Diabetic children often oblivious to hypoglycemia

Medical Tribune September 2009 P7

David Brill

Almost one in three children with type 1 diabetes cannot tell when their blood sugar dips low, and could face serious consequences from slipping into hypoglycemia, a study suggests.

A survey of 656 Australian children found that 29 percent had impaired awareness of hypoglycemia – a deficit in the adrenergic symptoms that ordinarily serve as a warning sign.

Children with impaired awareness were over twice as likely to have experienced a severe hypoglycemic episode in the previous year, involving loss of consciousness or seizure.

The effect was even more pronounced in the very young: children under 6 with impaired awareness were almost six times as likely to have had a serious episode.

Senior author Dr. Tim Jones said that hypoglycemia unawareness has traditionally been considered to be an adult problem, but urged physicians to step up screening among younger patients in light of the new findings.

“Ask the child: ‘do you get your usual symptoms? Do you still feel shaky when you go low? Or is the first thing you notice about being low that you find a low reading when you test yourself?’ It only takes a minute if you know what to ask,” he said.

Hypoglycemia unawareness appears to be caused by hypoglycemia itself, with repeated episodes successively dampening the adrenergic response, added Jones, head of the department of endocrinology and diabetes at Princess Margaret Hospital for Children, Perth, Australia.

The good news, however, is that the problem seems to some extent to be reversible, he said. Once impaired awareness is identified, the patient should meticulously ensure that they avoid hypoglycemia for around a month, and the warning symptoms may begin to return.

Further testing can also be carried out – particularly using continuous glucose monitoring systems to track a child’s blood sugar over time. This can help to identify and avoid episodes of hypoglycemia, regardless of whether the child is aware of it.

The study involved type 1 diabetic children aged from 6 months to 19 years. All were taking insulin – ranging from twice-daily injections to four times a day with insulin analogs and subcutaneous infusion therapy. [Diabetes Care 2009 Jul 8; Epub ahead of print]

A total of 161 hypoglycemic episodes had occurred in the year leading up to the study. The rate of episodes among children with impaired awareness was 37.1 episodes per 100 patient-years, compared to 19.3 per 100 patient-years in children with normal awareness.

Patients with impaired hypoglycemia awareness tended to be younger, had an earlier onset of diabetes, and had lower mean HbA1C levels since diabetes onset.

Hong Kong symposium: Facing up to the diabetes epidemic

Medical Tribune July 2009 P10
David Brill

The global diabetes epidemic has transcended medical specialties and become a priority for all healthcare professionals, say the organizers of this year’s Hong Kong Diabetes and Cardiovascular Risk Factors – East Meets West (EmW) symposium.

The meeting, to be held in September, will bring attendees up to speed on the latest research into the twin burdens of diabetes and cardiovascular disease (CVD).

With topics ranging from lifestyle interventions and nutrition to the management of diabetes in pregnancy, the symposium promises to deliver a host of practical insights for day-to-day patient care. Leading cardiologists will review strategies for assessing cardiovascular status in people with diabetes, while other sessions will address the crucial importance of good glycemic control, particularly in light of major recent studies such as ACCORD*, ADVANCE** and VADT***.

Other highlights include cutting-edge sessions on the pathogenesis of type 2 diabetes, including pancreatic beta-cell pathology, the developmental-origins hypothesis of diabetes and the role of lipid metabolism in insulin resistance.

“The rate of diabetes is now rampant in Asia, especially in young to middle-aged people. In some countries, the prevalence can be as high as 10 percent,” said Dr. Gary Ko, chairman of the organizing committee for the EmW symposium, now entering its eleventh year.

“The economic burden of diabetes to governments, and the health impact to individuals, cannot be overemphasized. Diabetes can be linked to all systems and specialties. We believe that a good and up-to-date understanding of diabetes is essential for all practicing doctors, be they family physicians, specialists or from other fields,” he said.

“We hope to arouse the attention of our clinicians, particularly those working in Asia, to the increasing epidemic of diabetes, its devastating morbidity and mortality, and what needs to be done to minimize the impact of diabetes and CVD on society.”

Managing weight and diet in type 2 diabetics is just one of the many challenging areas which will be addressed in depth at the EmW symposium, said Professor Ronald Ma, chairman of the EmW scientific committee. He highlighted a presentation by world-renowned endocrinologist Professor Harold Lebovitz, who will introduce a new gastrointestinal ‘pacemaker’ known as Tantalus, which can regulate appetite and help patients to lose weight. Leading Hong Kong nutritionist Ms. Lorena Cheung will offer a different angle – providing insights on how to advise patients on glycemic index and glycemic load.

US obesity expert Professor John Foreyt will also share his knowledge and experience as an investigator on the Look-AHEAD (Action for Health in Diabetes) trial – a successful lifestyle intervention study which helped overweight diabetics to lose an average of 8.6 percent of their weight, improve fitness, reduce medications and lower HbA1C by 0.7 percent, after just one year. [Diabetes Care 2007 Jun;30(6):1374-83]

The ACCORD, ADVANCE and VADT trials have shown the critical need to balance the benefits of blood glucose lowering against potential drug-related side effects, notably weight gain and hypoglycemia. In this session, Professor Brian Frier, of the University of Edinburgh, UK, will give an overview of hypoglycemia: its impact on cardiovascular events and the underlying mechanisms.

Hong Kong expert Professor Terrence Lao, meanwhile, will provide an Asian perspective on the ever-growing problem of gestational diabetes, while Professor Edwin Lee will probe the link between anti-psychotic medications and metabolic disorders. Finally, world expert Professor Edward Fisher will share his wisdom on the rationale and evidence for peer support in the management of diabetes.

Over 600 attendees from all over the world are expected at the EmW symposium, which will take place at the Hong Kong Convention and Exhibition Centre from 30 September to 1 October 2009.

The event is jointly organized by the Hong Kong Institute of Diabetes and Obesity at the Chinese University of Hong Kong, CMPMedica Pacific Limited, the Hong Kong Atherosclerosis Society, the Hong Kong Association for the Study of Obesity and the Hong Kong Foundation for Research and Development in Diabetes, with support from the Hong Kong Dietitians Association.

For more information, see: http://www.eastmeetswest.org.hk/

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*ACCORD: Action to Control Cardiovascular Risk in Diabetes
**ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation
***VADT: Veterans Affairs Diabetes Trial

Voglibose prevents diabetes in high-risk Asians

Medical Tribune July 2009 SFII
David Brill

Alpha-glucosidase inhibitors could play an important role in preventing, as well as treating, the growing epidemic of type 2 diabetes in Asia.

A recent trial found that adding voglibose to diet and exercise counseling almost halved the risk of developing diabetes in Japanese patients with impaired glucose tolerance (IGT).

The study extends similar findings from Western populations, where acarbose has been shown to reduce the progression from IGT to diabetes – notably in the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial. [Lancet 2002;359(9323):2072-7] Equivalent studies in Asian populations, however, were previously lacking.

The researchers, led by Professor Ryuzo Kawamori, Juntendo University School of Medicine, Tokyo, randomized subjects to placebo or voglibose (0.2 mg three times a day). The trial was terminated early, following an interim analysis. [Lancet 2009;373(9675):1607-14]

At a mean of 48 weeks of treatment, 50 of 897 patients taking voglibose had developed diabetes, compared to 106 of 881 who took placebo (hazard ratio 0.595, 95 percent CI 0.43 – 0.82; P=0.0014). More people achieved normoglycemia in the voglibose group: 559 of 897, versus 454 of 881 in the placebo group (P<0.0001).

Singapore diabetes expert Dr. Kevin Tan said that alpha-glucosidase inhibitors offer a good option in cases which need more aggressive intervention than lifestyle therapies alone.

“The results of this study mirror those of acarbose in STOP-NIDDM and demonstrate the efficacy of this group of alpha-glucosidase inhibitors in preventing type 2 diabetes – now in an Asian population as well,” said Tan, vice president of the Diabetic Society of Singapore and a private practitioner at Mount Elizabeth Medical Centre.

“Lifestyle interventions remain central as they are simple and available to all and, moreover, their effects are sustainable. However, lifestyle interventions are notoriously difficult to maintain at the same intensity over time and therefore safe and effective medications to complement them are needed as well. Alpha-glucosidase inhibitors are amongst the safest of compounds as there is minimal absorption into the body and no interference with the metabolism of other drugs,” he said.

The epidemic of type 2 of diabetes continues to boom in Asia, with total numbers predicted to increase from some 114 million patients in 2007 to 180 million in 2025. The prevalence of IGT is expected to rise from 157 million to 213. [JAMA 2009 May 27;301(20):2129-40]

The worst-affected countries appear to be those undergoing significant economic and dietary changes: the overall prevalence in China, for example, rose from 1 percent in 1980 to 5.5 percent in 2001. For affluent urban areas such as Hong Kong and Taiwan, the figure is as high as 10 percent. [Diabetes Res Clin Pract 2006 Aug;73(2):126-34]

Adverse events in the Japanese study were more common with voglibose than placebo (P<0.0001) – mostly comprising gastrointestinal symptoms such as flatulence, abdominal distention and diarrhea. There were also six serious advents in the voglibose group, consisting of colonic polyp, cholecystitis, inguinal hernia, liver dysfunction, rectal neoplasm and subarachnoid hemorrhage. Two placebo patients experienced serious events – one cerebral infarction and one case of cholecystitis.

Alpha-glucosidase inhibitors could feasibly be given in combination with metformin, which has also shown good results in diabetes prevention studies, wrote Dr. André Scheen of the University of Liège, Belgium, in an accompanying commentary. This dual approach, using acarbose, is currently being trialed in Canada. [Lancet 2009 May 9;373(9675):1579-80; Diabetes Obes Metab 2006;8(5):531-7]

Simple online tool predicts type 2 diabetes risk

Medical Tribune May 2009 P14
David Brill

A simple new tool could allow GPs to identify patients at high risk of developing type 2 diabetes without the need for laboratory tests.

The QDScore, developed with electronic medical record data from some 2.5 million patients, is quick and easy to use and is freely available online.

It is the first prediction algorithm to include ethnicity and social deprivation alongside conventional diabetes risk factors, and is intended for routine use in primary care.

The QDScore performed well in a recent study – accurately predicting 10-year diabetes risk in a diverse patient population drawn from 176 UK general practices. [BMJ 2009 Mar 17;338:b880]

“There is good evidence that lifestyle changes and medical intervention at an early stage can prevent type 2 diabetes in up to two-thirds of high-risk cases and that early diagnosis is likely to improve outcomes,” said lead researcher Professor Julia Hippisley-Cox, professor of clinical epidemiology and general practice at the University of Nottingham, UK.

“As the number of people diagnosed with diabetes in the UK continues to rise, this new algorithm will be an invaluable tool to help doctors identify those at greatest risk who are most likely to benefit from interventions.”

The QDScore calculates risk using age, sex, ethnicity, family diabetes history, personal cardiovascular disease history, hypertension medications, steroid usage, smoking status and body mass index. It was derived from a cohort of more than 2.5 million 25 to 79 year-olds – over 78,000 of whom developed type 2 diabetes over 10 years of follow up.

There were considerable differences in diabetes risk between ethnic groups. Bangladeshi men were the most likely to develop diabetes, with an adjusted hazard ratio (HR) of 4.53 as compared to Caucasian men. The subsequent male risk hierarchy was: Pakistani, Indian, Other Asian, Black African, Chinese and Black Caribbean (adjusted HRs 2.54, 1.93, 1.89, 1.67, 1.41 and 0.80 respectively).

The risk patterns were similar for women, although Chinese ethnicity conferred a greater risk than in men. Bangladeshi women were the most likely to develop diabetes, followed by those of Pakistani, Chinese, Indian, Other Asian, Black African and Black Caribbean origin (adjusted HRs 4.07, 2.15, 1.96, 1.71, 1.26, 0.81 and 0.80, respectively).

The QDScore was tested on records from more than 1.2 million patients – over 37,500 of whom developed diabetes. It scored highly on validation statistics, out-performing the Cambridge risk score in all domains for both men and women. It is available at: http://www.qdscore.org/.

Lifestyle program boosts diabetes control in overweight Chinese

Medical Tribune March 2009 SFV
David Brill

An integrated lifestyle intervention program, including dietary supplements and meal replacements, can help overweight Chinese diabetics lose weight and improve glycemic control, a new study has shown.

Patients who followed the program for 24 weeks lost an average of 2.7 kg and saw their HbA1c drop by 0.8 percent compared to baseline (P<0.001).>

Such were the benefits of the intervention that 15 of the 100 type 2 diabetics who followed it had had their diabetes medication dosages reduced by the end of the trial, while a further seven stopped taking them altogether.

The results of the study, led by Dr. Jianqin Sun of Fudan University, Shanghai, were announced at a recent Singapore press conference and published in the Asia Pacific Journal of Clinical Nutrition. [2008; 17(3):514-24]

The intervention program included diabetes education, nutritional counseling, meal replacement with dietary supplements, and weekly progress reports with a physician and a dietician. It was compared in a randomized prospective trial against a simpler intervention comprising only education on diet and physical activity. Fifty patients were included in this reference group.

Professor William Garvey, a US diabetes expert who commented on the study, described the reduction in HbA1c as “very impressive” given that the intervention patients were already well-controlled, with an average HbA1c of 7.1 percent at baseline. He also noted that the potential to reduce or stop medications provides a good incentive for diabetic patients to lose weight, but stressed that these adjustments should only be made following proper consultation with a physician.

Dr. Kevin Tan, vice-president of the Diabetic Society of Singapore, said that the study demonstrates the viability of meal supplements as a therapy for diabetes, adding that this option should be explored for all patients who are overweight.

“Meal supplements or replacements have not been talked about much so a lot of doctors don’t think about them, but they do play a part in diabetes management in terms of helping to reduce calorie intake and helping patients to lose weight. If GPs realize that this can be part of their usual holistic diabetes care, along with the medications, exercise and weight control, then I think it will help to improve sugar control in their diabetic patients,” he said.

Participants in the study were all type 2 diabetics aged 18 to 70 with a BMI of 23 kg/m2 or above. The lifestyle intervention also significantly improved blood pressure (BP), with patients in this group recording average reductions of 7.5 mmHg for systolic BP and 3.4 mmHg for diastolic BP, at 24 weeks as compared to baseline. These reductions were significantly greater for the intervention group compared to the reference group.

The waist-to-hip ratio was also reduced among patients in the intervention group compared to those in the reference group.

“Dietary supplements are not the magic answer for everybody but they can be helpful in many patients,” said Garvey, who is based at the University of Alabama at Birmingham, US.

“If you have a patient who needs to lose weight and you feel that they need more structure in terms of their dietary plan – less guesswork and more clear-cut guidance in terms of what the diet will be from day to day – a meal replacement is a really good tool to use,” he said.

Garvey acknowledged that the short duration of the trial makes it hard to assess the long-term sustainability of the intervention, but added that the structured nature of the program teaches important behavioral modification skills which continue to be applicable beyond the trial setting.

The burden of type 2 diabetes in China is increasing rapidly, according to the study authors, who note that the prevalence among large city residents rose from 4.6 percent in 1995 to 6.4 percent in 2002. In Singapore the burden could be even higher, with data from the 2004 National Health Survey suggesting a diabetes prevalence of 8.2 percent among residents aged 18 to 69.

The trial by Sun et al. was funded by Abbott Laboratories, which manufactures the dietary supplement used in the study.

Low glycemic index diet boosts glucose control and HDL in diabetics

Medical Tribune February 2009 P10
David Brill

Following a low glycemic index (GI) diet can improve blood sugar control and raise HDL-cholesterol levels in type 2 diabetics, according to a recent study in the Journal of the American Medical Association.

Researchers from St. Michael’s Hospital and the University of Toronto, Canada, randomized 210 patients to follow either a low-GI diet or a high-cereal fiber diet for 6 months.

At the end of the study, HbA1C had decreased by 0.5 percentage points among those in the low-GI diet group, compared to just 0.18 percentage points in those following the high-cereal fiber diet. When comparing the two diets the relative change in HbA1C was 0.33 percent (P<0.001). p="0.005).">JAMA 2008 Dec 17;300(23):2742-53]

Participants in the trial all had HbA1C values between 6.5 and 8 percent at baseline screening, and had not had their diabetes medications changed within the preceding 3 months.

The European Society of Cardiology (ESC) said in a statement that the study supports current recommendations on lifestyle advice for the control of diabetes.

“Treatment of type 2 diabetes should always be initiated with structured lifestyle advice. Results from the JAMA study suggest that such advice may be as effective as some drug interventions,” said ESC spokesman for diabetes and cardiovascular disease Professor Lars Ryden of the Karolinska University Hospital, Sweden.

“The JAMA study also shows that a well-balanced diet will improve not only blood glucose tolerance but also blood lipid levels, which are of great importance in decreasing cardiovascular complications. If drugs are still needed in these circumstances, their dose and number may be lower,” he added.

The usefulness of GI as a dietary guide has proved controversial in the past. The index gives a measure of the extent to which certain foods affect the body’s glucose levels, but critics have questioned the methodology used to determine the values. [Diabetes Care 2003 Aug;26(8):2466-8]

The American Diabetes Association does not specifically advocate the low-GI diet, but notes on its website that it “may be helpful in ‘fine-tuning’ blood glucose management” and could provide additional benefits for those individuals who wish to pay close attention to their dietary choices.

Another recent trial, involving 162 type 2 diabetics, found that following a low-GI diet for a year did not improve glycemic control compared to a high-GI diet, although it did reduce postprandial glucose and C-reactive protein levels. [Am J Clin Nutr 2008 Jan;87(1):114-25]

Managing diabetic retinopathy in primary care

Medical Tribune January 2009 P14-15

Diabetic retinopathy is a leading cause of visual loss in Asia and one of the major chronic eye diseases handled by GPs. Left untreated, it can result in permanent blindness from neovascular glaucoma or tractional retinal detachment arising from proliferative diabetic retinopathy.

The condition is expected to become more common as the prevalence of diabetes continues to rise in Asia.

A recent study found that 38.1 percent of diabetics who were referred for retinal assessment as part of a nationwide screening program in Singapore had retinopathy. [Ann Acad Med Singapore 2008 Sep;37(9):753-9] The Singapore Malay Eye Study, meanwhile, demonstrated a retinopathy prevalence of 35 percent among diabetics of Malay ethnicity, of whom 9 percent had vision-threatening retinopathy. [Ophthalmology 2008 Nov:115(11):1869-1875]. This high rate of diabetics suffering from retinopathy is consistent worldwide. The proportion of type 2 diabetics having retinopathy has been reported to be 40.3 percent in the US, 35 percent in Taiwan and 10.5 – 26.2 percent in India.

Pathogenesis

Diabetic retinopathy is a highly specific microvascular complication of both type 1 and type 2 diabetes mellitus, resulting from progressive damage to the retinal blood vessels caused by hyperglycemia in the blood. The condition is caused by increased vascular permeability at onset, leading to fluid accumulation in the retina. With time, there is vascular shutdown, causing ischemia of the retina. This leads to retinal neovascularization at the disc or elsewhere, vitreous hemorrhages, fibro-proliferative changes and retinal detachment. Neovascular glaucoma can also develop. The prevalence is strongly related to the duration of diabetes mellitus, and most diabetic patients will develop retinopathy with time.

See the sidebar for a classification of the different disease stages.

Screening

As patients with sight-threatening retinopathy may not show any symptoms, fundal screening of diabetic patients is crucial in helping to identify those at risk of developing complications that will impact on their vision and quality of life. The importance of regular screening for diabetics, therefore, cannot be understated.

All diabetic patients should be screened for retinopathy on an annual basis at the very least, beginning from the point of diagnosis. Those who are at high risk for developing retinopathy need to be monitored more closely and should be screened at least twice yearly. The major risk factors to consider are hypertension, high cholesterol, smoking, patient’s age, duration of diabetes and a history of poor glycemic control. The Singapore Malay Eye Study also found that a history of stroke, cardiovascular disease or chronic kidney disease was associated with vision-threatening retinopathy.

Female diabetics who are planning to conceive should be screened prior to conception and again in the first trimester. The regularity of follow-up should then be determined based on the results of the first trimester examination.

For patients with established retinopathy, the timing of follow up examinations depends on their disease status.

Physicians who are involved in providing diabetic care have a pivotal role in ensuring that patients are screened. This can be performed via fundal photography, indirect fundoscopy or direct ophthalmoscopy through a dilated pupil.

While the need for regular screening is well accepted by the medical community, it is an unfortunate reality that patients are often not screened as frequently as they should be. Many patients do not understand the progressive nature of the disease process, mistakenly believing that if there is nothing wrong with their vision, then they do not need to see an eye doctor. Many appointments are missed as a result, and the early signs of diabetic retinopathy can often go undetected. Accessibility can also be a problem, particularly in rural areas, and can also contribute to the missing of screening appointments.

We must educate patients on the importance of these check-ups, and help them to understand that by the time they discover they have developed visual problems, it may already be too late to treat them. GPs can also help patients to attend their screening appointments by checking regularly whether they are compliant with their schedules, reminding them about upcoming
visits and making sure that they are referred to the most appropriate and convenient center.

Practice guidelines

The most widely-used guidelines on diabetic retinopathy come from the American Academy of
Ophthalmology. These have been incorporated into clinical practice guidelines on the management of diabetic retinopathy from Singapore’s Ministry of Health, published in January 2004, which help GPs plan their management and screening schedules for their patients. Diabetic retinopathy guidelines are also available from the Academy of Medicine of Malaysia.

Treatment

Laser treatment is the major therapy for diabetic retinopathy but can lead to long-term side effects such as a reduced field of vision.

There is now a considerable weight of data showing the benefits of good glycemic control on
retinopathy outcomes. The Diabetes Control and Complications Trial (DCCT) found that an intensive strategy reduced the risk of developing retinopathy by 76 percent and slowed disease progression by 54 percent. [N Engl J Med 1993 Sep 30;329(14):977-86] Recent data from the United Kingdom Prospective Diabetes Study (UKPDS) show that the benefits of intensive glucose control extended long beyond the trial intervention, with a 24 percent risk reduction for microvascular disease noted 10 years after the conclusion of the study. [N Engl J Med 2008 Oct 9;359(15):1577-89]

Tight blood pressure control is also important. The original UKPDS data demonstrated a 47 percent reduction in the risk of having decreased vision in both eyes, after 9 years of follow up. [BMJ 1998 Sep 12;317(7160):703-13] The 2008 data showed that the benefits disappeared once treatment was withdrawn, suggesting that blood pressure control needs to be maintained in order to continue to derive the maximum benefits. [N Engl J Med 2008 Oct 9;359(15):1565-76]

Medication adherence is often a major obstacle in achieving these targets. GPs should continue to ensure that patients are well-educated on the importance of taking their drugs, making them aware that failure to do so increases their risk of retinopathy. Regular HbA1c and blood pressure tests should be carried out to monitor progress, and medication adjusted accordingly.

Disease management tools

In October 2006, the Ministry of Health in Singapore launched the Chronic Disease Management Program, focusing initially on diabetes and then on hypertension, dyslipidemia
and stroke. The plan is to transform management of these diseases by forming an effective
partnership among GPs, medical specialists and patients through effective information flow within the partnership throughout the healthcare continuum. The program aims to equip GPs with a better understanding of patients’ medical histories through up-to-date electronic records and, in turn, reduce medical costs and enable the provision of quality healthcare services customized to individual requirements.

This integrated clinic management system provides GPs with a complete system to manage their patients and clinic operations. Critical clinical indicators are stored, enabling GPs to use this data to track the progress of their patients. Clinical decision support tools are also built into the system to help GPs plan effectively and communicate care plans to their patients. In this way, schedules for retinopathy screening can be built into the patients’ management plan, helping doctors keep to the intended schedules.

Conclusion

Regular screening is the cornerstone of detecting, monitoring and managing diabetic retinopathy and should be arranged from the very point of diagnosis. Patients should be educated about the importance of screening and followed up at all stages to ensure compliance to their schedules. Good glycemic and blood pressure control are also of vital importance in preventing the development and progression of this potentially sight-threatening condition. It is strongly recommended that the organization of retinopathy screening be primarily the responsibility of the GPs, who will then refer all patients with retinopathy or media opacity to an ophthalmologist for more specialized treatment.

Online Resources:

The American Academy of Ophthalmology guidelines:

www.guideline.gov/summary/summary.aspx?doc_id=4350

ADA, EASD offer practical new guidance on diabetes treatment

Medical Tribune December 2008 P4
David Brill

An updated treatment algorithm has been released which promises to help guide primary care physicians through the ever-expanding field of treatments for type 2 diabetes.

The consensus statement, produced jointly by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), places a strong emphasis on early treatment and the maintenance of HbA1c levels below 7 percent.

Metformin therapy plus lifestyle intervention is recommended from diagnosis for all patients, with further medications to be added promptly if targets are not achieved.

The statement also makes new differentiations within drug class
– advocating pioglitazone over rosiglitazone and dropping glybenclamide and chlorpropamide from the list of recommended sulfonylureas.

"We’ve seen absolutely that if you do not keep glucose levels within reasonable bounds you will reap a harvest of microvascular disease," said Professor Rury Holman, one of the authors of the algorithm.

"The tide is changing. The view that complications are inevitable is no longer true. They will occur even in the best controlled-people but the risk can be substantially reduced, and therefore I think we have a duty of care to minimize HbA1c to the extent that we can," he said.

Holman, head of the Diabetes Trials Unit at The Oxford Centre for Diabetes, Endocrinology and Metabolism, UK, said that the new algorithm is "not a prescription" to be followed in all cases but rather an evidence-based starting point for primary care doctors, who should still seek specialist advice where appropriate.

He also stressed the need to adopt a more cautious approach to HbA1c lowering in patients with a long-standing history of disease, noting that physicians should weigh up the relative risks and benefits before attempting to push HbA1c levels below 7 percent.

The latest version of the ADA/ EASD treatment algorithm, first issued in 2006, was published online recently in the journals Diabetes Care and Diabetologia. The document will continue to be updated as and when new data become available, Holman said.

For cases where the initial metformin approach is unsuccessful, the algorithm divides the subsequent intensification of therapy into two tiers according to how well validated the medications are considered to be. Tier 1 sees the addition of either sulfonylurea or basal insulin, progressing to initiation or intensification of insulin therapy. Tier 2 recommends pioglitazone or the glucagon-like peptide-1 agonist exenatide, before moving on to sulfonylurea or basal insulin.

Besides the algorithm, the consensus statement also contains a literature review on the relative merits of the different medications, and guidance on the titration of metformin and the initiation and adjustment of insulin regimens.

Dr. Kevin Tan, vice president of the Diabetic Society of Singapore, agreed that doctors now have a duty to initiate early, intensive glycemic control and said that incorporating the new algorithm would help them to focus on the older, better-established drugs and view the newer options as alternatives to be used where necessary.

Aspirin ineffective for primary cardiovascular protection in diabetics

Medical Tribune December 2008 P4
David Brill

Aspirin is of no benefit for the primary prevention of cardiovascular events in diabetics, new randomized trial data suggest.

The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) study found that neither aspirin nor antioxidants reduced the incidence of cardiovascular events among 1,276 diabetic adults with asymptomatic peripheral arterial disease.

The findings of the study, which conflict with international guidelines, demonstrate that the medical community has extended its practices beyond the existing evidence base, the study’s lead researcher said.

"We do know that aspirin and antiplatelet agents are useful for secondary prevention in diabetes," said Professor Jill Belch of the Institute of Cardiovascular Research at the University of Dundee, UK.

"The trouble is, we have been guilty of therapeutic greed and we’ve extrapolated these findings back into primary prevention without any evidence.

"Although aspirin is a relatively safe drug we shouldn’t lose sight of the fact that it does have potential side effects … if something doesn’t benefit you, and has the potential to do harm, then the net effect is negative and perhaps we should wait until the evidence is available before writing our guidelines."

Belch said that the use of aspirin for primary cardiovascular prevention in diabetes is "endemic worldwide," yet the data from the POPADAD trial and other studies do not offer convincing support for the practice.

Doctors should instead focus strongly on getting patients’ lipid levels and blood pressure on target using statins and antihypertensive agents, she said, noting that aspirin can cause gastrointestinal bleeding and is one of the most common causes of drug-related hospitalizations.

She stressed, however, that aspirin remains a vital drug for secondary prevention, and urged doctors to reassure patients with established cardiovascular disease about the need to continue taking the drug.

Patients in the POPADAD trial were followed up for a median of 6.7 years. Of the 638 primary events that occurred during the study, 116 were among patients taking aspirin and 117 among those taking placebo or antioxidants alone. [BMJ 2008 Oct 16;337:a1840]

Patients in the study were aged over 40 with either type 1 or type 2 diabetes but no symptoms of cardiovascular disease, and had an ankle brachial pressure index of 0.99 or lower. Aspirin was given at a dosage of 100 mg once daily.

Further research is needed to confirm whether primary prevention could be achieved using a different aspirin dosing schedule or an alternative antiplatelet agent, Belch added.

The American Heart Association and American Diabetes Association jointly recommend that aspirin (75 – 162 mg/day) be used for primary prevention in diabetics at increased cardiovascular risk, including those aged over 40. [Circulation 2007 Jan 2;115(1):114-26]

There are similar recommendations in Asia. For example, guidelines from the Ministry of Health, Singapore, advocate aspirin (75 – 100 mg/day) for all type 2 diabetics over the age of 45, or those with dyslipidemia, hypertension or preexisting cardiovascular disease.

The POPADAD study is now the seventh well-controlled trial to show that aspirin is ineffective for this purpose, according to Professor William Hiatt from the University of Colorado Denver School of Medicine, US.

"Although aspirin is cheap and universally available, practitioners and authors of guidelines need to heed the evidence that aspirin should be prescribed only in patients with established symptomatic cardiovascular disease," he wrote in an accompanying editorial. [BMJ 2008;337:a1806]

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.”

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.

Mediterranean diet reduces diabetes risk

Medical Tribune August 2008 SFXV
David Brill

Following a Mediterranean diet – known to lower cardiovascular risk – can also reduce the chance of developing diabetes, Spanish researchers have shown.

The study, which was published in the British Medical Journal, followed 13,380 university graduates over a median period of 4.4 years and used questionnaires to rank their adherence to the diet on a scale of one to nine.

“Those who were highly adherent to this traditional dietary pattern exhibited a very low rate [of diabetes] and an impressive magnitude in the relative risk reduction of 83 percent,” said lead researcher Miguel Martinez-Gonzalez, Professor of epidemiology at the University of Navarra.

Interestingly, he added, people who adhered most closely to the diet were typically older with a higher prevalence of hypertension, smoking history and other risk factors for diabetes. The incidence among this group would therefore have been expected to be high.

“This may mean that the Mediterranean diet is highly protective against diabetes,” he said, but added that only 33 new cases were observed – a small number relative to the size of the study.

“This is fortunate for our participants indeed but this is a major limitation. We need further evidence from larger cohorts and trials,” he said.

The traditional Mediterranean diet comprises high amounts of olive oil, fruit, vegetables, nuts and fish, and relatively low amounts of meat and dairy products. The health benefits of the diet have been shown in various studies, including a randomized trial which demonstrated a beneficial effect on cardiovascular risk factors. [Ann Intern Med 2006 Jul 4;145(1):1-11]

Dr. Warren Lee, former Chairman of the Diabetic Society of Singapore, said that the study was interesting and comprised good quality data.

“I would certainly say this reinforces the old chestnut that one should take more fruit and vegetables and emphasize less on the meat,” he said.

It remains unclear at what point of adherence to the diet the benefits begin to accrue, added Lee, who is a pediatric endocrinologist in private practice and a senior consultant at KK Women’s and Children’s Hospital.

"This study was not able to show a threshold effect because it was designed to show that there was an effect in a relatively homogenous population of people who ate either more than the mean or less than the mean of certain foods.

“However it was heartening that a two point increase in a nine point score was able to reduce the incidence rate ratio – a measure of relative risk – by 35 percent, and that even those in the moderate adherence group had a significant benefit. This suggests that people trying to adhere to a healthy diet will be better off than those who do not even try,” he said.

Lee noted that the diet in Spain is rather different to that in Singapore, where food is frequently cooked using palm oil or pork lard rather than olive oil.

“Perhaps the next step is to see how we can incorporate elements of this diet into our food choices,” he concluded.