Tight glucose control leaves long-lasting legacy for diabetics

Medical Tribune November 2008 P1&3
David Brill

Intensive glucose control, starting early, reduces the long-term risk of death for type 2 diabetics, according to important new follow-up data from the UK Prospective Diabetes Study (UKPDS).

Ten years on from the trial’s conclusion, a 13 percent reduction in all-cause mortality risk and a 15 percent reduction in myocardial infarction risk has emerged among the intensively-controlled patients (P=0.007 and 0.01, respectively). These benefits – termed a “legacy effect” – were seen even though differences in glycated hemoglobin levels between the groups disappeared just 1 year after withdrawal of the randomized intervention.

The original study ran from 1977 to 1997. Surviving patients were then returned to their usual care but continued to be followed up with annual clinic visits for 5 years and questionnaires for a further 5 years.

A risk reduction for microvascular disease – first reported at the end of the trial – also persisted 10 years later for the intensively-controlled patients.

“What this is saying to me is that you can’t wait to treat diabetes,” Professor Rury Holman, lead investigator for the UKPDS, told a press conference at the 44th Annual Meeting of the European Association for the Study of Diabetes (EASD), held recently in Rome, Italy.

“You need to treat it early – at least from diagnosis – and you will get additional benefits in the long term, rather than just waiting until the blood glucose is high or, heaven forbid, they’ve had a complication and then suddenly getting interested in
treating them.”

The same legacy effects were not seen, however, for tight control of blood pressure in hypertensive type 2 diabetics. Risk reductions for diabetes-related death, stroke
and microvascular disease were reported in 1998 but these benefits disappeared within 2 years of the end of the intervention period.

“This doesn’t mean that blood pressure is not important,” said Holman, head of the Diabetes Trials Unit at The Oxford Centre for Diabetes, Endocrinology and Metabolism,
UK.

“We take this to mean that the full benefits of blood pressure control in the tight control group had emerged by trial end, and over the post-study period there is no additional benefit over and above that recorded in the trial.”

The new post-trial data from UKPDS were presented at the EASD conference and subsequently published online in two separate papers in The New England Journal of Medicine.

The original study involved 5,102 newlydiagnosed diabetics, 4,209 of whom were randomized to receive intensive or regular glucose control. [Lancet 1998;352:837-53] A total of 3,277 patients entered post-trial monitoring.

The blood pressure control arm of the study included 1,148 patients, 884 of whom entered post-trial monitoring. The original intervention regimen comprised up to 100 mg atenolol once daily or up to 50 mg captopril twice daily. [BMJ 1998;317:703-13]

Intensive glucose control in the UKPDS was carried out with insulin or sulfonylurea, or metformin for overweight patients. The target was to maintain a fasting plasma glucose level below 6 mmol/L.

A significant risk reduction for any diabetes-related endpoint was reported at conclusion of the trial, driven largely by the reduction in microvascular risk, but the results for all-cause mortality and myocardial infarction did not reach significance at the time.

The benefits of metformin among overweight patients were considerable, with risk reductions of 32 percent for any diabetes-related endpoint and 42 percent for diabetes-related death, reported in 1998. [Lancet 1998;352:854-65] These effects were attenuated in the 2008 data but nonetheless persisted, with significant risk reductions of 21 percent and 30 percent, respectively.

“When we started the study people didn’t believe that treating glucose was important. Many people thought that complications were genetically determined and that glucose was not relevant,” added Holman.

“After UKPDS showed you have to control glucose or you’ll get complications, everybody got into the game and started giving two, three or four treatments. Here I believe we are seeing the impact of that in clinical practice.”

Asia: The new frontier for cancer research

Medical Tribune November 2008 P2-3

Dr. Foo Chuan Kit, Bayer Schering Pharma’s medical director for South Asia and Hong Kong, addresses the importance of tackling cancer in Asia.

Asia is facing a population explosion which will change the global disease landscape. Sixty percent of the world’s inhabitants – some 4 billion people – currently live in Asia, with 40 percent in China and India alone. By 2050, the continent’s population is predicted to rise to a staggering 6.5 billion people.

As the population continues to grow it is also continuing to age. In 2005 just 10 percent of Asians were aged 60 and above; by 2050 this figure will be closer to 28 percent, with Japan and Singapore expected to have the world’s highest proportions of over-80s.

With these trends emerging it is no surprise that cancer rates are climbing fast. Asia is facing a new epidemic, and it will not be long before the majority of the world’s cancer patients will be living in the continent.

In the face of this threat there is an urgent need to redress the global balance of cancer research. Most clinical trials continue to take place in the US and Europe, yet there are many important differences in the evolution of the disease between continents which demand further investigation.

The distribution of cancer is different in Asia, where certain types predominate in comparison to the West. Stomach cancer was the most common newly-diagnosed cancer in East Asia in 2007, yet did not feature in the top four most common types for North America or Northern and Western Europe. Liver cancer is particularly common in both East and South-East Asia, with lung, breast, colorectal and nasopharyngeal cancers also highly prevalent in these areas.

For men, according to 2002 data, prostate is the most common cancer type in the US, Australia and most of Europe, yet lung, liver and oral cancer dominate in Asia. Breast cancer is the most common type for women in most countries worldwide whereas in China stomach cancer is the most prevalent. In India and several other South and South East Asian countries cervical cancer is the most common type among women.

Understanding the reasons for these discrepancies is an important emerging area of investigation. Liver cancer in Asians, for example, is largely caused by hepatitis B, whereas hepatitis C and cirrhosis from alcohol abuse are more common causes among Caucasians. For nasopharyngeal cancer, a higher prevalence has been observed in Southern Chinese than in Northern Chinese, so there appear to be intra-ethnic differences as well. For other cancers, however, these regional variations and their explanations remain unclear.

These geographical differences also raise interesting questions as to the efficacy of cancer drugs in Asian patients. Gefitinib, for example, yielded disappointing results in clinical trials of western adenocarcinoma patients but was recently shown to be effective in non-smoking Asians with this cancer.

The optimal dosing for Asian patients is another important area of research. Docetaxel and carboplatin for example, appear to induce more side effects among Asian lung cancer patients than among Caucasians, and the dosages need to be adjusted accordingly. The response to these drugs also seems to be higher among Asian patients, but more research is still needed to better understand these observed differences.

With so many unanswered questions the need to invest in Asia is greater than ever. At Bayer Schering Pharma we have committed S$20 million over the next 6 years into research in Singapore alone. In Asia Pacific as a whole we enrolled less than 100 patients in clinical trials in 2005; by the end of 2007 we had 3,700 patients participating in 64 different trials.

The growing investment from pharmaceutical companies is great news for Asia. The increasing number of research collaborations, such as our recently-signed agreement with the National University of Singapore, will give patients unprecedented access to exciting new drugs. The increasing focus on translational research, meanwhile, will help to minimize the time from bench to bedside, enabling new compounds to enter clinical trials as early as possible. The recruitment of patients also seems to be quicker in Asia Pacific, with our data suggesting that the enrollment process here is twice as fast as the global average.

As our understanding of cancer in Asia improves so too will our treatments. This investment in Asia-specific research must be sustained in order to strengthen our defences in the face of the future epidemic.

Asian women less aware of long-term risks after gestational diabetes

Medical Tribune November 2008 P6
David Brill

Asian-born women who experience gestational diabetes mellitus (GDM) during pregnancy may be less acutely aware of their subsequent risk of developing diabetes, according to an Australian study.

A large postal survey of women with a history of GDM revealed that 92.3 percent knew that the condition predisposes to later development of type 2 diabetes.

Less than 30 percent of the 1,176 respondents, however, considered themselves to be at high or very high risk.

Risk perception was particularly low among Asian-born women, with just 15.5 percent believing themselves to be at high risk – a significantly lower proportion than Australian-born women (P=0.013).

“This is of some concern considering that evidence suggests that this may be in fact the highest-risk group,” said Ms. Melinda Morrison, a pediatric diabetes dietician who presented the study findings.

“We’re talking about Asian women in Australia so it may be down to how the messages are getting through, as well as possible cultural differences,” she said.

She added, however, that the data have yet to be fully analyzed so it is difficult to speculate on possible explanations for the finding at this point.

American Diabetes Association guidelines identify Asians as a high-risk population for GDM. [Diabetes Care 2000 Jan;23 Suppl 1:S77-9] A study of 2,797 Asian pregnancies found that the incidence of GDM was 10.6 percent for Vietnamese women, 9.2 percent for Chinese women and 8.6 percent for Filipino women. [Diabetes Care 2001 May;24(5):955-6]

GDM affects between 3 and 8 percent of pregnancies in Australia, according to Morrison, who is based at the New South Wales section of the charity Diabetes Australia.

With these women at substantially higher risk for developing diabetes this group represents an important target for disease prevention through lifestyle modification, she said.

“Often these women really only have contact with their GP after pregnancy and are no longer in the system of diabetes care necessarily, so it is over to the GP to help them make those changes and raise that awareness,” she said.

Fenofibrate reduces diabetic amputation risk

Medical Tribune November 2008 P7
David Brill

Fenofibrate treatment can reduce the risk of amputations among type 2 diabetics, recent data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study show.

Patients who took the drug had a 38 percent risk reduction for all first amputations, after an average of 5 years of follow-up (P=0.011).

The effect was particularly marked for amputations related to microvascular disease, with a 47 percent risk reduction for this endpoint (P=0.025).

“In all subjects with diabetes fenofibrate should be considered as add-on therapy for both macrovascular and microvascular outcomes,” said Professor Anthony Keech, principal investigator for the FIELD study, who presented the latest results at a press conference.

“It is the only lipid-modifying agent which has been shown to reduce the microvascular complications of diabetes and as such it represents a major breakthrough in diabetes care. And the great news is that it turns out fortuitously that statins and fenofibrate can be given safely in combination, which is not necessarily true of other fibrates,” he said.

Previous reports from the FIELD trial have shown that fenofibrate has beneficial effects on the incidence of cardiovascular events, progression of albuminuria and the development of diabetic retinopathy. [Lancet 2005 Nov 26;366:1849-61; Lancet 2007 Nov 17;370:1687-9]

The study randomized 9,975 patients aged 50 – 75 with type 2 diabetes to either placebo or fenofibrate (200 mg/day).

All amputations that occurred over the study period were assessed by two clinicians who were blinded to treatment. Amputees were more likely to be male and a smoker, and to have a higher systolic blood pressure, a longer duration of diabetes, and a history of vascular disease.

The new data also revealed a 23 percent risk reduction for macrovascular disease-related amputations alone but this was not statistically significant (P=0.26).

Dr. Alberto Zambon, a lipoproteins and atherosclerosis expert from the University of Padua, Italy, said that data from the Steno study show that the majority of diabetic patients experience progression of microvascular disease even when receiving a multifactorial approach involving statins and control of glucose and blood pressure. [N Engl J Med 2003 Jan 30;348(5):383-93]

“Adding fenofibrate to the current optimal standard of care will lead to a further reduction of the excess risk we see in these patients as far as diabetic retinopathy and peripheral neuropathy are concerned,” he said.

He added that fibrates can bring benefits above and beyond those of statins as they modulate gene expression whereas statins interact with the metabolic pathways of cholesterol production.

Keech, a professor of medicine, cardiology and epidemiology at the University of Sydney, Australia, said that the amputation risk in diabetics is around 25 to 30 times higher than in non-diabetics.

“In some studies the risk of death within 5 years of the first amputation is as high as 70 percent so they really are bad news, reflecting severe vascular damage through the diabetes process,” he said.

“So the fact that overall amputations were reduced by 38 percent by fenofibrate, in the setting of angiotension-converting enzyme inhibitors and statin use, blood pressure control and excellent glycemic control, is a major advance.”

Diabetes conversation tool set to launch in Asia

Medical Tribune November 2008 P9
David Brill

A new interactive tool to help educate patients about diabetes is due to be unveiled in Asia next year.

The Diabetes Conversations programme provides healthcare professionals with a set of materials designed to engage patients in learning about the disease and making decisions around their treatment.

The packs, which are available free of charge, will be translated into more than 25 different languages and tailored to individual countries in order to make them culturally relevant.

The European version, developed in collaboration with the International Diabetes Federation Europe and sponsored by Eli Lilly and Company, was unveiled at the EASD in September. The Asian and Latin American editions, however, are expected to remain in development until December this year.

“It is increasingly up to GPs and primary care practitioners to educate patients, so having effective tools that they can leverage is becoming more and more important,” said Mr. Peter Gorman, a representative of Healthy Interactions Inc, the US-based company who manufacture Diabetes Conversations.

Healthcare professionals will be able to register for free training in how to use the materials, which include activity cards and table-top conversation maps.

These can then be used in small group sessions of three to 10 patients at a time, typically lasting around 45 minutes to an hour.

A similar version was launched in the US last year in conjunction with the American Diabetes Association. More than 14,000 healthcare professionals have already been trained in using the conversation tool, Gorman said, adding that the programme has been “extremely successful” so far.

“A lot of healthcare professionals recognize that having a Powerpoint presentation or a flip chart up in front of a group isn’t a very engaging way to get patients involved in education. That’s really the selling point of these – do you want to engage the patient and have them own their outcome?” he said.

Patient access to online health records helps doctors shake inertia

Medical Tribune November 2008 SFXIV
David Brill

Online personal health records can not only empower patients but also galvanize their physicians into action, a new study suggests.


Type 2 diabetics who used an online system were significantly more likely to have their medications adjusted during clinic visits, the randomized trial in US primary care practices found.

The system, which was directly linked into the electronic medical records used by the physicians, provided users with clinical information and enabled them to create their own diabetes care plan for discussion during consultations.

Patients were also encouraged to ask more questions and take an active role in their disease management.

Dr Richard Grant, who led the study, said that clinical inertia on the part of physicians can often contribute to patients failing to reach their targets.

“The study is very encouraging and underscores the point that the more patients know about what ought to be done, the more likely it is that medical management changes are made. If you empower patients, good things happen,” he said.

Associate Professor Thai Ah Chuan, a senior consultant and endocrinologist at National University Hospital (NUH) said that the system was interesting in principle but would be very difficult to implement in Singapore at present.

“First you’d have to improve the whole electronic medical records system, then you’d have to look into the medico-legal issues, and then there are the questions of motivation, training and money,” she said.

Phone consultations have proved popular for diabetes patients in Singapore, she said, but noted that online healthcare systems would only benefit a small proportion of people.

“My impression of local patients is that they use the internet for pleasure but never for health. To them health is the responsibility of their physician, so having a system like that … it’s providing information and some kind of empowerment but beyond that, whether it will then improve and benefit control is yet to be seen.”

Many hospitals in Singapore do not have fully electronic records and could not therefore adopt such a system yet, Thai added. NUH, for example, is still in the process of upgrading but hopes to be completely paper-free by next year.

Diabetes medication was changed in 53 percent of consultations among the study intervention group compared to 15 percent among controls (P<0.001).>Arch Intern Med 2008 Sep 8;168(16):1776-82]

There were no significant differences, however, in the control of diabetes-specific risk factors after 1 year – an effect that the authors attribute to low enrollment rates. Just 244 patients – 4 percent of the overall diabetes population – took part in the study.

Grant, who is based at Harvard Medical School, said that many diabetics are elderly and may not feel comfortable with using the internet.

He also noted, however, that there is a large population of younger people with computers who are simply reluctant to engage with health information systems. More research is needed to understand the reasons for these barriers, he added.

A sympathetic ear: The best medicine for irritable bowels

Medical Tribune November 2008 SFIX
David Brill

Listening to your patients could be an effective treatment for irritable bowel syndrome (IBS), a recent study has suggested.

Researchers from the US and UK found that 62 percent of patients reported adequate symptom relief when their doctor spent more time with them and asked questions in a warm and friendly manner, in addition to providing placebo acupuncture.

Forty four percent of patients showed the same improvement when acupuncture was given without the extra attention, and just 28 percent when no placebo therapy was given at all.

Professor Ted Kaptchuk, who led the study, said that it was one of the most important demonstrations of the placebo effect in the literature and the first to look at long-term outcomes in the clinical setting.

“The important implication is that the power of the placebo effect, and specifically the patient-doctor component of the placebo effect, was huge. The magnitude of that effect is comparable to any drug that’s ever been tested for irritable bowel,” said Kaptchuk, who is based at Harvard Medical School, US.

He added that the same principles could apply to situations such as chronic pain and depression, which also have a strong “subjective component” whereby the context of the healthcare situation can influence a patient’s interpretation of their condition.

“We’re not treating something that is defined biologically, say a tumor or a blood assay or something you find on an X-ray. We’re treating a complaint that’s very real, and the interactions of that complaint with the person’s sense of well-being and health is probably where the placebo effect is very important,” he said.

The study involved 262 patients who were randomized to receive one of the two placebo interventions or simply to remain on a waiting list. The effects were recorded at 3 weeks and remained similar after 6. [BMJ 336(7651):999-1003]

Dr. Gwee Kok Ann, a Singapore-based IBS specialist and president of the IBS Support Group, was not surprised by the study’s findings.

“I’ve always felt that IBS patients respond very well to treatment if you just make the effort to talk with them and explain things to them,” he said.

“A lot of times it’s just helping the patient first of all to understand what’s going on because I think that’s the main worry in a lot of them. They worry is it cancer, is it colitis, and that in itself reinforces the symptoms because anxiety drives the symptoms too,” said Gwee, an adjunct associate professor at the National University of Singapore and a consultant gastroenterologist at Gleneagles Hospital.

Addressing the diagnosis of IBS in a tactful way can also improve outcomes, he said, noting that doctors should take time to explain the condition thoroughly and convincingly so that the patient is comfortable with the diagnosis.

Patients view pain as a warning that something is wrong, he explained, so if their doctor can’t find an explanation for it then adrenaline and anxiety can rise, prompting the patient to demand more and more tests in the expectation that something has been missed. This situation can be avoided by introducing the diagnosis of IBS early rather than leaving it as a last resort for when everything else has been ruled out, he said.

Dengue epidemic avoided in Singapore

Medical Tribune November 2008 SFXII
David Brill

Efforts to control dengue in Singapore appear to have been a success this year, with early fears of a repeat outbreak proving to be premature.

Last year saw levels pass the epidemic threshold in early July, when 432 cases of dengue fever and dengue hemorrhagic fever were reported in a single week.

This year, however, the combined number of cases has so far remained comfortably below the warning level of 279 cases in a week.

That same week in July, the peak for 2007, saw just 160 cases reported in 2008, according to Ministry of Health (MOH) statistics.

Experts had raised concerns about the possibility of another epidemic when more cases were reported in the first 3 months of this year than last year.

In response the National Environment Agency (NEA) invested more resources into the Campaign Against Dengue, intensifying operations to identify and destroy mosquito breeding habitats.

In a joint statement with the MOH, the NEA said that this could be one of the reasons for the lower number of cases observed this year.

They also said that their annual ‘Intensive Source Reduction Exercise’ – an initiative targeting the town councils who manage the public housing estates – was launched earlier this year than last.

“We should nonetheless continue to monitor the dengue situation closely and sustain our efforts against the vector because the secular disease trend remains in the upward direction and epidemic transmission continues to be a problem,” the statement concluded.

Associate Professor Leo Yee Sin, head of the department of Infectious Diseases at Tan Tock Seng Hospital, said that the dengue patterns observed so far for 2008 are similar to typical non-epidemic years.

She also noted that last year’s outbreak was preceded by a distinct switch in the predominant circulating dengue strain from DEN-1 to DEN-2. The lack of epidemic this year could therefore be attributable to growing herd immunity against this strain, she said.

Leo added that the outbreak of the chikungunya virus in January this year prompted “massive search and destroy efforts” targeting the Aedes aegypti mosquito, which is also responsible for spreading dengue.

The worldwide incidence of dengue has “grown dramatically” in recent years according to the WHO, who estimate that two fifths of the global population is now at risk.

Singapore has experienced regular dengue epidemics since the first reported outbreak in 1901. These typically occur when there is a shift in the balance between the virus strains, all four of which are present in the country.

A recently-published analysis of the 2005 epidemic found that DEN-1 was responsible for 71.2 percent of cases and DEN-2 just 9.2 percent – a predominance that appears to have reversed in 2007. The development of an effective vaccine against all the strains could be the only definitive way to control dengue in Singapore in the long-term, the authors wrote. [Ann Acad Med Singapore 2008 Jul;37(7):538-45]

Remote disease detection in the palm of your hand

Medical Tribune November 2008 SFXII
David Brill

Scientists in Singapore have developed a simple battery-operated device that could be used to detect pathogens in remote medical clinics and war zones.

The palm-sized system, measuring around 10 cm in diameter, can detect a wide range of proteins and other molecules and does not need to be connected to a computer to function.

The researchers hope to make the device commercially available in the near future, estimating that it would cost around S$500 per unit once mass production was underway.

Dr. Pavel Neuzil, who led the project, said that the sensor took around 2 years to develop. He suggested that it could be used to detect diseases such as cancer or Alzheimer’s disease, or to identify toxins used in bioterrorism.

“This whole effort, lab-on-a-chip, is meant for simple tools which can be very economical and can go to places where people who don’t have electricity can do very simple things,” he said.

Neuzil and his colleague Dr. Julien Reboud, who are based at Singapore’s Institute of Microelectronics, reported their work last month in the journal Analytical Chemistry. [2008 Aug 1;80(15):6100-3]

The system employs a technique called localized surface plasmon resonance to measure the intensity of light reflected from the surface of the test molecule. Although the guiding principles are not new, the device is greatly simplified compared to its predecessors, Neuzil said.

He added that the ability to operate without a computer was a major advantage of the system, which was initially developed for performing polymerase chain reactions and for use in tackling avian influenza.

“At the beginning somebody told me you should power it from USB because everybody has a computer around. And I told him ‘you are very funny because if you want to talk about avian flu it would be for Indonesia, places where they don’t even have electricity,’” he said.

Quick, accurate HPV test for developing countries

Medical Tribune November 2008 SFXIX
Seah Yee Mey and David Brill

A new rapid screening test for the human papilloma virus (HPV), created specifically for use in developing countries, is 90 percent accurate in detecting precancerous cervical disease, a study has shown.

careHPV is a signal-amplification assay adapted from the hybrid capture test, which is widely regarded as the gold standard in HPV DNA screening. Fourteen high-risk types of carcinogenic HPV can be detected using careHPV in about 2.5 hours.

The test takes up only a small area of clean bench-top space, with no need for mains electricity or running water supply. The short assay time allows for testing and clinical follow-up the same day.

careHPV can be operated by non-technical support staff with just 1 or 2 days of training.

The prototype was tested on 2,530 women aged 30 to 54 years in Shanxi province, eastern China, with complete data available for 2,388 women. careHPV correctly indentified precancerous cells in 90 percent of cervical specimens, while 84.2 percent of those without precancerous disease were identified as negative.

The recent publication of the findings online in The Lancet Oncology represents the culmination of a 5-year collaboration between the Program for Appropriate Technology in Health (PATH), a US-based nonprofit organization, and QIAGEN, who manufacture the test.

PATH, who receive funding for the project from the Bill and Melinda Gates Foundation, will now oversee a further 5 years of operational research in public health clinics in India, Uganda and Nicaragua.

The test still needs to be commercialized and undergo registration studies before it will be widely available, said Professor John Sellors, corresponding author of the study.

It is hoped that the 3 test countries will serve as examples for their respective regions, he added, noting that the generation of operational data will enable PATH to work alongside policy makers in other countries and help them to implement their own projects in future.

“From these results in China, careHPV looks very promising as a test that will allow the rapid and highly accurate screening of women in developing regions for cervical cancer,” said Sellors, a professor of family medicine at McMaster University in Canada.

“If women 30 years and older could be screened at least once in their lifetimes with such a test, and appropriate treatment administered at the same visit, public health programmes would be affordable and deaths from cervical cancer would be reduced by a third.”

The cost of careHPV is yet to be confirmed and will be negotiated on an individual basis with each government or organization.

careHPV was designed by Attila Lorincz, professor of molecular epidemiology at Barts and the London School of Medicine and Dentistry, UK. The prototype study in China was led by Professor You-Lin Qiao of the Cancer Institute, Chinese Academy of Medical Sciences, Beijing.

Cervical cancer is the second most common cancer in women, with some 500,000 new cases and 300,000 deaths worldwide every year. Carcinogenic HPV causes almost 100 percent of the cancers.

Paracetamol in infancy raises childhood asthma risk

Medical Tribune November 2008 SFXX
David Brill

Exposure to paracetamol during infancy could increase the subsequent risk of developing asthma, new research suggests.

Children aged 6 to 7 had a 46 percent increased risk of having asthma symptoms if they had received paracetamol for fever during their first year of life, data from the International Study of Asthma and Allergies in Childhood showed.

Use of the drug in infancy was also associated with an increased risk of rhinoconjunctivitis and eczema (odds ratios 1.48 and 1.35, respectively).

The authors of the Lancet study reviewed questionnaires completed by the parents or guardians of 205,487 children in 31 countries. [372(9643):1039-48]

“Because it was an epidemiological study we were unable to determine whether the relationship was causal … but when you put it together with all the other evidence we have it does suggest that paracetamol might be an important risk factor for the development of asthma,” said lead researcher Professor Richard Beasley, Medical Research Institute of New Zealand, Wellington.

Paracetamol should remain the preferred drug for relief of fever and pain in infancy but should be used sparingly, he said, noting that WHO guidelines recommend that the drug only be used for those with high fever (38.5°C or higher).

Beasley stressed that infants should not be switched to aspirin, which can cause the rare but potentially fatal Reye’s syndrome.

Current usage of paracetamol also increased the risk of asthma in a dose-dependent fashion. Children taking the drug on a regular basis were over three times as likely to have symptoms compared to those who were not taking it at all (odds ratio 3.23).

Dr. Chiang Wen Chin, an associate consultant in the department of pediatric allergy, immunology and rheumatology at KK Women’s and Children’s Hospital (KKH), Singapore, said that paracetamol use over the past 50 years has been safe and that the drug would remain first line for the majority of children (10mg/kg 4 to 6 hourly).

She added that ibuprofen can be given as a second line antipyretic, with tepid sponging also an option if the fever does not resolve.

Chiang noted, however, that there is a group of children who display angioedema and uticaria from high doses of paracetamol. [Pediatrics 2005 Nov;116(5):e675-80]

“We have demonstrated this in our own local patients that have presented to our clinic in KKH. Most of these children have allergic rhinitis, although not all of these have asthma,” she said.

“Our understanding of this pathophysiology is that paracetamol is a nonspecific COX-1 and COX-2 inhibitor, especially at high doses, and that this may result in a shunting of arachidonic acid production to predominantly leukotriene production, resulting in the release of various mediators such as mast cells and histamine release,” she said.

Beasley added that further studies – including randomized controlled trials of paracetamol in infancy – are needed to better understand the association with asthma.

Compulsory CME to improve care in Indonesia

Medical Tribune November 2008 P12
David Brill

The introduction of mandatory continuing medical education(CME) in Indonesia will be of great benefit to both doctors and patients, according to the head of Ikatan Dokter Indonesia (IDI), the Indonesian medical association.

The new regulation, adopted in May last year, requires doctors to attain 250 continuing professional development (CPD) points every 5 years in order to obtain a certificate of competency, without which they cannot renew their registration and practice license.

“Every doctor in the world has an obligation – in keeping with the Hippocratic Oath and ethical codes of conduct – to continuously maintain, update and upgrade their knowledge and competencies,” said IDI president Dr. Fachmi Idris.

“The goal of CPD (and CME is the one of CPD activities) is ultimately to benefit patients,” he said. Other areas in which physicians can obtain CPD points include caring for patients, journal reading and teaching, among others.

Fachmi added that ensuring geographical and financial access to CME programs are the two major challenges that the IDI has faced so far in implementing the new system.

Doctors in Indonesia can gain CME points by participating in accredited symposia, seminars and workshops. Points will also be available through an online system which is currently under development.

Family physicians may obtain points through events organized for both general practitioners and specialists. However, family physicians will be able to obtain the necessary points faster by attending events that are organized for general practitioners than those organized for specialists, as they will be awarded more points for attending events geared towards general practice.

The association recently appointed CMPMedica, publisher of Medical Tribune, Medical Progress and the Journal of Paediatrics, Obstetrics and Gynaecology, as the first external, accredited CME provider in Indonesia. CMPMedica will help provide additional print, online and live avenues to help Indonesian doctors obtain the appropriate CME.

Globally, there is a trend toward making CME mandatory, although it remains voluntary in most countries in the Asia Pacific region. Singapore was among the first countries in the region to make the practice compulsory, beginning in January 2003.

The IDI was first given the authority to standardize and provide CME under the Medical Practice Law of 2004.

Chronic disease management: Depression

Medical Tribune November 2008 P14-15

Depression is a serious global health issue. Some 121 million people are affected worldwide, according to 2001 estimates from the WHO, with 1 million committing suicide each year and a further 10 to 20 million attempting to do so.

The prevalence of depression in the general adult population of Singapore is around 5 percent. This figure is lower than in the US but comparable to most developed European countries. The prevalence in developing Asian countries is unclear but is likely to rise, placing an increasing burden on society and healthcare systems.

The WHO, as part of a new program launched on World Mental Health Day 2008, recently called on governments and donors to urgently upscale mental health services and better integrate mental health into primary care. Depression in particular is increasingly treatable, and making an early and effective diagnosis in this setting will lead to considerable improvements in outcome.

Diagnosis

Routine screening for depression is not recommended but should be carried out among those who are at the highest risk. There are several risk factors which GPs should be aware of in order to effectively target these patients.

The presence of multiple medical problems is strongly associated with depression. Chronic but stable conditions such as heart disease, stroke and cancer all place a strain upon patients’ wellbeing, and the coexistence of more than three conditions has been shown to significantly increase depression risk.

The link between depression and diabetes, for example, is well established. Depressed patients often lose the motivation to take their medications, which contributes to a worsening of their diabetes. This can be a two-way process, with the resulting deterioration of blood sugar control affecting the vessels and tissues in the brain, leading to a further worsening of depressive symptoms and an even greater loss of motivation.

GPs should also consider the social factors affecting their patients, as this type of information is invaluable in identifying those who should be screened for depression. Do they live alone? Are they recently divorced or widowed? Is there support from their family? Are they likely to have financial problems?

Once the GP has identified a high-risk patient they can initiate screening with two quick, simple questions: “Have you persistently felt depressed in the last 2 weeks to a month? Have you experienced a loss of interest in your daily activities over this time period?” If the patient answers yes to either of these questions then the physician should move on to try and identify further symptoms. A formal diagnosis can then be established according to the criteria laid out in the relevant guidelines.

There are, however, two major obstacles to initiating this process. The first is shyness on the part of the patient. Asian patients tend to perceive doctors as being primarily concerned with their physical wellbeing and may not expect to discuss mental health issues with them. They are often shy and might find the subject awkward.

Doctors nonetheless have a responsibility to overcome this barrier and broach the subject. This can be done by gradually and tactfully guiding the conversation in the right direction. Ask the patient gently about their mood, how they have been feeling in light of recent problems, and whether there are any other issues they would like to discuss. If they clam up, try not to charge in and pry them open in a single visit. Primary care physicians have the advantage of seeing patients regularly, and introducing the subject in one visit might make it easier to return to at a later date.

The second barrier, however, lies with the doctor, since the process of diagnosing depression can only begin if they are willing to ask these difficult questions. There is sometimes a reluctance to open up Pandora’s Box which, although understandable, needs to be overcome. This fear typically lies in the unknown, so doctors can avoid this by reading around the subject and being prepared for what might follow. Continuing Medical Education courses and workshops are often available to help physicians gain confidence in dealing with these issues, while there is a wide range of useful information available on the internet for further reading (see below).

Once doctors are comfortable with broaching the subject they can also use their intuition to guide them in making an early diagnosis. Depressed patients may seem withdrawn and quieter than usual, or may display a steady deterioration in chronic conditions which were previously well controlled. These signs should all arouse suspicion that the patient is not simply having a bad day and may be in need of help.

Practice Guidelines

Practice guidelines on major depressive disorder are available from the American Psychiatric Association website. The Ministry of Health in Singapore also publishes its own guidelines on depression, most recently in March 2004. These state that a diagnosis can be made when a depressed mood or loss of interest is accompanied by a minimum of four specific symptoms (from a list of eight) over a period of 2 or more weeks.

Depression can be a culturally sensitive issue, and guidelines will need to be applied within the context of the local social environment. The ability to adhere to the various guidelines will also depend heavily on the availability of local resources.

A range of advice and information is also available from the Malaysian Psychiatric Association and the Hong Kong College of Psychiatrists.

Treatment

Once the criteria for diagnosis are fulfilled GPs should move on to discuss treatment with their patients. If the patient is not severely agitated or suicidal then it can be useful to spread this discussion over more than one clinic visit. Start by making them aware that they have a medical condition which goes beyond just experiencing difficulties in life, and let them know that it is treatable and that safe and effective medications are available. This will give the patient time to digest the information, discuss the options with their family and do their own research before committing to a plan of action.

This approach also gives the GP a little more time to review options and prepare for prescribing an antidepressant. Medication access and guidelines will vary by country, but GPs should typically aim to begin with a selective serotonin reuptake inhibitor (SSRI) or a tricyclic antidepressant (TCA) for 4 to 6 weeks and wait to see whether there is a response. Algorithms such as the Texas Implementation of Medication Algorithm (see below) can then be used to guide further decisions around medication use.

Patients may have common misunderstandings about medications which physicians should try to allay. They may fear that the medications are addictive, or they may expect them to provide instantaneous relief. Managing these expectations in advance is important, and can help prevent patients from becoming disappointed or frustrated and stopping their medications.

Close follow-up is also crucial. Guidelines suggest that medication use should continue for 6 months to a year even if the patient shows signs of recovery. Early discontinuation leads to a higher risk of relapse, so it is important to make sure that patients finish their course. Side effects such as gastrointestinal complaints, drowsiness, dry eyes and dry throat will also need to be managed and patients should be warned about these in advance.

Psychotherapy, where available, is also a useful tool for treating depression. Few GPs are trained in psychotherapy themselves, and they should prepare for this eventuality by thoroughly researching the options in the local community and knowing how and where to refer their patients.

Treatment can be augmented by attempting to tackle some of the underlying triggers for depression. Rather than focusing solely on medical issues, GPs should also explore a patient’s psychosocial problems to understand what is troubling them. Community resources and support groups may be on hand to help, and many patients will benefit from further advice and referrals. With patients facing many problems this approach can be time-consuming for GPs, and they may like to plan ahead and deal with these issues one session at a time.

Patients with multiple psychiatric disorders or very complex or refractory depression should generally be referred on to a specialist center, particularly if they show signs of suicidal thoughts or self-harming behavior.

These centers may also offer further training which can help primary care physicians to improve their knowledge of depression. The Institute of Mental Health, for example, offers a partnership program for GPs which seeks to provide continuity of care for stable patients and increase the accessibility of treatment within the community. Participants complete a series of lectures and guided clinical sessions on depression and other mental health disorders, and can subsequently receive case consults and phone advice for difficult cases. Having specialist advice on hand can take some of the pressure off busy GPs, and can help them feel more comfortable discussing depression with their patients.

Conclusion

Depression is becoming easier to treat as our understanding of the condition continues to improve. Medications are safer and more effective than ever before and there is a wide range of information available to guide our clinical decisions. Primary care is an important setting for making an early diagnosis, and physicians should be proactive in screening patients who are at high risk.


Online Resources:

The American Psychiatric Association practice guidelines:
http://www.psych.org/MainMenu/PsychiatricPractice/PracticeGuidelines_1.aspx

The World Psychiatric Association:
http://www.worldpsychiatricassociation.org/

Texas Implementation of Medication Algorithm (TIMA):
http://www.dshs.state.tx.us/mhprograms/disclaimer.shtm

Institute of Mental Health patient information: http://www.imh.com.sg/patient_education/depression.htm

Depression.com:
http://www.depression.com/

UPLIFT trial reassures on tiotropium safety

Medical Tribune November 2008 P16
David Brill

Doctors can be reassured about prescribing inhaled tiotropium as a treatment for chronic obstructive pulmonary disease (COPD), one of Singapore’s leading respiratory experts has advised in light of a recent trial publication.

The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study found that tiotropium was safe and significantly reduced the risk of cardiac adverse events among patients with moderate to very severe COPD.

The safety of inhaled anticholinergics had been called into question following the publication of two separate studies in September which linked the class of drugs to an increased risk of cardiovascular mortality.

One of the papers – a meta-analysis published in the Journal of the American Medical Association (JAMA) – reported a 58 percent increase in the risk of cardiovascular death, myocardial infarction or stroke among COPD patients taking either tiotropium or ipratropium. [2008 Sep 24;300(12):1439-50]

The US Food and Drug Administration (FDA) is conducting a thorough review of the findings from UPLIFT and expects to receive the full data set in November. However, the complete analysis could take several months, according to a statement on the FDA website.

The 4-year UPLIFT study, published in The New England Journal of Medicine, involved 5,993 patients from 37 countries who were randomized to tiotropium (18 μg once daily) or placebo. [2008 Oct 9;359(15):1543-54]

Dr. Ong Kian Chung, president of the Singapore COPD Association, said that he was happy with the safety data from UPLIFT and would continue to prescribe tiotropium as normal.

“I’m personally not too convinced that there is any significant complication from using these medications,” he said.

“The data from the meta-analysis isn’t enough to deny the patient the effectiveness of a long-acting anticholinergic. I think it’s more likely that it is a statistical fluke than a truly increased risk,” said Ong, who is currently a private practitioner at Mount Elizabeth Medical Centre, and was a co-investigator for the UPLIFT trial.

Patients in UPLIFT were allowed to continue their usual respiratory care with the exception of other inhaled anticholinergics, such as ipratropium, a shorter-acting formulation than the study
drug tiotropium. The use of these drugs was permitted, however, in the event of a serious exacerbation of COPD.

Dr. Sonal Singh, lead authorof the JAMA meta-analysis, questioned this aspect of the UPLIFT design and said that the trial does not invalidate the findings of the meta-analysis since the usage of ipratropium for exacerbations has not been reported.

“There might be differences in the risk between the long-acting and the short-acting, but UPLIFT is not going to answer that question because it was not designed that way,” he said.

“In one arm you have the long-acting and in the other arm you have people using the short-acting, so it’s not a valid comparison,” he said, adding that the meta-analysis demonstrated a higher cardiovascular risk with short-acting ipratropium than with long-acting tiotropium (risk ratios 1.70 and 1.43, respectively).

The meta-analysis incorporated 17 trials involving 14,783 patients.

A second paper, a nested case-control study including 32,130 cases and 320,501 controls, found an odds ratio of 1.34 for cardiovascular death associated with ipratropium. [Ann Intern Med 2008 Sep 16;149(6):380-90]

Tiotropium in UPLIFT was delivered with the HandiHaler inhalation device manufactured by Boehringer Ingelheim, which co-sponsored the trial with Pfizer.

Dr. Iylen Benedict, regional medical affairs director for Boehringer Ingelheim, said that the study by Singh et al. is methodologically flawed and pointed out that the majority of the evidence on ipratropium comes from a single study, the Lung Health Study. [Am J Respir Crit Care Med 2002;166(3):333-9]

“In this study, most of the cardiovascular deaths occurred among patients who were not using their medication,” she said.

“Other limitations [of the metaanalysis] include the inability to adjust for treatment duration and accounting for patients who discontinue the trial early, apparent double-counting of trials and combining placebo and active comparator drugs in the control group.”

Benedict also reiterated that the use of other anticholinergics such as ipratropium was not allowed in UPLIFT, and that the decision to allow any intervention in the face of a life-threatening exacerbation, as deemed necessary by a physician, was an ethical position.

She added that there are currently no plans for a trial looking specifically at cardiovascular outcomes with tiotropium, but confirmed that the full UPLIFT data will be provided to the FDA for the safety analysis.

UPLIFT did not reach its primary endpoint of significantly reducing the decline in forced expiratory volume 1, but did demonstrate significant improvements in lung function, exacerbations and quality of life with tiotropium therapy.

The trial included patients from seven Asian countries, including Singapore, Hong Kong, Malaysia and the Philippines. The results were first presented at the annual meeting of the European Respiratory Society, held recently in Berlin, Germany.