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At this point, the Diabetes Control and Complications Trial's (DCCT) finding that intensive insulin treatment reduces the number of long-term diabetes complications is, hopefully, only news to the recently diagnosed. What is less commonly known is that the same tight BG control that reduces the risk of complications has a darker side. The intensive insulin therapy (IIT) described by the DCCT presents a three fold risk of severe hypoglycemia - sometimes with dire consequences.
The DCCT Research Group published this finding in their original report and in a subsequent report in 1995. Now doctors and researchers are developing a greater respect for the potential dangers of hypoglycemia.
What is Hypoglycemia?
Hypoglycemia is the term used to describe a low blood glucose level (BG). All people with diabetes, regardless of type or their method of treatment, suffer from hyperglycemia (high BGs) when left untreated.
In type I diabetes, BGs run high because the pancreas is unable to produce insulin to process sugars for energy. In type II diabetes, the body has become resistant to insulin over time. The body can, in most cases, still process sugar, but not very efficiently. As a result, the sugars awaiting processing cause BGs to run high.
Chronic high BG levels result in a number of diabetic complications from retinopathy to kidney disease. As a result, a number of therapies have been created to keep hyperglycemia in check. It is some of these therapies that cause hypoglycemia, not the disease itself.
1993 saw the publication of the Diabetes Control and Complications Trial (DCCT). The trial revolutionized the treatment of type I diabetes, causing doctors the world over to aim for lower BGs for their patients.
Patrick Boyle, MD, associate professor at the University of New Mexico, was one of the DCCT researchers. He claims, "This [severe hypoglycemia] is an enormous problem and it is becoming more common across the world as people push harder to control their diabetes." As a result of aiming for lower BGs, "we saw a lot of seizures, comas and spouses trying to wake up their partners at night," he continues.
In 1995 the DCCT Study Group released the report, "Adverse Events and Their Association With Treatment Regimens in the DCCT." In this report, and the original study write-up, the authors noted that the intensive therapy that provides such powerful protection against the microvascular complications of diabetes also results in a "threefold increase in the risk of severe hypoglycemia with potentially serious [consequences]." Severe hypoglycemia was defined as seizure, coma or any disorientation or confusion requiring the assistance of another person.
Consequences of Hypoglycemia
A severe hypoglycemic event has a number of consequences. Some are well understood, others are surrounded by controversy. Hypoglycemia can result in accident and injury. Other times it can result in hypoglycemia so severe it can be fatal. Repeated episodes of hypoglycemia appear to affect a person's ability to recognize the warning signs of approaching attacks in the future. Some researchers have even claimed to have found evidence that hypoglycemia may affect brain function.
The easiest to imagine consequence of severe hypoglycemia is an accident caused by confusion or possible unconsciousness.
On August 29, 1996, the Wall Street Journal, in an article entitled "Patients Who Carefully Manage Diabetes May Face Hidden Risks to Their Health," reported the story of a pregnant woman with diabetes who drove into a tree at 73 miles per hour. According to the article there were no skid marks. "She evidently just passed out, and her foot hit the accelerator," said the victim's grieving father.
In May of 1997, an Ann Landers column featured a similar story. A woman was killed, and her fianc_ received permanent brain damage in a car accident caused by a man with diabetes who had gone unconscious at the wheel.
Stories like this are becoming more common and are a cause for great anxiety for people with diabetes on IIT. These tragic stories lead to the question, How common is this?
Even though the IIT patients had three times as many hypoglycemic reactions, the DCCT Study Group found no significant difference between the accident rates of the IIT and standard therapy groups.
The DCCT report points out that the similar accident rates of the two groups, despite their strikingly different rates of hypoglycemia, might be attributable to "the particular emphasis clinical staff placed on avoidance of hypoglycemia during driving."
The report continues, "Early in the study all of the clinics developed individual educational programs aimed at preventing hypoglycemia while operating a motor vehicle." These programs instructed patients to always check their blood sugars before driving, immediately stop driving at any signs of hypoglycemia, have a carbohydrate in the car at all times, and to test BGs frequently on long trips. Many type Is on IIT may get these same warnings at sometime or another, but whether or not they are presented as often or in as powerful a way is unknown.
Some research estimates that between four and 13 percent of the deaths of people with type I diabetes are the result of hypoglycemic events. "What's worrisome about these deaths is that they are due to the treatment," says Philip Cryer, MD, FACP president of the American Diabetes Association (ADA).
One especially frightening possibility for people on insulin that may be the result of severe hypoglycemia is what the journal Diabetic Medicine referred to in 1991 as "dead in bed syndrome." Victims of the syndrome are found dead in an undisturbed bed, observed to have been in good health the day before and are free from evidence of late diabetes complications.
As is the case with accidents, it is very hard to determine if these deaths are the result of hypoglycemia. Researchers in the U.K. note, however, that the timings of the deaths and other circumstantial evidence suggests that hypoglycemia or a hypoglycemic event is responsible.
There are major problems with diagnosing hypoglycemia after death (see page 18). Cryer explains that testing the blood sugar of someone found dead after an accident or mysterious death that appears to be the result of hypoglycemia "is of zero value." He explains that the body will continue to process glucose for some time after death. As a result, the BG of a person after death will most likely not be an accurate reflection of their BG prior to death.
Hypoglycemia and Cognitive Function
Of all the possible effects of hypoglycemia the most hotly debated is its effect on brain function. Some researchers and doctors claim that hypoglycemia has no detrimental effect on cognitive function. Others claim to have found evidence to the contrary.
The DCCT Study Group found that, "Despite their increased frequency of severe hypoglycemia, ... intensive treatment group subjects showed no trend toward worsening neuropsychological or cognitive functioning over time."
A clinical study, published in 1994 in the Journal of Neurology, Neurosurgery and Psychiatry, found no difference in brain function between patients with a history of more than 10 hypoglycemic comas and those without such events. The authors claim that their data suggest that IIT, "although increasing the frequency of hypoglycemic coma, may not always be harmful for the brain." They offer the possible explanation that this may be due to the limited duration of hypoglycemic coma.
Howard McEwen, MD, FRCP(C), FACP, a recently retired clinical professor of medicine at the University of Calgary has over 40 years of experience with insulin and type I diabetes. He claims to have noticed "no chronic damage to the brain" in his patients after the adoption of IIT.
Despite these findings, other researchers claim that their work shows that severe and recurrent hypoglycemia can cause mild deterioration of cognitive function. In addition, there is strong evidence that recurrent hypoglycemia leads to more hypoglycemic unawareness, a serious risk for people on insulin therapy.
A 1996 study published in Diabetes Care found a significant correlation between IQ discrepancy (before and after hypoglycemic events) and the reported frequency of severe hypoglycemic events. They note that their findings should be interpreted with caution and that "it was not always clear whether the cognitive impairment is an effect of severe hypoglycemia or a cause."
Authors of a 1997 study in the Journal of Clinical Endocrinology and Metabolism claim their work supports the theory that hypoglycemia impairs brain stem function.
Some of the strongest recent evidence in support of adverse effects of hypoglycemia on the brain comes from an article in the June 1997 issue of Diabetes Care. Using magnetic resonance imaging (MRI) researchers found that cortical (brain) atrophy was present in 45 percent of type I test subjects with a history of recurrent severe hypoglycemia. Cortical atrophy was nonexistent in type I subjects without such a history.
The authors of the study claim that "in contrast to the reassuring DCCT results" the association supports the hypothesis that hypoglycemia is detrimental to the brain. These "degenerative structural changes of the brain ... may, in a few individuals, promote cognitive dysfunction," they say.
Regardless of the association between hypoglycemia and brain function, the researchers also found that these abnormal MRIs were far more prevalent in type Is than in the nondiabetic population of comparable age (35 to 52 years old). The abnormalities discovered are normally associated with aging and are extremely rare in subjects of this age. The data suggest that they may "be a feature of diabetes and may represent accelerated brain aging associated with the metabolic disorder," they claim.
Why the Disagreement?
A review article in Diabetic Medicine, the journal of the British Diabetic Association, suggests that the inconsistencies may be the result of different researchers using different measurements.
Researchers investigating this issue use a wide range of methods for measuring cognitive function and inducing hypoglycemia, the authors note. They believe that "progress could be made if all groups agreed on a limited range of cognitive function tests and used them in a standardized manner."
Cryer explains that the primary debate surrounding the current research on hypoglycemia and brain function may be the result of technological short comings. The evidence is conclusive that people on IIT with HbA1cs closer to the non-diabetic range "require lower BG levels than non-diabetics and the poorly controlled to experience the symptoms of hypoglycemia," says Cryer. He also mentions that effectively controlled IIT patients require lower BG levels to trigger the counter-regulatory response of hormones like epinephrine.
The controversy, says Cryer, is whether or not these well controlled patients require lower BG levels to experience impaired cognitive function. He concedes that the answer may have to wait until more precise tools are available to measure these aspects of hypoglycemia.
The authors of the Diabetic Medicine article agree. They concede that definitive studies of hypoglycemia's effect on cognitive function "may have to await the development of advanced technology such as high resolution MRI or PET scanning."
It should be noted that very little is known about the consequences of hypoglycemia on children. Boyle points out that no subjects of the DCCT were under 14-years-old. Many researchers agree that the consequences of hypoglycemia could be much worse for children, however, because their brains are still developing.
A major disadvantage of repeated hypoglycemia is its effect on hypoglycemic awareness. A study from the journal Diabetes found that the enhanced rates of cerebral blood flow found at the onset of hypoglycemia are associated with a diminished perception of low blood glucose levels and weakening of the hormonal counter-regulatory response.
Generally, more severe hypoglycemic events equal more hypoglycemic unawareness. This can be remedied however.
According to Cryer, three separate studies have shown that hypoglycemic unawareness is "largely, if not entirely, the result of multiple hypoglycemic reactions." Two of these three studies also showed that as little as two to three weeks of "scrupulous avoidance of hypoglycemia will reverse hypoglycemic unawareness," says Cryer.
Some believe that hypoglycemic unawareness is made more extreme when people are switched over from animal to human insulin. In fact, the package inserts of the two companies marketing insulin in the U.S. have warnings about human insulin. "A few patients have reported that after being transferred to human insulin, the early warning symptoms of hypoglycemia were less pronounced than they had been with animal-source insulin," reads the warning from one of these companies. (The warning for the other company's human insulin is almost identical.)
Some people who use insulin (and the doctors that care for them) believe that they are better controlled on animal insulin rather than human insulin.
The Bellagio Report, published in 1996 by the Insulin Dependent Diabetes Trust (IDDT) in the U.K., recommends that those "who are at increased risk of hypoglycemia such as children, the elderly and those reporting frequent hypoglycemia should be prescribed natural animal insulins which are absorbed more slowly and have a slower onset of action."
Others believe that the apparent effects of human insulin on hypoglycemia and hypoglycemic unawareness may not be directly attributable to the insulin.
Cindy Onuffer, RN, MA, CDE, views reports of human insulins leading to more cases of hypoglycemic unawareness with caution. She says that, in her experience, those who originally start on human insulin don't seem to have more hypos than those on animal. In addition, she notes that when patients are switched from animal to human the switch may be accompanied by other changes in their treatment plan, like a switch from standard to intensive insulin therapy, instructions to change injection sites, or more frequent BG monitoring. "When more than one variable is changed [in an insulin treatment regimen] one has to be very careful about attributing reactions to just one of those variables," says Onuffer.
In addition, John Walsh, PA, CDE, points out that human and animal insulins have different times of action that may require modification of doses. He claims that many of the problems attributed to human insulin may be the result of neglecting to take these differing times of action into account.
Others agree with this caution but feel from experience that animal insulin provides better control for many patients. McEwen notes that he has had "plenty of patients who kept exactly the same treatment measures [after switching from animal to human] and have refused to stay on human" after experiencing more frequent hypoglycemia and hypoglycemic unawareness.
What Can be Done?
A study by Bruce Bode, MD, published in 1996 in Diabetes Care suggests that pump therapy can greatly reduce the incidence of severe hypoglycemia. The study documents a more than six-fold decline in the incidence of severe hypoglycemia during the first year of pump therapy. The rate remained significantly lower in the three year follow up as well.
DCCT researcher Patrick Boyle, MD, mentions that two clinical studies have also shown that severe hypoglycemia can be reduced by more frequent BG testing. In these studies, the participants received a great deal of attention and support from the researchers. They were called on the telephone up to three times each day and reminded to test their blood sugars. The research team also provided detailed and repeated instruction on how to time insulin injections in relation to food and activity. Boyle points out that this relationship is something that people on insulin can't learn enough about if they want to effectively prevent hypoglycemic reactions.
While Boyle realizes that this level of patient support is unrealistic for the everyday management of the 800,000 type Is in the U.S., he believes that an important lesson can be learned. It illustrates to patients and healthcare professionals that more testing and greater knowledge of how different factors affect insulin action equals more protection against severe hypoglycemia.
There are no easy answers on how to deliver this level of education and support for those working to achieve tight BG control. But Cryer sums up the current situation best in a review article published in Diabetes Care.
"To achieve and safely maintain near normoglycemia in most people with [type I diabetes] we must learn to deliver insulin in a much more physiological fashion, or learn to prevent, correct or compensate for [hypoglycemic unawareness]," he says.
"Pending such advances, application of the principles of current insulin therapy, including patient education, self-monitoring of blood glucose, and professional support, must be coupled with prudent glycemic goals to minimize the frequency of severe hypoglycemia without completely compromising metabolic control," adds Cryer.
Hypoglycemia is a multifaceted aspect of diabetes. It is affected by a great number of factors, and a great deal is yet to be learned. What is known is that hypos are the result of certain diabetes treatment regimens, and repeated episodes make hypoglycemic unawareness more pronounced.
Unfortunately, there is a lack of definitive clinical evidence documenting the consequences. But, as long as those at risk are aware of the causes of severe hypoglycemia and the potential risks involved, they can discuss these with their healthcare professionals and make their own decisions regarding their treatment regimens.
The intention of bringing up the potential risks of IIT is not to scare people away from the benefits of achieving tight control. The DCCT's findings definitively show that tight BG control drastically reduces the incidence of eye, kidney and nerve damage caused by diabetes.
Instead, the information should illustrate the importance of avoiding severe hypoglycemia, while still trying to maintain tight BG control. Each contributor to this article expressed the opinion that avoidance of hypoglycemia should not come at the expense of good control. They claim that, in light of the current clinical evidence, the benefits of tight control still outweigh the potential risks of severe hypoglycemia in most cases.
Their advice is to test more often and come to a better understanding of how BG levels are influenced by meals, physical activity, stress and the number of other factors that affect blood sugars.
"The majority of hypoglycemic events observed in the DCCT occurred at night. For that reason, patients should check their BG levels before bed and not go to sleep unless their BGs are in a good, safe range," adds Linda "Freddi" Fredrickson, MA, CDE, RN.