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.