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.
An additional 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.
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
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
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 Criteria.
Criterion 1 -- Strength of
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
All 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
The 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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