CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 6, July 2012
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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 glar-
gine 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 US (FDA),
the EU (EMA) and others have conducted
a review of insulin glargine data and have
not required changes in the package insert
regarding its use.
3,4
These agencies have
recommended that patients maintain their
treatment as prescribed. The ADA/ACS
Consensus statement on this matter concludes
that further research is needed to clarify these
issues.
5
The Sanofi Epidemiological Programme
Rationale
In September 2009, the company announced
it was collaborating with independent
experts on an epidemiological programme
aimed at generating methodologically robust
information on a potential association between
cancer risk and insulin treatment options.
The epidemiological programme 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
oncology outcomes.
The three studies
•
Northern European (prescription) database
study
•
US database study (northern and south-
ern California Kaiser-Permanente Diabetes
Registries)
•
International Study of Insulin and Cancer
(ISICA)
The studies have been designed independently
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 theAmerican Diabetes Association’s (ADA)
72nd scientific sessions, Sanofi announced
results from the US 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,
complementing the existing wealth of data
already available. Endorsed by the EMA and
FDA, the epidemiological programme is the
largest observational programme 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
comprising 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
important knowledge for understanding the
safety of insulin glargine.
US study (Kaiser-Permanente Collaboration)
The main analyses of this US 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 US 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 glar-
gine 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
methodology (counting of dose), there was
a suggestion of a very modest increase of
breast cancer in patients with two or more
years of insulin 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 US 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 US 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 stud-
ies 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:
/
DrugSafety/ucm239376.htm. Date accessed: June
2012.
4. European Medicines Agency 2009. European
Medicines Agency update on safety of insu-
lin glargine – update. Available at:
.
ema.europa.eu/ema/index.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 consen-
sus report.
Diabetes Care
2010:
33
(7): 1674–1685
Press release from Sanofi. Released at ADA 72nd
congress, Philadelphia, USA, 2012
