DRUG TRENDS
SA JOURNAL OF DIABETES & VASCULAR DISEASE
140
VOLUME 9 NUMBER 3 • SEPTEMBER 2012
Insufficient information on patients’ prior
•
and subsequent use of insulin products
Inadequate control of confounding risk
•
factors for cancer (e.g. smoking, family
history of cancer and obesity)
Insufficient duration of patient follow-up
•
In light of the shortcomings in study design,
the FDA did not conclude that insulin glargine
increased the risk of cancer and the review
determined that prescription of insulin
glargine by healthcare professionals and its
use by people with diabetes should remain
unchanged.
3
Drug regulatory agencies in the U.S. (FDA),
the EU (EMA) and others have conducted a
review of insulin glargine data and have not
required changes in the package insert regard-
ing its use.3,4 These agencies have recom-
mended that patients maintain their treatment
as prescribed. The ADA/ACS Consensus state-
ment on this matter concludes that further
research is needed to clarify these issues.
5
The Sanofi Epidemiological Program
Rationale
In September 2009, the company announced it
was collaborating with independent experts on
an epidemiological program aimed at generat-
ing methodologically-robust information on a
potential association between cancer risk and
insulin treatment options.
The epidemiological program comprises
three major studies designed to overcome the
methodological limitations of the
Diabetologia
papers and to provide further evidence about the
safety of insulin glargine with respect to oncol-
ogy outcomes.
The three studies
Northern European (Prescription) database
•
study
U.S. database study (Northern and Southern
•
California Kaiser-Permanente Diabetes
Registries)
International Study of Insulin and Cancer
•
(
ISICA)
The studies have been designed independ-
ently of the company by the lead investigators
and endorsed by the EMA and FDA. They
use state-of-the-art biostatistical methodology
with protocols that have been discussed with a
senior-level Biostatistics Advisory Group and
European regulators.
Results
At the American Diabetes Association’s (ADA)
72
nd Scientific Sessions, Sanofi announced
results from the U.S. and Northern European
observational database studies providing further
evidence that there was no increased risk of
cancer in people with diabetes treated with
insulin glargine, compared to those treated with
other insulins.
These findings reinforce the established
safety profile of insulin glargine, complement-
ing the existing wealth of data already availa-
ble. Endorsed by the EMA and FDA, the epide-
miological program is the largest observational
program designed for this purpose to date.
Northern European database study
The Northern European Study, conducted in
Denmark, Finland, Norway, Scotland and
Sweden is the largest study of its kind compris-
ing 447,821 people with diabetes using insulin,
over 1.5 million person-years of observation.
The average follow-up time is longer than
any other follow-up study, at 3.1 years for
those on insulin glargine and 3.5 years for other
insulins. This study looked at the risk for all
cancers, as well as individually for breast, lung,
pancreas, colorectal and prostate cancers.
The study was led by Peter Boyle, President
of the International Prevention Research
Institute based in Lyon, France.
In answering the primary hypothesis, among
all users of insulin, and similarly among users of
human insulin, this observational study found:
no evidence of an increased risk of breast
•
cancer in women, prostate cancer in men
and colorectal cancer in men and women
no evidence of an increased risk in users of
•
insulin glargine vs. other insulins relative
to the pre-specified secondary hypothesis
(
risk of all forms of cancer combined) and
the exploratory hypothesis (risk of lung or
pancreatic cancer)
in conclusion, the study showed no increased
•
risk for cancer in association with the use of
insulin glargine compared to users of other
insulins.
The Committee for Medicinal Products for
Human Use (CHMP) in Europe expressed that
the Northern European study results add impor-
tant knowledge for understanding the safety of
insulin glargine.
U.S. study (Kaiser-Permanente Collaboration)
The main analyses of this U.S. database study
(
using the Northern and Southern California
Kaiser Permanente diabetes registries included
115,000
patients with median duration of 1.2
years for glargine use and 1.4 years for neutral
protamine Hagedorn (NPH) among all insulin
users (insulin glargine and NPH insulin). They
examined cancer risk in people treated with
each of these insulins as well as those who had
switched from one to the other.
Results from the U.S. database study, led
by John Buse, former President of the ADA,
and Director of the Diabetes Care Center at
the University of North Carolina, were also
presented at ADA 2012:
The main analyses among all insulin users
(
insulin glargine and NPH insulin) showed:
no association between use of insulin
•
glargine and increased risk of breast cancer,
prostate cancer or colorectal cancer (prima-
ry endpoints)
no association between insulin glargine use
•
and increased risk of all cancers combined
(
secondary endpoints)
In the sub-analysis of NPH insulin users
•
switching to insulin glargine:
no association with an increased risk of
•
breast, prostate, colorectal or all cancers
combined
Among new users of insulin:
•
no association between insulin glargine use
•
–
or duration of insulin glargine use – and
risks for prostate, colorectal or all cancers
combined.
In a sub-analysis using one specific methodol-
ogy (counting of dose), there was a suggestion
of a very modest increase of breast cancer
in patients with two or more years of insu-
lin glargine use. When another methodology
was adopted (counting of prescriptions), no
such suggestion existed. Principal Investigator
Laurel Habel, PhD, Research Scientist at
the Kaiser Permanente Northern California
Division of Research, noted that results of their
study should be viewed cautiously, given the
relatively short duration of glargine use and the
large number of associations examined.
Additionally, the U.S. database study was
complemented by findings from researchers
at the University of North Carolina, using
the healthcare database MedAssurant (43,306
patients on glargine and 9,147 on NPH; mean
duration of treatment: 1.2 years for glargine
group and 1.1 years for NPH group). There was
no evidence of an increased risk for cancer, and
specifically for breast cancer.
As with the results of the Northern European
Study and data from the U.S. Kaiser Permanente,
the MedAssurant study showed no association
between use of insulin glargine and increased
risk of the cancers evaluated among all insulin
users tested.
International Study of Insulin and Cancer
Additional results are expected from another
observational study, the International Study
of Insulin and Cancer (ISICA), led by Lucien
Abenhaim, Professor of Public Health at the
University of Paris and former Director General
for Health in France, which will be completed
in 2012.
References
1.
Home P, Lagarenne P. Combined randomised controlled
trial experience of malignancies in studies using insulin
glargine.
Diabetologia
2009:
52
(9): 2499–2506.
2.
Safety Monitoring Report, April 2012.
3.
US Food and Drug Administration. FDA drug safety
communication: update to ongoing safety review of
Lantus
®
(
insulin glargine) and possible risk of cancer.
Available at:
ucm239376.htm. Date accessed: June 2012.
4.
European Medicines Agency 2009. European Medicines
Agency update on safety of insulin glargine – update.
Available at:
jsp?curl=pages/news_and_events/news/2009/11/news_
detail_000066.jsp&murl=menus/news_and_events/
news_and_events.jsp&mid=WC0b01ac058004d5c1.
Date accessed: June 2012.
5.
Giovannucci E
et al
.
Diabetes and Cancer. A consensus
report.
Diabetes Care
2010:
33
(7): 1674–1685
Press release from Sanofi. Released at ADA 72nd
congress, Philadelphia, USA, 2012
