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World Water Day

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World Water Day
Observed by	All UN member states
Date	22 March

World Water Day has been observed on 22 March since 1993 when the United Nations General Assembly declared 22 March as World Day for Water.^[1]

This day was first formally proposed in Agenda 21 of the 1992 United Nations Conference on Environment and Development (UNCED) in Rio de Janeiro, Brazil. Observance began in 1993 and has grown significantly ever since; for the general public to show support, it is encouraged for the public to not use their taps throughout the whole day, the day has become a popular Facebook trend.

The UN and its member nations devote this day to implementing UN recommendations and promoting concrete activities within their countries regarding the world's water resources. Each year, one of various UN agencies involved in water issues takes the lead in promoting and coordinating international activities for World Water Day. Since its inception in 2003, UN-Water has been responsible for selecting the theme, messages and lead UN agency for the World Day for Water.

In addition to the UN member states, a number of NGOs promoting clean water and sustainable aquatic habitats have used World Day for Water as a time to focus public attention on the critical water issues of our era. Every three years since 1997, for instance, the World Water Council has drawn thousands to participate in its World Water Forum during the week of World Day for Water. Participating agencies and NGOs have highlighted issues such as a billion people being without access to safe water for drinking and the role of gender in family access to safe water. In 2003, 2006 and 2009, the UN World Water Development Report was launched on the occasion of the World Water Day. The fourth Report is expected to be released around 22 March 2012.

Source: http://en.wikipedia.org/wiki/World_Water_Day

World Water Day

International Year of Water Cooperation - 22 Maech 2013

Water cooperation

The fulfilment of basic human needs, our environment, socio-economic development and poverty reduction are all heavily dependent on water.

Good management of water is especially challenging due to some of its unique characteristics: it is unevenly distributed in time and space, the hydrological cycle is highly complex and perturbations have multiple effects. Rapid urbanization, pollution and climate change threaten the resource while demands for water are increasing in order to satisfy the needs of a growing world population, now at over seven billion people, for food production, energy, industrial and domestic uses. Water is a shared resource and its management needs to take into account a wide variety of conflicting interests. This provides opportunities for cooperation among users.

In designating 2013 as the UN International Year of Water Cooperation, the UNGA recognizes that cooperation is essential to strike a balance between the different needs and priorities and share this precious resource equitably, using water as an instrument of peace. Promoting water cooperation implies an interdisciplinary approach bringing in cultural, educational and scientific factors, as well as religious, ethical, social, political, legal, institutional and economic dimensions.

Source: http://www.unwater.org/water-cooperation-2013/water-cooperation/en/

 

 

Masked Hypertension in Diabetes Mellitus

Treatment Implications for Clinical Practice

 

Abstract

Although distinguishing features of masked hypertension in diabetics are well known, the significance of antihypertensive treatment on clinical practice decisions has not been fully explored. We analyzed 9691 subjects from the population-based 11-country International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes. Prevalence of masked hypertension in untreated normotensive participants was higher (P<0.0001) among 229 diabetics (29.3%, n=67) than among 5486 nondiabetics (18.8%, n=1031). Over a median of 11.0 years of follow-up, the adjusted risk for a composite cardiovascular end point in untreated diabetic-masked hypertensives tended to be higher than in normotensives (hazard rate [HR], 1.96; 95% confidence interval [CI], 0.97–3.97; P=0.059), similar to untreated stage 1 hypertensives (HR, 1.07; CI, 0.58–1.98; P=0.82), but less than stage 2 hypertensives (HR, 0.53; CI, 0.29–0.99; P=0.048). In contrast, cardiovascular risk was not significantly different in antihypertensive-treated diabetic-masked hypertensives, as compared with the normotensive comparator group (HR, 1.13; CI, 0.54–2.35; P=0.75), stage 1 hypertensives (HR, 0.91; CI, 0.49–1.69; P=0.76), and stage 2 hypertensives (HR, 0.65; CI, 0.35–1.20; P=0.17). In the untreated diabetic-masked hypertensive population, mean conventional systolic/diastolic blood pressure was 129.2±8.0/76.0±7.3 mm Hg, and mean daytime systolic/diastolic blood pressure 141.5±9.1/83.7±6.5 mm Hg. In conclusion, masked hypertension occurred in 29% of untreated diabetics, had comparable cardiovascular risk as stage 1 hypertension, and would require considerable reduction in conventional blood pressure to reach daytime ambulatory treatment goal. Importantly, many hypertensive diabetics when receiving antihypertensive therapy can present with normalized conventional and elevated ambulatory blood pressure that mimics masked hypertension.

Source / Read more: http://hyper.ahajournals.org/content/early/2013/03/11/HYPERTENSIONAHA.111.00289

A Step toward Personalized Asthma Treatment

Jeffrey M. Drazen, M.D.

N Engl J Med 2011; 365:1245-1246September 29, 2011DOI: 10.1056/NEJMe1102469

 

Inhaled glucocorticoids are used every day by millions of patients with asthma. As with all asthma-controller treatments, there is marked patient-to-patient variability in the therapeutic response1; about one in three patients with asthma who use inhaled glucocorticoids may not benefit from this treatment. It would be advantageous if we could identify, in advance, patients who would respond to such treatment, but we have not been able to do so, despite major efforts during the past decade. In this issue of the Journal, Tantisira and colleagues appear to have made progress toward reaching this goal with the identification of a genetic variant associated with the response to inhaled glucocorticoids in the treatment of asthma.2

To identify this genetic variant, the group first used the clinical data and DNA resources from patients enrolled in the Childhood Asthma Management Program (CAMP), sponsored by the National Heart, Lung, and Blood Institute.3 Children 5 through 12 years of age who had asthma of moderate severity were enrolled in CAMP and were treated for 5 years with budesonide (an inhaled glucocorticoid), nedocromil sodium, or placebo. The frequent measurements of lung function and careful monitoring for asthma exacerbations resulted in a rich database of clinical information for use in the genetic studies. But what made the cohort most useful to these investigators was the availability of DNA from the children with asthma and from their parents — so-called DNA trios. Armed with one sample from an affected child and one sample from each of the child's parents, the investigators were able to use family-based statistics to identify 13 single-nucleotide–polymorphism (SNP) candidates from the hundreds of thousands of SNPs they had genotyped.4 The authors then tested these potential candidates in four replication populations and identified a variant in the glucocorticoid-induced transcript 1 gene (GLCCI1), rs37972, associated with a decrease in forced expiratory volume in 1 second (FEV₁) in response to treatment with inhaled glucocorticoids. To offer additional reassurance that they had identified a causative SNP, the investigators provided data from isolated cell systems containing the pharmacogenetically identified SNP (and rs37973, which is in complete linkage disequilibrium with rs37972) to show that the presence of these sequence variants was associated with biologic changes that would be consistent with a decreased response to these agents.

 

 

Read more/ Source: http://www.nejm.org/doi/full/10.1056/NEJMe1102469

Effect of Bronchoconstriction on Airway Remodeling in Asthma

Christopher L. Grainge, Ph.D., Laurie C.K. Lau, Ph.D., Jonathon A. Ward, B.Sc., Valdeep Dulay, B.Sc., Gemma Lahiff, B.Sc., Susan Wilson, Ph.D., Stephen Holgate, D.M., Donna E. Davies, Ph.D., and Peter H. Howarth, D.M.

N Engl J Med 2011; 364:2006-2015May 26, 2011DOI: 10.1056/NEJMoa1014350

 

BACKGROUND
Asthma is a common chronic respiratory condition characterized clinically by an excessive tendency toward reversible airway narrowing. This may arise in response to everyday environmental exposure and is worsened both by intercurrent infection and, in sensitized persons, by allergen exposure. In pathological terms, asthma is characterized by airway inflammation and by structural changes in airway tissues, such as epithelial goblet-cell hyperplasia, subepithelial collagen deposition, and smooth-muscle hypertrophy — collectively referred to as airway remodeling.1-3 Since an inhaled-allergen challenge in atopic asthma induces eosinophilic inflammation of the airway and changes in the extracellular matrix,4 and since a reduction in airway eosinophils has been reported to reduce certain markers of airway remodeling,5 such structural changes in the tissues have been considered a consequence of eosinophilic airway inflammation.6 This paradigm, however, fails to account for the potential contribution of airway narrowing to airway remodeling. Bronchoconstriction generates excessive mechanical forces within the airways that distort tissue cells,7,8 and mechanical forces within other organs are known to induce tissue remodeling.9-11 In vitro studies in a variety of models have shown that ex vivo compression of the airway epithelium results in changes that mimic those identified and associated with remodeling in vivo.12-15 We therefore hypothesized that the airway narrowing induced by allergen exposure in vivo in patients with asthma may in itself be a sufficient stimulus for the development of airway remodeling and that such remodeling is not solely dependent on induced recruitment of airway eosinophils.

To test this hypothesis, we performed repeated challenges with exposure to either allergen (to induce bronchoconstriction with airway eosinophil recruitment) or methacholine (to induce bronchoconstriction alone) in volunteers who had mild atopic asthma. Two additional groups of volunteers with asthma served as controls, undergoing repeated challenges with either saline placebo (to control for the challenge procedures) or methacholine after they had received albuterol to prevent bronchoconstriction (to control for any additional nonbronchodilator, receptor-mediated actions of methacholine within the airways). The effect of these challenges on the airway was evaluated by assessing changes in markers of airway remodeling in endobronchial tissue obtained by fiberoptic bronchoscopy before and after the challenge.

>>>Read more: http://www.nejm.org/doi/full/10.1056/NEJMoa1014350#t=articleBackground

Treating Asthma

Treating asthma

The aim of treatment is to get your asthma under control and keep it that way. Everyone with asthma should be able to lead a full and unrestricted life. The treatments available for asthma are effective in most people and should enable you to be free from symptoms.

What is good asthma care?

Your doctor or nurse will tailor your asthma treatment to your symptoms. Sometimes, you may need to be on higher levels of medication than at other times.

You should be offered:

• care at your GP surgery provided by doctors and nurses trained in asthma management
• full information about your condition and how to control it
• involvement in making decisions about your treatment
• regular checks to ensure your asthma is under good control and your treatment is right for you (which should be at least once a year)
• a written personal asthma action plan agreed with your doctor or nurse

It is also important that your GP or pharmacist teaches you how to properly use your inhaler as this is an important part of good asthma care. See 'taking asthma medicines' below for a video on inhaler techniques.

 

Source / Read More:
http://www.nhs.uk/Conditions/Asthma/Pages/Treatment.aspx

Have we found a cure for HIV?

Have we found a cure for HIV? Child born with virus is now free of infection after 'miraculous' treatment

• Child's mother was only diagnosed as HIV positive after going into labour
• Baby was given extra-strong programme of medication to 'blast' the virus
• This prevented the virus from taking hold in the baby's cells
• Two years after beginning treatment, tests show no virus in the child's blood
• Breakthrough hailed as 'major landmark' in the battle to find cure

By Anna Hodgekiss

PUBLISHED:22:32, 3 March 2013| UPDATED:01:04, 5 March 2013

• Comments (121)
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Miraculous: Dr Hannah Gay, a paediatric HIV specialist at the University of Mississippi, treated the two-year-old girl who is now 'cured' of the virus

Doctors have made a landmark breakthrough in the treatment of HIV after they 'cured' a baby with the virus.

The baby girl had been infected by her mother who was diagnosed as HIV positive during labour.

Because of the high infection risk, the baby was given an accelerated programme of medication.

She received three standard HIV drugs instead of the usual one when she was just 30-hours old.

This appears to have blasted the virus into remission and prevented it from taking root in the baby's cells.

Now two-years-old, the girl from Mississipi is in remission with blood tests showing no signs that the virus is present. This is known as a 'functional cure.'

Experts say the groundbreaking development paves the way for other children to be treated before the virus takes hold.

Last night at a major AIDS meeting in Atlanta, the case was declared a major landmark in the battle to find a cure for the disease.

Study leader Dr Deborah Persaud, of Johns Hopkins Children's Centre in Baltimore, said the toddler is now free from the potentially fatal disease.

Dr Anthony Fauci of the National Institutes of Health said: 'You could call this about as close to a cure, if not a cure, that we've seen.'

He added that the child, which is only the second patient ever recorded to have been 'cured' of AIDS, 'opens up a lot of doors' for the treatment of other children born with HIV.

The child's mother was rushed to a rural emergency room in July 2010 in advanced labour and tests showed she was HIV positive.

Because the mother had not had any treatment, doctors knew the child was at high risk of infection.

Normally, they would have given the newborn a low dose of the medication nevirapine in the hope that it would prevent the HIV from taking hold.

However the small hospital didn't have the right kind of liquid to give the treatment and so she was rushed to specialist centre run by Dr Hannah Gay, a paediatric HIV specialist at the University of Mississipi.

Read more: http://www.dailymail.co.uk/health/article-2287564/Have-cure-HIV-Child-born-virus-free-infection-miraculous-treatment.html#ixzz2O4Zqc6Hi
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Source: http://www.dailymail.co.uk/health/article-2287564/Have-cure-HIV-Child-born-virus-free-infection-miraculous-treatment.html

More Near-Cures for HIV

Early treatment may be key to a drug-free life for a small percentage of patients.

Last week, scientists reported that a baby had been "functionally cured" of HIV (see "A Toddler May Have Been Cured of HIV Infection"). Now, other researchers report in PLoS Pathogens that 14 HIV-infected adults—four women and 10 men—have survived with the virus in check even though they have stopped taking their antiretroviral medications.

The authors write that while combined antiretroviral drugs reduce HIV-associated illness and death, they cannot cure the infection. The 14 patients in the study are functionally cured, meaning they are not completely rid of the virus—although they have no symptoms, very low levels of HIV can still be detected in their blood. "Given the difficulty of eradicating [HIV], a functional cure for HIV-infected patients appears to be a more reachable short-term goal," they write.

But bear in mind that the 14 adults who were functionally cured were part of a larger study of 70 people who had gone off of their antiretroviral drugs. The majority of the group relapsed when their treatment stopped. The key now is to find out what makes the 14 adults different. They did not carry known protective genetic variants and actually had more severe infections and more symptoms before starting treatment. This sensitivity may have helped by prompting the patients to seek treatment sooner than most people, write the researchers who conclude that:

"These findings argue in favor of early [combined antiretroviral therapy] initiation and open up new therapeutic perspectives for HIV-1-infected patients."

 

 

Source: http://www.technologyreview.com/view/512596/more-near-cures-for-hiv/

Meta-analysis: low-dose aspirin (modestly) reduces risk of pre-eclampsia.

A large meta-analysis of patient-level data has found that low-dose aspirin given to pregnant woman at risk of pre-eclampsia modestly but consistently reduced their risk of adverse outcomes. Pre-eclampsia affects between 2% and 8% of pregnancies and can have severe adverse effects on both mother and baby. While the cause is not yet known, abnormalities of clotting and platelet function occur and suggest the potential for benefit from anti-platelet drugs: many studies have been carried out over the past two decades, but their results have not been clear-cut. Previous systematic reviews suggested a benefit overall, however there was still controversy. The authors of this meta-analysis aimed to used patient-level data from as many previous trials as possible in an attempt to clarify the situation.

They carried out a comprehensive literature search using a relevant secondary database that is regularly updated from other databases. Eligible studies were randomised controlled trials of women at risk of pre-eclampsia treated for primary prevention with one or more anti-platelet agents, against controls of placebo or no treatment. Where potentially eligible trials included both primary and secondary prevention arms, only patients in the primary prevention arm were included in the analysis. Variables for the analysis were pre-specified, and anonymised data for patients in all eligible trials was requested from the original study authors; this was re-coded if necessary, checked for consistency, corrected where necessary, and finally agreed with the original authors. Four primary outcomes were defined: pre-eclampsia, death in utero or before hospital discharge, delivery pre-term at less than 34 weeks gestation, and infant small for gestational age. These were combined as an additional composite outcome - 'pregnancy with serious adverse outcome' (pregnancy where the mother dies or develops pre-eclampsia or if any baby is preterm, small for gestational age, or does not survive to discharge from hospital). Results were analysed on an intention to treat basis, but analysis for each outcome was restricted to trials having at least 80% of the data available for that outcome. Analyses compared the effect of the anti-platelet agent against placebo or no treatment for each outcome.

There were 115 trials identified initially, of which 50 were excluded as having no comparison group or treating women with established eclampsia only and two were excluded because patients were not truly randomised. Of the 63 remaining, including a total of 38,026 women, data could not be obtained for 27 (accounting for about 10% of the total participants; trial authors not traceable n=7, refused n=1, original data lost or irretrievable n=17, or not supplied n=2). This left 36 trials involving 34,288 women for which data could be analysed. Of these, 31, including 32,217 women and their 32,819 babies, were primary prevention studies and were thus included in this analysis. In 27, accounting for the great majority of the data, aspirin was given alone (dose 50mg to 150mg daily). Three small trials used only other anti-platelet drugs, and three tested aspirin and dipyridamole in combination. Just over half the women included were in their first pregnancy, 70% were aged 20 to 35, and 90% had at least one risk factor. Overall, 8% developed pre-eclampsia.

Compared to control, treatment with an anti-platelet agent was associated with a small but robust reduction in the relative risk of both pre-eclampsia (RR 0.90, 95% CI 0.84 to 0.97, p=0.004) and preterm birth before 34 weeks' gestation (RR 0.90, 95% CI 0.83 to 0.98, p=0.011). They also reduced the risk of the composite outcome to a similar extent (RR 0.90, 95% CI 0.85 to 0.96, p=0.001). There were also similar reductions in the other two primary outcomes (baby small for age, stillborn, or died before discharge), however these were not statistically significant. Maternal outcomes were similar for the two groups, with no significant increase in bleeding in the anti-platelet group. Subgroup analyses did not reveal any subgroup in which there was particular benefit.

The authors conclude that the data shows that treatment with an anti-platelet drug, mainly aspirin, reduces the risk of pre-eclampsia and some adverse pregnancy outcomes by about 10%. It is not possible to determine from the available data whether any particular subgroup benefits, although as the risk reduction is relative the absolute benefit will depend on a woman's underlying risk. The trials recruited mainly women at low to moderate risk of pre-eclampsia, so the data for women at high risk is limited. The analysis does not suggest that aspirin treatment is associated with significant adverse effects, although because some of the data on post-partum haemorrhage is uncertain, this outcome needs to be treated with caution.

An accompanying Comment discusses the paper and its implications. They authors discuss the possible mechanism of the benefit, and suggest questions that still need answers. They agree with the trial authors that use will depend on the mother's pre-existing risk level, and should be after full discussion of the potential risks and benefits. There have been a number of media reports of this study, and UK experts caution that pregnant women should not start taking aspirin without discussion with their doctor.

Lancet, published early online 18 May 2007; DOI:10.1016/S0140-6736(07)60712-0 (link to abstract); Lancet, published early online 18 May 2007; DOI:10.1016/S0140-6736(07)60713-2 (Comment; link to full text, available to subscribers only); BBC News report.

Case report: erythropoietins affecting HbA1c in a diabetic not on dialysis

In this case report, they authors describe an interaction between two erythropoietins and haemoglobin A1c (HbA1c) levels in a diabetic patient not on dialysis.

Some evidence suggests that treatment with erythropoietins can reduce HbA1c levels in patients on haemodialysis, however this has not previously been reported in non-dialysed patients. They authors describe a case in which this effect occurred in a diabetic patient not on dialysis and resulted in a prolonged period of under-treatment of his diabetes.

The patient was a male aged 64 with long-standing insulin-treated type 2 diabetes and chronic renal failure, amongst other problems. He presented with severe anaemia (Hb 4.4gm/100ml) and was treated with epoetin. His HbA1c level subsequently fell, and his insulin dose reduced in consequence. His most recent stable pre-admission insulin dose was 156 units daily with no hypoglycaemic episodes. Subsequent management involved home-based darbepoetin: his HbA1c level was consistently in the range 4.4 to 5.8 and his daily insulin dose was reduced to 22 units daily: this was despite raised blood glucose levels and no hypoglycaemic episodes. After 31 months, he started haemodialysis and the darbepoetin stopped: after three months, his HbA1c rose to 8.8%.

The authors conclude that in this case, treatment with erythropoietin resulted in a falsely reduced HbA1c level, and that the patient’s insulin dose would have been managed differently without this. The effect was seen with both epoetin and darbepoetin, and can thus be considered a class effect. Healthcare professionals treating diabetic patients should be aware of agents that can affect HbA1c levels, and that in patients receiving erythropoietins diabetes should be controlled on the basis of blood glucose levels and hypo- or hyper-glycaemic episodes rather than on HbA1c alone.

Pharmacotherapy 2009; 29: 468-72 (link to abstract); from Medscape, 8th July 2009 (free registration required)

Validation study for the QRISK cardiovascular risk assessment tool

An independent validation study of the QRISK score found that it was better at identifying cardiovascular risk in a UK population than the established scoring system in current use and based on the Framingham equations.

The authors note some of the problems with risk prediction models, commenting that many of those published are of poor methodological quality. An essential step often missed is independent external validation, and in this paper they describe an independent validation study on the QRISK cardiovascular risk scoring tool that has been developed using UK data. QRISK has been validated by its original authors, revised following criticism, and re-validated by its original authors.

The study population came from the THIN database, which comprises anonymised patient data from UK GP practices running one of the standard GP software packages in use. Exclusion criteria were pre-existing cardiovascular disease, invalid data, age under 35 years, or over 75 years, were missing Townsend scores, had a diagnosis of pre-existing diabetes, or were prescribed statins at baseline. The authors then calculated the QRISK score for each patient in the cohort, using age-sex reference values for missing risk-factor data.

Predictive performance of QRISK was assessed against observed cardiovascular risk by examining measures of calibration and discrimination. Calibration measures how closely predicted 10 year cardiovascular disease risk agrees with observed 10 year cardiovascular disease risk; discrimination is the ability of the risk prediction model to differentiate between patients who experience a cardiovascular disease event during the study and those who do not. QRISK performance was then compared with scores using the Anderson Framingham equation described in current UK guidelines.

There were data on 1,787,169 patients in the THIN database. After exclusions, 1,072,800 patients were eligible for analysis: median follow-up for this cohort was 4.9 years (range 0 to 12 years), and 36,483 patients were followed for at least 10 years. One of the three main risk factors (total : HDL serum cholesterol ratio, systolic blood pressure, and BMI) was missing for almost two-thirds of patients (63%) and all were missing for 9%: standard values were used for these patients. Overall 10-year observed risk of a cardiovascular event in men aged 35-74 years was 9.87% (95% CI, 9.71% to 10.03%) and in women was 6.55% (95% CI, 6.43% to 6.68%). Observed 10-year risk was significantly higher for patients with all risk factors recorded (19.9% for men, 12.8% for women) compared to those with at least one risk factor missing (5.0% and 3.4% respectively).

In comparison to the Anderson Framingham equation, QRISK gives a more accurate estimate of predicted 10-year cardiovascular risk for both men and women. QRISK tended to under-predict risk (by 13% for men, 10% for women), whereas Anderson Framingham tended to over-predict risk (32% for men and 10% for women).

The authors conclude that the QRISK cardiovascular risk equation offers an improvement over the Anderson Framingham equation in terms of identifying a high risk population for cardiovascular disease in the United Kingdom. While QRISK underestimates 10 year cardiovascular disease risk, the magnitude of under-prediction is smaller than the over-prediction with Anderson Framingham. QRISK also identified a group of high risk patients who will go on to experience more cardiovascular events over the next 10 years than a similar high risk group identified by Framingham. The authors note potential weaknesses of their study, and discuss other cardiovascular risk scoring systems; they also note areas for future research.

BMJ 2009; 339: b2584 (link to abstract, full text freely available at time of posting)

Famotidine reduces peptic ulcer risk in patients receiving low-dose aspirin

A controlled trial found that over the short-term, famotidine, a histamine-H2 receptor blocker, was effective in reducing new gastric and duodenal ulceration in patients taking low-dose aspirin.

The incidence of upper-gastrointestinal complications associated with low-dose aspirin has increased along with its wider use, however there is debate over the most effective prophylaxis because effective drugs and clinical trials are few. Proton-pump inhibitors (PPI) are widely used, but may be costly and recent studies suggest a possible adverse interaction between PPI and clopidogrel – often co-prescribed with aspirin. The authors of this study aimed to determine whether a histamine-H2 blocker, famotidine, was effective in reducing peptic ulceration and erosive oesophagitis in patients taking low-does aspirin.

Participants were adult patients of the cardiovascular, cerebrovascular, and diabetes clinics of one UK hospital, who were eligible for low-dose aspirin treatment that was likely to last at least 12 weeks (the intended study duration). Other anti-platelet treatment was not a criterion for exclusion.

Potential study patients had a baseline endoscopy and those with active serious upper gastro-intestinal disease excluded: those eligible were randomised to receive famotidine 20mg twice daily or matching placebo. They had a further endoscopy at 12 weeks after randomisation, and the primary outcome was development of new peptic ulcers or erosive oesophagitis at this point.

The study was stopped early before the planned full recruitment (700 patients) because interim analysis indicated overwhelming evidence of benefit. At this point, 14,515 had been assessed for eligibility and 404 randomised (famotidine n=204, placebo n=200). The main reason for exclusion was ineligibility (n=9,085). There were 90 withdrawals (famotidine n=37, placebo n=53), the most common reasons being withdrawal of consent (n=29) and loss to follow-up (n=17).

In the intention to treat analysis, peptic ulcers and erosive oesophagitis were less frequent in the famotidine group compared to the placebo group: any endpoint component developed in 5.4% vs. 32.5%, with an odds ratio (OR) of 0.12 (95% CI, 0.06 to 0.23; p<0.0001).

In terms of individual components, gastric ulcers were found in 3.4% vs. 15.0% (OR, 0.20; 95% CI, 0.09 to 0.47; p=0.0002), duodenal ulcers in 0.5% vs. 8.5% (OR 0.05%; 95% CI, 0.01 to 0.40; p=0.0045), and erosive oesophagitis in 4.4% vs. 19.0% (OR, 0.20; 95% CI, 0.09 to 0.42; p<0.0001). There were 24 reported adverse events (famotidine n=9, placebo n=15), none of which were considered to be related to the study treatment. There was no indication of any interaction with clopidogrel, nor were patients taking famotidine more likely to have a cardiac event.

The authors conclude that famotidine is effective in prevention of peptic ulcers and erosive oesophagitis in patients taking low-dose aspirin. It may therefore offer an alternative option to PPI in such patients.

An accompanying Comment discusses the study, including the observation that famotidine was more effective in patients with H. pylori infection.

Lancet, published early online 6 July 2009; doi:10.1016/S0140-6736(09)61246-0 (link to abstract); Lancet, published early online 6 July 2009; doi:10.1016/S0140-6736(09)61245-9 (Comment, link to full text; subscription required for access)

Early RAS-blockade in type 1 diabetes slows retinal damage, but not kidney damage

Early renin-angiotensin system (RAS) blockade in patients with type 1 diabetes slows the progression of retinopathy, but does not affect nephropathy according to a long-term controlled trial.

Diabetic nephropathy is responsible for a significant proportion of cases of end-stage renal disease, and there is evidence that once it is clinically detectable by the presence of albuminuria, drugs that block the RAS are effective in slowing its progression. Despite the lack of trial evidence for value in patients without overt nephropathy, it has therefore been accepted that RAS blockade at all stages will be beneficial in reducing diabetic nephropathy. This trial aimed to test that concept over the longer term using a hard clinical outcome measure: it was partly-industry sponsored, but designed, carried out, analysed, and written-up without industry input.

Participants were patients with type 1 diabetes, normotensive, and with normal albuminuria. Exclusion criteria included glomerular filtration rate (GFR) of less than 90ml/min (80ml/min for strict vegans) and urinary albumin excretion greater than 20microgm/min; a two-week placebo run-in period was used to exclude those poorly compliant with treatment (<85% of doses taken). Eligible patients were randomised to treatment with enalapril 10mg, losartan 50mg, or placebo daily for a study duration of five years. Drug doses were doubled during the study on the basis of trial data published after it started. Primary outcome measured actual kidney damage over the study period by determining change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. Secondary renal outcomes included incidence of microalbuminuria and GFR. Retinopathy progress was assessed in those for whom lack of baseline (within one year of randomisation) retinopathy could be confirmed: the measure for this outcome was a progression on a retinopathy severity scale of two steps or more.

A total of 1,065 patients was screened for eligibility - most (n=707) declined to participate and 73 were ineligible, leaving 285 randomised participants. Of these, 256 were available for the renal outcome (29 had no exit biopsy, mostly due to withdrawal of consent/loss to follow-up), and 223 for the retinal outcome (32 no baseline photograph; 30 no final photograph, mostly due to withdrawal/loss).

There was no significant difference between the groups in the primary outcome: change in mesangial fractional volume per glomerulus over the 5-year period was 0.016 units in the placebo group compared to 0.005 units in the enalapril group (P=0.38) and 0.026 units in the losartan group (P=0.26). Albumin excretion rate increased significantly from baseline only in the losartan group, and the 5-year cumulative incidence of microalbuminuria was 6% in the placebo group, 4% in the enalapril group, and 17% in the losartan group (P=0.01 by the log-rank test vs. placebo). GFR declined at a similar rate in all three groups (6.6 to 8.9 ml/min).

Both enalapril and losartan reduced the rate of retinopathy progression compared to placebo: rates over five years were 25%, 21%, and 38% respectively, for odds ratios vs. placebo of 0.35 (95% CI, 0.14 to 0.85) and 0.30 95(% CI, 0.12 to 0.73) respectively. These differences were independent of differences in blood pressure.

There were three serious adverse events related to biopsy, all of which resolved, and three deaths unrelated to the study drugs or procedures. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 on placebo.

The authors conclude that early RAS blockade in patients with type 1 diabetes did not affect the progression of diabetic nephropathy. It did, however, significantly slow diabetic retinopathy. They comment that the effect of losartan on albumin excretion was unexpected and is not currently confirmed by other studies, nevertheless, they suggest that urinary albumin should be carefully monitored when angiotensin-receptor blockers are prescribed to similar patients. They comment that this study is not comparable to earlier work, and suggest that the inclusion criteria may have selected for patients at lower intrinsic risk of nephropathy.

An accompanying editorial comments on the study and its implications.

NEJM 2009; 361: 40-51 (link to abstract); NEJM 2009; 361: 83-5 (Editorial, link to extract)

HTA report: Research assesses the use of glucose monitoring for type 1 and type 2 diabetes

The National Institute for Health Research Health Technology Assessment (NIHR HTA) programme has published two new studies focusing on self-monitoring of blood glucose (SMBG) levels in the management of both type 1 and type 2 diabetes.

The first study, (the Diabetes Glycaemic Education and Monitoring [DiGEM] tested whether self-monitoring of blood glucose alone, or with training in incorporating the findings into self-care, compared with standardised usual care improved glycaemic control in non-insulin treated patients with type 2 diabetes. The DiGEM trial has previously been published in the BMJ (see previous NeLM news report link below).  The trial involved 453 participants recruited from 48 general practises in Oxford and South Yorkshire and found that the routine use of SMBG, with or without additional training, was associated with higher costs and lower quality of life in patients with well controlled non-insulin treated type 2 diabetes.


The second study assessed the effectiveness and acceptability to patients of two minimally invasive continuous glucose monitoring devices (Glucowatch® and the MiniMed® Continuous Glucose Monitoring System) to help improve diabetes control. The study randomised 404 participants into four groups: group one wore the Glucowatch a minimum of four times per month and a maximum of four times per week for the first three months; group two had the MiniMed Continuous Glucose Monitoring System fitted three times over the first three months of the study; group three received standard treatment with three nurse feedback sessions during the first three months; and group four received standard treatment only.

The results found no significant difference between any of the groups and indicated no advantage in having the additional information provided by a continuous glucose monitoring device. The study found that continuous glucose monitors do not lead to improved clinical outcomes in individuals with poorly controlled, insulin-requiring diabetes.

Health Technology Assessment 2009; Vol. 13: No. 28 (MITRE study);
Health Technology Assessment 2009; Vol. 13: No. 15 (DiGEM study)
NIHR HTA media release

Meta-analysis: statins for primary prevention of cardiovascular disease in those with risk factors

A meta-analysis of controlled trial data found that in a range of people with cardiovascular risk factors but no overt cardiovascular disease, statin treatment reduced overall mortality and risk of major cardiovascular and cerebrovascular events. Absolute risk reductions, however, were fairly small.

Statin treatment for secondary prevention of cardiovascular disease is well accepted, however its use for primary prevention is still debated as this would have significant public health implications. In particular, the effects in women, older people, and those with diabetes are unclear. The authors of this meta-analysis aimed to use published clinical trial data to determine the effects of statins as primary prevention including assessment in the three subgroups mentioned. They carried out an extensive literature search to locate randomised controlled trials that compared statins with control in people with cardiovascular risk factors but no established cardiovascular disease. Eligibility criteria included follow-up for at least one year, mortality or cardiovascular disease as primary outcomes, at least 80% of participants without established cardiovascular disease or complete separate reporting of this subgroup. Primary end point of the meta-analysis was all cause mortality; secondary end points included composite major coronary events and composite major cerebrovascular events.

The initial search located 1,230 reports: 1,188 were excluded on the basis of title or abstract. Of the remaining 42 studies retrieved for full assessment, 32 were excluded to leave 10 eligible studies for analysis. These included 70,388 people, of whom 23,681 (34%) were women and 16,078 (23%) had diabetes. Specific data on the subgroups of interest were available for six of the studies, for one (ALLHAT) in the published paper and for five others from the original investigators. About 6% of the included participants were actually secondary prevention patients that could not be excluded from analysis, which was therefore also carried out excluding the three studies involved. Treatment allocation was evenly balanced (statin n=35,138, control n= 35,250); mean age was 63 years, and mean follow-up was 4.1 years.

Statin treatment was associated with a reduction in overall mortality: over the 4.1 years, this was 5.7% in the control group compared to 5.1% in the statin group for a relative risk reduction (RRR) of 12% (odds ratio 0.88; 95% CI, 0.81 to 0.96) and an absolute risk reduction (ARR) of 0.6% (NNT over 4.1 years 167).

There was also a reduction in major cardiovascular events: 5.4% in the control group vs. 4.1% in the statin group for a RRR of 30% (OR 0.70, 95% CI, 0.61 to 0.81) and an ARR of 1.3% (NNT over 4.1 years 77).
Similarly, cerebrovascular events were reduced: 2.3% vs. 1.9%, RRR 19% (OR 0.81; 95% CI, 0.71 to 0.93), ARR 0.4% (NNT over 4.1 years 250). There was no association between statin use and risk of cancer over the study period (OR, 0.97; 95% CI, 0.89 to 1.05).

Analysis by the defined subgroups showed no evidence of heterogeneity between the groups, and analysis without the studies that included secondary prevention patients did not change the results significantly.

The authors conclude that primary prevention with statins in patients with cardiovascular risk factors has similar relative effects on cardiovascular risk as secondary prevention, and that these are not significantly different in women, older people, and patients with diabetes. They comment that the absolute treatment benefit is low, however, and the current data do not allow identification of those patients who would most benefit. Correct identification of these people remains a challenge, however current risk scoring systems, as well as current data, indicate that older men (>65 years) with risk factors, or older women with diabetes and risk factors are the highest risk groups and would be most likely to benefit from long-term statin use.

BMJ 2009; 338: b2376 (link to abstract, fulltext freely available at time of posting)

Drug in development: taspoglutide in type 2 diabetes

Taspoglutide, an anti-diabetic drug in late stage development as a prolonged-release injection, was effective in maintaining blood glucose control over the short term in patients with type 2 diabetes when given once weekly or fortnightly.

A number of drugs that target glucagon-like peptide-1 (GLP-1) system have been recently launched or are in development. Two different drug types acting on this system are currently being used researched – the ‘gliptin’ class drugs inhibit the enzyme that degrades endogenous GLP-1 (dipeptidyl peptidase-4, DPP-4), and the GLP-1 analogues that act as agonists resistant to degradation to DPP-4. Taspoglutide is a GLP-4 analogue that has been shown to have anti-diabetic effects: this study tested a prolonged-release formulation suitable for once-weekly dosing. Participants were adults with type 2 diabetes not adequately controlled on metformin 1.5gm daily. They were randomised to receive taspoglutide 5mg, 10mg, or 20mg weekly, or 10mg or 20mg every two weeks, or matching placebo (in addition to their existing dose of metformin). Study duration was eight weeks with an additional four weeks follow-up, and the primary outcome was glycaemic control assessed as haemoglobin A1c (HbA1c) change from baseline one week after eight consecutive weeks of treatment.

A total of 306 patients was randomised to treatment from 572 screened. After nine weeks, HbA1c levels were significantly lower in all the taspoglutide groups compared to placebo. Baseline value was 7.9% (SD ± 0.7%): at assessment, values compared to baseline were -1.0 ± 0.1% (5 mg once weekly), –1.2 ± 0.1% (10 mg once weekly), –1.2 ± 0.1% (20 mg once weekly), –0.9 ± 0.1% (10 mg fortnightly), and –1.0 ± 0.1% (20 mg fortnightly) vs. –0.2 ± 0.1% with placebo. Weight loss, a secondary outcome, was significantly greater than placebo in the 10mg and 20mg weekly groups, and in the 20mg fortnightly group.
Based on their results, the authors conclude that in patients with type 2 diabetes inadequately controlled on metformin, adding taspoglutide to therapy significantly improves glycaemic control. It also improved weight loss in a dose-dependent fashion, and was generally well tolerated.

[Editor’s note: taspoglutide is currently in phase 3 clinical trials – if these are successful, it might be expected to be marketed in around 3 to 4 years time.]

Diabetes Care 2009; 32: 1237-43 (link to abstract)

Insulin glargine: three observational studies raise a possible link with cancer

Three observational studies conducted in Sweden, Germany and Scotland, all suggesting a possible link between the use of insulin glargine (Lantus) and an increased risk of cancer compared to human insulin, have been published in Diabetologia.  A fourth study from the UK found that insulin analogues were not associated with any increased risk of cancer above that of human insulin. 

All of these studies, alongside a statement from the European Association for the Study of Diabetes (EASD), an expert commentary (webcast) and information for patients, are available to access freely at the link below.

In brief, the studies were as follows:

German cohort study:

• The aim of this study was to investigate the risk of malignant neoplasms and mortality in patients treated with either human insulin or with one of three insulin analogues.  Data were provided from the largest statutory German health insurance fund between Jan 1998 and June 2005 on 127,031 adults receiving first-time insulin therapy for diabetes (mean follow-up of 1.63 years).  A positive association between cancer incidence and insulin dose was found for all insulin types; when adjusted for dose, a dose-dependant increase in cancer risk was found for treatment with insulin glargine compared with human insulin: HR 1.09 (95% CI 1.00 to 1.19) for daily dose of 10 IU; 1.19 (1.10 to 1.30) for 30 IU; and 1.31 (1.20 to 1.42) for 50 IU.  The risks associated with the other insulin analogues studied (lispro and aspart) were not statistically significantly higher than that associated with human insulin.  The press release notes that compared with people using similar doses of human insulin, out of every 100 people who used Lantus insulin over an average of about one-and-a-half years, one additional person was diagnosed with cancer.  

Swedish study:

• This was conducted upon request by the EASD.  A total of 114,841 individuals who were aged 35-84 years at the end of 2005 and who had at least one prescription for insulin dispensed between July and Dec 2005 were included in this analysis; the outcome of interest was the occurrence of a first diagnosis of a primary malignancy, occurring between Jan 2006 and Dec 2007.  Individuals using insulin glargine monotherapy were found to have an increased risk of breast cancer (RR of 1.99; 95% CI 1.31-3.03) compared to users of other types of insulin (grouped together); no statistically significant results were obtained for other individual cancer types studied or for the category ‘all malignancies’.  

Scottish study:

• Using a nationwide diabetes clinical database, a fixed cohort based on insulin exposure during a 4 month period in 2003 (n=36254, in whom 715 cases of cancer occurred) and a cohort of new insulin users across the period (n=12852 in whom 381 cancers occurred) were defined. Records from these cohorts were linked to cancer registry data.  Although the subset of patients using insulin glargine alone (n=447) had a higher incidence of all cancers than those using other insulins only (n=32295) (HR 1.55, 95% CI 1.01–2.37, p=0.045), other findings presented taking into account overall use (i.e. use in combination with other insulins) lead the authors to conclude that ‘insulin glargine use was not associated with an increased risk of all cancers or site-specific cancers in Scotland over a 4 year time frame’.  

UK study

• This retrospective cohort study involved a total of 62,809 patients treated in UK general practices participating in The Health Information Network (THIN).  They were divided into groups according to whether they received monotherapy with metformin, combination therapy with metformin and a sulfonylurea, or insulin.  The risk of progression to any solid tumour for those on basal human insulin alone was not statistically significantly different compared to those on insulin glargine alone (HR 1.24; 95% CI 0.90 1.70), although in general those on insulin of any kind were more likely to develop solid cancers than those on metformin (combination with metformin appeared to abolish most of this excess risk).       

The EASD have communicated their findings to the EMEA and are in contact with sanofi-aventis with regards to further analyses.  While further research is awaited to either confirm or refute these initial findings, the EASD as advising patients not to stop using Lantus insulin on the basis of the current research findings.  However the patient information produced by the EASD notes that people with diabetes do have the option of using long acting human insulin or a mixture of long- and short-acting human insulin twice a day as alternatives if they wish, and that they may wish to consider this option if they already have cancer or, for women, if there is a family history of breast cancer.  They stress however that patients should not make any changes to their insulin treatment without consulting their own doctor, and should on no account stop using their insulin. 

Sanofi-aventis has issued the following statement to NeLM:
“Sanofi-aventis is aware of the data published in Diabetologia from four retrospective studies conducted within patient registries investigating the possible link between the use of insulin and the risks of cancer. The authors of these studies recognise that the results of these data are inconclusive, and that no conclusion can be drawn regarding a possible causal relationship between insulin glargine (Lantus®) use and the occurrence of malignancy. Of note, the UK study found no link between insulin glargine and cancer.

Clinical studies, which represent the gold standard of evidence, do not indicate an association between insulin glargine and cancer. This includes data from clinical studies covering over 70 000 patients as well as data from post marketing surveillance which confirm the strong safety profile of Lantus. Over 24 million patients-years of exposure to Lantus equally confirm its benefits.

Patient safety is the primary concern of sanofi-aventis. The Group will continue to vigorously monitor the safety of Lantus® in close collaboration with regulatory agencies and scientific experts.
Sanofi-Aventis considers the benefit risk ratio of Lantus to be unchanged and we see no need to change therapeutic strategy with regards to its use. The EASD and the ADA advise that patients do not stop taking Lantus insulin on the basis of the findings reported in Diabetologia.” 

In a press release, the European Medicines Agency (EMEA) has stated that it is looking into four recently published registry studies investigating a possible link between insulin analogues, in particular insulin glargine, and the risk of cancer. The studies were published on the Diabetologia website on 26th June 2009 (see NeLM report). The Agency has concluded in the interim that “on the basis of the currently available data, a relationship between insulin glargine and cancer cannot be confirmed nor excluded. However, the concerns raised by the four studies require further in-depth evaluation.” The Agency’s Committee for Medicinal Products for Human Use (CHMP) will perform a detailed assessment of the studies and any other relevant information. Sanofi-Aventis, the Marketing Authorisation Holder for Lantus® and Optisulin®, has been asked to comment on this potential safety concern. The Agency has advised that patients on insulin glargine continue their treatment as normal, and reiterated that at this time, there is no recommendation that patients should change their current treatment. In case of any concerns, patients should consult their doctor. Further information will be provided once the CHMP has concluded its review.

The published papers, an EASD media report and advice for patients are available from Diabetalogia;
the EMEA media release is here

Comment: hazards of dual renin-angiotensin blockade in chronic kidney disease

Dual renin-angiotensin system (RAS) blockade using ACE-inhibitor plus angiotensin-receptor blocker (ARB) has uncertain benefits and significant potential harms in chronic kidney disease (CKD), according to the authors of a Comment article in Archives of Internal Medicine. In consequence, they recommend that the combination should not be used for the average CKD patient in the community.

The authors briefly note the epidemiology of CKD and discuss the physiological rational behind dual RAS blockade in these patients. They note that its use appears to be increasing in primary care, but comment that the mechanism behind its use is still speculative. They then discuss the evidence for use, particularly the landmark COOPERATE trial that randomised patients with non-diabetic kidney disease to losartan, trandolapril, or both. While 11% of the combination group reached the study endpoint (doubled serum creatinine or ESRD) after three years, 23% of those on the individual drugs alone did so. Although the results appear impressive, a number of questions have subsequently arisen over the study that cast doubt on their robustness.

A further problem with COOPERATE and other trials of combined RAS blockade is that the patients involved mostly had primary glomerulonephropathic diseases, however in most patients with kidney failure it is consequent on diabetes or hypertension.

A meta-analysis recently examined the question: this excluded COOPERATE due to concerns over statistical reporting, however it still found a potential benefit for dual blockade. The authors of the comment note that in two of the large studies included, patients in the combination groups had lower blood pressure than those in the monotherapy groups, raising doubts over whether the effect was purely due to better blood pressure control. They also comment on issues raised by the authors of the meta-analysis – there is no robust evidence on appropriate dose escalation and limited evidence on adverse effects with the combination.

More recently, a large (n>25,000) relevant study has reported. The ON-TARGET trial compared dula blockade with monotherapy in patients with vascular risk factors. Renal outcomes were secondary (to all-cause mortality), however both primary and secondary outcomes were found to occur with combination treatment compared to monotherapy. While there are still some concerns over the results of this study, the authors suggest that it should still raise caution over use of dual RAS blockade.

They conclude that while there is no doubt over the benefits of ACE-inhibitor or ARB monotherapy in the treatment of CKD, they question the notion that dual blockade is superior. Although there is some physiological rationale, the harms may outweigh the benefits and until more efficacy and safety data are available they suggest that it should not be used by the general practitioner.

Arch Intern Med 2009; 169: 1015-8 (link to extract)

Pre-launch trial data: liraglutide appears better than exenatide in type 2 diabetes

Patients with type-2 diabetes treated with liraglutide had better glycaemic control over 26 weeks than those treated with exenatide in an open-label trial published in the Lancet.

Liraglutide and exenatide are glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 is released by intestinal cells: it stimulates insulin secretion by the pancreas, slows intestinal motility, and promotes satiety. As these characteristics are potentially helpful in the treatment of type-2 diabetes, drugs that act via this pathway are of significant clinical interest. Exenatide is a GLP-1 agonist of animal origin that is currently in clinical use whereas liraglutide is an analogue of human GLP-1 in late stage development. This trial compared liraglutide with exenatide in patients with type-2 diabetes poorly controlled on maximal oral antidiabetic therapy.

Participants were adults with confirmed type-2 diabetes who were poorly controlled (glycated haemoglobin [HbA1c] level 7% to 11%) on maximal doses metformin, sulphonylurea, or both, for 3 months or more. Exclusion criteria included severe obesity (BMI 45 kg/m2 and above), previous long-term insulin treatment, and previous exposure to study drugs. They were randomised to liraglutide 1.8mg daily or exenatide 10microgm twice daily, both by s/c injection, reached after two weeks and four weeks respectively of dose escalation. Background oral antidiabetic therapy was continued, with up to 50% dose reduction of a sulphonylurea allowed if hypoglycaemia occurred. Study duration was 26 weeks from randomisation, and the primary outcome was change in HbA1c level from baseline to study end. Safety outcomes included hypoglycaemic episodes grouped as minor (could be self-treated) or major (third-party assistance needed to treat).

Of 663 patients screened, 464 were randomised, 233 to liraglutide and 231 to exenatide: 202 and 187 respectively completed the study, with nausea being the commonest reason for withdrawal. Three additional patients received study drugs without randomisation and were included in the safety but not efficacy analyses. Mean baseline HbA1c was 8.2% overall and over the course of the study it fell further in patients receiving liraglutide (by 1.2%) than in those receiving exenatide (by 0.79%) for an estimated treatment difference of −0.33% (95% CI −0.47 to −0.18; p<0.0001). p="0.0015)." p="0.0131).">

Lancet, published early online 8 June 2009; doi:10.1016/S0140-6736(09)60659-0 (link to abstract); Lancet, published early online 8 June 2009; doi:10.1016/S0140-6736(09)60942-9 (Comment; link to full text, access to subscribers only)

Antidiabetic therapy may affect risk of pancreatic cancer

A case-control study from a large US cancer centre suggests that treatment of diabetes may affect risk of pancreatic cancer, metformin reducing it and insulin and sulphonylureas increasing it.

Patients with type 2 diabetes seem to be at increased risk of several cancers, and there is evidence that it may have a role in pancreatic cancer. Other studies have suggested that metformin reduces and insulin and sulphonylureas increase risk of any cancer, but have not examined the risk of pancreatic cancer specifically. The authors of this paper used data from an existing case-control study that is ongoing at their institution (University of Texas M. D. Anderson Cancer Centre) to study the potential association. This study started in 2004 and aimed to define environmental and genetic factors that contribute to the development of pancreatic cancer.

Cases were consecutively recruited from patients with newly diagnosed and confirmed pancreatic ductal adenocarcinoma seen at the Centre. Controls were recruited from healthy individuals accompanying patients being treated at non-gastrointestinal centres within the institute: they were spouses and non-related relatives and friends of patients with cancers other than gastrointestinal or smoking-related. They were matched by age (+/- 5yr), sex, and race. Neither cases nor controls had a previous cancer history except for non-melanoma skin cancer. Diagnosis of diabetes, and frequencies of use of insulin, insulin secretagogues, metformin, and other antidiabetic medications among diabetic patients were compared between cases and controls. The risk of pancreatic cancer was then estimated using unconditional logistic regression analysis.

There were 973 cases (259 diabetic) and 863 controls (109 diabetic); the two groups were generally comparable except that cases included more black people and people aged over 70. After adjustment for potential confounding factors, diabetics who had taken metformin had a significantly lower risk of pancreatic cancer compared with those who had not (odds ratio[OR], 0.38; 95% CI, 0.22 to 0.69; P = 0.001). The association remained present when analysis was restricted to those with a duration of diabetes >2 years, and those who had never used insulin (OR 0.44; 95% CI, 0.22 to 0.87; and OR, 0.41; 95% CI, 0.19 to 0.87 respectively). Diabetics who had taken metformin also had a lower risk than non-diabetics (OR, 0.38; 95% CI, 0.21 to 0.67; P = .001), however the difference between non-diabetics and diabetics who had taken insulin secretagogues was not significant.

Diabetics who had used insulin or taken insulin secretagogues had a significantly higher risk of pancreatic cancer than diabetics who had not (OR, 4.99; 95% CI, 2.59 to 9.61; P<0.001; and OR, 2.52; 95% CI, 1.32 to 4.84; P=0.005, respectively).

The authors conclude that in this study population, patients with type 2 diabetes who had used metformin, especially for >5 years, had a significantly reduced risk of pancreatic cancer compared to never users. Additionally, although the numbers were smaller and therefore the confidence intervals wider, there was also an indication that use of insulin or insulin secretagogues was associated with an increased risk. They caution that although the overall study had a large sample size, statistical power was limited for diabetic subjects only: as a result, they consider that the observations need to be confirmed in larger studies.

An accompanying editorial discusses the study.

Gastroenterology 2009; 137: 482–8 (link to abstract, full text available free at time of posting); Gastroenterology 2009; 137: 412-5 (link to full text, available free at time of posting); from Medscape for 18th August 2009 (free registration required)

Glitazones appear to increase fracture risk in men and women, pioglitazone possibly more so

A prospective cohort study in patients with type 2 diabetes found that treatment with a thiazolidinedione (glitazone) increased fracture risk in both men and women; pioglitazone appeared to be associated with a greater risk than rosiglitazone.

Observational studies and analysis of clinical trial data indicate that treatment with a glitazone increase the risk of bone fractures in women, however the evidence is still uncertain especially in relation to effects on risk in men. The authors of this study used healthcare data on a large population to study the association between bone fractures and treatment with a glitazone or a sulphonylurea. Their study population was derived from all residents of British Columbia at any time between January 1998 and December 2007 who were registered for healthcare services in the Province. Using prescription data, they identified all users of either a glitazone or a sulphonylurea between January 1996 and December 2007: sulphonylureas were chosen as the comparator because they were, like glitazones, more likely to be used second line. They then obtained data on peripheral and all fractures, and estimated adjusted hazard ratios for fracture in the two user groups.

After general exclusions, the source population was about 4.2 million people; of these, 127,581 began treatment with one of the study drugs during the relevant period, and 84,339 were eligible after exclusion (mainly because of treatment with a drug from the other study group). Average age of the study cohort was 59 years, and 43% were women.

There were 2,214 fractures in the study patients, most (76%) peripheral. Average time to fracture was 1.71, 1.66, and 1.44 patient-years in the sulfonylurea, rosiglitazone, and pioglitazone cohorts respectively.

Compared to those treated with sulphonylureas, patients receiving a glitazone had an increased risk of peripheral fracture (adjusted hazard ratio [HR], 1.28; 95% CI, 1.10 to 1.48) across the group. When the glitazones were examined separately in comparison to sulphonylureas, the risk with rosiglitazone for women was not significant (HR, 1.17; 95% CI, 0.91 to 1.50) whereas that for pioglitazone was (HR, 1.77; 95% CI, 1.32 to 2.38).

Overall fracture risk for men was not significantly different in the glitazone group (HR, 1.20; 95% CI, 0.96 to 1.50), however analysis by individual drug found no significant risk with rosiglitazone (HR, 1.00; 95% CI, 0.75 to 1.34) but a significant increase for pioglitazone (HR, 1.61; 95% CI, 1.18 to 2.20).

The authors conclude that their analysis further supports the association of glitazones with increased risk of fractures in women, and indicates a possible association between pioglitazone use and increased risk in men. They caution, however, that the 95% CI in the subgroup analysis overlap and the association should thus be regarded as a basis for further research rather than a definitive result. Overall, they conclude that glitazone treatment increases fracture risk in both men and women compared to sulphonylureas, and that the effect may be stronger with pioglitazone than with rosiglitazone. Further research is needed to gain greater certainty.

Arch Intern Med 2009; 169: 1395-402 (link to abstract)

Another study shows benefits of healthy lifestyle

Results from part of a major European study of the effects of diet and lifestyle on chronic illness confirm the benefits of a range of healthy behaviours, showing significant reductions in risks of cancer and cardiovascular disease.

European Prospective Investigation into Cancer and Nutrition (EPIC) is a large (n>500,000, recruited between 1994 and 1998) ongoing study involving ten European countries; it is designed to investigate the relationships between diet, nutritional status, lifestyle and environmental factors and the incidence of cancer and other chronic diseases. This report is from EPIC-Potsdam, which covers the German participants in the study. The authors examined the effects of four potential factors: never smoking, having a body mass index (BMI) lower than 30, performing 3.5 h/wk or more of physical activity, and adhering to healthy dietary principles (high intake of fruits, vegetables, and whole-grain bread and low meat consumption). The 4 factors (healthy, 1 point; unhealthy, 0 points) were summed to form an index that ranged from 0 to 4. Outcomes included confirmed incident type 2 diabetes mellitus, myocardial infarction, stroke, and cancer; mean follow-up was 7.8 years.

There were 27,548 participants originally recruited, of whom 23,153 (8965 men and 14 188 women) were included in the analyses: main reason for exclusion was self-report of diabetes, cardiovascular disease or cancer at baseline (n=3,130). Mean age at baseline was 49.3 years; few had no healthy factors (score 0, 4%) and 9% had all four. Over the follow-up period reported, 2,006 developed an outcome event: despite the small number of individuals with a zero score, enough adverse events occurred in this group to allow reliable evaluation.

After adjustment for confounding factors, the hazard ratio for developing a chronic disease decreased progressively as the number of healthy factors increased. Participants with all 4 factors at baseline had a 78% (95% CI, 72% to 83%) lower risk of developing a chronic disease: compared to those with zero scores, reductions in risk for the specific diseases were diabetes, 93% (95% CI, 88% to 95%), myocardial infarction 81% (95% CI, 47% to 93%), stroke 50% (95% CI, –18% to 79%), and cancer 36% (95% CI, 5% to 57%). Those with intermediate scores had lower risks, with some combinations being more protective than others (e.g. never smoking plus BMI <30: HR 0.28; 95% CI, 0.23 to 0.34).

Overall, the authors conclude that their results confirm the benefits of a healthy lifestyle, and note that adoption of a few healthy behaviours can result in significant reductions in morbidity. They therefore reinforce current recommendations for lifestyles: adherence to all four could produce enormous reductions in the onset of chronic diseases such as diabetes, cardiovascular disease, and cancer.

An accompanying Comment discusses the study.

Arch Intern Med 2009; 169: 1355-62 (link to abstract); Arch Intern Med 2009; 169: 1362-3 (Comment, link to abstract)
Further information on EPIC is available from the study website

Meta-analysis: effects of intensive glucose control on cardiovascular outcomes in type 2 diabetes

Intensive blood glucose control in patients with type 2 diabetes decreases the risk of some cardiovascular disease (CVD), but does not decrease the risk of death in the medium term and increases the risk for severe hypoglycaemia, according to this systematic review and meta-analysis: recent studies with stringent control suggest an increased risk for cardiovascular death.

Type 2 diabetes is a major risk factor for CVD. Intensive control of blood glucose reduces microvascular complications in people with type 2 diabetes, but its effect on clinical CVD is uncertain. Earlier trials suggested benefits, however later studies found no effect or adverse effects. There were fewer than expected events in later studies, so the authors of this paper carried out a meta-analysis of the available trials to clarify the effects of intensive control on CVD as a whole and on a range of individual clinical outcomes.

They searched the literature using Medline, and experts contacts and reference lists only. Eligible studies were large (>500 participants), randomised controlled trials comparing intensive blood glucose control with conventional treatment in patients with type 2 diabetes, that had clinical CVD as a primary endpoint. From these, they extracted data on all-cause mortality, and CVD mortality, along with coronary heart disease (CHD), congestive heart failure (CHF), and stroke events. Additionally, they recorded single endpoints for fatal and non-fatal myocardial infarction (MI) and strokes, and peripheral artery disease. The main safety outcome was severe hypoglycaemic events. Individual patient data were not obtained.

The initial literature search identified 341 reports, of which 304 were excluded on the basis of title and abstract. From the remaining 37 reports, 5 papers were eligible for analysis (23 duplicate reports, 5 not type 2 diabetes, 2 n<500, and 2 did not include groups of interest). The five eligible studies included 27,802 participants (range 753 to 11,140) and had durations of between 3.4 and 10.7 years. The two earlier studies (UKPD 33 and 34) recruited newly diagnosed patients whereas participants in more recent studies (ADVANCE, ACCORD and VADT) had established diabetes (average duration from 7.9 to 11.5 years).

Analysis of the summary results found that intensive control was associated with a 10% reduction in risk of CVD compared to conventional control (relative risk [RR], 0.90; 95% CI, 0.83 to 0.98). The risk difference (RD, per 1000 patients over 5 years of treatment) for CVD was -15 (95% CI, –24 to –5), and intensively treated patients also had a reduced risk of CHD (RR, 0.89; 95% CI, 0.81 to 0.96; RD, –11; 95% CI, –17 to –5).

Intensive control was associated with a 16% overall reduction in risk of non-fatal MI, however the absolute reduction (i.e. RD) was 9 events per 1000 patients over 5 years of treatment. There were no significant effects on fatal MI, or on fatal or non-fatal stroke, or peripheral artery disease.

Intensive control was not associated with a reduced risk of cardiovascular death (RR, 0.97; 95% CI, 0.76 to 1.24; RD, –3; 95% CI, –14 to 7), nor was it associated with reduced all-cause mortality (RR, 0.98; 95% CI, 0.84 to 1.15; RD, –4; 95% CI, –17 to 10).

Overall, intensive treatment was associated with a doubled risk of severe hypoglycaemia (RR, 2.03; 95% CI, 1.46 to 2.81; RD, 39; 95% CI, 7 to 71), absolute increase of 39 events per 1000 patients over 5 years). Most of this increase came from the three later studies, in which the absolute increase was 54 events per 1000 patients over 5 years.

The authors conclude that in patients with type 2 diabetes, intensive blood glucose control reduces the risk for some CVD, such as non-fatal MI, but does not (over the period studied) reduce cardiovascular or all-cause death. It does, however, double the risk of severe hypoglycaemia. They note that the earlier trials suggested a reduction in cardiovascular death, however the later studies, which had more stringent blood glucose control, suggested an increase. There were significant differences between the trials in the treatments used in both active and control groups, and in the patients recruited. Limitations include use of summary rather than individual patient data, and the short duration of the more recent studies.

Ann Intern Med, published early online 21 July 2009; 151(6) (link to abstract)

Perspective: aggressive blood pressure lowering is of uncertain benefit

A short ‘News and Perspectives’ piece in JAMA discusses a recently released Cochrane Review that found no evidence to support aggressive blood pressure lowering.

The Review aimed to determine whether aggressive blood pressure targets (≤ 135/85 mmHg) improved clinical outcomes (mortality and serious morbidity) any more than standard targets (≤ 140-160/ 90-100 mmHg). Its authors found no trials comparing systolic targets and seven trials (n=22,089) comparing diastolic targets; primary outcomes for the review were total mortality; total serious adverse events; total cardiovascular events; myocardial infarction, stroke, congestive heart failure and end stage renal disease.

The analysis found that although BP was lower in groups treated to more aggressive targets, there was no significant benefit in any of the outcome measures studied. Because only one trial reported serious adverse effects and withdrawals, the net health effects of aggressive targets could not be assessed. Subgroup analysis in patients with diabetes and patients with chronic renal disease also found no significant benefit: as guidelines are recommending lower targets still for these patients, the authors are currently conducting systematic reviews in these specific patients.

The JAMA article notes that two major guidelines on hypertension treatment are currently under review (European and US), and quotes members of the respective review committees on the new evidence. It also notes that two clinical trials in progress may help to answer some of the questions raised by the review.

JAMA 2009; 302: 1047-8 (link to extract);
Cochrane Review: Cochrane Database Syst Rev. 2009;3:CD004349 (link to abstract)
11Sept2009