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Is there a link between Lantus (insulin glargine) and cancer? A commentary on reports from the FDA and the EASD on the possible association.

2009-07-02 15:42:54
By: Richard Hellman, MD, FACP, FACE

Recently, four articles and one letter were published in Diabetologica that set the diabetes world into a state of "high alert". The four articles, all observational studies and retrospective population studies, looked at the possible association between insulin glargine and cancer, and showed evidence of a possible association. The FDA has reviewed the data from the studies published in Diabetologica, and concluded that more data collection is needed.

The initial paper by Hemkens et al, was received by Diabetologica on 29 August 2008, but was not accepted until 26 May 2009, and was published only after the journal asked for and received papers from three other registries so a cross-continent, multinational comparison could be obtained. Although the study by Hemkens examined administrative data from more than 127,000 patients, the study was weakened by the fact that there was no randomization of the studied groups, the study was relatively short in duration, and, in this retrospective study, there was a limited ability to directly measure any allocation bias. In fact, the groups under comparison were known to be dissimilar with respect to both weight and age, and very possibly numerous other factors as well, factors that could well affect the relative incidence of cancer.

In the Hemkens study, they noted a dose-dependent relationship between the insulin glargine and the relative risk of cancer, but other observational studies published at the same time did not confirm this relationship. In fact, in the study from the Scottish Diabetes Research group, overall insulin glargine use was not associated with an increased risk of all cancers in Scotland over a four year time frame. But in one subgroup, patients only on one insulin, insulin glargine, there was an excess incidence of both breast cancer and overall cancer. However, the authors concluded that this finding was due to an allocation bias rather than an effect of insulin glargine itself.

Interestingly, in one of the studies reported, there was evidence that with the concurrent use of metformin, the increased cancer risk noted with insulin glargine was not present. This was interpreted as evidence of the cancer protective effect of metformin. In an accompanying editorial, there was discussion of the proposed mechanism by which metformin may reduce the risk of cancer.

Observational studies of the kind reported in Diabetologica are prone to great difficulties in interpretation because of the problems in dealing with confounding variables that are unmeasured. The results of the four studies, when compared, are conflicting in a variety of ways, leaving us in a bit of a quandary.

A much smaller study by Rosenstock and Fonseca et al, published as a letter in Diabetologica, gives data from a randomized trial that compared insulin glargine and NPH, and in a secondary evaluation, examined the incidence of cancer in the two groups over a four year period. They did not find any increased incidence of cancer in the group that was on insulin glargine.

On the other hand, there is clear evidence, from experimental laboratory studies, that insulin glargine has a six to eight-fold increased affinity for the IGF-1 receptor as compared to human insulin. This is associated with an increased mitogenic potency of the same degree (Kurtzhals et al.). Whether this increased affinity to the IGF-1 receptor translates in vivo to an increased risk for cancer was unclear before the articles in Diabetologica, and is still unclear.

What is clear is that high risk populations may deserve special scrutiny, since if in fact there is an increased risk for cancer due to insulin glargine above the well-known mitogenic potency of insulin in some experimental systems, the patients at highest risk for cancers may be the most at risk. Accordingly, there is a need to examine the data that has been obtained from patients on long-term use of insulin glargine and scrutinize it more carefully for any evidence of risk for malignancy.

It would, of course, be unethical to perform a randomized prospective study at this time to examine the questions raised by the studies on insulin glargine, but there may be other methods that will provide useful data that is more powerful than the aforementioned studies. Perhaps the relatively new technique of Mendelian Randomization may be utilized here in order to provide more cogent data. There may be yet other creative ways that are scientifically sound to provide new and useful information for us and for our patients.

It is clear that individualization of patient therapy will remain key. It is unlikely that anyone will have an appetite for the use of insulin glargine during pregnancy. But there may be other groups of patients in which this insulin analogue should also be avoided. At this time, however, the data are too scanty to be sure, and there is no convincing evidence that insulin glargine is unsafe as we are currently using it.

However, we hope that better data will be forthcoming soon so we can see whether Lantus (insulin glargine), which has had an exceptional safety record, will continue to be one of the mainstays of modern insulin therapy, or whether this new information regarding increased risk of cancer with the use of insulin glargine will be validated by more definitive studies. Stay tuned.

Leave a Comment

There are 7 comments

Prasanna Rao-Balakrishna – UK

July 14, 2009 - 17:23

Subject: Preventing Hypoglycaemia is as important as the tight glycaemic control

Preventing hypoglycaemia is as important as the tight glycaemic control. It is important to note that glycaemic control depends on the insulin regimen, patient's own counter regulatory hormone response & insulin resistance status, the calorie intake, frequency of testing for blood glucose, interpretation and acting on the results. During acute illness it is not possible to control the counter-regulatory hormone response and the insulin resistance status, but with adequate training, frequent testing and appropriate structured response should be possible, thereby preventing a hypoglycaemia. A trial which focuses as much on hypoglycaemia avoidance as well as tight glycaemic control is needed.

Reply to Prasanna Rao-Balakrishna

Richard Hellman MD

July 16, 2009 - 11:25

Subject: RE: Preventing Hypoglycaemia is as important as the tight glycaemic control

Dr Rao-Balakrishna makes a very interesting suggestion, that preventing hypoglycemia is as important as the tight glycemic control, and suggests a trial that focuses on two end-points, the avoidance of hypoglycemia as a co-equal goal in importance to tight glycemic control.

In fact, there is a great deal we do not know about hypoglycemia in critically ill states, and it is far from clear what the short and long term consequences are of mild, moderate, or even brief periods of severe ypoglycemia for critically ill patients. We do know that severe hypoglycemia can be a marker for increased mortality, as it was clearly shown in the VADT trial, but interestingly, those deaths did not usually occur during the hypoglycemic episodes, and the relationship between severe hypoglycemia and subsequent mortality was strongest in the conventional therapy group, suggesting that the hypoglycemic events may have been a consequence of an underlying vulnerability rather than the cause of mortality.

One of the limitations of an approach focused just on the outcomes of glycemia is that from the patients' standpoint, the most important issues are their clinical outcomes: mortality, morbidity, and disability. In contrast, those outcomes may not match the relative frequency of hypoglycemia at all. For example, there is a disconnect between the very high frequency of hypoglycemia in the Van Den Berghe RCT's in critical care published in 2001, 2006, and 2009. Both the surgical ICU study of 2001 and the 2009 pediatric studies showed very excellent outcomes with respect to mortaliy and morbidity in the presence of relatively frequent hypoglycemia.

I again would like to thank Dr Rao-Blakrishna for pointing us again to this very unsettled issue of the importance of hypoglycemia prevention, for the debate as to what we can and should do rages on. There are many creative ideas that have been proposed, but we need more data to guide us as to how to obtain the best clinical outcomes with the tools we have without either unacceptably high levels of hypoglycemia or hyperglycemia.

Richard Hellman MD
Editor-In-Chief
Patient Safety Exchange Website

MRR – Texas

March 31, 2009 - 16:29

Subject: NICE_SUGAR

Several interesting points came to mind when I reviewed the NICE-SUGAR study; the degree of severe hypoglycemia, the degree of cardiovascular mortality, the conventional group’s blood glucose levels are significantly lower than the vast majority of other outcome studies, and the number of severe septic patients in the intensive control branch of the study. According to the 2008 sepsis guidelines, the glycemic control target level for the septic patient is already in question and perhaps sepsis should be an exclusion criteria?

I was tasked with the development and oversight of a Tight Glycemic Control Program pilot study from May 2006 through April 2008 for a South Texas community hospital/level 2 trauma center. This included a 14 bed CCU, 12 bed M/S ICU and 12 bed trauma ICU as well as 4 M/S wards. Clinical inertia was our most difficult element to overcome and for the most part this was never accomplished. Clinical inertia was not only evident on physician's part, but also administration, nursing, nutritional services, pharmacy, and the patients themselves. Accountability to noncompliance to protocols was lacking as well. The philosophy that inpatient glycemic control was not necessarily treating diabetes, yet acute hyperglycemia was never fully accepted. When results like ACCORD, ADVANCE, and VADT were released, I would usually take the phone off the hook and leave the hospital because those wbeepdo not support inpatient glycemic control would come out en mass wishing to compare apples to oranges. That is not necessarily the case with NICE-SUGAR. In our Trauma ICU, where support was highest, for the entire year of 2007, we had only 7% BG > 200mg/dL, less than 2% hypoglycemia under 50 mg/dL, and nearly 75% BG between 80 - 150 mg/dL.

Overall, I applaud the NICE-SUGAR research team for a job very well done and thank them for their contribution to this ongoing discussion. I do support further research to differentiate specific glycemic control target ranges for specific diagnosis, but I too fear this could cause a pendulum swing in the opposite direction resulting in less facilities participating in inpatient glycemic control resulting in less data for differentiation.

NISSIM GABAY – VENEZUELA

March 26, 2009 - 15:25

Subject: NICE -SUGAR

I think that the central goal of the ADA/AACE impatient glucose targets is safe with the protocols .
Hospitals should have protocols in place for using insulin to treat and prevent hyperglycemia.
Subcutaneous insulin may be used for both purposes in most noncritically ill patients, whereas intravenous infusion of
insulin is preferred in critically ill patients.
Be careful with this trial [NICE -SUGAR] to overcome clinical inertia.

Dr. Orlin Sergev – Charleston, SC

March 16, 2009 - 16:28

Subject:

Dear Dr Hellman:
I enjoyed all the editorials on patients' safety that you have recently published. I think that they raise questions which we as physicians are not always open about. Safety itself is frequently a topic that we love to discuss but it's never our fault. In this connection, the article about overconfidence and medical errors is timely - especially, at this time of expected health care changes. Briefly, I do not think we as physicians are different from any other specialists in different areas. Lack of adequate knowledge in a special area is always a good reason to be noisy and seemingly overconfident. Most of us agree that the more you know the more you realize how much more you do not know. Overconfident behavior in front of outsiders seem to be the cover of ignorance. I think we have to improve medical education in order to make medical decisions safer. Just remember the pilot of the plane that landed in Hudson river - quiet professional on top of his performance. We in medical profession must lead in patients' safety. In order to do that we have to lead the health care reform. We have to regain our authority, responsibility and accountability. (accountability without authority and responsibility is meaningless - see Dr Hellman's article on Medicare). We have to lead the health education of the society - most of the tragic mistakes in life happen from ignorance. First and foremost, of course, we have to maintain the superiority in medical knowledge. We must improve the quality of medical education. Instead of multiple choice questions we have to put back in place the stern professor wbeepmade clinical judgements based on knowledge, experience, and gut feeling and set up a good personal example for the next generation of physicians. Pilot "Sully" did not read the manual and the guidelines how to handle the critical situation - all his life before, however, prepared him for the right on the spot decision. Decisions based on profound knowledge and experience are the safest! Let's start the health care reform with ourselves.
Do not stop learning and teaching your team about sound and safe medical practices. When we have achieved that, we can confidently go out and regain our authority over various bureaucracies (government agencies-Medicare, insurances, medical malpractice law, etc).

james t poulos – west lafayette in

March 03, 2009 - 15:09

Subject: NICE-SUGAR

There was an article in acta scandinavia in january that showed very little hypoglycemia when intensive therapy is done right! I came across the article on medlinx in mid January, but it was actually published in October 2008. authors: Kaukonen KM et al in acta anaethesiol scandinavia and titled severe hypoglycemia in intensive insulin therapy.

Reply to james t poulos

Dr Hellman

March 04, 2009 - 16:12

Subject: Further thoughts related to the NICE-SUGAR study

Dear Dr. Poulos,

Thank you for calling attention to the study by Kaukonen KM et al. Your excellent point adds to the discussion generated by the NICE-SUGAR study. Their preliminary data analysis showed that error by provider was the most common cause of hypoglycemia. Their data implied, as I stated in my recent editorial, that improving the training and performance of those managing the insulin infusions greatly decreases the threat of hypoglycemia.

In this study by Kaukonen, done at the Helsinki University Central Hospital in Helsinki, Finland, the authors evaluated the incidence of hypoglycemia in all patients treated in two intensive care units between February 2005 and June 2006. They showed that severe hypoglycemia during intensive insulin therapy was rare in clinical practice. Analyzing data for 1124 patients and 61,203 glucose measurements, they found 36 measurements of severe (≤ 2.2mmol/L) hypoglycemia in 25 patients, with an incidence of 0.06% of severe hypoglycemia.

They commented that the frequency of blood glucose monitoring correlated inversely with the frequency and magnitude of severe hypoglycemia. In surgical patients, it is of note that five of the six instances of hypoglycemia occurred when a nurse failed to comply with the protocol.

The Helsinki group’s observations are entirely in keeping with the preliminary data from the NICE-SUGAR study and make a good deal of common sense. When the rate of decrease of glucose is rapid, for example greater than 1mg/dl/minute, simple arithmetic can tell us when the next glucose determination needs to occur to be able to safely avoid severe hypoglycemia. But if the frequency of checking of glycemic levels is arbitrary, and set too low, then hypoglycemia is to be expected much more often. The Kaukonen group avoided this by making sure the blood glucose sampling was relatively frequent.

In our clinical practice setting as well, the principles of safe handling of insulin infusions have been:

1.frequent monitoring, always at least hourly in ICU settings, more often when dealing with lower glycemic levels;
2.intensive training of nurses to make them expert in understanding how best to use algorithms;
3.specific points at which prolonged hyperglycemia or hypoglycemia necessitates immediate consultation with the responsible physician;
4.review of data to indicate variations in performance and appropriate correction and retraining when appropriate.

We too have extensive experience over many years with the safe use of insulin infusions in inpatient settings with relatively rare severe hypoglycemic episodes and little morbidity.

The NICE-SUGAR study should provide important information. We should not get too far ahead of their forthcoming data, but there is already abundant data, such as the important study from Helsinki, which show us that with a safer system of care, more ambitious glycemic control is both achievable and safe.

Kaukonen KM et al. Severe hypoglycemia during intensive insulin therapy, Acta Anaesthesiol Scand. 2009 Jan;53(1):61-65. Epub 2008 Oct 20.