 Email: enquiry.ph@mims.com

S I N G A P O R E

Jason Bernstein, Carrie Ong, Josephine Cheong, Melanie Nyam Tel: (65) 6290 7400 Email: enquiry.sg@mims.com

T H A I L A N D

Wipa Sriwijitchok Tel: (662) 741 5354 Email: enquiry.th@mims.com

V I E T N A M

Nguyen Thi Lan Huong, Nguyen Thi My Dung Tel: (848) 3829 7923 Email: enquiry.vn@mims.com

E U R O P E / U S A

Kristina Lo-Kurtz Tel: (852) 2116 4352 Email: kristina.lokurtz@mims.com

Medical Tribune is published 12 times a year (23 times in Malaysia) by MIMS Pte Ltd. Medical Tribune is on controlled circulation publication to medical practitioners in Asia. It is also available on subscription to members of allied professions. The price per annum is US$48 (surface mail) and US$60 (overseas airmail); back issues at US$5 per copy. Editorial matter published herein has been prepared by professional editorial staff. Views expressed are not necessarily those of MIMS Pte Ltd. Although great effort has been made in compiling and checking the information given in this publication to ensure that it is accurate, the authors, the publisher and their servants or agents shall not be responsible or in any way liable for the continued currency of the information or for any errors, omissions or inaccuracies in this publication whether arising from negligence or otherwise howsoever, or for any consequences arising therefrom. The inclusion or exclusion of any product does not mean that the publisher advocates or rejects its use either generally or in any particular field or fields. The information contained within should not be relied upon solely for final treatment decisions.

© 2014 MIMS Pte Ltd. All rights reserved. No part of this publication may be reproduced in any language, stored in or introduced into a retrieval system, or transmitted, in any form or by any means (electronic, mechanical, photocopying, recording or otherwise), without the written consent of the copyright owner. Permission to reprint must be obtained from the publisher. Advertisements are subject to editorial acceptance and have no influence on editorial content or presentation. MIMS Pte Ltd does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature.

Philippine edition: Entered as second-class mail at the Makati Central Post Office under Permit No. PS-326-01 NCR, dated 9 Feb 2001. Printed by KHL Printing Co Pte Ltd, 57 Loyang Drive, Singapore 508968.

ISSN 1608-5086