The burden of hypoglycaemia on people with diabetes extends beyond its clinical consequences. Read on to learn about the quality-of-life impact of hypoglycaemia and the unanswered questions that remain.
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Like any diabetes intervention, hybrid closed loops have their strengths and limitations. Read on to learn more about the place of hybrid closed loops in diabetes management.
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The burden of hypoglycaemia on people with diabetes extends beyond its clinical consequences. Read on to learn about the quality-of-life impact of hypoglycaemia and the unanswered questions that remain.
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Dr Ulrik Pedersen-Bjergaard and Dr Elizabeth Seaquist discuss their experiences implementing CGM technology in clinical practice to support patients with diabetes and reduce the incidence of hypoglycaemia
Reducing the risk of hypoglycaemia depends on having the right information—and using it.
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Dead in bed syndrome understandably strikes terror in the hearts of people with type 1 diabetes and their families. Clinicians, for their part, may find it difficult to discuss the syndrome with patients and thus avoid the topic. Fortunately, the syndrome is rare enough that the key message to patients is reassurance. In this insight piece, a globally recognized clinician and researcher suggests how clinicians might handle the topic.
There are very few things more upsetting, in the life of a physician, than having to speak with the parents of a young person who died. I still remember vividly the day I spoke to the parents of a 21 year old who died from ‘dead in bed’ (DIB) syndrome. They had found me on the Internet, and visited me in my city of Sheffield, UK to learn more about the syndrome. In addition to being devastated, they were angry. It seemed that nobody had told them about the syndrome, and they insisted the family should have been warned of the risks.
What followed was a difficult discussion in which I tried to explain the risks and benefits of bringing up the syndrome to young people with diabetes and their families. I noted that this mode of death was very rare and that discussing it was liable to cause disproportionate fear, thus eroding everyone’s quality of life.
At the same time, I took the parents’ words to heart: is there a way for professionals to discuss the syndrome with families without unduly scaring them?
DIB syndrome denotes the sudden, unexplained nighttime deaths of people under 40 with type 1 diabetes. The patient is found dead in an undisturbed bed after having gone to sleep without undue medical concerns. DIB accounts for an estimated 6% of deaths in people with type 1 diabetes under 40.1 It bears noting that death from any cause is infrequent in this group, making DIB a very rare condition. Indeed, a UK survey, in 1991 of all deaths of people under 40 identified 22 deaths consistent with DIB syndrome—fewer than 1 in 10,000.2 What’s more, sudden unexplained death with no cause found at post-mortem can also occur in young people without diabetes, though one study found that it was about 10 times more frequent in diabetes.
While the etiology of DIB syndrome remains unclear and may vary from case to case, evidence to date suggests that the deaths could be caused by disturbances in cardiac repolarization (and thus rhythm) triggered by nighttime hypoglycaemia, with a possible contribution from cardiac autonomic neuropathy. Although epinephrine, produced when the body responds to hypoglycaemia is an important defence mechanism against severe hypoglycaemia, some studies have suggested that it may contribute to abnormal cardiac repolarization. Genetic studies have not uncovered any significant associations to date, though the numbers may be too small to tease out culprit genes.
So how does a physician discuss this frightening but rare syndrome with families? Let’s start with patients with frequent severe nocturnal hypoglycaemic episodes or parents who have witnessed their child having a nocturnal hypoglycaemic seizure. In my view, it is reasonable to ask whether they worry about nocturnal death from severe hypoglycaemia, then move into a discussion of DIB, emphasizing how rare it is.
And what about patients without a history of severe hypoglycaemia? In our current medicolegal climate, it makes sense to at least enquire whether they ever worry about the possiblity that a severe hypoglycaemic episode during the night might have serious consequences. However, the discussion should focus on reassurance.
In all cases, patients should be educated about strategies to minimize the risk. The greater their sense of control, the less likely they will live in fear. Above all, patients should know about measures to avoid nocturnal hypoglycaemia, such as monitoring blood glucose before going to sleep and larger bedtime snacks to compensate for borderline values. Such measures are especially important in people with IAH. The increasing use of continuous glucose monitoring as a clinical tool would provide further reassurance.
In patients with prolonged QT intervals at rest, medications associated with further prolongation should be discontinued. Some studies suggest that medications that act on the renin-antiogensin system, such as ACE inhibitors and angiotensin receptor blockers, have beneficial effects on cardiovascular autoregulation and may thus reduce the risk of DIB syndrome.3
On a health-systems level, coordinated collection of data from people who died of DIB syndrome—for instance, through patient registries—will enable us to identify at-risk individuals and better understand the condition.
Dogs serve an important role in enhancing human health and well-being, from guiding people with disabilities and calming people on the autism spectrum to sensing allergens and other potential medical emergencies—such as hypoglycaemia. The use of diabetes alert dogs (DADs) has been steadily gaining in popularity, and research is yielding new insights into their benefits and limitations. In this article, an expert on hypoglycaemia detection strategies provides a balanced overview of DADs and evidence-based guidance on their use.
Dogs help humans in many ways: they provide companionship, comfort, and motivation to be more physically active. Service dogs go a step further and help people stay safe. It’s hardly surprising, then, that so many people with diabetes have taken an interest in diabetes alert dogs (DADs)—dogs trained to smell chemical changes in the human body when blood glucose falls outside the normal range.
I believe that DADs have value. At the same time, they should not be regarded as a panacea or substitute for vigilant glucose monitoring with reliable technologies. In order to provide informed advice to their patients, health providers need to understand how DADs have fared in scientific studies and to balance this information with the well-established contribution of dogs to human well-being.
Early detection of hypoglycemia is critical for the prevention of more severe and potentially dangerous episodes. Patients and their families, especially parents of children with type 1 diabetes, are understandably eager to find better tools to avoid severe hypoglycaemia. While technologies such as continuous glucose monitoring (CGM) can help in this regard, a growing number of people with type 1 diabetes are turning to DADs, in some cases as a substitute for CGM.
DADs are especially popular with people who have impaired awareness of hypoglycaemia (IAH), defined as a compromised ability to perceive or experience hypoglycemic symptoms. DADs can alert these individuals to check their blood glucose and treat hypoglycaemia before it becomes serious. While DADs cannot and should not replace glucose monitoring devices, they provide an extra layer of protection—at least in theory.
In practice, it can take time and (in some cases) a lot of money to find a well-trained DAD. As with all purchases, caveat emptor applies here, as there are no standards regulating the training and performance of DADs. Ideally, the dog should be no younger than 1.5 years, adequately trained to perform distinct “alert behaviours”, and obtained from an organization willing to provide references from past clients.1
There’s a further reason for caution: while patient surveys and anecdotal reports almost uniformly praise DADs for their ability to detect lows and improve diabetes control,2,3 clinical-trial evidence for the accuracy of DADs remains scant and inconclusive. Here’s what we know so far.
Only a few studies have tested the accuracy of DADs under experimental conditions. In one study, trained dogs were largely unable to identify a “hypoglycaemic scent” in skin swabs obtained from subjects with type 1 diabetes (who were not the owners of the dogs).4 However, a later, similar study found that DADs’ ability to recognize hypoglycaemia in human perspiration samples was statistically significant.5
In a different type of study, 18 DAD owners completed diaries of DAD alerts during the first year after they obtained their dogs.6 Diary readings included daily blood glucose readings and DAD alerts (in response to perceived low or high glucose). Results showed that DAD alerts had a sensitivity of just 57%, with a slightly better sensitivity to low than to high glucose, and a specificity just under 50%.6 In addition, high variability was observed across DADs, suggesting that dog’s detection abilities may vary widely.
Because CGM readings are a reliable method of detecting hypoglycaemia, it makes sense to study how DADs compare to CGM. At least two studies have done just that. In the first, participants reported a high level of satisfaction with their DADs, but the dogs provided timely alerts in just 36% cases of hypoglycaemia (sensitivity), and showed a high rate of false positives.7 Time to detection was also significantly longer with DADs than with CGM (median difference of 22 minutes).7 The second study also found low sensitivity and specificity (with high inter-dog variability), and rate-of-change analyses indicated that the dogs were responding to absolute blood glucose levels rather than rapid changes in glucose.8
Most diabetes health providers already have or will soon have patients interested in using DADs and need to be prepared to discuss the science behind DAD performance in a balanced way. While the evidence to date suggests that DADs are not as accurate as tools such as CGM, an appraisal of DADs must also consider their demonstrated benefits which include improvements in quality of life and diabetes control. . We cannot discount these positive reports and more research is needed to understand how DADs help people to manage their diabetes more effectively.
Impaired awareness of hypoglycaemia (IAH) is a common, frustrating, and potentially dangerous problem for people with diabetes who use insulin. While researchers have yet to unravel the physiological underpinnings of IAH, neuroimaging studies have shed light on how the brain responds to hypoglycaemia—and how these responses may change as IAH sets in. In this article, two internationally recognized experts on the physiology and psychology of IAH review some of the patterns identified in neuroimaging studies and suggest how this knowledge could help lift hypoglycaemia’s clinical burden.
Neuroimaging studies are helping us understand how impaired awareness of hypoglycaemia affects the brain—and mind
Habituation is a physiological blunting process that occurs in response to repeated stimuli. Hypoglycaemia offers a case in point. Normally, the body and brain mount a strong counterregulatory response to a falling blood glucose that helps preserve glucose levels; however, recurrent episodes of hypoglycaemia may blunt this response on various levels, with the result that the affected person does not experience the expected warning signals in a timely fashion. This phenomenon, known as impaired awareness of hypoglycaemia (IAH), affects about a quarter of people with type 1 diabetes and 10% of those with type 2 diabetes who use insulin.
The brain’s responses to hypoglycaemia serve the adaptive purpose of preserving brain function and protecting the brain against structural damage. The progressive loss of awareness, however, is maladaptive in that it impairs the affected person’s ability to self-treat, thus raising the risk that the hypoglycaemia will become severe.
While the pathophysiology of IAH remains unclear, the science of neuroimaging offers intriguing clues. The technology identifies brain regions that become active in response to a stimulus, using a variety of markers—such as localized changes in blood flow or metabolic rate—to detect changes in brain activity. When studied in the context of hypoglycaemic stress, neuroimaging can help us understand some of the brain changes accompanying IAH and help us devise better ways of managing the problem.
In individuals without diabetes, experimentally-induced hypoglycaemia causes several regions of the brain to become active, including the basal ganglia, hypothalamus, pituitary, thalamus, and parts of the frontal cortex. Other regions, especially those involved in forming memories, may become deactivated. Neuroimaging studies have found these responses to differ in people with type 1 diabetes and between those with and without IAH.
In a study of men with type 1 diabetes, for example, subjects with IAH showed subtle differences not only in regions associated with the awareness of physiological responses to hypoglycaemia, but in regions associated with executive control, reward, memory, and emotional significance.1 In addition, differences in operculum activation in the IAH group raised the possibility that this group may be less driven to eat than those with intact awareness of hypoglycaemia.1
Another study involving people with type 1 diabetes found even more striking discrepancies: those with preserved awareness of hypoglycaemia showed changes in prefrontal cortex and angular gyrus activity in response to mild hypoglycaemia, but those with IAH failed to show any such changes.2
These alterations in neural activity have metabolic correlates. In one study, subjects with IAH showed increases in global cerebral blood flow compared to those without IAH and to healthy controls.3 The researchers speculated that “an increase in global cerebral blood flow may enhance nutrient supply to the brain, hence suppressing symptomatic awareness of hypoglycemia.”3 Another study saw brain levels of the non-glucose metabolic fuel lactate fall by about 20% in subjects with IAH—but not in those with normal awareness of hypoglycaemia and people without diabetes.4
Taken together, findings from neuroimaging studies underscore the fact that the experience of IAH goes beyond reduced awareness of symptoms. Affected individuals fail to perceive their condition as unpleasant or dangerous and lack the motivation to treat it. They may also fail to create normal memories of these incidents. These aberrations may prevent patients from engaging in healthy behaviours to avoid hypoglycaemia in the future, thus exacerbating and perpetuating the problem.
Strategies to help people with IAH “override” the perceptual distortions experienced in IAH may be the most effective clinical approach to reducing the occurrence of IAH and of hypoglycaemia itself. As a successful example, a pilot intervention targeting motivation and cognitions in people with resistant IAH (called DAFNE-HART) significantly improved hypoglycaemia awareness,5 supporting the hypothesis that problematic perceptions are key in persistent IAH.
Tight glucose control improves clinical outcomes. While this evidence-based principle continues to guide diabetes management, the truth is not so simple.
Some people with type 2 diabetes may reach glucose targets through lifestyle modification alone, especially in the early years after diagnosis. Diabetes being a progressive disease, however, most of these patients come to rely on glucose-lowering medications, as do all patients witih type 1 diabetes. Some of these medications—especially insulin—incur a substantial risk of hypoglycaemia and its potentially serious consequences. For certain populations, a slavish adherence to strict glucose targets may cause more harm than good and may thus constitute overtreatment.
The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recognized the need to individualize glucose targets in a 2012 joint position statement. The authors of the document maintained that glucose targets “should be considered within the context of the needs, preferences, and tolerances of each patient and that “individualization of treatment is the cornerstone of success.”1
In my experience, however, time pressures and other barriers—especially in busy practices with patients presenting with multimorbid conditions—make it a challenge to individualize therapy. At worst, therapeutic inertia may set in and obscure patients’ changing needs.
When setting glucose targets, factors to consider include age, disease duration, risk of hypoglycaemia and chronic comorbidities. Tight glucose control tends to increase the risk of hypoglycaemia, and recent studies suggest that older adults, in particular, incur significant risks from hypoglycaemic episodes. Indeed, hypoglycaemia accounts for more hospitalizations than hyperglycaemia in older US adults receiving Medicare.2
Despite this very real risk, older people are often encouraged to pursue the same targets as their younger counterparts. In a cross-sectional analysis of over 1,000 subjects with diabetes from the National Health and Nutrition Examination Survey (NHANES), the proportion with a HbA1C less than 7% did not differ based on health status.2 Similarly, health status did not have a bearing on the proportion being treated with insulin or sulfonylureas—medications associated with hypoglycaemia.2
Patients with recurrent hypoglycaemia constitute an especially vulnerable group. Repeated hypoglycaemic episodes promote impaired awareness of hypoglycaemia (IAH), a condition characterized by lack of subjectively perceived hypoglycaemia symptoms. In a study of 153 unselected patients with type 1 diabetes, asymptomatic hypoglycaemic events were tightly correlated with the risk of severe hypoglycaemia, indicating that this group of patients merits particular consideration in clinical practice.3
Patient preferences and attitudes also come into play. In a study estimating the effect of HbA1C reduction on diabetes outcomes and quality-adjusted life years (QALYs), investigators concluded that for most patients over 50 with a HbA1C below 9% on metformin, further glycaemic treatment offers only modest benefits, which are contingent on patient perceptions of the treatment burden.4 By the same token, even small adverse treatment effects may result in net harm in this group.4
My own practice includes nurse practitioners who have more time to spend with patients and who take a holistic approach that considers not just target HbA1c, but patient circumstances and preferences. I have found this approach to support patient motivation and adherence.
Despite the evidence and guideline recommendations for glucose targets, many clinicians delay treatment intensification, resulting in suboptimal glucose control.5 At the other end of the spectrum are those patients being treated to lower targets than required. When individualizing therapy, clinicians need to take into account the risks of hypoglycaemia in groups such as the elderly, the frail, those with IAH, and those with chronic co-morbidities. Patient preferences and quality-of-life issues must also be given reasonable consideration.6
Health providers who manage patients with diabetes need to know not only when to escalate therapy but also to recognize those patients who will get more harm than benefits from tight glucose control. Failure to de-intensify therapy in these patients is as much a form of “therapeutic inertia” as failure to intensify therapy.7 Clinician awareness and education can help counter these tendencies.
Asymptomatic hypoglycaemia (AH) is where clinical and biochemical realities diverge.
Defined as a plasma glucose level below 3.0 mmol/L (54 mg/dL) without any of the typical symptoms of hypoglycaemia, AH tends to occur more commonly in people with a history of frequent hypoglycaemic episodes.1 While not synonymous with impaired awareness of hypoglycaemia (IAH), asymptomatic hypoglycaemia may both lead to and result from IAH.
AH has been recognized since the pre-technological era of diabetes management, and every decade has brought new insights into the phenomenon. In an illuminating 1990 study,2 66 subjects on conventional insulin regimens for type 1 diabetes recorded their blood glucose levels at specified intervals during a 3-week period. Subjects were asked to report whether they “felt hypoglycaemic” at sampling times and to collect extra samples if they felt low at any time during the study period.
The study found that biochemical hypoglycaemia was present in only 29% of the symptomatic episodes, while only 16% of the biochemical episodes were accompanied by symptoms. These dramatic divergences between biochemical and clinical realities underscored the unreliability of symptoms as an indicator of low blood glucose.
Modern-day research has corroborated this reality. Based on accumulated evidence to date, experts believe that AH accounts for up to three-quarters of all hypoglycaemic events in type 1 diabetes. The figure for type 2 diabetes is likely lower.
I have found AH to be particularly frequent in patients with HbA1c in or close to the target range, who do not bring glucose data to the consultation. They may not measure much and may be heavily burdened by AH without knowing it.
While generally mild from a biochemical standpoint, AH episodes still take a toll on the body. It is also worth noting that non-severe bouts of hypoglycaemia, including silent hypoglycaemia, account for a significant minority of expenses associated with diabetes.3
How much does a history of hypoglycaemia play into AH? A recent study addressed the question. The prospective observational trial, which involved 153 unselected subjects with type 1 diabetes, explored the association between hypoglycaemic exposure, AH, and the resultant risk of severe hypoglycaemia.1 Over a 6-day period, subjects underwent blinded continuous glucose monitoring (CGM) and their hypoglycaemia symptoms were recorded, with the proportion of AH events as the main outcome measure.
Most (87%) patients presented with at least one episode of biochemical hypoglycaemia during the study period, with an average of 6 events per patient. Patients were segmented into 4 groups based on the number of hypoglycaemic events during the recording period: 1, 2-3, 4-6 and ≥7 events. These events occurred without symptoms in 57%, 61%, 65%, and 80% of cases, respectively (p < 0.001), demonstrating a significant association between hypoglycaemic exposure and AH. In addition, a higher fraction of AH events predicted a greater risk of severe hypoglycaemia (IRR 1.3, p = 0.003).
Asymptomatic hypoglycaemia remains underrecognized by primary care physicians, who often lack the knowledge and training to ask patients about it. Indeed, a 2012 review of studies on hypoglycaemia found that physicians were not consistently prompting people with diabetes to discuss or track their silent lows.4
Asking patients about their symptomatic episodes—a standard clinical approach—does not uncover the true hypoglycaemic burden. Assessing symptoms and glucose data jointly, as done in the above-mentioned study, is a much sounder practice as it enables physicians to get a sense of the frequency of asymptomatic events, which are associated with IAH and increased risk of severe hypoglycaemia. Particular attention should be given to patients with a history of frequent hypoglycaemia, who stand to derive the greatest benefit from therapeutic strategies to reduce the risk of future episodes.
I always collect SMBG data and try to map the occurrence of AH in the recent data. If I suspect frequent AH, I use blinded CGM together with a detailed diary. This will often lead to interventions such as review of insulin therapy, adjustment of glycaemic target, or behavioural or dietary changes.
