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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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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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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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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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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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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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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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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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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.