Three epidemiological studies (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.
study from the UK found no association with the insulin analogues and an 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 on the Diabetologia Web site at http://www.diabetologia-journal.org/cancer.html.
The results of the studies were:
German Cohort Study
Data for this study 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 with an average 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.
This study was conducted at request by the EASD and involved a total of 114,841 individuals who
had at least one prescription for insulin dispensed between July and December 2005. 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 as 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. No statistically significant findings were obtained for other cancer types studied or for
the category "all malignancies".
This study used a
nationwide diabetes clinical database. 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). These authors to concluded 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
based on other findings presented taking into account overall use, for example, use in combination
with other insulins.
This retrospective cohort study involved 62,809
subjects. Patients 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.
The following is our analysis of a possible cause and
effect relationship between the use of insulin glargine and cancer using the Bradford-Hill
Criterion 1 -- Strength of Association
Strength of Association is somewhat
subjective, however, there was an over 3-fold increased risk of breast cancer found in the Swedish
Study. In interpreting this safety data the upper limit of the 95% confidence interval is used to
estimate the worst case scenario.
Criterion 2 - Consistency of the Association
four studies demonstrated an increased risk of some types of cancer, however, not all of these
results were statistically significant.
Criterion 3 - Biologically Plausible Mechanism
There is a possible mechanism for the epidemiological findings, in that insulin is a growth
factor for a number of epithelial tumors in cell culture systems, and hyperinsulinemia also
produces a secondary increase in the availability of IGF-1 (Insulin Like Growth Factor - 1) which
is a known tumour growth factor that is mediated by a reduction in IGF binding protein-1 levels
(IGFBP-1). Changes in the insulin-IGF-1 axis have the potential to support self sufficiency in
growth signals and resistance to apoptosis, and may thus offer an adaptive advantage to cancer foci
struggling to survive in a hostile environment.
Criterion 4 - Dose Response Relationship
The German Cohort Study found a dose dependent (dose response) increase in cancer risk with the
use of insulin glargine.
Human Insulin and Long Acting Insulin Analogues
available science does not support important differences, if any, for the long acting insulin
analogs, including insulin glargine, over human insulin.
It may be argued
that the Bradford Hill Criteria have not been fully met for a clear presumption of causality
between insulin glargine and cancer. Nevertheless, there is sufficient concern about a link to
approach the prescribing and recommendation of this long acting insulin analogue cautiously.
There is no compelling scientific reason that patients concerned about insulin glargine and
cancer cannot successfully use human insulin.
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