MARCH 2014

AHA rolls out stroke prevention guidelines for women

NEWS
Asthma gene profile distinct in Chinese individuals

IN PRACTICE
Management of osteoporosis: Diagnosis and treatment

DRUG PROFILE
Linagliptin/ metformin combination therapy for T2DM

RESEARCH REVIEWS
Snus use not linked to neoplastic and oral conditions

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AHA rolls out stroke prevention guidelines for women

ELVIRA MANZANO low-dose aspirin (about 81mg) after the first trimester 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 pregnancy, 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 unsafe 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 explained. 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 endorsed the new guidelines.

he 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 hypertension, diabetes, quitting smoking, healthy diet, and exercise. The new AHA guidance focuses on women-specific issues such as hypertension during pregnancy, use of oral contraceptives, childbirth, menopause, hormonal replacement and other risk factors more frequently seen in women such as obesity and metabolic syndrome, atrial fibrillation and migraine 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 important to emphasize prevention and decrease womens 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 prior to pregnancy, they should be considered for

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Two doses of HPV vaccine may suffice for genital warts prevention
RADHA CHITALE

ust two of the recommended three doses of human papillomavirus virus (HPV) vaccine

may be enough to reduce the risk of condyloma (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 difference, 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, followed 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 inA study suggests that two doses of the vaccine may be sufficient.

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 vaccination programs include substantial numbers of

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women who do not complete the full vaccination schedules, the researchers said. HPV serotypes 6 and 11 cause about 90 percent of condylomas, which are the first measurable 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 cant or wont seek medical care, nor did it account for disease outcomes other than condyloma.

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FORUM

Most recent data from UK point to substantial public health benefits of electronic cigarettes
Dr. Michael Siegel
Professor, Department of Community Health Sciences Boston University School of Public Health Boston, Massachusetts, US

hile most anti-smoking organizations continue to oppose electronic cigarettes

(e-cigarettes), warning of the hypothetical risks of these products, new data from the UK suggest 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 dramatically, ever since the fourth quarter of 2011. 2.  Precisely coincident with the rise in e-cigarette use in the UK has been a significant increase in quit smoking attempts. 3.  E-cigarettes have surpassed nicotine replacement therapy (NRT) and other drugs as the most commonly used smoking cessation method. 4.  Overall motivation to quit has increased Report STS140122 (Electronic cigarettes in England - latest trends) draws the following conclusions:  The increase in e-cigarette use prevalence 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 exsmokers are using e-cigarettes.

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FORUM

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 story Based 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 cessation or impeding the decline in smoking prevalence. 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 precluding these smokers from reaping any health benefits. In contrast, however, to the lack of evidence that e-cigarettes are having any negative public 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 smoking, 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 smokers. 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. Ironically, the results of public health efforts have been to impede smoking cessation, lower the overall motivation of smokers to quit, and decreasing 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 abstinence-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 permission.

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FORUM

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.

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Study highlights discrepancies in diabetes management in ethnic minorities

JENNY NG

ethnic minority groups, as a recent study highlighted discrepancies in comprehensive management of their condition compared with Chinese patients. The study, conducted by the Queen Elizabeth Hospitals 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 Nepalese, Indians, Filipinos, Pakistanis and Indonesians) 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 HDLcholesterol (1.19 vs 1.28 mmol/L; p=0.001) than Chinese patients. Within the group of ethnic minorities, researchers found differences in measures of disease 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 Indonesians 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 patients were found to have lower diastolic blood pressure (84 mm Hg) than patients of other ethnicities. However, demographic differences between 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

hysicians in Hong Kong should pay attention to the needs of diabetes patients from

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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 monitoring and surveillance programs, suggested the researchers. Local doctors should therefore pay particular attention to the needs of different ethnic groups and offer a flexible care package that reflects 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 elderly

CHRISTINA LAU

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 sessions in the 8-week treatment program. According to investigators from the Chinese University of Hong Kongs School of Chinese Medicine and Department of Psychiatry, improvements were more significant in the participants delayed recall. The treatment, lasting 30 minutes per session, 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 memory-related diseases focuses on regulation of brain function and tonification of the kidney, explained Professor Albert Leung, Director of

lder adults with mild cognitive impairment (MCI) can benefit from improved memory

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the School of Chinese Medicine. Stimulation of these acupuncture points can enhance cognitive function. The pilot study, launched in August 2013, aimed at ascertaining and quantifying the efficacy of acupuncture in MCI treatment. Assessments of cognitive function were carried out at baseline, end of treatment, as well as 2 and 4 months post treatment, using widely recMCI: Facts and figures

ognized tools such as the Cantonese version of the Mini-Mental State Examination and Alzheimers Disease Assessment Scale-cognitive subscale (ADAS-cog). With the promising initial results, the investigators 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 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.

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Asthma gene profile distinct in Chinese individuals

JACKEY SUEN

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 casecontrol 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. Nearly half of the studied SNPs showed differences in minor allele frequencies of 0.2 or above between Chinese and Caucasians/Africans. The researchers also sequenced 10 asthma loci in 24 healthy Hong Kong children. Compared with six other ethnic groups studied in the 1,000 Genome Project, the Hong Kong children had distinct haplotype structures (constructed 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 populations, suggested the authors.

hinese individuals possess a distinct asthma gene profile and haplotype structures

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Vitamin D supplementation lacks benefits, study suggests

CASSIE-ANNE LOW

he results of a new study suggest that vitamin 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 myocardial 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 justification for prescribing vitamin D supplements to prevent [such outcomes], wrote the study authors, 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 unlikely to alter these conclusions. Investigators and funding bodies should consider the probable 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 supA large meta-analysis found that vitamin D supplementation had little, if any, health benefits.

port by several leading scholars in the field and this has had a major impact on health practitioners 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 Michalsson from Uppsala University in Sweden, 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 Endocrinol Metab 2011;96:53-58] Without stringent indications ie, supplementing those without true insufficiency there is a legitimate fear that vitamin D supplementation might actually cause net harm, said Michalsson.

Treatment Updates on Diabetes and Lipid Disorders

Find out what these experts have to say about upcoming treatments for diabetes and lipid disorders and the risks related to obesity

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

Professor Brian Tomlinson

Future therapies to treat familial hypercholesterolemia and difficulties in measuring the prevalence of this disease in Asia

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

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

MIMS Video Series features

interviews with leading experts

For A 5-minute Update Go to www.mims.asia/video_series

SCAN TO WATCH VIDEO

Brought to you by MIMS

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Defer dialysis in ESRD: New guidelines

ELVIRA MANZANO greater resource use, she added. The new guideline covers adult patients (age ew clinical practice guidelines from the Canadian Society of Nephrology recommend >18 years) with ESRD (stage 5 CKD) initiating 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 conservative management without dialysis. The Canadian guidance does not recommend earlier initiation of dialysis in higher-risk subgroups, such as patients with diabetes. It also dropped previous recommendations to initiate dialysis based only on a decline in nutritional status (as measured by serum albumin, lean body mass, etc). The recommendation differs from that of the National Kidney Foundations Kidney Disease Quality Outcomes Initiative (KDOQI), which calls for nephrologists to evaluate 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 recommend initiation of dialysis at eGFR <10 mL/ min or if uremic symptoms or signs of malnutrition occur. The guideline is intended not only for nephrologists but for primary care physicians, other internal medicine subspecialties, and nursing specialists caring for, referring, or co-managing treatment for patients with CKD.

deferred over early initiation of dialysis in patients 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 toward 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

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Exercise, bodyweight influence future CVD risk in male teens

RADHA CHITALE

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]
Good aerobic fitness and low BMI of teenage males were linked to lower rates of CVD in later years.

ood health in the teenage years could signal whether or not someone will be at risk

Our study suggests that its more important not to be overweight or obese than to be fit, but that its even better to be both fit and a normal weight,
Our study suggests that its more important not to be overweight or obese than to be fit, but that its even better to be both fit and a normal weight, said lead researcher Professor Peter Nordstrm, of Ume University in Sweden. Nordstrm and colleagues examined health records of 743,498 18-year-old Swedish men between 1969 and 1984 when they were conscripted into military service. Aerobic fitness

was assessed with a cycling test and muscle strength was determined by tests for knee extension, 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 researchers adjusted the data for age, body mass index (BMI), diseases, blood pressure, education and other socioeconomic factors. For each 15 percent increase in aerobic fitness, 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-

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tween 18.5 and 25 kg/m2) and overweight (BMI between 25-30 kg/m , p<0.05 for all), except for
2

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. Smoking, a critical cardiovascular disease (CVD) risk factor, was not accounted for. Nordstrm 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.

obese men (BMI more than 30 kg/m2). Muscle strength did not appear to be strongly correlated with later risk of MI. The researchers reported 271,005 (43.7 percent) of the men were normal or lean whose aerobic fitness was better than average, and there were 2.176 MIs in this group, suggesting that regular cardiovascular training in late adolescence is independently associated with

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Management of osteoporosis: Diagnosis and treatment

Dr. Eugene Wong
Consultant Orthopedic & Spine Surgeon Adjunct Assistant Professor Perdana University Graduate School of Medicine Serdang, Selangor Malaysia

steoporosis is a common problem. It is responsible 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 percent of men over the age of 50 have osteopenia, or osteoporosis. It is defined by systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading 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. Table 1: Types of osteoporosis. Postmenopausal osteoporosis (type I) C  aused by lack of estrogen C  auses parathyroid hormone (PTH) to overstimulate osteoclasts. E  xcessive loss of trabecular bone Age-associated osteoporosis (type II) B  one loss due to increased bone turnover  Malabsorption  Mineral and vitamin deficiency

Table 2: Risk factors for osteoporosis. A. Non-pharmacologic I ncreasing age F  emale gender F  amily history of osteoporosis L  ow body weight (BMI <18.5) C  aucasian (Northern European descent) and Asian ethnicity L  ate menarche N  ulliparity E  arly menopause A  norexia nervosa or bulimia L  ow testosterone levels in men

B. Modifiable risk factors D  iet excessive consumption of caffeine and salt. I nadequate consumption of calcium and vitamin D. S  edentary lifestyle M  edical problems anorexia, thyroid problems, bowel diseases and rheumatoid arthritis. U  se of certain medications C  igarette smoking E  xcessive use of alcohol E  xcessive exercise (resulting in amenorrhea).

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In osteoporosis, there is loss in total mineralized bone and disruption of the normal balance of bone breakdown and build up. There are imbalances in bone remodeling. There is a reduction in bone build up and accelerated bone breakdown during the postmenopausal period. Up to 5 percent 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 factors to be considered in reducing fragility fractures include preventing falls and decreasing the risk of fracture by using hip protectors. Diagnosis A fragility fracture is one that results from mechanical forces that would not ordinarily cause a fracture in a healthy young adult. A high suspicion of osteoporosis is warranted in any patient with a fracture caused by minimal trauma. Vertebral 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 patient clinically into low, medium and high risk. Patients with medium or high risk are advised to undergo a dual energy x-ray absorptiometry (DEXA) scan. A DEXA scan measures bone density at the femoral neck, spine and distal radius. The fracture risk doubles for every standard deviation T-score decrease in BMD. Blood tests needed include a comprehensive metabolic panel, complete blood count, thyroid stimulating hormone

Table 3: Etiology of osteoporosis. Idiopathic secondary Nutritional: Lactose intolerance, vegetarian diet, low dietary calcium and excessive alcohol intake Lifestyle: Smoking and physical inactivity Medical: Type 1 diabetes, Cushings syndrome, chronic renal disease, inflammatory bowel disease, cystic fibrosis, hyperparathyroidism, hyperthyroidism, anorexia nervosa, celiac disease, idiopathic hypercalciuria and premature ovarian failure. Medications: Glucocorticoid drugs, long-term lithium therapy, chemotherapy, anticonvulsants (phenytoin, phenobarbital, valproate and carbamazepine), long-term phosphatebinding antacid use, thyroid replacement drugs and methotrexate. level and vitamin D levels. The Fracture Risk Assessment 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. Treatment Treatment can reduce fracture risk considerably and aims to minimize fracture risk by achieving normal bone strength with a drug therapy that is safe, well-tolerated, easy to administer and cost effective. The management also includes various non-pharmacological measures as listed in Table 4. All fragility fractures are associated with morbidity. Patients will be unable to carry out normal activities of daily living, walk independently

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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.

Table 4: Management of osteoporosis. 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

Figure 1: OSTA Score

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

Figure 2: Femur fracture

Figure 3: Osteoporotic fracture L3

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Linagliptin/metformin combination therapy for type 2 diabetes mellitus

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.

EE LYN TAN, PHD Introduction Diabetes affects 382 million people worldwide 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 complications, [Diabetes Care 2010;33:1090-1096; Diabetes 2010;59:1244-1253; Lancet 1998;352:837853] prognosis in patients with diabetes is

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strongly influenced by disease control. Type 2 diabetes mellitus (T2DM accounts for approximately 90 percent of patients with diabetes.[http://www.who.int/mediacentre/factsheets/ fs312/en/] The results of the United Kingdom Prospective Diabetes Study (UKPDS) study underscored the importance of glycemic control in patients with T2DM. [Lancet 1998;352:837-53] The goals of treatment are to eliminate symptoms and to prevent, or at least slow, the development of both micro- and macrovascular complications.[ 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 adequate glycemic control with monotherapies, [JAMA 2002;287:360-372] eventually necessitating combination therapy. Useful combination therapies comprise of individual agents that have complementary mechanisms of action. Ideally, the core pathophysiologies of T2DM insulin resistance and loss of pancreatic beta-cell function should be targeted. [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 Information] 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 involved in the inactivation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both hormones are involved in the regulation of glucose homeostasis. Incretins are constantly secreted at low basal levels, but levels peak following meals. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic 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 incretin levels. Linagliptin can cause a glucosedependent 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 gluconeogenesis and glycogenolysis (thereby reducing hepatic glucose production), improvement of peripheral glucose uptake and utilization (thereby improving muscular insulin sensitivity), and delay of intestinal glucose absorption. Independent 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

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combination therapy with linagliptin and metformin 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 inadequate glycemic control (HbA1c 7.511 percent) to one of six treatment arms: two free combination 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 compared with placebo. However, mean change in HbA1c from baseline to week 24 was significantly greater in the combination arms compared with their respective metformin monotherapy arms (p<0.0001). [Diabetes Obes Metab 2012;14:565-574] Response to initial combination therapy was greater in patients with high baseline HbA1c levels (8.511 percent) compared with moderate baseline HbA1c levels (7.5<8.5 percent). Those with severe hyperglycemia who received openlabel 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 combination with metformin (1,500 or 2,000 mg) in treatment-nave adults with newly diagnosed (<12 months) uncontrolled T2DM. [Abstract P-1104] The study randomized 316 treatment-nave 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 reductions 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/metformin achieved the target HbA1c (<7 percent) at week 24 (vs 39 percent for patients on linagliptin monotherapy). In this study, linagliptin/metformin combination treatment was associated with a low rate of adverse reactions. Adverse effects Gastrointestinal disorders are most frequently reported in clinical trials. These usually occur at the initiation of therapy and usually resolve spontaneously. [Trajenta Duo Prescribing Information] In the Haak study, the rates of diarrhea in patients taking the combination treatment were found to be comparable with those taking metformin alone. [Diabetes Obes Metab 2012;14:565-574]

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Hypoglycemic episodes are also uncommon. This adverse event occurs more often in patients treated with linagliptin/metformin tablets combined with sulfonylureas. [Trajenta Duo Prescribing Information] This combination therapy is not associated with clinically significant changes in body weight or waist circumference. Neither metformin nor linagliptin is associated with weight gain. In the phase III trial described above, the combination was found to be weight neutral. [Diabetes Obes Metab 2012;14;565-574] Similarly, body weight was stable with linagliptin and decreased 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 linagliptin/1,000 mg metformin. Doses should be individualized for each patient, up to a maximum of 5 mg linagliptin/2,000 mg metformin a day. In patients inadequately controlled on the maximum tolerated dose of metformin monotherapy, the usual starting dose is linagliptin 2.5 mg twice daily (5 mg total daily dose) plus the dose of metformin already being taken. Patients well controlled with separate formulations of both linagliptin and metformin should start Trajenta Duo at the dose of linagliptin and metformin already being taken. Patients inadequately controlled on dual combination therapy with the maximum tolerated dose of metformin and a sulfonylurea may be prescribed the starting 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

C  ombination treatment with linagliptin and metformin showed superior efficacy compared with monotherapy (using either agent 
Pooled analysis of clinical trials demonstrated that linagliptin was not associated with increased rates of cancer and infections. [Diabetes Obes Metab 2012;14:470-478] During post-marketing surveillance, pancreatitis has been associated with DPP-4 inhibitors, including sitagliptin and saxagliptin. However, the incidence 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

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in patients with high HbA1c levels. The ADA/EASD position statement published in 2012 recommends a patient-centric approach to diabetes management. [Diabetes Care 2012;35: 1364-1379] Glucose targets and pharmacological treatments should be individualized, with lifestyle modifications (diet, exercise and education) forming the basis of any treatment strategy. If not contraindicated and tolerated, the ADAs Standards of Medical Care in Diabetes reaffirms metformin as the preferred initial pharmacological treatment of T2DM. [Diabetes Care 2013;36 (Suppl 1):S11-66] As diabetes is a chronic progressive disease, other antiglycemic agents may be required to maintain glucose control.

When metformin fails to achieve or maintain glycemic goals, another agent should be added. [Diabetes Care 2013;36(Suppl 1):S11-66] DPP-4 inhibitors (eg, linagliptin) and metformin 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 outcomes. As this combination therapy is generally well tolerated, the oral combination therapy of linagliptin plus metformin may be appropriate for many T2DM patients.

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Gum chewing reduces hospital stay after laparoscopic colorectal cancer surgery

is a common method for reducing postoperative ileus and stimulating intestinal motility. Gum chewing has also recently been shown to significantly 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 patients did not chew gum after surgery and 65 did. Gum chewing was initiated on the first postoperative day and was continued three times a day for 10 to 20 min at a time, until normal feeding 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
Hwang D Y et al. Effect of gum chewing on the recovery from laparoscopic colorectal cancer surgery. Ann Coloproctol 2013; 29:248-251

ham feeding patients who can poorly tolerate food by initiating gum chewing

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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Snus use not linked to neoplastic and oral conditions

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 periodontitis or dental caries despite the presence of the characteristic snuff-dippers lesion. Although there is no evidence of snus use being associated with the onset of myocardial infarction, there is some evidence of reduced
Lee PN. Epidemiological evidence relating snus to health an updated review based on recent publications. Harm Reduction Journal 2013;10:36.

wedish-type moist snuff (snus), which consists of finely ground tobacco, salt, water,

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 confounding by socioeconomic status or other factors. However, he noted that even if snus use does have some adverse health effects, these are clearly far less than those associated with smoking.

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Abatacept vs adalimumab in RA: Two-year outcomes

with Background Methotrexate (AMPLE) trial is a phase IIIb, 2-year, randomized, investigator-blinded study that was initiated to compare the safety, efficacy, and radiographic outcomes of subcutaneous abatacept and adalimumab in combination with methotrexate (MTX) in patients with rheumatoid arthritis (RA). The present report summarizes the 2-year outcomes. In the study, 646 biologic-nave patients with active RA and an inadequate response to MTX were randomized to subcutaneous 125 mg abatacept weekly (n=318) or subcutaneous 40 mg adalimumab bi-weekly (n=328) in combination with a stable dose of MTX. A total of 79.2 percent of the abatacept recipients and 74.7 percent of the adalimumab recipients completed year 2 of the study. Comparable American College Rheumatology 20, 50, and 70 responses were observed at year 2 among the abatacept and adalimumab reSchiff 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

he Abatacept versus Adalimumab Comparison in Biologic-Naive RA Subjects

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 discontinuations in the abatacept group.

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Risk factors linked to mortality in Taiwanese patients with methanol poisoning

the production of illegal alcoholic beverages, but very little is known about the risk factors and outcomes of methanol poisoning in Asian patients. A recent study thus examined the predictive potential of a number of clinical variables to determine which, if any, were predictive of mortality 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 appear after 9.3 10.1 hours, and included renal failure (59.4 percent), respiratory failure (50 percent), 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 antidote (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
Lee C et al. Risk factors for mortality in Asian Taiwanese patients with methanol poisoning. Therapeutics and Clinical Risk Management 2014:10 61-67

ethanol poisoning is a serious public health issue in Taiwan due to its use in

percent) had died. Multivariate Cox regression revealed that GCS score (odds ratio [OR] 0.816, 95% CI 0.682-0.976, p=0.026), hypothermia (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.

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LUTS and BPH in Asian men

urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) with or without erectile dysfunction (ED) was published recently. The review was based on literature identified by Medline 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, approximately 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; approximately 70 percent of men with either condition also experienced ED, and the severity of one condition was often correlated with that of the other. Tadalafil, the phosphodiesterPark HJ et al. Urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) and LUTS/BPH with erectile dysfunction in Asian men: a systematic review focusing on tadalafil. World J Mens Health 2013 December 31: 193-207

systematic review of the epidemiology, treatment, and pathophysiology of lower

ase-5 inhibitor, was the only treatment recommended for co-existing BPH and ED. Tadalafil 5mg was reported to be both efficacious and safe in Asian men with LUTS or BPH, and reportedly 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.

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Sit for the Part 1 of the AUSTRALIAN MEDICAL COUNCIL EXAMS MCQ

Commences 23rd April 2014 in Kuala Lumpur

Fast Track 5 week intensive Course (100% passes for previous students) Lecturers will be flying in from Australia. Total cost: AUS $ 3,950.00 Full details on the exam is explained on the AMC website: www.amc.org.au
Coordinator: Mr. Ganson Govender Mobile: +61- 414 546 561 (Australia) Email: gansong2@gmail.com Local Contact: Mr. Palani Murugappan Mobile: +60-12-212-5422 Email: palani@avimursolutions.com

21st Regional Conference of Dermatology (RCD) 2014 9/4/2014 to 12/4/2014 Location: Danang, Vietnam Info: Congress Administration Tel: (603) 4023 4700 Fax: (603) 4023 8100 Email: secretariat@asianderm.org Website: http://asianderm.org/21rcd/ index.htm European Society for Pediatrics, Hepatology and Nutrition (ESPGHAN) 47th Annual Meeting 9/6/2014 to 12/6/2014 Location: Jerusalem, Israel Info: MCI UK Limited Tel: (44) 0 845 1800 360 E-Mail: ESPGHAN2014-Reg@ mci-group.com Website: www.espghan2014.org/ contact-us European League Against Rheumatology (EULAR) 2014 11/6/2014 to 14/6/2014 Location: Paris, France Info: EULAR Secretariat Tel: (41) 22 33 99 590 Website: www.eular.org/index. cfm?framePage=/congress_2014.cfm E-Mail: eular.reg@mci-group.com 20th ASEAN Federation of Cardiology Congress 2014 12/6/2014 to 15/6/2014 Location: Kuala Lumpur, Malaysia Info: AFCC Secretariat Tel: (60) 3 7955 6608 Fax: (60) 3 7956 6608 Website: www.nham-conference. com/?event=3&cmd=home 19th Congress of the European Association of Hematology 12/6/2014 to 15/6/2014 Location: Milan, Italy Info: EHA Organizing Committee Tel: (31) 0 70 3020099 E-Mail: info@ehaweb.org Website: www.ehaweb.org/congressand-events/annual-congress/19thcongress/key-information/

U R L : w w w. G r a d A u s m e d . c o m
MARCH 5th Congress of Asia Pacific Pediatric Cardiac Society (APPCS) 6/3/2014 to 9/3/2014 Location: New Delhi, India Info: APPCS Secretariat Tel: (91) 11 2658 8116 Fax: (91) 11 2658 8663 E-Mail: appcs2014@gmail.com Website: www.appcs2014.org Asian Pacific Association for the Study of the Liver (APASL) 2014 12/3/2014 to 15/3/2014 Location: Brisbane, Australia Info: Gastroenterological Society of Australia Tel: (61) 3 9001 0279 Fax: (61) 3 9802 8533 E-Mail: apasl2014@gesa.org.au Website: www.apasl2014.com Royal College of Gynaecologists (RCOG) World Congress 2014 28/3/2014 to 30/3/2014 Location: Hyderabad, India Info: Royal College of Obstetricians and Gynaecologists Tel: (44) 0 20 77726200 Website: http://www.rcog.org.uk/ rcog2014 American College of Cardiology (ACC) Annual Scientific Sessions 2014 29/3/2014 to 31/3/2014 Location: Washington DC, US Info: ACC Resource Center Tel : 202-375-6000, ext. 5603; (202) 375-6000, ext. 5603 E-Mail: accregistration@jspargo.com Website: http://accscientificsession. cardiosource.org/ACC.aspx 16th Asia Pacific League of Associations for Rheumatology (APLAR) 31/3/2014 to 5/4/2014 Location: Cebu, Philippines Info: APLAR Conference Committee Tel: (65) 6292 0723 Fax : (65) 6292 4721 E-Mail: info@aplar.org Website: www.aplar.org/About/Pages/ AboutAPLAR.aspx UPCOMING WCO-IOF-ESCEO World Congress of Osteoporosis 2/4/2014 to 5/4/2014 Location: Seville, Spain Info: Yolande Piette Communication Tel: (32) 4 254 12 25 Fax: (32) 4 125 12 90 Email: info@piettecommunication.com Website: www.wco-iof-esceo.org

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Its a broad!

Dont you worry. Doctor Reckonedwith is a giant in his field!

Its remarkable, hes actually looking much better. I think they should run some more tests to make sure!

All I can tell you Doctor Lipstine is that the pain goes away as soon as I go to sleep!

Why didnt you tell me you were allergic to penicillin?

Why such a large nicotine patch? Because youre addicted to cigars thats why!

What would you like for your last meal?

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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.

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