The discussion surrounding the long-acting insulin analogue, Lantus®, has left many parents wondering: Do people with diabetes really carry a higher risk of cancer? What role do insulin analogues play in all this? Professor Thomas Danne explains why there is no need to worry. 

It has long been known that people with type 2 diabetes are more likely to suffer from cancer of the breast, colon, or the pancreas. Overweight and lack of exercise not only promote the development of type 2 diabetes, but also various forms of cancer. Insulin functions as a growth factor. Because, in type 2 diabetes, the organs become less and less sensitive to insulin, the blood has to constantly carry increased levels of the hormone – sometimes for years before diagnosis. This is why it is so important to change eating habits and lifestyle with diabetes.

In type 1 diabetes, however, overweight and elevated insulin levels (insulin resistance) hardly play a role. Therefore, the outcomes of controversial studies are, for children and adolescents, irrelevant.

Authorities Give the All-Clear 
Triggering this discussion about cancer and diabetes was an article published in the journal ‘Diabetologia’ by the Institute for Quality and Economy in Health Care (IQWiG). The study involved diabetes patients being solely treated with the long-acting insulin analogue, Glargine (trade name: Lantus®). They were claimed to suffer more frequently from cancer than other patients on other insulins. Closer investigations into the data revealed so many flaws that not only the German organization, diabetesDE, but also national and international diabetes Associations saw no reason for anybody with diabetes to have to alter their present therapy on the basis of the results of this study.

On the 23rd of July, four weeks after the study was published, the European Medicines Agency (EMEA) made an official statement. It stated that, in view of the data presented, they see no reason for concern and no reason for physicians to change their prescription patterns.

Above all, the experts criticized the choice of patient groups that were compared, as well as how the study results were adjusted. Without these particular alterations, the results revealed a much different picture. In fact, there was no increased risk, but a decreased risk of cancer with Glargine. Even the risk of death using Glargine was found to be less than in the comparison groups.

Why Insulin Analogues?
The molecules of insulin analogues have been altered from human insulin to form rapid-acting insulin analogues (Lispro (Humalog®, Liprolog®), Aspart (Novorapid®), Glulisin (Apidra®)) – that act fast with a short effect, making it easier to fine-tune the blood sugar levels, especially in relation to meals or when using a pump – and long-acting insulin analogues (Glargine (Lantus®), Detemir (Levemir®)), which, on the other hand, are used to achieve a longer and more steady effect and, when used as a basal insulin, protect against hypoglycaemia.

Children especially profit from the fact that there are insulins with two different profiles, because when and how much kids eat is so difficult to plan.

Insulin Must Not Stick!
Right from the beginning, in view of their unique effects, much attention has been paid to the safety of insulin analogues, especially regarding carcinogenic risks. Indeed, the very first insulin analogue, B10Asp, which underwent extensive investigation, did show indications of cancer risk in rats, hence it was never tried on humans. However, it was quickly determined as to what caused this effect: B10Asp adhered longer than conventional insulin to the insulin receptors in the cells, responsible for the blood-sugar lowering effect of the insulin. As a consequence, instead of lowering blood sugar, the receptors switched their role to growth promotion.

In the development of the succeeding insulin analogues, this problem was eradicated. The insulin analogues used in humans today bind to the insulin receptors for a short time only. The differences in the onsets of action are dependent upon the uptake of insulin in the fatty tissue or in the bloodstream. 
Another issue is that insulin has the ability to bind to the insulin-like growth factor (IGF), which activates cell division. For people on insulin, however, this binding capability is of no importance because the dosages used in insulin treatment are too little. The growth factor IGF-1, that normally docks onto the receptor, is present in much higher levels in the body than insulin. Even large swings in insulin levels, which can occur, for example, by an accidental overdosage, would have no effect upon these receptors.  

Cell Cultures React Differently 
Laboratory conditions, however, present another story. Here, the effect of insulin and insulin analogues can be examined on cell lines. In this case, the insulin analogue, Glargine, reveals a higher tendency for cell proliferation compared to human insulin. The amounts of insulin used in these studies, however, as well as the types of cells, render the findings inapplicable to patients. In any case, and after extensive investigation, the experts and supervisories have established that the use of insulin analogues pose no safety risk in children.

More Security with Fewer Hypos 
Like with all new medications, a high degree of attention must be paid to its possible advantages and disadvantages. As the analogues have been in use for over 10 years now, much experience has been gained. One must consider that long-acting insulin analogues such as Glargine are known to reduce the frequency of hypoglycaemia. This, in contrast to human insulin, gives the user a higher degree of security. This was also acknowledged in the recent IQWiG’s report.

Switching from a long-acting insulin analogue such as Lantus® to human insulin with an intermediate duration of action (NPH insulin) leaves the patient more vulnerable to dangerous hypoglycaemic events. Furthermore, one can expect the fasting blood sugar values to deteriorate, especially in those patients in which even the longer acting human insulins are not sufficient for the whole night.  

Physical Exercise Reduces Risk 
In general, the whole discussion on diabetes and cancer underlines the importance of physical exercise. In obese women, for example, the risk of breast cancer doubles. Many studies have shown that diet alone is not enough to combat this risk. The combination between regular physical exercise and a reduced caloric intake reduces cancer risk in overweight people. One also mustn’t forget the subject of screening for early detection. This is particularly important for people with type 2 diabetes, who should make time for these check ups. The earlier cancer is detected, the more effective the treatment, and the higher the chances of recovery. 

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Professor Thomas Danne MD
Editor-in-Chief
Paediatric Diabetologist, 
President 
German Diabetes Association (DDG), and 
diabetesDE