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Category: Insights

Pediatric Diabetes

Children and teens are a lot of wonderful things. “Easy” is not one of them. When dealing with pediatric diabetes, clinicians should prepare for a different clinical picture, different behaviours, and different thresholds for hypoglycaemic symptoms. They should also anticipate a high level of parental stress and worry. With decades of experience treating and researching pediatric diabetes, Tim Jones describes salient issues in pediatric diabetes and hypoglycaemia management—and offers guidance to clinicians treating this population.

Physicians treating pediatric diabetes are a bit like veterinarians: unable to count on their young patients to describe symptoms and feelings, they must rely on third parties (i.e. parents, caregivers, pet owners) to fill in the clinical picture. Parents, for their part, face the daily challenge of subduing their children’s restless energy and willfulness in the service of diabetes management.

Not just small adults

Children with diabetes differ in several obvious ways from their adult counterparts. For one thing, their organs are still “under construction”—including that all-important pancreas—and their body systems haven’t matured yet. Accordingly, children may differ from adults in their response to dropping blood glucose—for example, developing a counterregulatory response and subjective symptoms at a higher glucose level than adults.

Children’s behaviour can also complicate diabetes treatment: think of the toddler who refuses to eat after an insulin dose or the preschooler who won’t sit still for a shot. To add a further layer of complication, odd behaviours in children don’t necessarily mean the same thing they do in adults. An adult speaking incoherently raises immediate red flags for hypoglycaemia. A babbling or sputtering child, meanwhile, could be showing signs of low blood glucose—or simply be playing make-believe.

As parents know all too well, adolescence brings its own set of diabetes management challenges. Embarrassed at the mere thought of a hypoglycaemic episode, a teenager may prioritize hypo avoidance over meeting glucose targets. Some teenagers may loosen their vigilance in general, putting themselves at risk of harmful glucose swings in either direction. In fact, the DCCT trial revealed severe hypoglycaemia to be more prevalent in young people than in adults. At the same time, clinicians and parents can find reassurance in knowing that, despite the higher rates, long-term cognitive function did not decline in the youngest cohort of DCCT patients.1

Child-friendly approach

While plenty of adults thrive on diabetes gadgets and gizmos, it’s in children that the technology really comes into its own. By automating key functions of diabetes management, high-tech aids such as insulin pumps and continuous glucose monitoring (CGM) systems sidestep many of children’s unpredictable and confusing behaviours. Several pediatric studies have also found technology to yield modest gains in glucose control. In an analysis of over 16,000 children participating in the type-1 diabetes SWEET registry, for example, pump-treated children had lower HbA1C and required less insulin than children on multiple daily injections.2

As the technology keeps improving, so too do the options for high-tech interventions. In a study conducted earlier this year, children with type 1 diabetes used a remote monitoring system that let them share weekly information about blood glucose, insulin delivery and physical activity with their medical teams. Compared to the control group of conventionally managed children, the remotely monitored group experienced better glucose control and quality of life over the course of the 6-month study.3

Parents may need treatment, too—for anxiety. While it’s natural for the parent of a child with diabetes to worry about hypoglycaemia, the worry often becomes all-consuming, thus weakening the parent’s effectiveness as a guide and steadying force. As several studies have found, this fear of hypoglycaemia (FOH) can compromise diabetes control itself. In one such study, published in the journal Diabetic Medicine, parents with significant FOH-related distress had children with higher blood glucose levels. Perhaps surprisingly, these children also had a higher frequency of problematic hypoglycaemic episodes in the past year.4

For clinicians, monitoring the frequency and severity of hypoglycaemia in patients with diabetes is simply part of good care.  It also falls to physicians to explore whether parents are fearful of hypoglycaemia as not all parents will readily admit it. If FOH is an issue, clinicians and diabetes educators need to arm parents with strategies to bring the anxiety down to manageable levels. Proven approaches include systematic hypoglycaemia education and cognitive behavioural therapy to address the FOH head-on.5 At the same time, parents need to be warned that an episode of severe hypoglycaemia puts the child at increased risk of a further episode.

Parents also play a crucial role in helping their older children transition to self-management. If the parent has always taken responsibility, some children may reach adolescence without understanding hypoglycaemia. Parents should be encouraged to provide age-appropriate explanations to their children and help them transition to self-monitoring and self-care.

It goes without saying that anyone involved in caring for the affected child—from parents and babysitters to teachers and daycare workers—should have an action plan to deal with hypoglycaemic episodes. When people have the right information, they feel more in control—and stress levels go down all around.

References

  1. Musen G et al. Impact of diabetes and its treatment on cognitive function among adolescents who participated in the Diabetes Control and Complications Trial. Diabetes Care 2008; 31:1933.
  2. Szypowska A. Insulin pump therapy in children with type 1 diabetes: analysis of data from the SWEET registry. Pediatr Diabetes 2016; Suppl 23:38.
  3. Gandrud L et al. Intensive remote monitoring versus conventional care in type 1 diabetes: A randomized controlled trial. Pediatric Diabetes 2018; 19:1086.
  4. Haugstvedt A et al. Fear of hypoglycaemia in mothers and fathers of children with Type 1 diabetes is associated with poor glycaemic control and parental emotional distress: a population-based study. Diabet Med 2010; 27:72.
  5. Driscoll KA. Fear of Hypoglycemia in Children and Adolescents and Their Parents with Type 1 Diabetes. Curr Diab Rep 2016; 16:77.

Dead in bed syndrome

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?

What and why

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.

Balanced discussion

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.

References

  1. Dead in bed syndrome. Diabetes.co.uk. Accessed at https://www.diabetes.co.uk/diabetes-complications/dead-in-bed-syndrome.html
  2. Tattersall RB, Gill GV. Unexplained deaths of type 1 diabetic patients. Diabet Med 1991; 8:49-58.
  3. Weston PJ. Dead in bed syndrome: a review of the evidence. Diabetes Manage 2012; 2:233-41.

The Sniff Test – Benefits and limitations of diabetes alert dogs

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.

The role of DADs in hypoglycaemia

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

The evidence

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).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

Conclusion

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.

References

  1. Cattet J, Hardin DS. Diabetes alert dogs: buyer beware. Diabetes forecast 2014. Accessed at http://www.diabetesforecast.org/2014/11-nov/diabetes-alert-dogs-buyer.html
  2. Petry NM et al. Perceptions about professionally and non-professionally trained hypoglycemia detection dogs. Diabetes Res Clin Pract 2015;109:389-96.
  3. Gonder-Frederick LA et al. Diabetic alert dogs: a preliminary survey of current users. Diabetes Care 2013:e47. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609496/.
  4. Dehlinger K et al. Can trained dogs detect a hypoglycemic scent in patients with type 1 diabetes? Diabetes Care 2013;36:e98-9.
  5. Hardin DS et al. Dogs can be successfully trained to alert to hypoglycemia samples from patients with type 1 diabetes. Diabetes Ther 2015;6:509-17.
  6. Gonder-Frederick LA et al. Variability of Diabetes Alert Dog Accuracy in a Real-World Setting. J Diabetes Sci Technol 2017. doi:1932296816685580.
  7. Los EA et al. Reliability of Trained Dogs to Alert to Hypoglycemia in Patients With Type 1 Diabetes. J Diabetes Sci Technol 2016. doi:1932296816666537.
  8. Gonder-Frederick LA et al. Diabetes alert dogs (DADs): an assessment of accuracy and implications. Diabet Res Clin Pract 2017; 134:121-30.

A Blow to the Brain

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.

The hypoglycaemic brain in action

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

Inside the patient’s head

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.

References

  1. Dunn JT et al. The impact of hypoglycaemia awareness status on regional brain responses to acute hypoglycaemia in men with type 1 diabetes. Diabetologia 2018; 61:1676–87.
  2. Hwang JJ et al. Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia. J Clin Invest 2018; 128:1485-95.
  3. Wiegers EC et al. Cerebral blood flow response to hypoglycemia is altered in patients with type 1 diabetes and impaired awareness of hypoglycemia. J Cereb Blood Flow Metab 2017; 37:1994-2001.
  4. Wiegers EC et al. Brain Lactate concentration falls in response to hypoglycemia in patients with type 1 diabetes and impaired awareness of hypoglycemia. Diabetes 2016; 65:1601-5.
  5. de Zoysa N et al. A psychoeducational program to restore hypoglycemia awareness: the DAFNE-HART pilot study. Diabetes Care 2014;37:863-6.

Tailored Targets – When to loosen the reins on glucose control

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.

Vulnerable populations

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.

A patient-centred approach

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.

References

  1. Inzucchi SE et al. ADA/EASD Position Statement. Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach. Diabetes Care 2012; 35:1364-1379.
  2. Lipska KJ et al. Potential overtreatment of diabetes mellitus in older adults with tight glycemic control. JAMA Intern Med 2015;175:356-62.
  3. Henriksen MM et al. Hypoglycemic Exposure and Risk of Asymptomatic Hypoglycemia in Type 1 Diabetes assessed by Continuous Glucose Monitoring. J Clin Endocrinol Metab 2018 Mar 29. doi: 10.1210/jc.2018-00142.
  4.  
     
    [Epub ahead of print]
  5. Vijan S et al. Effect of patients’ risks and preferences on health gains with plasma glucose level lowering in type 2 diabetes mellitus. JAMA Intern Med 2014;174:1227–34.
  6. Khunti K et al. Clinical Inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people. Diabetes Care 2013; 36:3411-17.
  7. Sleath JD. In pursuit of normoglycaemia: the overtreatment of type 2 diabetes in general practice. Br J Gen Pract 2015;65:334-35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484914/
  8. Khunti K, Davies MJ. Clinical inertia—Time to reappraise the terminology? Primary Care Diabetes 2017; 11:105-6.

Invisible Damage – When hypoglycaemia goes silent

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

The past predicts the future

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.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).

An underrecognized impact

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.

References

  1. Henriksen MM et al. Hypoglycemic Exposure and Risk of Asymptomatic Hypoglycemia in Type 1 Diabetes Assessed by Continuous Glucose Monitoring. J Clin Endocrinol Metab. 2018 Mar 29.
  2. Pramming S et al. The relationship between symptomatic and biochemical hypoglycemia in insulin-dependent diabetic patients. J Intern Med 1990; 228:641-6.
  3. Harris B et al. Out of pocket costs of managing hypoglycemia and hypoglycemia in patients with type 1 diabetes and insulin-treated type 2 diabetes. Can J Diabetes 2007; 31:25-33.
  4. Unger J. Uncovering undetected hypoglycemic events. Diabetes Metab Syndr Obes 2012; 5:57-74.

Restoring Awareness, Reducing Severity: A strategic approach to mitigating the damage of hypoglycaemia

An awareness of hunger prompts people to open the refrigerator. The same process allows people to limit the damage of hypoglycaemia: a mental awareness of symptoms gives people a chance to take corrective action.

Impaired awareness of hypoglyclycaemia (IAH) robs people of this opportunity. Defined as a reduced ability to realize that plasma glucose is falling, IAH typically occurs in people with long-standing diabetes and/or recurrent exposure to hypoglycaemia.1 In this group, the thresholds for counterregulatory responses and clinical symptoms get reset to lower levels of blood glucose.1

Not surprisingly, IAH increases the risk of severe hypoglycaemia (SH)—defined as an episode that requires assistance from someone else or results in loss of consciousness—by a factor of six in people with type 1 diabetes. The converse also holds true: having SH episodes increases the risk of IAH. Thus, the two phenomena coexist in a negative feedback loop.

Regaining awareness

Fortunately, hypoglycaemia awareness can be restored. The basic strategy is conceptually simple, though not easy to implement: do everything possible to avoid future episodes of  hypoglycaemia. Research has established that avoiding glucose levels under 3 mmol/L (54 mg/dL) is associated with restored subjective awareness of hypoglycaemia.2

But how? Research has shown that patient education is key. Though informal education can certainly work, structured education programmes supporting flexible self-management of insulin regimens provide a reliable framework to jump-start the process. Based on a range of studies, we know that structured education in flexible insulin therapy can restore subjective awareness of hypoglycaemia to the point that the risk of SH goes down by over 60%.3-4

A boost from technology

Technology, in turn, can add a layer of protection against SH, including in people with IAH. Specifically, insulin pump therapy has been shown to reduce SH by about 75%5 and continuous glucose monitoring (CGM) by 60-70%.6-7  Glucose-sensor technology can further potentiate the SH-reducing benefits of pump therapy.8 Of course, the technology only provides this protection if used as intended and does not offer guarantees. In a retrospective study of type 1 diabetes patients with problematic hypoglycaemia awareness, for example, CGM reduced SH but did not restore awareness of hypoglycaemia.9 Futhermore, not everyone with IAH can engage with available technology to effect a cure.10

If education and technology do not achieve the desired objectives, islet cell transplantation offers another avenue of hope. In a study of patients with IAH and intractable SH, islet cell transplantation not only led to freedom from SH events, but yielded significant improvements in overall glucose control and condition-specific quality of life.11

Removing the barriers

In the real world, people do not always behave like their textbook counterparts. For various reasons, patients may resist interventions that will ultimately make their lives easier. Some patients are reluctant to engage with technological solutions, perhaps because of previous negative experiences or fear of being unable to manage the technology. Age and socioeconomic barriers may also come into play.

For example, a recent study analyzed attendance patterns of adults with Type 1 who had been invited to attend the Dose Adjustment For Normal Eating (DAFNE) structured education program in London, UK. The analysis showed that attendance was significantly higher in patients with higher baseline HbA1c level (OR 1.96), younger age (OR 0.98), and lower social deprivation (OR 0.52).12 These findings suggest that older patients and those with socioeconomic challenges may need extra support and/or alternative engagement strategies to overcome their reluctance to attend.

In another study, patients with type 1 diabetes who had received instruction in use of bolus advisors during a structured education course were interviewed right at the end of the course and 6 months later. Participants who considered their mathematical skills to be poor relied heavily on advisors, while others preferred using advisors because they saved time and effort in calculating doses.13 The follow-up interviews revealed that patients who lost the habit of calculating their own doses lost skill and confidence, thus becoming increasingly dependent on their advisors.13

It is likely that technological solutions have a lower efficacy and uptake in those who stand to benefit most from those very solutions.10 There is a clear need for simple calculation strategies supported by encouragement and follow-up training. It also bears noting that IAH itself has a negative effect on adherence to insulin regimens.14  This stands to reason, given that people who lack hypoglycaemia symptoms may also have trouble recognizing the seriousness of the problem and prioritizing its avoidance.15 Researchers are investigating how psychological approaches may help overcome this barrier.16

Our collective responsibility

Identifying people at high risk of SH because of IAH is a key responsibility for health care professionals supporting people with diabetes. Simple questions about how well the patient recognises the onset of hypoglycaemia, whether this happens with a blood sugar above or below 3 mmol/l (54 mg/dl), and who first notices a person’s hypoglycaemia can help identify this high-risk group.

Care providers must consider that each patient comes with unique abilities and challenges, thus calling for a personalized approach to care. Identifying IAH and promoting patient knowledge and actions to avoid hypoglycaemia are key to improving the safety of insulin therapy.

Take-home messages

  • Identifying and eliminating problematic hypoglycaemia needs to be a priority in the management of people with type 1 diabetes.
  • Expert self-management of insulin therapy allows people with diabetes to minimise hypoglycaemia risk.
  • Glucose-monitoring and insulin-delivery technologies and islet replacement therapies promise resolution of hypoglycaemia problems, but have not been developed to the point of universal reliability, ease of use, and accessibility.
  • Patient education, supplemented by technology as appropriate, offers the best pathway to minimising IAH and SH.
  • Ongoing research is needed to identify and address uptake and adherence barriers.

References

  1. Olsen se et al. Impaired awareness of hypoglycemia in adults with type 1 diabetes is not associated with autonomic dysfunction or peripheral neuropathy. Diabetes Care 2016; 39:426-433.
  2. Cranston I et al. Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes. Lancet 1994; 344:283-7.
  3. Hopkins D et al. Improved biomedical and psychological outcomes 1 year after structured education in flexible insulin therapy for people with type 1 diabetes: the U.K. DAFNE experience. Diabetes Care 2012; 35:1638-42.
  4. Yeoh E et al. Interventions that restore awareness of hypoglycemia in adults with type 1 diabetes: A systematic review and meta- analysis. Diabetes Care Diabetes Care 2015; 38:1592-609.
  5. Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta-analysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion. Diabet Med 2008; 25:765-74.
  6. van Beers CAJ et al. Continuous glucose monitoring for patients with type 1 diabetes and impaired awareness of hypoglycaemia (IN CONTROL): a randomised, open-label, crossover trial. Lancet Diabetes Endocrinol 2016; 4:893–902.
  7. Heinemann et al. Real-Time Continuous Glucose Monitoring in Adults With Type 1 Diabetes and Impaired Hypoglycaemia Awareness or Severe Hypoglycaemia Treated With Multiple Daily Insulin Injections (HypoDE): A Multicentre, Randomised Controlled Trial. Lancet 2018; 391:1367-1377.
  8. Ly TT et al. Effect of sensor-augmented insulin pump therapy and automated insulin suspension vs standard insulin pump therapy on hypoglycemia in patients with type 1 diabetes: a randomized clinical trial. JAMA 2013; 310:1240–47.
  9. Choudhary P et al. Real-Time Continuous Glucose Monitoring Significantly Reduces Severe Hypoglycemia in Hypoglycemia-Unaware Patients With Type 1 Diabetes. Diabetes Care 2013 Dec; 36(12): 4160-2.
  10. Choudhary P, Amiel SA. Hypoglycemia in type 1 diabetes: Technological treatments, their limitations, and the place of psychology. Diabetologia 2018; 61:761-769.
  11. Foster ED et al. Improved Health-Related Quality of Life in a Phase 3 Islet Transplantation Trial in Type 1 Diabetes Complicated by Severe Hypoglycemia. Diabetes Care. 2018;41:1001-8.
  12. Harris SM et al. Factors influencing attendance at structured education for Type 1 diabetes in south London. Diabet Med 2017; 34:828-33.
  13. Lawton et al. Perceptions and experiences of using automated bolus advisors amongst people with type 1 diabetes: a longitudinal qualitative investigation. Diabetes Res Clin Pract 2014; 106:443-50.
  14. Smith CB et al. Hypoglycemia unawareness is associated with reduced adherence to therapeutic decisions in patients with type 1 diabetes: evidence from a clinical audit. Diabetes Care 2009;3 2:1196-8.
  15. Rogers HA et al. Patient experience of hypoglycaemia unawareness in Type 1 diabetes: are patients appropriately concerned? Diabet Med 2012; 29:321-7.
  16. De Zoysa N et al. A psychoeducational program to restore hypoglycemia awareness: the DAFNE-HART pilot study. Diabetes Care 2014; 37:863-6.

Hypoglycaemia on the Road

Driving is a complex activity that requires cognitive integrity, and hypoglycaemia impairs cognition across a range of domains. The inevitable result? Impaired driving performance.

Studies certainly bear this out. In one study of patients with type 1 diabetes, 52% of the drivers reported at least one driving mishap over the past 12 months, and 5% reported six or more.Not surprisingly, the risk was higher in people with a history of severe hypoglycaemia and in those who did not measure their blood glucose before getting behind the wheel.1

Another study, which monitored  blood glucose, symptom perception, and corrective actions in patients with type 1 diabetes using a driving simulator, found driving performance was significantly impaired across a range of low glucose levels, including relatively mild hypoglycaemia.2  Anecdotally, impaired awareness of hypoglycaemia (IAH) has also led to road traffic accidents, though most large studies have not identified it as a significant risk.3

In an ideal world, all drivers would stop their car at the first symptom of low blood glucose. The trouble is, many hypoglycaemic drivers do not realise when their driving performance is impaired, and other at-risk individuals may not take the problem seriously enough—for which deficient knowledge among health providers may be partly to blame.4,5 For example, few drivers at risk of hypoglycaemia routinely monitor their blood glucose and some believe it safe to drive even with a blood glucose level below 3.0 mmol/L (54 mg/dL).6

At a societal level, regulations for issuing driving licences to individuals with insulin-treated diabetes may be lacking or inconsistently enforced, particularly in less developed parts of the world.7 Compounding this challenge, individuals who depend on driving to make a living may be tempted to conceal information when answering some assessment questions for fear of losing their licence.8

Taking the high road

Regulators and researchers continue to make efforts to identify drivers at high risk of hypoglycaemia-related driving accidents. As a notable example, U.S. investigators recently developed an 11-question scale called RADD, using self-reported data from over 1,000 individuals with type 1 diabetes.9

At the same time, health providers can help people with diabetes minimise the risks by communicating the following points to their patients:

  • The act of driving itself can cause blood glucose to fall and provoke hypoglycaemia because the brain consumes a significant amount of glucose during driving.10 Drivers should test their blood glucose before driving and consume a prophylactic snack if the level is below 5.0 mmol/L (90 mg/dL).5 If below 4 mmol/L (72 mg/dL), the individual should not drive.5
  • People driving for more than 30-60 minutes should test their blood glucose at regular intervals.11
  • Drivers with insulin-treated diabetes should be made aware that failure to measure blood glucose could have major medicolegal consequences.12
  • People who experience a progressive decline in their awareness of hypoglycaemia should consult a health care provider to assess their fitness to drive.11
  • Particular care should be taken during changes in routine, which range from adjustments in lifestyle or insulin regimen, to travel and pregnancy.

Hypoglycaemia poses a risk to all insulin-treated individuals. Although the magnitude of its effect on driving safety continues to be debated, it undoubtedly can cause road traffic accidents, some of them fatal. That said, people at risk of hypoglycaemia do not necessarily need to hand over their keys. With proper guidance and commitment to following safe driving practices, most insulin-treated drivers can stay safe while on the road.

 

References

 

  1. Cox DJ et al. Driving mishaps among individuals with type 1 diabetes: a prospective study. Diabetes Care 2009; 32:2177-2180.
  2. Cox DJ et al. Progressive hypoglycemia’s impact on driving simulation performance. Occurrence, awareness and correction. Diabetes Care 2000; 2:163-170.
  3. Inkster B, Frier BM. Diabetes and Driving. Diabet Obes Metabol 2013; 15:775-783.
  4. Watson WA et al. Driving and insulin treated diabetes: who knows the rules and recommendations? Pract Diabet Int 2007;24:201-06.
  5. Graveling AJ, Frier BM. Driving and diabetes: problems, licensing restrictions and recommendations for safe driving. Clin Diabet Endocrinol 2015; DOI 10.1186/s40842-015-0007-3.
  6. Graveling AJ et al. Hypoglycaemia and driving in people with insulin-treated diabetes: adherence to recommendations for avoidance. Diabetic Medicine 2004; 21:1014-19.
  7. Beshyah SA et al. A global survey of licensing restrictions for drivers with diabetes. Br J Diabetes 2017;17: 3-10.
  8. Pedersen-Bjergaard et al. The influence of new european union driver’s license legislation on reporting of severe hypoglycemia by patients with type 1 diabetes. Diabetes Care 2015; 38:29–33.
  9. Cox DJ et al. Predicting and reducing driving mishaps among drivers with type 1 diabetes. Diabetes Care 2017; 40:742-750.
  10. Cox DJ et al. The metabolic demands of driving for drivers with type 1 diabetes mellitus. Diabetes/Metabolism Research and Reviews 2002; 18:381-385.
  11. American Diabetes Association. Diabetes and Driving. Diabetes Care 2012; 35 (Suppl 1): S81-S86.
  12. Graveling AJ, Frier BM. Driving and diabetes: are the changes in the European Union licensing regulations fit for purpose? Br J Diabetes 2018; 18::25-31.