Sunday, September 27, 2009

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

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