Diabetes
Voice
March 2014
•
Volume 59
•
Issue 1
40
coUntry perspectiVes
More and more frequently insulin
is being recommended as an
‘add-on’ to oral hypoglycaemic
therapy for the achievement of
blood glucose targets in people
with established type 2
diabetes. Indeed, there are
now trials of insulin therapy in
type 2 diabetes from diagnosis.
Concerns have been raised in
the recent medical literature
that long-term insulin therapy
in type 2 diabetes increases
the risk of cardiovascular
disease and some cancers.
We have asked specialists in
the fields of clinical diabetes
and pharmacoepidemiology to
comment on the question:
DEBATE:
long-term
safety of insulin
in type 2 diabetes
Insulin therapy in people with type 2 diabetes:
is it safe in terms of the risk of cardiovascular
disease, cancer and all-cause mortality?
NO
Sarah Holden and Craig Currie
Insulin has an unlimited potential
to lower blood glucose and is a well-
established treatment for type 2
diabetes. The International Diabetes
Federation (IDF) recommends that
it should be used as an optional
third line when a combination of
metformin, where indicated, and
one other glucose-lowering medi-
cation has failed to adequately con-
trol blood glucose. ADA and EASD
guidelines recommend a patient-
centred approach with the aim of
achieving adequate glucose control
while minimising side effects.
Two common side effects associated
with insulin injections are weight
clinical care
Diabetes
Voice
March 2014
•
Volume 59
•
Issue 1
41
coUntry perspectiVes
gain and hypoglycaemia. Weight gain
is associated with an increased risk of
cardiovascular disease and should be
minimised in type 2 diabetes. Both
insulin and hypoglycaemia may have
vascular effects which are thought
to be greatest in people with pre-
existing cardiovascular disease and
diabetes.
1,2
In addition, as a growth
factor, insulin may affect cancer pro-
gression.
3
However, this is a complex
area where high glucose levels have
also been linked to increased cancer
risk.
4
Some epidemiological studies
have shown that the use of insulin is
associated with an increased risk of
cardiovascular events, cancer and all-
cause mortality in comparison with
other glucose-lowering therapies.
5,6,7
In one of these studies (a retrospec-
tive cohort study using data from
the UK General Practice Research
Database)
6
mortality and other dia-
betes-related outcomes for just under
85,000 individuals were examined in
relation to five diabetes therapies –
monotherapy with either metformin,
sulfonylurea or insulin, metformin
plus sulfonylurea or insulin plus met-
formin. Treatment with insulin alone
conferred a statistically significantly
increased risk of a first major cardiac
event or a first diagnosis of cancer
ranging from 1.8 to 2.6 times the risk
seen in those treated with metformin
alone (the comparison group). This
excess risk was lower in the group
treated with insulin plus metformin
than in the insulin monotherapy
group, though was still significant at
1.3 times the risk of the comparison
group. However, even though these
results are consistent and despite the
use of statistical adjustment, obser-
vational data such as these should be
interpreted with caution due to the
risk of a form of analytical bias that
is termed ‘confounding by indication’.
This form of confounding is a com-
mon feature of studies of outcomes in
relation to drug and other therapies
simply because the reasons patients
have been prescribed the therapies
may themselves be related to the per-
ceived risks of any particular outcome
occurring. In other words, people may
be prescribed insulin partly because
they are perceived of being at risk to
adverse outcomes, including risk of
cardiovascular disease.
In contrast, large randomised con-
trolled trials such as Action to Control
Cardiovascular Risk in Diabetes
(ACCORD) found no adverse safety
signals associated with the use of in-
sulin.
8
However, these studies were
designed to assess the benefits of in-
tensive glucose control rather than the
safety of insulin, and subjects could re-
ceive multiple glucose-lowering thera-
pies making individual comparisons
difficult. Also, the Outcome Reduction
with an Initial Glargine Intervention
(ORIGIN) trial demonstrated that in-
sulin glargine had a neutral impact on
cardiovascular outcomes and cancers
compared with standard treatment.
9
However, it should be noted that peo-
ple included in ORIGIN were newly
diagnosed with type 2 or impaired
glucose tolerance, impaired fasting
glucose or only using one glucose-
lowering therapy. In addition, by the
end of the study, 65% of the insulin
glargine group were also using other
glucose-lowering agents, including
47% using metformin.
When used in combination, metform-
in may attenuate any risks associated
with insulin. Metformin is thought to
protect against cancer and have car-
dio-protective effects that cannot be
fully explained by its ability to lower
blood glucose.
10
When used in con-
junction with insulin, metformin has
been associated with similar glucose
control, but lower insulin doses and
less weight gain.
11
In addition, relative
to the use of insulin alone, the use of
metformin in combination with insu-
lin has been associated with a reduced
risk of cardiovascular events, cancer
and death from any cause.
6
Current
ADA, EASD and IDF guidelines ad-
vocate that, when starting insulin,
it should be added to existing met-
formin therapy and not replace it.
Any potential risks associated with
insulin therapy need to be seen in the
context of its clear benefits for achiev-
ing good glucose control. However, the
shortage of randomised controlled tri-
als examining the risks and benefits of
using insulin on long term clinical out-
comes such as cardiovascular events,
cancer and death from all causes needs
to be addressed in order to provide
more evidence on the safety of insulin
in people with type 2 diabetes.
In the UK, the Medical and Healthcare
Products Regulatory Agency will soon
report on the safety of insulin in people
with type 2 diabetes. Regardless, there
are question marks about the safety
of insulin in type 2 diabetes. There
is, therefore, a need to show caution
while our lack of understanding of
this potential problem is addressed,
and we can recommend injection of
insulin in people with type 2 diabetes
with confidence.
clinical care
Diabetes
Voice
March 2014
•
Volume 59
•
Issue 1
42
Insulin is an established glucose-lower-
ing therapy for both type 1 and type 2
diabetes. However, insulin is a growth
factor. It is administered in an un-phys-
iological manner and it is present in the
circulation at levels that are far higher
than in the non-diabetic population. For
these reasons, concerns regarding insu-
lin safety have been long-standing and
this has led to them being extensively in-
vestigated and, to my mind, repudiated.
First the concerns regarding cancer:
these emerged following suggestions
that the long-acting insulin analogue,
glargine, increased the risk of cancer
12
and were supported by papers suggest-
ing that insulin or insulin secretagogues
were associated with a higher cancer
risk.
7
However, slowly the picture be-
came less certain. Scrutiny of the orig-
inal report showed that the patients
receiving glargine were on tiny doses
of insulin, the cancer risk disappeared
completely if they were on any other
glucose lowering medications (includ-
ing other insulins) and the increased
risk was only seen after an 'adjustment'
by the authors.
12
Attempts to replicate
the original findings floundered, despite
analyses of huge data sets. Finally a pro-
spective randomised clinical trial (RCT)
was published which demonstrated that
YES
Steve Bain
exogenous insulin therapy (with glar-
gine) over more than six years' follow-
up was associated with no evidence of
increased risk of cancer.
9
So, concerns
raised by pharmacoepidemiology, which
can only identify possible safety signals
and generate hypotheses, were laid to
rest by an RCT.
The case of cardiovascular disease has
been longer and more convoluted. Once
again, insulin had been implicated be-
cause of its potential to act as a growth
factor and thereby promoting and/or
enhancing the development of athero-
ma in the circulation. This hypothesis
seemed to be supported by observations
from epidemiological studies suggest-
ing an association between hyperinsu-
linaemia and cardiovascular mortality.
13
Subsequently, a meta-analysis of data
from eleven different studies in non-
diabetic men and women concluded
that hyperinsulinaemia was significantly
associated with cardiovascular mor-
tality.
14
However, this does not imply
causality since the fasting insulinaemia
seen in these studies may have been a
consequence of insulin resistance, and
hence an innocent surrogate.
An RCT was clearly needed – the United
Kingdom Prospective Diabetes Study
(UKPDS). In the seminal publication
of 1998, the introduction clearly stated
that ‘there is concern that sulphonylu-
reas may increase cardiovascular mor-
tality in patients with type 2 diabetes
and that high insulin concentrations
may enhance atheroma formation’.
UKPDS conclusively demonstrated
no such increase and, almost, showed
a benefit from tight control using in-
sulin and the sulphonylureas.
15
Now
the hypothesis had changed leading to
attempts to demonstrate a beneficial
impact of tight glycaemic control on
cardiovascular outcomes; ultimately
this led to the controversy surrounding
the ACCORD study.
8
ACCORD enrolled middle-aged and
elderly people with type 2 diabetes and
a very high risk of cardiovascular dis-
ease. To the researchers' surprise, near-
normal glucose control, achieved with
the use of multiple drugs, was associated
with increased all-cause mortality and
cardiovascular mortality. At five years of
follow-up, nonfatal myocardial infarc-
tion was reduced, but five-year mortality
was increased in patients who received
intensive glucose-lowering therapy. Of
note, over 75% of the intensive group
were using insulin at study end.
Meta-analyses were subsequently per-
formed to include all major studies ex-
amining the impact of tight glycaemic
control on cardiovascular outcomes and
drew the opposite conclusion from that
reported in ACCORD.
16
These trials did
not compare insulin with non-insulin
regimens, however, all had higher pro-
portions of insulin users in the intensive
therapy arms. Given the large numbers
involved in the studies, one might have
expected that any intrinsic harmful ef-
fect of insulin would show up as a con-
sistently increased hazard ratio in the
intensive arms of the trials but it did not.
Cue the pharmaco epidemiologists:
Currie et al. conducted a retrospective
database study of 84,622 primary care
patients, defined a primary endpoint
of all-cause mortality, incident can-
cer, or major cardiac adverse events,
and reported hazard ratios (relative
to metformin monotherapy) of 1.808
for insulin monotherapy and 1.309
for insulin plus metformin.
6
Several
other observational studies, based on
databases, supported the association
between increasing insulin use and
serious events.
17
Fortunately, an RCT
coUntry perspectiVes
clinical care
Diabetes
Voice
March 2014
•
Volume 59
•
Issue 1
43
was already in progress which, for most
people, would settle the argument.
The ORIGIN trial
9
randomised 12,537
people with cardiovascular risk factors
as well as impaired fasting glucose, im-
paired glucose tolerance or type 2 dia-
betes, to receive standard care or insulin
glargine. The aim was to identify any
intrinsic benefit on cardiovascular out-
comes from early use of insulin and the
population of ORIGIN included patients
who were very well controlled (indeed,
approximately 10% were non-diabetic),
with HbA
1c
values of 6.3% or less in the
insulin glargine group and 6.5% or less
in the standard care group. Early use of
titrated basal insulin had no impact on
cardiovascular outcomes compared with
standard guideline-suggested glycae-
mic control. The ORIGIN investigators
pointed out that a large between-group
difference in insulin use was achieved,
and only a small difference in HbA
1c
;
the results were therefore relevant to
the effect of insulin therapy rather than
the effect of glucose lowering on cardio-
vascular outcomes. Once again, an RCT
had come to the rescue.
The final question is whether the con-
troversies about cancer and cardiovas-
cular disease affect clinical practice. For
people with type 1 diabetes, insulin is
currently the only therapy option. For
patients with type 2 diabetes, the pro-
gressive nature of the condition means
that, given current therapies, everyone
will eventually need insulin for symp-
tomatic relief of hyperglycaemia (as-
suming they survive the complications
of the condition). In the UK at least,
the average starting HbA
1c
for insulin
of over ~9.5%, suggests that neither
patients nor clinicians feel that insulin
is an easy or early treatment option. In
this setting, the debates around safety
can be seen as rather academic.
Sarah Holden, craig currie and Steve bain
Sarah Holden is PhD student at the Department of Primary Care and Public Health,
School of Medicine, Cardiff University, UK.
Craig Currie is Professor of Applied Pharmacoepidemiology, The Pharma Research Centre,
Cardiff Medicentre, Cardiff, UK.
Steve Bain is Professor of Medicine (Diabetes), College of Medicine, Swansea University,
Swansea, UK.
references
1. Rensing KL, Reuwer AQ, Arsenault BJ, et al. Reducing cardiovascular disease risk in patients with type 2
diabetes and concomitant macrovascular disease: can insulin be too much of a good thing?
Diabetes Obes Metab 2011; 13: 1073-87.
2. Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence.
Diabetologia 2010; 53: 1552-61.
3. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 2008; 8: 915-28.
4. Jee SH, Ohrr H, Sull JW, et al. Fasting serum glucose level and cancer risk in Korean men and women.
JAMA 2005; 293: 194-202.
5. Currie CJ, Peters JR, Tynan A, et al. Survival as a function of HbA1c in people with type 2 diabetes:
a retrospective cohort study. Lancet 2010; 375: 481-9.
6. Currie CJ, Poole CD, Evans M, et al. Mortality and other important diabetes-related outcomes with insulin
vs other antihyperglycemic therapies in type 2 diabetes. J Clin Endocrinol Metab 2013; 98: 668-77.
7. Currie CJ, Poole CD, Gale EAM. The influence of glucose-lowering therapies on cancer risk in type 2
diabetes. Diabetologia 2009; 52: 1766-77.
8. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al.
Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-59.
9. ORIGIN Trial Investigators, Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular
and other outcomes in dysglycemia. N Engl J Med 2012; 367: 319-28.
10. Zakikhani M, Dowling R, Fantus IG, et al. Metformin is an AMP kinase-dependent growth inhibitor for
breast cancer cells. Cancer Res 2006; 66: 10269-73.
11. Goudswaard AN, Furlong NJ, Rutten GE, et al. Insulin monotherapy versus combinations of insulin with oral
hypoglycaemic agents in patients with type 2 diabetes mellitus. Cochrane Database Syst Rev 2004: CD003418.
12. Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human
insulin or insulin analogues: a cohort study. Diabetologia 2009; 52: 1732-44.
13. Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic
heart disease. N Engl J Med 1996; 334: 952-7.
14. DECODE Insulin Study Group. Plasma insulin and cardiovascular mortality in non-diabetic European men
and women: a meta-analysis of data from eleven prospective studies. Diabetologia 2004; 47: 1245-56.
15. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or
insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes
(UKPDS 33). Lancet 1998; 352: 837-53.
16. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes
and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials.
Lancet 2009; 373: 1765-72.
17. Östgren CJ, Sundström J, Svennblad B, et al. Associations of HbA
1c
and educational level with risk of
cardiovascular events in 32,871 drug-treated patients with type 2 diabetes: a cohort study in primary care.
Diabet Med 2013; 30: e170-7.
coUntry perspectiVes
clinical care
Dostları ilə paylaş: |