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

Mediterranean-style diet better than low-fat diet in early type 2 diabetes

In patients with newly diagnosed type 2 diabetes, a low-carbohydrate Mediterranean-style diet improved glycaemic control and reduced the need for drug treatment compared to a high-carbohydrate, low fat diet.

US guidance on initial therapy of type-2 diabetes recommends starting therapy with pharmacotherapy in addition to dietary measures: either low fat, high carbohydrate, or low carbohydrate calorie-restricted diets are recommended, however there have been no direct comparisons of the two types of diet. This study investigated the medium-term efficacy and safety of a low-carbohydrate Mediterranean-style diet containing a high-proportion of unsaturated fat, compared with a standard low-fat, high carbohydrate diet.

Participants were patients newly diagnosed with type 2 diabetes at the diabetic clinic of one Italian university hospital. Eligibility criteria included BMI >25kg/m2, haemoglobin A1c (HbA1c) <11%, minimal physical activity level (<1 hour/week), and stable weight for at least six months. They were randomised to either a low-fat diet (based on American Heart Association guidelines) in which no more than 30% of energy was from fat, or a Mediterranean-style diet with no more than 50% energy from carbohydrates and at least 30% from fat (mainly as olive oil). Both were calorie-controlled (women 1,500 daily, men 1,800 daily). All patients received guidance on increasing their energy levels. Primary outcome was time to initiation of hypoglycaemic drug therapy according to a specified protocol, and planned follow-up was for four years: those who assessed study outcomes were blind to group allocation. Power calculations based on a pilot study indicated a study size of 87 patients per group.

Of 283 patients assessed for eligibility, 215 were randomised to the study (108 to the Mediterranean diet and 107 to the low fat diet); only 20 patients (10 in each group) were lost to follow-up. Average age at baseline was about 52, average BMI just under 30kg/m2, and average HbA1c 7.75% (Mediterranean diet) and 7.71% (low-fat diet). On intention to treat analysis at four years, those in the Mediterranean diet group were significantly less likely to require drug treatment: 44% vs. 70% (absolute difference, –26.0 percentage points; 95% CI, –31.1 to –20.1 percentage points; hazard ratio [HR], 0.63; 95% CI, 0.51 to 0.86).

More patients in the Mediterranean diet group lost weight (absolute difference -2kg; 95% CI -3.0 to -0.9kg): after adjustment for weight loss, the difference in likelihood of requiring drug treatment remained significant (HR 0.70; 95% CI, 0.59 to 0.90; P < 0.001). Reported energy intake and physical activity levels were similar in the two groups. Adverse events were similar in both groups, and one patient died in each group (of causes unrelated to the study).

The authors conclude that in patients with newly diagnosed type 2 diabetes, a Mediterranean-style diet delayed the need for hypoglycaemic drug therapy compared with a high-carbohydrate low fat diet. It was also associated with greater weight loss and some improvements in cardiac risk factors. They note that the study was inevitably only single blind, and that participants received intensive encouragement to continue with the recommended treatment. Nevertheless, they suggest that their study results reinforce the potential benefits of lifestyle intervention in type 2 diabetes.

Ann Intern Med 2009; 151: 306-14 (link to abstract)

Meta-analysis: Aspirin for cardiovascular primary prevention in patients with and without diabetes

According to a report published early online in Diabetes Care, the relative benefit of aspirin for primary prevention of cardiovascular events is similar in patients with and without diabetes.

This finding comes from a systematic review and meta-analysis, which set out to estimate the efficacy of aspirin for the primary prevention of cardiovascular events among patients with diabetes, and to estimate the extent to which the effect of aspirin differs in patients with and without diabetes.

Nine RCTs of aspirin for primary prevention of cardiovascular events with moderate to high methodological quality were identified. The ratios of relative risks of the benefit of aspirin among patients with diabetes compared to patients without diabetes for the following outcomes were reported:

• Mortality: 1.12 (95% CI, 0.92 to 1.35)
• Myocardial infarction: 1.19 (0.82 to 1.17)
• Ischaemic stroke: 0.70 (0.25 to 1.97)

The researchers conclude “while there are insufficient data among patients with diabetes to conclusively show a benefit of aspirin therapy for the primary prevention of cardiovascular events, our data suggest, but do not confirm, that the relative benefit of aspirin is similar in patients with and without diabetes. Additional evidence from RCTs and individual-patient-data meta-analyses may help to further clarify this issue.”

Diabetes Care, published early online 9 September 2009; doi: 10.2337/dc09-1297 (link to abstract)
11 September 2009

Top Searched Men's Health Topics

Statistics show that men are more likely to turn to the Internet for information on health topics rather than call a nurse or doctor for advice. Men generally don't like discussing their health issues due to embarrassment.

To help drive awareness to common problems, I decided to find out what the top searched men's health topics are on AOL Search. As you can see from the list below, prostate cancer, urinary tract infections and insomnia are among the top three. Men are also searching for everything from ulcerative colitis to prostatitis to hair loss. They also want to learn more about vasectomies and indigestion.

Is there a health topic that you go online to learn more about? If you think you are experiencing any of these health issues you should see your doctor, but you can also learn more by searching for men's health on AOL Search or going to AOL Health for information.

Top Searched Men's Health Topics on AOL Search:
1. Prostate Cancer
2. Urinary Tract Infection
3. Insomnia
4. Hair Loss
5. Vasectomy
6. Ulcerative Colitis
7. Diabetes
8. Impotence
9. Prostatitis
10. Indigestion

More Sponsored Links For: prostate cancer treatment, insomnia cures, hair loss treatment.

Source:
HOT SEARCHES

New US guidance: HbA1c targets for glycaemic control in type 2 diabetes.

The American College of Physicians has issued updated guidance on the use of haemoglobin-A1c (HbA1c) levels in monitoring glycaemic control of patients with type 2 diabetes.

It is accepted that good glycaemic control is necessary in diabetes and if achieved will significantly reduce the likelihood of adverse complications. HbA1c is widely used as a means of monitoring diabetic control, and this paper is intended to summarise the evidence base for monitoring and for suitable HbA1c levels in particular. As there are already many guidelines available on this topic, the College considered that it was appropriate to provide a rigorous review of suitable existing guidelines rather than produce a new guideline from first principles.
A comprehensive search strategy was used to locate guidelines that included discussion of diabetic control. Eligibility was restricted to English language because of the difficulties in translating non-English documents, and only most recent updates were used. Eligible guidelines were assessed using the Appraisal of Guidelines, Research and Evaluation in Europe (AGREE) collaboration method to get an assessment of guideline quality. Recommendations on glycaemic control were extracted from high quality guidelines and used to synthesise overall recommendations.

Nine sets of guidelines were accepted as being of sufficient quality and included specific recommendations on control. Based on these, the authors recommend the following (taken directly from the article summary with Anglicisation of spellings):

• Statement 1: To prevent microvascular complications of diabetes, the goal for glycaemic control should be as low as is feasible without undue risk for adverse events or an unacceptable burden on patients. Treatment goals should be based on a discussion of the benefits and harms of specific levels of glycaemic control with the patient. A haemoglobin A1c level less than 7% based on individualized assessment is a reasonable goal for many but not all patients.
• Statement 2: The goal for haemoglobin A1c level should be based on individualized assessment of risk for complications from diabetes, comorbidity, life expectancy, and patient preferences.
• Statement 3: We recommend further research to assess the optimal level of glycaemic control, particularly in the presence of comorbid conditions.

The authors comment that there are still challenges in understanding the benefits and harms of particular levels of control, especially in complex patients, and further research would be valuable. Attention should also be paid to control of blood pressure and lipid levels.

Ann Intern Med 2007; 147: 417-22

Adding insulin to oral agents in poorly controlled type 2 diabetes - trial evidence to guide practice

Interim results from a controlled trial in patients with type 2 diabetes and poor glycaemic control showed that adding one of three simple insulin regimens to maximally tolerated oral antidiabetic drugs benefited some patients; regimens giving greater control also caused more adverse events.

The 4-T (Treating to Target in Type 2 Diabetes) study aims to clarify the use of insulin in patients with type 2 diabetes poorly controlled despite maximum tolerated doses of oral antidiabetic drugs. While the addition of insulin is widely practised in such patients, there is little evidence from large clinical trials to guide such use: the first year of the three-year 4-T study, reported here, compared three simple insulin regimes - more complex regimens are being compared in the remaining two years. Patients were adults with type 2 diabetes not previously treated with insulin, and had poor glycaemic control (glycated haemoglobin, HbA1c, 7-10%) with maximally tolerated doses of sulphonylurea plus metformin, or individual drugs if the other was not tolerated. They were randomised to open-label treatment with one of three regimens: basal insulin (insulin detemir at bedtime), prandial insulin (insulin aspart immediately before meals), or biphasic insulin (NovoMix 30 twice daily). Primary outcome was glycaemic control as HbA1c at one year; secondary outcomes included weight gain and hypoglycaemia as well as other measures of control.

A total of 936 patients were screened for inclusion, and 708 were randomised; 235 to biphasic, 239 to prandial, and 234 to basal insulin. The most common reason for exclusion was a baseline HbA1c outside the range 7-10%. Withdrawals were not statistically different across the three groups (5.5%, 7.1%, and 4.3% respectively). Maximum fall in HbA1c levels was achieved by week 24 in all groups, however at week 52 the biphasic and prandial groups had significantly lower mean levels than the basal group (7.3% and 7.2% vs. 7.6% respectively, p<0.001 for both comparisons): most differences were in patients with poorest baseline control - there was less difference between the three regimens in patients with a baseline HbA1c of <8.5%. Patients in the prandial group were most likely to reach HbA1c of 6.5%, however even in this group only a quarter did so (prandial 25%, biphasic 17.0%, basal 8.1%). Patients in the prandial group were most likely to have hypoglycaemic events and also gained the most weight (basal least for both).

The authors conclude that adding a single insulin to maximal oral therapy in these patients achieved target glycaemic control, measured as HbA1c level, in only a minority of patients. Biphasic and prandial insulin gave better control but at the cost of more hypoglycaemic events and more weight gain. They conclude that the results support basal insulin therapy for a first line option, as it has lowest levels of adverse effects, and is simple and convenient for patients; however many will need rapid intensification of therapy. The final phase of the study is examining more complex regimens in this patient group.

According to an accompanying editorial, “the 4-T study provides a clear indication that prandial and biphasic insulin formulations are suboptimal choices for insulin initiation and probably expose patients to an unnecessarily high risk of hypoglycemia without clinically important benefit.” Results are awaited from the second phase of the study to define the best next step for patients who do not reach their glucose target whilst on basal insulin alone, since they are most likely to benefit from additional prandial insulin.

For now, the author suggests that the recommendations for starting insulin therapy need not change as a result of this study: for patients with a HbA1c > 7% on maximal doses of two oral agents, the best approach is to continue metformin and add a basal insulin; sulfonylureas are not synergistic with insulin and should generally be stopped. He adds that choice of strategies for insulin initiation is probably less important than taking steps to start insulin in patients who need it. Furthermore, he stresses that though it is important to focus on glucose levels, clinicians should be aggressive with BP management since hypertension contributes at least as much as glucose to overall cardiovascular risk. In addition, aspirin, lipid-lowering therapies, smoking cessation, exercise and weight-loss programmes should be initiated when appropriate. He concludes that “achieving these integrated goals saves lives, whatever insulin formulation is chosen.”

New Engl J Med, published early online 21 September 2007; doi: 10.1056/NEJMoa075392 (link to abstract); New Engl J Med, published early online 21 September 2007; doi: 10.1056/NEJMe078196

Ten minute consultation: Ramadan, fasting and Diabetes.

This ‘ten minute consultation,’ part of a series of occasional articles in the BMJ on common problems in primary care, looks at issues to cover and subsequent management, when a patient with type 2 diabetes mellitus turns up for advice on how he might fast safely during Ramadan. The main advisory points are as follows:

• If blood glucose is well controlled by diet alone, advise him that fasting is safe
• Encourage him to eat foods high in dietary fibre and have a low glycaemic index at the pre-dawn (Suhur) and sunset (Iftar) meals to promote glycaemic control and discourage foods with a high glycaemic index until about half an hour after taking drugs to minimise sharp rises in blood sugar at sunset.
• Self monitoring of blood glucose is essential for safe fasting in patients taking antidiabetic drugs, particularly before and after the pre-dawn and sunset meals.
• To minimise the risk of hypoglycaemia in patients on oral therapy, those on a long acting sulphonylurea should be switched to a short acting preparation or metformin, or both. If a single daily dose is used, take this with the sunset meal, if two or three doses are taken daily, take half the normal evening dose before dawn and the normal morning (and any midday) dose after sunset.
• To minimise the risk of hypoglycaemia in patients on insulin, those on a once daily regimen should be switched to a twice daily regimen whilst those on a twice daily regimen should use half of the evening dose before dawn and the normal morning dose after sunset. If basal bolus insulin is used, reduce the long acting component to two thirds of normal, split into two equal doses taken during the sunset and pre-dawn meals; take the rapid acting component as before, but omit the middle dose.
• Emphasise the need to carry glucose tablets at all times to treat hypoglycaemia and explain the importance and legitimacy of breaking the fast in emergency situations.
• Arrange for a review one week into Ramadan or earlier if concerns arise.

BMJ 2007; 335: 613-4

Statins safe and effective in patients with very low LDL cholesterol.

Statins used in patients with extremely low LDL cholesterol levels are safe and may lead to improved survival, according to the results of a new study. This survival benefit, was observed across multiple subgroups, including patients with LDL cholesterol levels <40mg/dl>

The study investigated the safety and clinical outcomes associated with statin therapy in patients with very low LDL levels, such as <60 style=""> More than 6000 consecutive patients were identified from a tertiary-care medical centre or affiliated community clinic. Statin therapy was defined as a prescription during the 150 days after the low LDL value (<60mg/dl) style="">

During a median follow-up of two years, there were 510 deaths. After controlling for the propensity to receive a statin, statin therapy was associated with a significant 35% reduction in the risk of death. The lower mortality was observed across various subgroups, including a 42% reduction in total mortality among those treated with a statin at baseline, a 49% reduction among those with LDL cholesterol levels <40 style="">

In terms of potential side effects, statin therapy was not associated with an increase in any adverse events. No cases of rhabdomyolysis were reported, nor was there a risk of developing liver enzyme elevations. There was also no increase in the risk of malignancy or renal insufficiency.

Circulation 30 July 2007; 116:613-618
Heartwire News Service per Medscape News 3 August 2007(registration required)

Cochrane review: anticoagulants better than antiplatelets for stroke prevention in AF patients.

According to a Cochrane review,adjusted-dose warfarin and related oral anticoagulants are superior to antiplatelets in the prevention of stroke and major vascular events in patients with non-valvular atrial fibrillation (AF).

The authors of the review note that non-valvular AF ‘carries an increased risk of stroke mediated by embolism of stasis-precipitated thrombi originating in the left atrial appendage’. Although both oral anticoagulants and antiplatelets have proven effective for stroke prevention in most patients at high risk for vascular events, they sought to separately characterise their relative effects in primary stroke prevention, i.e. in those patients without a history of stroke or transient ischaemic attack (TIA).

The authors carried out a comprehensive search of the literature and located eight relevant RCTs (n=9,598) comparing long-term (more than four weeks) adjusted-dose oral anticoagulant treatment to antiplatelet therapy in patients with chronic non-valvular AF and no history of stroke or TIA. The trials included were: ACTIVE W; AFASAK 1; AFASAK II; ATHENS; NASPEAF; PATAF; SPAF IIa and SPAF IIb. All trials used warfarin as the oral anticoagulant except NASPEAF (acenocumarol) and PATAF (several oral anticoagulants including warfarin). Aspirin was the antiplatelet agent tested (75-325mg/day), except ACTIVE W (combination of aspirin plus clopidogrel) and NASPEAF (triflusal).

Oral anticoagulants were associated with lower risk of all stroke (odds ratio (OR) 0.68, 95% CI 0.54 to 0.85; p="0.0007"), ischaemic stroke (OR 0.53, 95% CI 0.41 to 0.68; p ≤ 0.00001) and systemic emboli (OR 0.48, 95% CI 0.25 to 0.90).Assuming an estimated annualised rate of stroke of 4% per year on antiplatelet therapy for primary prevention, about 13 strokes (ischaemic and haemorrhagic) and 19 ischaemic strokes (fatal and non-fatal) per year would be prevented for every 1000 AF patients given oral anticoagulants instead of antiplatelet therapy.

No statistically significant differences were observed between the two treatments in terms of disabling or fatal strokes (OR 0.71, 95% CI 0.59 to 1.04), myocardial infarction (OR 0.69, 95% CI 0.47 to 1.01), vascular death (OR 0.93, 95% CI 0.75 to 1.15) or all cause mortality (OR 0.99, 95% CI 0.83 to 1.18). Intracranial haemorrhages (OR 1.98, 95% CI 1.20 to 3.28; p="0.008") were increased by oral anticoagulant therapy.

Cochrane Database of Systematic Reviews 2007, issue 3 Link to abstract
Ann Int Med (NeLM)

Reassessment of the cardiovascular risks of Rosiglitazone.

A recent meta-analysis of 42 clinical trials concluded that rosiglitazone was associated with an approximately 43% increased risk for myocardial infarction and an approximately 64% increased risk for cardiovascular death. The sensitivity of these conclusions to several methodological choices was not assessed. The meta-analysis was not based on a comprehensive search for all studies that might yield evidence about rosiglitazone’s cardiovascular effects. Studies were combined on the basis of a lack of statistical heterogeneity, despite substantial variability in study design and outcome assessment. The meta-analytic approach that was used required the exclusion of studies with zero events in the treatment and control groups. Alternative meta-analytic approaches that use continuity corrections show lower odds ratios that are not statistically significant. The authors of this commentary conclude that the risk for myocardial infarction and death from cardiovascular disease for diabetic patients taking rosiglitazone is uncertain - neither increased nor decreased risk is established.

The authors state that their analysis is restricted by the same limitations as those in the original analysis: short follow-up; low event rates; absence of patient-level data about time to event; variable and probably incomplete outcome ascertainment; and inability to reliably assess total mortality rate or composite outcomes, such as death or myocardial infarction. Neither analysis is a comprehensive systematic summary of all available evidence about the potential cardiovascular risks of rosiglitazone. Only prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone will resolve the controversy about its safety. They conclude that the available evidence does not justify the recommendations for action of the original study.

Ann Intern Med 7 Aug 2007 – Early online(to be published 16 October 2007)

Cochrane review: corticosteroids to reduce relapse following asthma exacerbation.

The Cochrane Collaboration has produced a systematic review on the benefit of corticosteroids for the treatment of asthmatic patients discharged from an acute care setting (i.e. usually the emergency department) after assessment and treatment of an acute asthmatic exacerbation. Researchers evaluated six randomized controlled trials involving 374 people comparing two types of corticosteroids (oral or intramuscular) with placebo for outpatient treatment of asthmatic exacerbations in adults or children. One study used IM corticosteroids, five used oral corticosteroids.

The following results were reported:

· Significantly fewer patients in the corticosteroid group relapsed to receive additional care in the first week (Relative risk (RR) 0.38; 95% confidence interval (CI) 0.2 to 0.74). This favourable effect was maintained over the first 21 days (RR 0.47; 95% CI 0.25 to 0.89) and there were fewer subsequent hospitalizations (RR 0.35; 95% CI 0.13 to 0.95).

· Patients receiving corticosteroids had less need for beta2-agonists (mean difference (MD) -3.3 activations/day; 95% CI -5.6 to -1.0).

· Changes in pulmonary function tests (SMD 0.045; 95% CI -0.47 to 0.56) and side effects (SMD 0.03; 95% CI -0.38 to 0.44) in the first 7 to 10 days, while rarely reported, showed no significant differences between the treatment groups. Statistically significant heterogeneity was identified for the side effect results; all other outcomes were homogeneous.

· From these results, as few as ten patients need to be treated to prevent relapse to additional care after an exacerbation of asthma.

The authors conclude that “a short course of corticosteroids following assessment for an asthma exacerbation significantly reduces the number of relapses to additional care, hospitalizations and use of short-acting beta₂-agonist without an apparent increase in side effects. Intramuscular and oral corticosteroids are both effective”.

Cochrane Database of Systematic Reviews 2007 Issue 3

Periconceptional multivitamin use and risk of preterm or small-for-gestational-age births

This study examined the relationship between periconceptional multivitamin use and the risk of small-for-gestational-age (SGA: <>th to <> preterm ( <>

Data were collected from Women in the Pregnancy Exposures and Preeclampsia Prevention Study (1997–2001) who had reported their regular multivitamin use in the past 6 months (n = 1823) at enrolment. The following findings were reported:

• 47% of women regularly used periconceptional multivitamins
• Periconceptional multivitamin use was associated with a reduced risk of preterm births (<> (OR) = 0.29, 95% CI: 0.13 to 0.64) and spontaneous preterm births (<>

• There was a trend towards a lower risk of SGA (<> 0.64: 0.40 to 1.03).
• There was no effect of multivitamin use on risk of preterm births (34 to <> weeks) or SGA (5^th to <>
• Sensitivity analysis for unmeasured confounding by folate intake supported these findings.

The authors of the study suggest from these preliminary findings that “periconceptional vitamin use is associated with lower rates of severe preterm births and extreme SGA.” However they stress that these data should be considered cautiously until they have been replicated as there were several important limitations of their data such as the self-reported nature of vitamin use, and unmeasured factors relating to lifestyle, nutrition, access to health care, and maternal genetic variation.

Am J Epidemiol 2007;166:296-303 - Abstract

Review – new antithrombotics in cardiology.

In this article, the authors review new antithrombotic agents, with emphasis on those that have been or are likely to be introduced into clinical practice in cardiology. They also briefly review the limitations and advantages of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) as ‘it is these limitations that provide opportunities for new parenteral anticoagulants’. The following agents are discussed:

• Thrombin inhibitors – hirudin, bivalirudin, argatroban, ximelagatran, dabigatran, odiparcil
• Factor Xa inhibitors – fondaparinux, idraparinux, rivaroxaban, razaxaban, otamixaban
• Factor IXa inhibitors
• Role of new anticoagulants by indication – acute coronary syndrome, prevention of arterial thromboembolism in AF, active ischaemic stroke

The authors note that “improvements of new over established anticoagulants are likely to relate to properties other than their inhibition of a specific activated clotting factor. These properties include freedom from non-haemorrhagic side effects, more favourable pharmacokinetics, a predictable dose response that obviates the need for coagulation monitoring, and more appropriate dose selection for the indication of interest”.

Circulation 2007; 116: 552-60 (link to full text, free at time of posting)

Effect of antibiotic prescribing on antibiotic resistance in children in primary care

A prospective cohort study has assessed the effect of antibiotic prescribing for acute respiratory infection on the prevalence of antibiotic resistance in individual children in primary care. The study involved general practices in Oxfordshire and 119 children, of whom 71 received a beta-lactam antibiotic, (amoxicillin 70, cephradine 1) at presentation and 48 received no antibiotic. The main outcome measures were antibiotic resistance as assessed by the geometric mean minimum inhibitory concentration (MIC) for ampicillin and presence of the ICEHin1056 resistance element in up to four isolates of Haemophilus species recovered from throat swabs at recruitment, 2 and 12 weeks.

The following findings were reported:

• In children who did not receive an antibiotic, the MIC for ampicillin was the same (2.7 microg/ml) at both follow-up points, with no significant change from the initial level of 4.1 microg/ml.
• In children who received an antibiotic, the MIC increased about fourfold to 9.2 microg/ml at the two week follow-up (ratio to no antibiotic group 3.5, p = 0.005); at the 12 week follow-up, it fell back to 5.7 microg/ml (ratio to no antibiotic group 2.1, p = 0.06).
• The ratio of MIC at 12 weeks vs initial visit was 2.33 in children on an antibiotic and 0.71 in those not on them (p = 0.05).
• Prescribing amoxicillin doubled the risk of isolation of the ICEHin1056 resistance element in Haemophilus isolates (67% vs 36%; relative risk 1.9, 95% CI, 1.2 to 2.9) two weeks later; this increase was transient and ampicillin resistance fell close to baseline by week 12. This element was recovered from most children from whom Haemophilus species were isolated (83%, 95% CI, 76% to 89%) at some point in the study, irrespective of whether they received an antibiotic.

Based on these findings, the authors suggest that in the few cases where it is appropriate to repeat the prescription of an antibiotic in under 3 months, it may be sensible to choose one that has activity against beta lactamase producing strains, rather than give a further course of amoxicillin. They add that from a population perspective, the issue of concern is the high (35%) equilibrium level of recovery of resistant Haemophilus species to which the children receiving antibiotics returned after 12 weeks and the endemic carriage of the ICEHin1056 resistance element by nasopharyngeal Haemophilus species. Therefore any reduction in community resistance is likely to need a substantial and sustained reduction in community prescribing; one option that deserves further investigation is to reduce the duration of each course of antibiotics prescribed in the community, another more radical option is to stop prescribing antibiotics to any child with respiratory infection in the community except in well defined and exceptional circumstances, though it does run the risk of some children with bacterial disease being treated later in the course of their illness.

The study concluded that prescribing amoxicillin to a child in general practice doubles the risk of recovering a beta lactamase encoding resistance element from that child's throat two weeks later; this risk falls back to the level seen before treatment within 12 weeks. The researchers note that though the short term effect of amoxicillin is transitory in the individual child, it is sufficient to sustain a high level of antibiotic resistance in the population. They add that “the ICEHin1056 resistance element is endemic in UK children, but reversal of this will require further substantial and sustained changes in antibiotic prescribing in the community.”

BMJ, published early online 26 July 2007; doi:10.1136/bmj.39274.647465.BE (link to abstract)