Insulin Glargine and Cancer—An Unsubstantiated Allegation
Satish K. Garg, M.D.,1Irl B. Hirsch, M.D.,2and Jay S. Skyler, M.D., M.A.C.P.3
To kill an error is as good a service, and sometimes even better than the establishing of a new truth or fact.
For type 2 diabetes, this has been particularly recognized with
It has long been known that insulin can stimulate breast
cancer growth in tissue culture.16Many papers have exam-
ined the relationship between insulin and insulin-like growth
factor (IGF) signaling in neoplasia and the possible effects of
insulin in stimulating neoplasia via binding to the IGF-1 re-
ceptor.17It is upon that background that recent events have
erupted, bringing confusion to the situation.
On Friday, June 26, 2009, the EASD (European Associa-
tion for the Study of Diabetes) released on its website
(http:= =webcast.easd.org=press=glargine=glargine.html) and
that of its journal Diabetologia (http:= =www.diabetologia-
journal.org=cancer.html) a series of papers, an editorial, a
press release, a video statement, and patient information, all
concerning a ‘‘possible link between insulin glargine and
cancer,’’ as the press release was titled, or ‘‘Lantus insulin: a
possible link with cancer which requires further investiga-
tion,’’ as both websites heralded. This triggered a global panic
among patients with diabetes and those who care for them, as
insulin glargine (Lantus?, sanofi-aventis, Paris, France) is the
most widely prescribed insulin in the United States, ac-
counting for 37.5% of all prescriptions. Position statements
have been issued by multiple organizations, including the
American Diabetes Association, the American Association of
Clinical Endocrinologists, the Endocrine Society, and the In-
ternational Diabetes Federation, in addition to the original
EASD statement. As a group, these statements asserted that
there wasonlyanunproven linkbetweeninsulinglargineand
cancer and advised patients to consult their physician before
changing insulin. Theyurgedfurther research. Unfortunately,
the statements generally were unhelpful to physicians need-
ing to make patient care decisions. This situation has
prompted the authors to write this editorial assessing the
papers, the data, and the circumstances and recommending a
course of action.
First, we should examine how it came to be that there were
t has long been known that both obesity1–4and type 2
diabetes5–15are associated with an increased risk of cancer.
of insulin glargine and cancer. The editorial explains this and
hypothesizes how insulin in general (and insulin glargine in
particular) could increase cancer risk, specifically through an
increase in binding to the IGF-1 receptor.18
The original article submitted was an examination of a
German claims database19carried out by The Institute for
Quality and Efficiency in Health Care (IQWiG), a German
group that makes healthcare recommendations and that
previously took the position that insulin analogs offer no
benefit over conventional human insulin.20This raises ques-
tions as to the motivation of IQWiG in conducting the re-
ported analyses. So, what did they find? First, it should be
appreciated that the mean age of subjects in the analysis was
69.5 years. Because of the way the information was collected,
there is no information available on their duration of diabetes,
their degree of diabetes control (e.g., glycosylated hemoglo-
bin), or their body mass index—all important information.
Furthermore, in the German study,19for all cancers, when
insulin glargine is compared to human insulin the unadjusted
hazard ratio (HR) is 0.85 (95% confidence interval [CI], 0.79–
0.93), indicating a significant 15% decrease in cancer with in-
sulin glargine. A similar outcome is seen when adjusted for
age and gender, namely, an HR of 0.86 (95% CI, 0.79–0.94).
And, a similar finding was seen for all-cause mortality: an HR
of 0.68 (95% CI, 0.65, 0.72). All of these HRs are statistically
significant. An increased cancer risk for insulin glargine is
only evident if there is further adjustment for dose of insulin.
However, for that to be a valid adjustment, the subjects
should have been classified by dose group when enrolled;
instead, the investigators calculated an average dose over the
duration of exposure. Moreover, any subject who changed
insulin type during the study was removed from the analysis,
resulting in a large number of exclusions. Further, there was a
large imbalance in the proportion of subjects in the highest
dose category—for glargine, this group was 13.5% of all
subjects using glargine, whereas for human insulin it was
46.0% of subjects. Thus, in the highest dose group (>40 units
daily), there were 103 events among glargine users and 2,075
1Barbara Davis Center for Childhood Diabetes, Aurora, Colorado.
2University of Washington Medical Center–Roosevelt, Seattle, Washington.
3Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida.
Dr. Garg is Editor-in-Chief and Dr. Skyler is Associate Editor of Diabetes Technology and Therapeutics.
DIABETES TECHNOLOGY & THERAPEUTICS
Volume 11, Number 8, 2009
ª Mary Ann Liebert, Inc.