COMMENTARY

Why Is Hypoglycemia So Dangerous?

Tight Glucose Control Raises Concerns About Complications

Leszek Czupryniak, MD, PhD; Brian M. Frier, MD

Disclosures

October 24, 2012

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Leszek Czupryniak, MD, PhD: Hello. My name is Leszek Czupryniak, and we are in Berlin for the 48th annual meeting of the European Association for the Study of Diabetes. Our guest today is Professor Brian Frier from Scotland. He is a world expert on hypoglycemia in diabetes.

Hello, Professor Frier. It is an honor to have you here. Hypoglycemia has increased in importance in recent years. For years, we knew that it was there, but we didn't think it was as important as we do now. What happened to change the view on the importance of hypoglycemia, and what do we know about the risks associated with it?

Brian M. Frier, MD: I am very pleased that you have decided to focus on this area of hypoglycemia, because it is a major problem in many patients who are treated with insulin as well as sulfonylureas, and this has become apparent in recent years. Beforehand, it was thought to be solely related to the use of insulin in type 1 diabetes, but it is now quite clear that many patients with type 2 diabetes, particularly those on insulin and intensive therapy, are exposed to frequent severe hypoglycemia. The recent trials that you mentioned -- ACCORD, ADVANCE, and VADT (Veterans Affairs Diabetes Trial) -- have highlighted this.[1,2,3] Hypoglycemia has been considered a potential cause for the excess mortality seen in ACCORD and possibly also in VADT.

Dr. Czupryniak: Yes, but studies or deeper analysis of this data are needed to show whether hypoglycemia is especially harmful for select patients or not all of them. Hypoglycemia would not kill everybody; it's not that simple. There are probably people who would be at greater loss having suffered hypoglycemia than others. Am I right?

Dr. Frier: You are right. The data that have emerged from the studies are very complex and difficult to analyze, but they have made us look again at why people may die from this complication. It would appear that the main cause of death is cardiac. Neurologic death, brain death occurring from hypoglycemia, is actually relatively rare. The brain is very resistant to protracted neuroglycopenia, and from anecdotal accounts it would appear that you need to have at least 6 hours of exposure to very deep hypoglycemia before you get permanent brain damage and subsequent death. What is much more likely is that hypoglycemia is causing cardiac arrhythmia, cardiac ischemia, or exacerbating cardiac failure in people who have already established macrovascular disease and ischemic heart disease. As you know, in many people with type 2 diabetes, it is asymptomatic. They don't have symptoms of angina to alert you to the fact that they have this problem.

Dr. Czupryniak: When I look at data from ACCORD and the publications that came afterwards and then see new drugs coming into the market, I feel that any new innovative treatment for type 2 diabetes should be free of hypoglycemia risk. Do you think that is the direction in which we are going -- that hypoglycemia will be recognized as a frequent and sometimes deadly complication, and the pharmaceutical companies would rather look to develop drugs that have minimal or no risk for hypoglycemia?

Dr. Frier: This is undoubtedly an aspiration. If we could have medications that have no risk for hypoglycemia, that is clearly advantageous. Unfortunately, many patients with type 2 diabetes advance to a stage where none of these oral or injectable agents are effective, and there is no choice but to put them on insulin. We have seen in recent studies that the longer they are on insulin, the greater their risk for hypoglycemia. I think we have to then decide what level of glycemic control is acceptable and safe in people, particularly those who are at high risk. I am talking about people with established ischemic heart disease.

Dr. Czupryniak: This was the subject of a session that you took part in. There was a session on mortality and hypoglycemia. I can't remember any session like this in previous years. It is a clear acknowledgement of the importance of the problem.

Dr. Frier: Yes. I think it is a very good thing from a clinical point of view to appreciate that the selection of treatment and intensification of control comes at a potential risk. It is hazardous in certain patients. I don't wish to give the impression that we should not strive for good glycemic control in our patients. Certainly, in the early stages of type 2 diabetes and in all young patients with type 1 diabetes, that is the aim, the goal. But once people have reached a fairly advanced stage of type 2 diabetes and they have a lot of macrovascular disease, whether it is silent or not, then we have to be very careful. What I think ACCORD has shown is that there are potential dangers associated with certain types of treatment. Insulin is clearly the major one. You have mentioned drugs like sulfonylureas. They do have a place in treating type 2 diabetes, but in the older patient who is frail and may have a lot of other comorbidities, they might be dangerous. What emerged from the symposium yesterday was that there are different types of problems that arise in the young patient with type 1 diabetes. There is a recognized syndrome called dead-in-bed syndrome. It is relatively rare, but it is probably caused by cardiac arrhythmia induced by nocturnal hypoglycemia. In type 2 diabetes, we enter not only the cardiac arrhythmia problem but that of cardiac ischemia. There is increasing evidence to show that coronary blood flow may be compromised during hypoglycemia in older patients.

Dr. Czupryniak: That is all fascinating. Diabetes treatment is, in a way, becoming easier because we have many more agents now than we did 10 years ago. On the other hand, it is getting more complex and complicated. The decisions we have to make as physicians or clinicians are much more burdensome in thinking and responsibility.

Dr. Frier: The bottom line at the moment is that we must tailor the treatment to the individual, which means looking at the patient characteristics in detail before deciding on particular glycemic goals or intensifying therapy. Otherwise, we run the risk of exposing them to the dangers, morbidity, and potential fatal consequences of hypoglycemia.

Dr. Czupryniak: It is more complicated for us but definitely much more beneficial for the patient. Thank you very much, Professor Frier, for sharing your thoughts on the latest data on hypoglycemia risk in diabetes.

Dr. Frier: Thank you.

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