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Insulin Therapy and Cancer
PHILIP HOME, DM, DPHIL
T
hat diabetes is associated with an
increased lifetime risk of developing
malignancy is now well establish ed
(1,2). For some specific malignancies, ex-
planation of that increa sed risk is possi-
ble, though usually unproven. For
example, the marked increase in pancre-
atic cancer incidence in type 2 diabetes
may or may not be due to misattribution
of type of diabetes where the reality is sec-
ondary diabetes. Also markedly increased
is hepatic malignancydsomething that
may be secondary to hepatic steatosis or,
rather, hepatosteatitis and subsequent
fibrotic/regenerative disease. Lesser increa-
ses in large-bowel malignancy are also
found in association with obesity and mod-
ern low-r esidue high-fat diets, and both
obesity and such diets are associated with
diabetes (1,3). In contrast, it is notable that
high-conce ntration insul in given repeat-
edly into the same injection site for many
decades has not generated even one report
of a subcutaneous sarcoma in .90 years in
tens of millions of people.
Type 2 diabetes and other types of
diabetes, once vascular dama ge is occ ur-
ring, are inflammatory states, which may
provide an environment for oncogenesis
of some malignanc ies. However, the in-
flammatory state might also might pro-
vide enhancement of immune cancer
surveillance mechanisms. The reduction
of prostat e cancer incidence is potentially
expl aina ble in the context o f relative re-
duction in circulating testosterone levels
in m en with type 2 diabetes.
A second concern over diabetes and
malignancy is regarding glucose-low ering
therapies. However, only in the case of
PPAR-ag agonists is there reasonably
strong data once information from pre-
clinical studies, randomized controlled
trials (RCTs), and ob servational studies
is taken together (4–6). For insulin, the
data are more complex to assess. Preclin-
ical animal data of concern are limited
to an analog with unusual receptor bind-
ing properties. However, mechanistic
data do suggest mechanisms by which in-
creased malignancy r isk could operate,
and this has raised concerns about some
licensed insulin analogs, nota bly insulin
glargine.
This review is meant to be an over-
view of the concerns surrounding insulin,
with the intention of seeking the level of
probability that endogenous or exoge-
nous insulin could be contributing to
malignancy risk in clinical practice and
looking for research pathways to i nform
this fu rther.
METHODSdLiterature searching for
this review was not systematic. Search
terms around insulin, ma lignancy, and
cancer and narrowed for specificareasto
observational studies, randomized con-
trolled trials, insulin therapy, growt h pro-
motion, and insulin analog(ue)s still
revealed very large numbers of sources
in the literature (.2,000,000), from
which the reviewer then selected, with
potential bias, papers of higher quality
or interest and those more often quoted
by other authors and supported by
studies refe rred to from the initially
identified reports.
In han dling the evidence, I at tempt to
take the data from a study in the context
of prior know ledge and asks the question,
‘‘How does this study shift the probability
that such and such an effect is real to the
exte nt that it should help determine rou-
tine clinical practice or promote further
rese arch activity?’’ The limitations of the
available literature restrict the conclu-
sions that can be made, as in any scientific
review.
MECHANISTIC DATAdThe exis-
tence of potential mechanisms by
which a substance (in this case, insulin
or derivatives) can promote malignanc y
does not by itself signifi
cantly raise con-
cerns that such a problem will occur.
Indeed, without other evidence, whether
preclinical (animal studies), observa-
tional, or controlled studies, mechanistic
data on how such an effect might occur
provide very little indication of probabil-
ity that it will occur in clinica l practi ce.
This is contra ry to human intuition be-
cause the opposite approach, of attaching
a mechanism to a described adverse event,
provides a good opportunity for avoiding
or ameliorating the event, and accordingly
we instinctively give mechanistic explan-
ations quite a lot or even excessive weight.
As will be seen below, the evidence from
animal and clinical studies for insulin
being a causative factor in human malig-
nancy is weak, so the mechanistic discus-
sions that fol low currently have limited
clinical relevance.
Most of the potential mechanisms
for insulin being a risk factor for cancer
concern growth promotion. Studies
looking for genotoxicity have been un-
successful (7). There is no evidence that
insulin regulates or affects expression of
established oncogenes, includin g those
of the tyrosine kinase family. Growth
promotion c ould affect the lifetime clin-
ical incidence of cancer by allowing pro-
tective cellular and immune surveillance
mechanisms to be overcome. Further-
more, in the short term it might appear
to increase the incidence rate of cancers
by causing thos e already present to be
detected sooner.
Two putative mechanisms may be
identified. Firstly, and attracting much
attention with rega rd of insulin therapy, is
the cross-reactivity between bindi ng for
thei r respective receptors (and subtypes)
of insulin and IGF-1 (8). Insulin is in
any case, and distinct from its glucose-
lowering activity, a n anabolic hormone
with actions on amino acid uptake and
protein synthesis, which is the basis of
its misuse by athletes. Of interest here
is the existence of a growth-promoting
(fetal) insulin receptor (A), which is
cccccccccccccccccccccccccccccccccccccccccccccccc c
From the Institute of Cellular Medicine–Diabetes, Newcastle University, Newcastle upon Tyne, U.K.
Corresponding author: Philip Home, philip.home@ncl.ac.uk.
This publication is based on the presentations from the 4th World Congress on Controversies to Consensus in
Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this supplement were
made possible in part by unrestricted educational grants from Abbott, AstraZeneca, Boehringer Ingelheim,
Bristol-Myers Squibb, Eli Lilly, Ethicon Endo-Surgery, Janssen, Medtronic, Novo Nordisk, Sanofi, and
Takeda.
DOI: 10.2337/dcS13-2002
© 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/
licenses/by-nc-nd/3.0/ for details.
S240 DIABETES CARE, VOLUME 36, SUPPLEMENT 2, AUGUST 2013 care.diabetesjournals.org
DIABETES AND CANCER
sometimes overexpressed in tumors,
notably breast malignancies, and of hy-
brid insulin–IGF-1 receptors (9,10). Fur-
thermore, insulin receptor A has higher
binding affinity for IGF-1, though it is still
an order lower than for insulin (11).
Higher concentrations of insulin receptor
substrate 1 can be found in malignant tu-
mors but are reported to be highest in
those with ben ign outcome (12).
Clinically, the property that has
raised concerns for insuli ns has been its
IGF-1–to–insulin re ceptor binding affin-
ity. How ever, as insulin is mainly cleared
through its receptor, insu lins with low in-
sulin receptor affinity are present in the
circulation in higher concentration than
native human insulindsomething that
will also enhance IGF-1 receptor binding.
Insulins of the B-terminal diargi nyl series
(i.e., B31-B32 diarginyl insulins) are of
particular conc ern, a s without o ther
amino acid change they have an ~20:1
IGF-1:insulin receptor binding ratio com-
pared with human insulin (8). However,
even at this ratio i t is debatable whether
insulin would contribute s ignificant
growth factor activity compared with the
tissue levels of IGF-1 itself, given that the
latter has much higher affinity for its own
receptor than does insulin and because it
circulates at much higher concentrations
than insulin (11).
Studies of malignancy rates in acro-
meg aly have resulted in uncertainty as to
whether malignancy is increased or not
(13). A particular concern might, how-
ever, arise with breast cancers (other ma-
lignancies are less well studied), some of
which have markedly enhanced expres-
sion of insulin or IGF-1 receptors (14,15).
The second mechanism of insulin
growth promotion is less well documen-
ted but did result in mammary tumors in
susceptible rats. Asp-B10 insulin is an
unusual human insulin analog that h ad
apparently markedly enhanced binding
to hepatocytes i n vitro. However , that
may be an artifact of another rec eptor
property of that insulin, namely, slow
insu lin receptor dissociation rate (16). It
is hypothesized that this propert y might
have bee n the cause of increased signaling
down the mitogen-activated protein ki-
nase pathway (and thus growth prom o-
tion and mitogenesis) rather than the
phosphatidylinositol 3-kinase or CAP
(Cbl-associated protein) pathways in-
volved in metabolic signaling. Studies of
other insulins suggest that this was a fairly
unique property of Asp-B10 insulin; it is
not a problem for any of the other human
insulin analogs in clinical use, such as in-
sulin glargine (17).
PROPERTIES OF INSULIN
GLARGINE dInsulin glargine is an
end-chain diarginyl insulin (see ab ove)
but addit ionally has a Gly-A21 amino acid
substitutionda s ubstitution that reduces
relative IGF-1–binding activity (8). A c-
cordingly (and dependent on the cell
model used for testing ) the 320 increase
in binding of the B-chain substitution is
reduced to 36 for insulin glarg ine itself
(8). As noted above, t his difference is
unlikely to be significant in canc er-
promoting terms, as recognized at the
point of licensing, partic ularly as detailed
receptor studies did not reveal any Asp-
B10 insulin–like continued receptor sig -
naling (17).
Diarginyl insulin is a natural product
of endogenous insulin production and
circulates in al l people with an intact
pancreas, though in very small amounts
relative to insul in. Indeed, the diarginyl
bond is a regular cleav age site in proteins,
and many tissues contain pepti dases to
remove such residues, including subcu-
taneous tissue. T his raises the q uestion as
to whether insulin glargine, during its
long residence time in the subcutaneous
tissues or after rel ease from its insoluble
subcutaneous complexes b ut before ab-
sorption, might be partly or lar gely de-
graded to the A21-Gly human insulin
with low IGF-1 receptor binding. Indeed,
this turns out to be the case, with three
studies reporting that the overwhe lming
circulating species of insulin after sub-
cutaneous glargine injection is its so-
called M1 metabolite, A21-Gly human
insulin ( 18–20).
OBSERVATIONAL STUDIES
Methodology and biases
Observational studies with insulin in
people with type 2 diabetes often find
that it is associated with wors e outcomes
and more deranged metaboli sm (what-
ever outcome is me asured), as indeed is
the case for malignancy (21). In some
studies, it is recognized that for the most
part, sin ce insulin is used late in the ther-
apeutic pathway, it is useful to a djust for
age and duration of diabetes. Unfortu-
nately, even this cannot control f or b iases
introduced by people with other illness
being in closer conta ct with the medical
profession and the risk that in the com-
plex disease environment the cli nical site
(e.g., university hospital) where insulin is
started may be more likely to be using the
latest glucose-lowering technologies (2).
Observational studies should usually
therefore be regarded as hypothesis gen-
erating.
Some studies have suggested insulin to
be associated with lower rates of cancer and
lower rates of progression to an extent that
has been noted by commentators to be
remarkable (22,23). Again, this is likely to
be an association confounded by hidden
factors; people presenting with cancer or
progressing with disseminated disease will
tend to be anorexic, such that if they have
type 2 diabetes the need for therapies will
be reduced.
Biases that can result in confounding
effects in clude drug use indication bias,
prevalent user bias, detecti on bias, and
time-rel ated biases. The potential for in-
dication bias is very large in type 2 di-
abetes owing to the complexity of the
condition and its association with obesity
(and thus dietary change), cardiovascular
risk factors, and inflammation . As a sim-
ple example, obesity and hyperglycemia
are associated with malignancy and with
insulin insensit ivitydthus the ea rlier use
of insulin and of insulin in higher doses.
Indication bias might result in people
subject to adverse health outcomes such
as malignancies being more likely to come
into contact with hospital-based care
teams and then more likely to start
diabetes therapies inclu ding insulin ear-
lier than those continuing to be seen in
family practice. This might account for
the detection bias (high rates in early
months falling rapidly th ereafter) seen in
some studies (24). Currie et al. (25) found
that insulin users with cancer were more
likely to have cardiovascular disease at di-
agnosis, confirming that they were not the
same populati on as the comparator non-
insulin users. Lind et al. (26) noted rapid
falls in prost ate cancer incidence over 5
years from abnormally high levels w ith
duration of use of insulin glargine. This
might then even apply to particular ther-
apies if, for example, one group of practi-
tioners were more likely to use insulin
analogs than another using pre do mi-
nantly human insulins. Other issues
surround contraindications and com-
parators; metformin, for example, has
tended to be used less in anyone with
liver, renal, or gut disturbance, so pop-
ulations taking metformin tend to do
better in observational cohorts for
many types of outcomes. However, for
cancer th is w as not confirmed in a meta-
analysis of randomized controlled trials
care. diabe tesjournals.org DIABETES CARE, VOLUME 36, SUPPLEMENT 2, AUGUST 2013 S241
Home
(27). A dditionally, metformin is usually
prescribed early in the course of diabetes
and insulin later, so studies need to ad-
just for duration o f diabetes, which ap-
parently was not done even in a recent
database study (25).
Prevalent user bias can arise in vari-
ous ways and someti mes can be as simple
as poor ascertainment of when a drug is
started in relation to an o utco me (if, for
example, the drug is started in the hospi-
tal but the first record is later from a
prescription issued in family practice)
(28). The issue of time-related biases in
diabetes therapy studies has been dis-
cussed by Suissa and Azoulay recently
(29).
Outcomes of studies
In the light of the above problems, can
anything useful be concluded from pub-
lished observational studies of cancer (in-
sulin glargine is cons idered separately
below) and insulin use? Even if they are
taken to be hypothesis generating, the
literature is quite contradictory as to asso-
ciations of increased or decreased preva-
lence, incidence, or progression (28).
Given these conflicting findings and the
unresolved methodological issues dis-
cussed above, the best conclusion is per-
haps that the studies as a whole do not
contribute to clinical decision making in
the management of people with diabetes,
although individual studies are useful in
contradicting the findings of others.
There does seem to be an impro ve-
ment in methodological quality or at-
tempts to address it in the las t 5 y ears.
The China/Hong Kong studies from Yang
and colleagues are helpful in this regard,
but as noted above the findings from
some of these are surprisingly favorable
with rega rd to insulin therap y to an extent
that is difficult to understand mechanis-
tically (2,22). Furthermore, study of ori-
ental populations with BMI well b elow
30.0 kg/m
2
on average may not help to
answer the underlying question of
whether obese people with unphysio-
logically high (32–8) endogenous with
or without exogenous insulin exposure
suffer a growth-promoting or other ef-
fect of insulin if they develop susceptible
tumors.Boyleetal.(30)haverecently
published a detailed meta-analysis
of breast cancer in diabetes, conclud-
ingthattheremaybea27%increase
in type 2 diabetes but not in type 1 di-
abetes or gestational diabetes mellitus
where insulin use is universal or more
common.
Insulin glargine
As noted above, the issues surrounding
insulin glargine are not s upported by
mechanistic studies, but once raised the
questions cannot be ignored (31). The
RCT evidence is di scussed separately be-
low. The issue came to prominence with
the publication of four studies in Diabeto-
logia, which taken together suggested no
malignancy association with gl argine, de-
spite being su bject to some of the meth-
odological issues discussed above (32–
35). In one study, which suggested an
overall but small benefit of association
wit h insu lin glargi ne use, the data were
clearly flawed by the study populations
having very different i nsulin dose use,
meaning they were different noncompa-
rable populations for unascertained rea-
sons (32). In t hese circumstances, no
adjustment for the limited range of cova-
riates would help (propensity ana lysis
mighthavegonesomewaytoreducing
biases, using pair matching for all avail-
able characteristics including dos e), and
therefore the authors’ finding of increased
dose-adjusted risk for glargine has very
little value. In another of the four stud-
ies, specific site malignancy (breast) has
increased association with glargine
(34), but in the circumstance of no prior
specific hypothesis and with multiple
sites t ested statistically without adjust-
ment, this too has very low evidence
impact.
A number of studi es have attempted
to address this area of investig ation, and
atte ntion has been drawn to their li mita-
tions (36– 38). Boyle and colleagues
performed a detailed meta-analysis of
the insulin glargine observatio nal data.
This was presented at the International
Diabetes Federat ion annual meeting
(2011) and American Diabetes Associa-
tion Scientific Sessions (20 12), and the
presentations are available online
(39,40). As such, t hey are no t subject to
formal prior peer review, while the ac tiv-
ity was sponsored by the manufacturer of
insulin glargine. Nevertheless, the analy-
sis is comprehensive, and sensitivi ty anal-
yses address such issues as allowing the
effect of the Hemkens and colleagues dose
adjustment to be understood within the
context of the other published findings.
Other studies presented in symposia at
the American Diabetes Association Scien-
tific Sessions 2012 from a U.S. insurance
company and the Kaiser Permanente da-
tabase reached similar conclusions: that
there is no associ ation with overall malig-
nancy or with any specifictumorsite,
although even with meta-analysis there
are limitations in the amount of data avail-
able for breast or any other single site can-
cer, and of co urse du rati on of exposure is
limited by the introduction of insulin
glargine from 2003. How s uch limitations
should affect clinical pra ctice is discussed
below.
RCTs
Methodological issues
It might seem as though, as the gold
standard of treatment comparisons, RCTs
should be able to answer the questions
posed here. However, there are also issues
with the RCTs in this area. The most basic
of these is that all but one of the studies
(Outcome Redu ction With Initi al Glar-
gine Intervention [ORIGIN]) (see below)
were not set up to assess cancer outcomes,
which thus were for the most part col-
lected as serious adverse event (SAE)
repo rts. In areas such as cardiovas cular
disease, this is recognized as being prob-
lematic, as investigators m ay not be sure
what constitutes an event and may have
limited access to diagnostic information
from other medical servic es, perhaps
from health events that happened to the
pati ent in other cities. For malignancies,
this may n ot seem to be such a problem,
but w hen trawling through SAE and AE
data it becomes obvious that there are
problems with materials originating from
study sites
dnot least in the diverse ter-
minology used. Despite specification that
malignancies should be SAEs, some are
still reported as a dverse events (mi xed in
with a large number of benign tumors),
and the use of words like “neoplasm” of-
ten seems to be investigator solutions to
not knowing the nature of a lesion. Liver
metastases (or merely deposits on scans)
give similar problems as to origin. Only
rarely is some kind of post hoc adjud ica-
tion of m alignant events und ertaken, of-
ten without recourse to retrospective
inquiry for more details from investig ator
sites (a process t hat anyway is usually very
unrewarding). Additionally, many RCTs
are phase 3 studies of duration of ,12
months, which may not give time for
any drug effect to become manifested
and often contribut e less than three
events per study.
Meta-analysisisinsomeminds
given a magic al aura to deal with the
problems of RCTs. This is mostly not the
case, as meta-analysis is only as good as
the underlying data it considers, and
problems such as heterogeneity of the
S242 DIABETES CARE, VOLUME 36, SUPPLEMENT 2, AUGUST 2013 care.diabetesjournals.org
Insulin therapy and cancer
populations studied may even worsen
that compared with the better RCTs
alone. Ultimately, meta-analysis is only
useful for the purpose of gaining power
where the patient exposure i n available
studies is smalldoften thus b eing based
largely on the short-term phase 3 studies
with all their limitations.
RCT findings
However, the ORIGIN study, an RCT of
insu lin glargine ver sus standa rd care in
persons ranging from prediabe tic to tak-
ing two oral agents at entry, is useful in
being of relatively high exposure, having
sizeable pa rticipant numbers followed
for a median of 6.2 years, and having
adjudicated cancer outcomes (41). By
studying insulin glargine, it effectively
deal s with the issues of both insulin and
that specific analog. The findings were of
no benefit or harm, with large numbers of
events (953) and thus tight CIs for all can-
cer (95% CI 0.88–1.13) and deaths from
malignancy (0.77–1.15) versus a mix of
other glucose-lowering therapies used
slightly less intensively. For specificma-
lignanci es, the results are inevitably less
certain owing to smaller numbers, but
the spread of findings on either side of a
hazard ratio o f unity po ints to no identifi-
able signal. Even for quite larg e CIs (say,
up to an 80% in creased risk as chosen by
the U.S. Food and Drug Administration
for cardiovascular events when licensing
new medications), statistical power re-
quires event numbers of .100 and ab-
sence of multiple testing, neither of
which can be expected to be att ained in
our current RCTs for any one organ sit e
malignancy. The weakness of the study is
that diabetes duration at entry was rela-
tively shor t (indeed, a small proportion of
particip ants had just glucose intolerance)
andBMInotashighasinsometreated
populations (mean ,30.0 kg/m
2
), so re-
sulting insulin dose in the treated group
was modest, even in those conti nuing in-
sulin treatment at 6 years (end of study
mean ;40 units/day). Accordingly, the
study does not deal with the question of
high exogenous insulin doses added to
high endogenous secretion in the more
markedly obese person.
A me ta-analysis of the insulin glargine
studies r epor ted findings in both types of
diabetes, against NPH insulin, and in both
longer- and shorter-du ration studies (42) .
The ap proach has all of the problems dis-
cussed above, with only one study (the
reti nopathy study ) having duration of di-
abetes .1 year and that with limited
participant numbers (n = 514 exposed)
(43). Accor dingly, with only 91 persons
(glargin e and comparator) experiencing a
new malignancy, the upper CI was 1.36,
while for specific site malignanc ies such
as breast cancer the upper CI was .2.0.
There was no signal fo r an increase in ma-
lignancy in the retinopathy study. Boyle
and colle agues later extended these anal-
yses of the RCTs reporting hazard ratios of
0.88 (95% CI 0.80–0.97) for glargine versus
comparators, but suggested caution should
be exercised in overinterpreting the results
as indicating a small benefit (39,40).
CONCLUSIONSdPresently, it is dif-
ficult to conclude that there is any evi-
dence of risk of m alignancy from
exogenous insulin of a size great enough
to modify clinical practice decisions. Fur-
ther studies mi ght be directed at people
who have already had one neoplasm (and
therefore have a particularly hig h back-
ground ri sk), those with high background
risk for other reasons (e.g., genetic
makeup predisposing to breast cancer,
expo sure to asbestos), and those women
whose breast cancers overexpress insulin
receptor subtypes and IGF-1 receptors.
However, the issue of high-dose insulin
therapy has not been properly studied,
and such people nearly always have high
endo genous insulin secretio n and some
tendency to an enhanced inflammatory
state, putting them at risk. It cannot
presentl y be argued that any of the groups
of people at higher risk should be denied
the benefits of insulin therapy if they need
it, particularly as nearl y all other glucose-
lowering therapies have other putative or
real safety risks.
For insulin analogs, it mig ht s eem
unwise to introduce and develop another
diarginyl i nsuli n where other approaches
are possible, but insulin glargine–type
molecules seem safe . An issue will arise
if small-molecule insulin receptor ago-
nists are develo ped: these might end up
missignaling down the mitogen-activ ated
protein kinase pathway as insulin Asp-
B10 was presumed to do and, as such,
will need careful and fu ll preclinical and
toxicological review, including avoidance
of insulin receptor A binding. This will
not be an easy undertaking, as overdosing
of insulin kills animals from hypoglyce-
mia, limiting the use of conventional tox-
icologic al studies.
AcknowledgmentsdP.H. or institutions with
which he is connected receive funding from all
insulin manufacturers marketing products in
Europe and North America for his advisory,
education, and research activities. No other
potential conflicts of in teres t releva nt to this
article were reported.
P.H. is resp onsible for the entire content of
the article, which was pre pared without ref-
erence to any other party excepting Diabetes
Care reviewers and editors.
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Insulin therapy and cancer
