Artigo joga dúvidas sobre a necessidade/ ou mesmo contraindicação de insulina em DM2. A hiperinsulinemia que precede a clínica do DM, quando associada à aplicação exógena do hormônio pode trazer efeitos adversos. O artigo põe em dúvida a aplicação de insulina no DM.

1. The safety profile of exogenous insulin in people with type 2 diabetes: justification for
concern
Craig J. Currie, PhD
Reader in Diabetes Pharmacoepidemiology, School of Medicine, Cardiff University, Cardiff,
United Kingdom
Jeffrey A. Johnson, PhD
Professor and Canada Research Chair, School of Public Health, University of Alberta, Edmonton,
Canada
Abstract
There is no doubt about the value of exogenous insulin for people with type 1
diabetes. The purpose of this commentary is to discuss emerging evidence that
this may not be the case for the majority of people with type 2 diabetes.
This is an Accepted Article that has been peer-reviewed and approved for publication in the
Diabetes, Obesity and Metabolism, but has yet to undergo copy-editing and proof correction.
Please cite this article as an "Accepted Article"; doi: 10.1111/j.1463-1326.2011.01469.x
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2. In general, exogenous insulin is a good thing. It has enjoyed a long history as a
life-saving therapy for innumerable patients with type 1 diabetes. Insulin’s
introduction revolutionised the management of these patients, and over the
past 90 years it has saved countless organs, limbs and lives1. But is this true for all
patients with diabetes? Every drug has both benefits and risks, and therapy is
indicated when the former outweighs the latter. Insulin, whether in its human
form or as an analogue, is no different. While the benefits clearly outweigh the
risks in the management of type 1 diabetes, emerging evidence suggests this
may not be the case for all people with type 2 diabetes.
The market for insulin continues its rapid expansion2 due in large part to the
increasing prevalence of type 2 diabetes, and a focus on intensifying glycaemic
control. Insulin is the most effective therapy for reducing hyperglycaemia, and
therefore remains high amongst the choices of add-on therapy for those
patients whose HbA1c remains above recommended targets3,4. A lower HbA1c
is much easier to achieve when using insulin-based regimens, and in a
glucocentric culture of ‘treatment-to-target’5,6, insulin represents an attractive
treatment preference.
Nevertheless, the strategy of such intensive glucose control for type 2 diabetes is
rightly being questioned because of emerging evidence suggesting a lack of
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3. substantial benefit in the face of potential risks7,8. In this regard, the glucose-
lowering benefit of insulin is generally weighed against the acute risks of
hypoglycaemia (postulated to cause arrhythmia, “dead-in-bed” syndrome, and
other cardiovascular sequelea9), weight gain, and the underappreciated
disutility and distress patients with type 2 diabetes experience with insulin
injections and glucose self-monitoring. It is important; however, to consider an
even broader risk profile for insulin.
A hallmark of type 2 diabetes is resistance to insulin action10. What is becoming
clearer though, is that the insulin resistance of type 2 diabetes is largely limited to
muscle and adipose tissues, whereas other tissues or organs either retain normal
sensitivity or become hypersensitive to insulin actionError! Bookmark not defined..
And furthermore, the broader negative clinical consequences of insulin
resistance are―for the most part―a result of compensatory
hyperinsulinaemiaError! Bookmark not defined.. This being the case, it would
plausibly seem counter-productive to add to the problem with exogenous insulin
therapy.
What is the evidence for these broader clinical consequences of insulin
resistance and hyperinsulinaemia? From the physiologic perspective, insulin
plays a major regulatory role in many tissuesError! Bookmark not defined.. The
kidneys remain sensitive to insulin, and compensatory hyperinsulinaemia leads to
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4. increased retention of salt, water and uric acid, contributing to increased risk of
cardiovascular disease11. Hyperinsulinaemia also increases sympathetic nervous
system activity, which may further contribute to increased blood pressureError!
Bookmark not defined.. Finally, there has been a re-focusing of attention
recently on insulin’s well-established role on cell growth, differentiation and
proliferation12,13. In the face of insulin resistance, endogenous or exogenous
hyperinsulinaemia results in an exacerbation of insulin’s mitogenic and
atherogenic effectsError! Bookmark not defined..
If these physiologic effects of insulin resistance and compensatory
hyperinsulinaemia are of clinical concern, we might also expect to see
increased risk of cardiovascular events and cancer, and then a corresponding
increased risk of mortality. Could it be that these more long-term clinical
outcomes of insulin therapy in type 2 diabetes have been somewhat
overlooked? There could be a number of reasons if this is the case. For
example, people with type 2 diabetes are in a complex, heterogeneous, multi-
morbid state. Furthermore, there is an overt glucocentric view of diabetes
management and, potentially, a blind over-confidence in making wider
inference from data characterising the benefit-to-risk ratio observed in type 1
diabetes. We believe there is, in fact, accumulating evidence that these risks
may be real and a cause for concern.
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5. Recent studies provide support for the biological plausibility of adverse effects
relating to hyper-insulinisation in patients with type 2 diabetes. Data that first
raised questions about negative outcomes of higher versus more standard doses
of insulin in type 2 diabetes were published from a pilot, randomised trial in
199714. Consistent with this virtually ignored trial were data from a large,
population-based cohort study where a dose-response relationship was
observed between increasing insulin use and all-cause mortality in people with
type 2 diabetes15. This study reported an almost three-fold increase in risk of
death in the highest insulin exposure group, in an insulin-dose-dependent
pattern. Similarly, in an epidemiologic study of patients with type 2 diabetes
treated in a UK primary-care setting, those treated with insulin-based regimens
had a 50% increased risk of dying than did comparable patients treated with a
combination therapy of metformin plus sulfonylureas16. More recently, data
from the randomised controlled trial DIGAMI-2 suggest that intensified insulin
treatment was associated with increased risk of non-fatal cardiovascular events,
with a corresponding trend for increased cardiovascular mortality17. A 2.5-fold
increased risk of cardiac events in those with type 2 diabetes treated with insulin
was reported from another recent, large, observational study from the US18.
Insulin has been found to be associated with worse cardiovascular disease
outcome in people with type 2 diabetes19, and independently in people with
heart failure20.
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6. There is also accumulating evidence of increased risk of malignancy with
increased use of insulin in patients with type 2 diabetes. Yang and colleagues
first reported an increased risk of colorectal cancer in people treated with
insulin, observing an escalating risk with longer duration of insulin use21.
Increased risks of liver22 and pancreatic23,24,25 cancers have also been
associated with insulin use, but there is likely to be some degree of “reverse
causality” in these relationships. Insulin use in type 2 patients has also been
associated with increased risk of overall cancer incidence26 and cancer
mortality27. Interestingly, the recently published extended follow-up from
DIGAMI-2 also demonstrated that insulin treatment was associated with an
increased risk of cancer mortalityError! Bookmark not defined..
The counter argument to the above intelligence favouring the use of insulin in
people with type 2 diabetes is largely based upon a lack of any convincing
adverse-event signals from large randomised controlled trials such as the
UKPDS28,29. Unfortunately, while insulin therapy was one of the options for
intensified glycaemic control in the UKPDS, it is important to recognise that the
overarching aim of the study was achievement of lower HbA1c, as it is in all
recent large randomised trials of intensified glycaemic control. In these trials,
objectives were typically pursued with protocol-driven treatment escalation―or
‘rescue therapy’―resulting in the post-randomisation addition of multiple oral
agents to insulin30. This sort of design makes it difficult to discern the effect of
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7. individual drug therapies, since the risk associated with any one agent would be
largely confounded by exposures to other glucose-lowering agents; most
notably metformin, which is associated with reduced risk of macrovascular
events or cancer outcomes31. Finally, company-sponsored regulatory trials for
insulin products are typically short-term trials and inevitably compare insulin
product versus another insulin product, thus data from commercial sponsors
generally offer little to this debate.
The ongoing ORIGIN trial intends to assess whether early initiation of treatment
with insulin glargine will reduce cardiovascular events32, but it too allows for the
use of other glucose-lowering agents at the discretion of local investigators, and
therefore it is unlikely to clarify any unique benefits or risks relating to insulin
therapy. In general, published RCT data can only suggest that overall
improvements in glycaemic control achieved through combination glucose-
lowering therapies do not appear to decrease the risk of all-cause or
cardiovascular mortality33 or cancer34.
So where do we go from here? From the research perspective, there is a clear
need to better understand the existing data on the safety and benefits of insulin
therapy in patients with type 2 diabetes (including, if possible, unpublished
company trial data). However, if current RCT data are inadequate due to
complex therapeutic regimens and epidemiological data are always open to
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8. criticism; then equipoise exists. There is then a need for a new, long-term
randomised trial to assess efficacy; perhaps with a simpler design of varying
insulin doses in the absence of oral therapy changes. Regardless, since it is
unethical to power a trial to characterise harm, in the absence of such a trial we
will necessarily have to rely on accumulating evidence from mechanistic and
observational studies.
From a clinical perspective, there is no question that the absolute need and
benefit related to treatment with exogenous insulin in people with type 1
diabetes outweighs its risks. Furthermore, there will always remain a small group
of patients who require insulin replacement therapy in type 2 diabetes. Broadly
speaking, these people are treatment-compliant patients who are already on
maximally tolerated doses of oral agents who still have osmotic symptoms and
weight loss. However, the considerations for insulin in the majority of people with
type 2 diabetes are very different. While hyperglycaemia is associated with
increased risks of death and cardiovascular disease35,36; for the vast majority of
patients with type 2 diabetes there is no unequivocal evidence of benefit from
insulin. At the same time, hyperinsulinaemia is also associated with increased risk
of deathError! Bookmark not defined., and there is mounting evidence from
both controlled and observational studies suggesting that aggressive insulin
treatment in people with type 2 diabetes may be associated with
unacceptable risks. In the meantime it would seem prudent to minimise insulin
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9. resistance through healthy eating, physical activity and other non-
pharmacologic means, and then through non-insulin, anti-hyperglycaemic
drugs.
Including the corresponding article in this edition of Diabetes, Obesity and
Metabolism37, we are aware of at least one other commentaries have published
a similar opinion suggesting that there exists good reason to challenge the
safety profile and the role of insulin in type 2 diabetes38. The order of magnitude
of the differences in event rates emanating from the epidemiological evidence
questioning insulin is such that this matter should be investigated urgently. The
regulatory agencies have a duty to investigate, and manufacturers have a duty
to prove the safety of their products.
Whilst unlikely, it remains theoretically plausible that these concerns are
unfounded. However, until such time that there is clear evidence of relative
benefit in the majority of people with type 2 diabetes, we should aim to use as
little exogenous insulin as possible to achieve reasonable glycaemic control.
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Conflict of interest details: CC wrote the first draft and JJ amended the draft comprehensively.
Authorship details: A statement will be made in the published mansucript.
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