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Prescribing Advice for GPs

An NHS Prescribing Advisers' Blog

MeReC Bulletin - Implementing key therapeutic topics: 3

The National Prescribing Centre has published a MeReC Bulletin (PDF), the third in a series of three, that focuses on the therapeutic areas of the QIPP agenda.

This bulletin focusses on type 2 diabetes and covers the following topics:

  • Hypoglycaemic agents in patients with type 2 diabetes
  • Long-acting insulin analogues in patients with type 2 diabetes
  • Self-monitoring of blood glucose in patients with type 2 diabetes

For each of these therapeutic topic areas within type 2 diabetes the evidence base is summarised and current prescribing data are reviewed.

Action: Clinicians who prescribe for patients with type 2 diabetes and who are striving to deliver value for money while maintaining or improving the quality of care will find this information is useful and informative.

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New contraindications for strontium ranelate

The European Medicines Agency (EMA) has completed a review of strontium ranelate (Protelos®). A positive benefit-risk balance has been confirmed but new contraindications and revised warnings have been recommended.

The review was initiated by a French study that identified almost 200 adverse drug reports. Approximately half of these were reports of venous thromboembolism (VTE) and about a quarter were skin reactions. These are both known reactions; VTE was identified during clinical trials and skin reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) identified during post-marketing surveillance.

The review identified that VTE risk is highest in individuals with a personal history of VTE or who are temporarily or permanently immobilised. Skin reactions are best managed by early diagnosis and immediate discontinuation of any suspect drug.

The EMA has made the following recommendations:

  • Strontium ranelate should not be prescribed to patients with current VTE or a history of VTE, as well as patients who are temporarily or permanently immobilised.
  • Current treatment with strontium ranelate in such patients should be reviewed at the next routine appointment.
  • Patients should be warned about the potential for serious skin reactions. SJS and TEN usually occur in the first weeks of treatment while DRESS more usually occurs between 3 and 6 weeks.
  • Patients should be advised to stop treatment immediately if severe allergic reactions arise (including skin reactions) and treatment should never be recommenced

Action: Clinicians should be aware of this review and implement any changes to practice made necessary by these new recommendations.

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Aspirin for cancer?

The Lancet has published the results of a meta-analysis that aimed to assess the effects of daily aspirin on cancer incidence, mortality, and non-vascular death. The results of this study have been widely reported in the media (BBC).

This analysis included data from 51 studies involving 77,549 patients. 40,269 were assigned to treatment with aspirin and 37,280 to a control. Trials were included if treatment allocation was random and included an intervention of daily aspirin with a follow up of at least 90 days. The trials were designed to assess cardiovascular outcomes included both primary and secondary prevention of events. The dose of aspirin use varied.

The data were analysed for vascular and non-vascular deaths and cancer death data was accessed at individual patient level where this was possible, otherwise it was extracted from the original trial report or subsequent publications.

Aspirin was reported to reduced cancer deaths (OR 0·85, 95% CI 0·76–0·96, p=0·008) in a dataset involving 34 trials. This became more apparent after 5 years of follow up and onwards (OR 0·63, 95% CI 0·49–0·82, p=0·0005).

In an analysis of primary prevention trials using low dose aspirin cancer risk was reduced from 3 years onwards (OR 0·76, 95% CI 0·66–0·88, p=0·0003) and this effect was present in men and women. It was noted that benefits in reduction of cardiovascular events were offset by an increased risk of major bleeds initially but that over time both of these effects diminished while the cancer benefit appeared to remain.

An analysis to examine consistency across gender, age and smoking status found that the absolute risk reduction is approximately 3 cases per 1000 patient-years across all groups but only after a minimum of three years of treatment.

This analysis does have some limitations. The Women's Health Study was excluded from the analysis as the aspirin was dosed on alternate days; it has not shown a reduction in cancer incidence. The trials were not designed to examine cancer outcomes and in some cases the data for non-fatal cancers was patient reported although this was usually supported by a review of medical records.

The authors conclude that, "prevention of cancer could become the main justification for aspirin" but also note that "more research is required to identify which individuals are likely to benefit most".

An accompanying editorial notes that data are awaited for additional trials. Longer term follow up from the Women's Health Study and Physicians’ Health Study is also awaited, especially as these two studies have not shown a cancer benefit after 10 to 12 years of alternate day dosing of aspirin.

Action: Clinicians should be aware of this recent study and its broad media coverage. The absolute benefit is small; it may be wise to await national guidance before recommending aspirin for use in this way.

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Meta Analysis of DPP-4 Inhibitors

The British Medical Journal has published the results of a meta analysis of trials of dipeptidyl peptidase-4 (DPP-4) inhibitors for treatment of type 2 diabetes mellitus.

This review included data from 19 studies involving 7,136 patients randomised to treatment with a DPP-4 inhibitor and 6,745 patients randomised to another active treatment. The analysis reviewed several outcome measures including reduction in HbA1c, proportion of participants reaching a target HbA1c of 7%, change in body weight, adverse events and mortality.

In 8 studies where DPP-4 inhibitors were compared to metformin, DPP-4 inhibitors were inferior in terms of reduction in HbA1c, proportion reaching target and weight loss.

When compared to second line agents including sulphonylureas, glitazones and glucagon-like peptide-1 (GLP-1) agonists the results were more variable.

DPP-4 inhibitors had similar effects on HbA1c and a similar proportion of patients reached the HbA1c target when compared to sulphonylureas and pioglitazone. DPP-4 inhibitors were superior to these two drug classes in terms of weight. When compared to GLP-1 agonists, DPP-4 inhibitors were inferior in all three of these measures.

The authors conclude that, "DPP-4 inhibitors can lower HbA1c, in a similar way to sulphonylureas or pioglitazone, with neutral effect on body weight" but that higher cost and "uncertainty about their long term safety, should also be considered".

There are limitations in this study. Data were not analysed individually for each DPP-4 inhibitor and the comparative data against GLP-1 agonists and pioglitazone are not very robust due to the limited research data currently available. There was also no correction for baseline characteristics and none of the studies included any cardiovascular end points so no hard outcome endpoints could be analysed.

NICE currently recommend a sulphonylurea as second line with alternatives considered where there is a significant risk of hypoglycaemia and its consequences or there is intolerance or contraindications to such medication.

Action: Clinicians who see and treat patients with diabetes will find this analysis useful. This analysis confirms that DPP-4 inhibitors offer similar benefits in terms of HbA1c to other oral therapies with some advantages in weight but at a higher acquisition cost.

Thanks to Kevin Ashworth for spotting this article

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Saxagliptin safety information

The manufacturer has written to healthcare professionals regarding new safety information for saxagliptin (Onglyza®).

The letter advises that saxagliptin has been associated with serious hypersensitivity reactions and acute pancreatitis. The following recommendations have now been made:

  • Saxagliptin is contraindicated in patients with a history of serious hypersensitivity reactions including anaphylactic reactions, anaphylactic shock and angioedema to saxagliptin or any other dipeptidyl peptidase 4 (DPP-4) inhibitor
  • Patients should be advised of the symptoms of acute pancreatitis and rapidly report such symptoms
  • Where hypersensitivity reactions or pancreatitis are suspected, saxagliptin should be discontinued

Action: Clinicians should be aware of this new safety information and implement any necessary changes to practice.

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